70let years 6 3 5 1 7 0 6 1 6 9 8 7 9 ISBN 978-961-6071-53-6 PRE@IVETJE BOLNIKOV Z RAKOM, ZBOLELIH V LETIH 1991–2005 V SLOVENIJI SURVIVAL OF CANCER PATIENTS, DIAGNOSED IN 1991–2005 IN SLOVENIA Pre`ivetje bolnikov z rakom, zbolelih v letih 1991–2005 v Sloveniji Survival of cancer patients, diagnosed in 1991–2005 in Slovenia Maja Primic-@akelj Vesna Zadnik Tina @agar Branko Zakotnik register raka republike slovenije cancer registry of republic of slovenia ljubljana 2009 naslovnica.qxd 30.7.2009 14:14 Page 1 Onkolo{ki in{titut Ljubljana Epidemiologija in register raka Register raka Republike Slovenije 2009 Institute of Oncology Ljubljana Epidemiology and Cancer Registry Cancer Registry of Republic of Slovenia 2009 Maja Primic-@akelj Vesna Zadnik Tina @agar Branko Zakotnik PRE@IVETJE BOLNIKOV Z RAKOM, ZBOLELIH V LETIH 1991–2005 V SLOVENIJI SURVIVAL OF CANCER PATIENTS, DIAGNOSED IN 1991–2005 IN SLOVENIA Rak.qxd 22.7.2009 12:38 Page 1 CIP – Katalo`ni zapis o publikaciji Narodna in univerzitetna knji`nica, Ljubljana 616-006-036.8(497.4) PRE@IVETJE bolnikov z rakom, zbolelih v letih 1991–2005 v Sloveniji = Survival of cancer patients, diagnosed in 1991–2005 in Slovenia / Maja Primic-@akelj … [et al.] ; [prevod Olga Schrestha]. – Ljubljana : Onkolo{ki in{titut, 2009 ISBN 978-961-6071-53-6 1. Vzp. stv. nasl. 2. Primic-@akelj, Maja 245077248 Rak.qxd 22.7.2009 12:38 Page 2 Avtorji: Maja Primic-@akelj, Vesna Zadnik, Tina @agar, Branko Zakotnik Authors: Sodelavci: Franc Anderluh, Nikola Be{i}, Peter ^ernel~, Tanja ^ufer, Andrej Debeljak, Ibrahim Edhemovi}, Co-workers: Janez Er`en, Albert Peter Fras, Eldar M. Gad`ijev, Marko Ho~evar, Janez Jazbec, Barbara Jezer{ek-Novakovi}, Andrej Kmetec, Elga Majdi~, Uro{ Mlakar, Mojca Modic, Irena Oblak, Janja Ocvirk, Mirko Omejc, Stane Rep{e, Boris Sedmak, Uro{ Smrdel, Miha Sok, Primo` Strojan, Breda [krbinc, Lojze [mid, Marjetka Ur{i~-Vr{~aj, Vaneja Velenik, Samo Zver, Matja` Zwitter, Janez @gajnar, Mirjana @umer-Pregelj Analiza slovenskih podatkov: Tina @agar Analysis of Slovenian data: Analiza podatkov EUROCARE-4 in SEER: Silvia Francisci Analysis of EUROCARE-4 and SEER data: Recenzenta: Vera Pompe-Kirn, Matja` Zwitter Reviewers: Lektor za sloven{~ino: Jo`e Faganel Reader for Slovenian language: Prevod: Olga Schrestha Translation: Oblikovanje: Monika Fink-Ser{a, Samo Rovan / NAVA arhitektura in oblikovanje Design: Fotografija: Andrej Koren~ Photo: Priprava za tisk: SYNCOMP d. o. o. Typesetting: Tiskarna: Birografika Bori d. o. o. Printed by: Izdajatelj: Onkolo{ki in{titut Ljubljana Published by: Institute of Oncology Ljubljana Naklada: 800 izvodov Published in: 800 copies Strokovni in akademski nazivi ter ustanove zaposlitve vseh sodelujo~ih so na zadnji strani. Professional and academic titles with affiliations of all contributors are published at the end. Rak.qxd 22.7.2009 12:38 Page 3 VSEBINA Pre`ivetje bolnikov z rakom, zbolelih v letih 1991–2005 v Sloveniji SEZNAM OKRAJ[AV .................................................................................................................................................................................................................... 6 PREDGOVOR .......................................................................................................................................................................................................................................... 8 UVOD .................................................................................................................................................................................................................................................................. 10 Registriranje raka v Sloveniji in spremljanje bolnikov .................................................................................................................................. 12 Priprava podatkov za ra~unalni{ko obdelavo ............................................................................................................................................................ 14 Kakovost podatkov registra in popolnost registracije .................................................................................................................................... 16 Izbor bolnikov, vklju~enih v analizo pre`ivetja ...................................................................................................................................................... 16 Izra~un pre`ivetja ...................................................................................................................................................................................................................................... 18 Prikaz rezultatov ........................................................................................................................................................................................................................................ 22 RAK PRI ODRASLIH ................................................................................................................................................................................................................ 26 Ustno `relo ...................................................................................................................................................................................................................................................... 28 Ustna votlina .................................................................................................................................................................................................................................................. 36 Spodnje `relo ................................................................................................................................................................................................................................................ 44 Po`iralnik .......................................................................................................................................................................................................................................................... 52 @elodec ................................................................................................................................................................................................................................................................ 60 Debelo ~revo .................................................................................................................................................................................................................................................. 70 Danka .................................................................................................................................................................................................................................................................... 80 Jetra, jetrnoceli~ni rak .......................................................................................................................................................................................................................... 90 @ol~nik in `ol~ni vodi ........................................................................................................................................................................................................................ 98 Trebu{na slinavka .................................................................................................................................................................................................................................. 106 Grlo ...................................................................................................................................................................................................................................................................... 114 Plju~a .................................................................................................................................................................................................................................................................. 122 Mehka tkiva ................................................................................................................................................................................................................................................ 134 Ko`a, melanom ........................................................................................................................................................................................................................................ 142 Dojka .................................................................................................................................................................................................................................................................. 152 Materni~ni vrat ........................................................................................................................................................................................................................................ 164 Materni~no telo ...................................................................................................................................................................................................................................... 172 Jaj~nik ................................................................................................................................................................................................................................................................ 178 Prostata ............................................................................................................................................................................................................................................................ 186 Modo .................................................................................................................................................................................................................................................................. 200 Ledvica .............................................................................................................................................................................................................................................................. 208 Se~ni mehur ................................................................................................................................................................................................................................................ 218 Mo`gani .......................................................................................................................................................................................................................................................... 228 [~itnica .............................................................................................................................................................................................................................................................. 236 Hodgkinov limfom ............................................................................................................................................................................................................................ 244 Ne-Hodgkinov limfom .................................................................................................................................................................................................................. 250 Plazmocitom .............................................................................................................................................................................................................................................. 260 Akutna limfoblastna levkemija ............................................................................................................................................................................................ 268 Kroni~na limfocitna levkemija .............................................................................................................................................................................................. 274 Akutna mieloi~na levkemija .................................................................................................................................................................................................... 280 VSE RAKAVE BOLEZNI BREZ KO@NEGA RAKA PRI ODRASLIH .......................................................... 286 RAK PRI OTROCIH IN MLADOSTNIKIH ...................................................................................................................................... 292 KAJ VSE POVEDO PRIKAZANI REZUL T ATI ................................................................................................................................ 302 Uvod .................................................................................................................................................................................................................................................................... 302 [tevilo in kakovost podatkov, zbranih v Registru raka Republike Slovenije .................................................................. 302 Kaj delamo dobro, kaj slabo in kaj moramo izbolj{ati .............................................................................................................................. 304 PREGLED NAJPOMEMBNEJ[IH UGOTOVITEV ................................................................................................................ 310 STROKOVNI IN AKADEMSKI NAZIVI TER UST ANOVE ZAPOSLITVE VSEH SODELUJO^IH ........................................................................................................................................................ 315 Rak.qxd 22.7.2009 12:38 Page 4 CONTENTS Survival of cancer patients, diagnosed in 1991–2005 in Slovenia LIST OF ABBREVIATIONS ................................................................................................................................................................................................ 7 FOREWORD .............................................................................................................................................................................................................................................. 9 INTRODUCTION .......................................................................................................................................................................................................................... 11 Cancer registration and follow-up of patients in Slovenia ...................................................................................................................... 13 Preparation of data for computer processing .......................................................................................................................................................... 15 Data quality and completeness of registration ...................................................................................................................................................... 17 Selection of patients included in the survival analysis .................................................................................................................................. 17 Calculation of survival ........................................................................................................................................................................................................................ 19 The presentation of results ............................................................................................................................................................................................................ 23 CANCER IN ADUL TS ................................................................................................................................................................................................................ 27 Oropharynx .................................................................................................................................................................................................................................................... 29 Oral cavity ........................................................................................................................................................................................................................................................ 37 Hypopharynx ................................................................................................................................................................................................................................................ 45 Esophagus ........................................................................................................................................................................................................................................................ 53 Stomach .............................................................................................................................................................................................................................................................. 61 Colon ...................................................................................................................................................................................................................................................................... 71 Rectum .................................................................................................................................................................................................................................................................. 81 Liver, hepatocellular carcinoma .............................................................................................................................................................................................. 91 Gallbladder and bile ducts ............................................................................................................................................................................................................ 99 Pancreas ............................................................................................................................................................................................................................................................ 107 Larynx ................................................................................................................................................................................................................................................................ 115 Lung .................................................................................................................................................................................................................................................................... 123 Soft tissue ...................................................................................................................................................................................................................................................... 135 Skin, melanoma ...................................................................................................................................................................................................................................... 143 Breast .................................................................................................................................................................................................................................................................. 153 Cervix uteri .................................................................................................................................................................................................................................................. 165 Corpus uteri ................................................................................................................................................................................................................................................ 173 Ovary .................................................................................................................................................................................................................................................................. 179 Prostate ............................................................................................................................................................................................................................................................ 187 Testis .................................................................................................................................................................................................................................................................... 201 Kidney ................................................................................................................................................................................................................................................................ 209 Urinary bladder ...................................................................................................................................................................................................................................... 219 Brain .................................................................................................................................................................................................................................................................... 229 Thyroid ............................................................................................................................................................................................................................................................ 237 Hodgkin's lymphoma ...................................................................................................................................................................................................................... 245 Non-Hodgkin's lymphoma ...................................................................................................................................................................................................... 251 Plasmacytoma .......................................................................................................................................................................................................................................... 261 Acute lymphoblastic leukemia .............................................................................................................................................................................................. 269 Chronic lymphocytic leukemia ............................................................................................................................................................................................ 275 Acute myeloid leukemia ................................................................................................................................................................................................................ 281 ALL CANCER SITES BUT SKIN IN ADUL TS ................................................................................................................................ 287 CANCER IN CHILDREN AND ADOLESCENTS .................................................................................................................... 293 WHAT CAN BE DERIVED FROM THE PRESENTED RESUL TS .................................................................. 303 Introduction ................................................................................................................................................................................................................................................ 303 The number and quality of data collected by the Cancer Registry of Republic of Slovenia ........................ 303 What are we doing well, what are our weaknesses and what should be improved .................................................. 305 OVERWIEV OF THE MOST IMPORT ANT FINDINGS ................................................................................................ 311 PROFESSIONAL AND ACADEMIC TITLES WITH AFFILIATIONS OF ALL CONTRIBUTORS .............................................................................................................. 315 Rak.qxd 22.7.2009 12:38 Page 5 5-FU 5-fluoruracil ABVD Doksorubicin, bleomicin, vinblastin, dakarbazin AP Melfalan, prednizolon BEACOPP Cikolfosfamid, doksorubicin, etoposid, vinkristin, bleomicin, prokarbazin, prednizon BFM Shema Berlin-Frankfurt-Münster CT Ra~unalni{ka tomografija ECF Epidoksorubicin, cisplatin, fluoruracil ERC Endoskopska retrogradna holangiografija EUZ Endoskopska ultrazvo~na preiskava HPV Humani papilomski virus MKB 10 Mednarodna klasifikacija bolezni in sorodnih zdravstvenih problemov za statisti~ne namene, 10. revizija MRI Magnetnoresonan~no slikanje NHL Ne-Hodgkinov limfom OI Onkolo{ki in{titut PET Pozitronska izsevna tomografija PKMC Presaditev krvotvornih mati~nih celic PSA Za prostato specifi~ni antigen RFA Radiofrekven~na ablacija RRS Register raka Republike Slovenije rhTSH Rekombinantni humani TSH RTG Rentgenska preiskava SB Splo{na bolni{nica SEER Nadzor, epidemiologija in kon~ni rezultati TACE Transhepati~na arterijska kemoembolizacija TUR Transuretralna resekcija UKC Univerzitetni klini~ni center UZ Ultrazvo~na preiskava VAD Vinkristin, doksorubicin, deksametazon VATS Z videom podprta torakoskopska kirurgija SEZNAM OKRAJ[AV 6 Pre`ivetje bolnikov z rakom, zbolelih v letih 1991–2005 v Sloveniji Rak.qxd 22.7.2009 12:38 Page 6 5-FU 5-fluoruracil ABVD Doxorubicin, bleomycin, vinblastine, dacarbazine AP Melphalan, prednisolone BEACOPP Cyclophosphamide, doxorubicin, etoposide, vincristine, bleomycin, procarbazine, prednisone BFM Berlin-Frankfurt-Münster scheme CRS Cancer Registry of Republic of Slovenia CT Computer tomography ECF Epidoxorubicin, cisplatin, fluoruracil ERC Endoscopic retrograde cholangiography EUS Endoscopic ultrasound examination GH General hospital HPV Human papiloma virus ICD 10 International Statistical Classification of Diseases and Related Health Problems, 10 th Revision IO Institute of Oncology MRI Magnetic resonance imaging NHL Non-Hodgkin's lymphoma PET Positron emission tomography PKMC Hematopoietic stem cell transplantation (HSCT) PSA Prostate-specific antigen RFA Radiofrequent ablation rhTSH Recombinant human TSH RTG X-ray, radiography SEER Surveillance, Epidemiology and End Results TACE Transhepatic arterial chemoembolization TUR Transuretral resection UMC University medical center US Ultrasound examination VAD Vincristine, doxorubicin, dexamethasone VATS Video-assisted thoracoscopic surgery LIST OF ABBREVIATIONS 7 Survival of cancer patients, diagnosed in 1991–2005 in Slovenia Rak.qxd 22.7.2009 12:38 Page 7 Mnogo ve~ kot le statistika. To bi lahko bil najkraj{i opis knjige, ki predstavi breme raka v Slo- veniji v zadnjih dveh desetletjih. Knjiga o pre`ivetju bolnikov z rakom v Sloveniji je izjemen dose`ek celotne posadke RRS in {e nekaj stotin sodelavcev v skoraj vseh zdravstvenih ustano- vah v Sloveniji, ki RRS vestno po{iljajo podatke. Pred nami je nepogre{ljiv temelj in vodnik za vse bodo~e razprave o preventivi, diagnostiki in zdravljenju raka. Knjiga je kot otrok. V nose~nosti si le megleno predstavlja{, kaj prihaja na svet, in {ele pozne- je spozna{ vse njegove odlike, a tudi pomanjkljivosti. Kakor otrok ni nikoli po okusu prav vseh tet, stricev in sosedov, tako bodo tudi v tej knjigi nekateri pogre{ali to in ono. Delo, ki so ga opravili uredniki, je res obse`no, a obseg knjige je omejen, zato vsega, kar bi morda koga zani- malo, preprosto ni bilo mogo~e zajeti. Osebno bi pri pogostej{ih rakih rad videl prikaz uspe{nosti zdravljenja po posameznih regijah Slovenije, saj bi nam bilo to v dragoceno pomo~ pri odprav- ljanju slabosti zdravstvene oskrbe. Nekateri se bodo morda ustavili pri velikih skokih in nenavadno `agastih krivuljah incidence, ki lahko ka`ejo na nedoslednosti pri prijavljanju. Naj se ta kriti- ka usmeri v {e skrbnej{i popis vseh, ki so zboleli za rakom. Tako se bomo izognili mo`nosti, da si zaradi nepopolnega prijavljanja ri{emo slab{o podobo o uspe{nosti zdravljenja, kot je v re- snici. Rak sodi med bolezni z mo~no socialno razse`nostjo: ljudje iz ni`jih socialnih slojev zboleva- jo pogosteje, kasneje pridejo do prave diagnoze in si te`je izborijo optimalno zdravljenje. Pogosteje zbolijo zaradi nezdravih `ivljenjskih navad in zaradi zdravju {kodljivega delovnega in bival- nega okolja. Nizka splo{na raven izobrazbe in nizko socialno okolje predstavljata oviro pri pravo~asni diagnostiki in pri dostopnosti do optimalnega zdravljenja. Zakaj ob knjigi o pre- `ivetju bolnikov z rakom omenjam te razumljive, pa vendar pogosto spregledane okoli{~ine? Zato, ker bodo mnogi v tej knjigi gledali le eno: primerjavo med odstotki ozdravljenih pri nas, v Evropi in v ZDA. Ta primerjava je seveda dragocena, pa vendar jo moramo jemati z veliko rezervo. Vedeti moramo, da na{ register pokriva celotno populacijo Slovenije, torej tudi njene najbolj revne odro~ne predele. Primerjava med tak{nim populacijskim registrom in med zbirko podatkov, kakr{no predstavljata evropska raziskava EUROCARE, ali pa med oceno progra- ma SEER ameri{kega Dr`avnega in{tituta za raka je v najbolj{em primeru le orientacijska. Za evropsko raziskavo, ki temelji na poro~ilih izbranih regij izbranih dr`av, zanesljivo lahko napo- vemo, da slabo pokriva revne, socialno zapostavljene predele Evrope. Dvom v reprezentativnost podatkov je {e toliko ve~ji pri ZDA, kjer so vsi statisti~ni podatki zgolj ocena in kjer znaten del populacije ostaja brez osnovne zdravstvene oskrbe, pa seveda tudi zunaj vseh analiz. Najpomembnej{e sporo~ilo te knjige ni nezanesljiva primerjava z Evropo in z ZDA, pa~ pa zelo o~iten napredek pri nas. V 15 letih se je petletno pre`ivetje odraslih bolnikov z rakom zve- ~alo z 39,6 % na 51,8 %, otrok pa s 70,6 % na 82,7 %. Rak, ki je bil neko~ kot trdna stena, se po~asi ru{i. Ne bo padel v enem zamahu kot berlinski zid, toda vsi vidimo, da ni nepremag- ljiv. Ni ga, ki bi ob misli na rakavo bolezen ostal neprizadet – pa naj gre za bolnika, sorodnika, prijatelja, zdravnika, medicinsko sestro. V imenu vseh naj zato kon~am z zahvalo vsem ime- novanim in neimenovanim sodelavcem te knjige, da so nam ponudili to dragoceno spodbudo. Matja` Zwitter PREDGOVOR 8 Pre`ivetje bolnikov z rakom, zbolelih v letih 1991–2005 v Sloveniji Rak.qxd 22.7.2009 12:38 Page 8 Much more than just a statistics. This could be the briefest description of the book that pre- sents cancer burden in Slovenia in the last two decades. The book on cancer patient survival in Slovenia is an outstanding achievement of the whole staff of the CRS, as well as of a few hun- dred co-workers from almost all Slovenian health institutions, who have been accurately sending their data to the CRS. Thus we have obtained an indispensable foundation and a guidebook for all further discussions about the prevention, diagnosis and therapy of cancer. A book is like a child. During pregnancy, you have but a vague idea what is about to be born, and later only you come to know all the advantages as well as drawbacks of the »newborn«. Likewise a child that can never meet the expectations of all his aunts, uncles and neighbors, also in this book some readers may miss one thing or the other. The work performed by the editors is really huge, and given the limited volume of the book, not everything that might be of interest to various readers could be included into it. As regards frequent cancers, personal- ly I would appreciate a presentation of treatment success by individual regions of Slovenia, since this would be a valuable help in eliminating the shortcomings of healthcare. Some may won- der about the underlying causes of rapid changes and unusually fluctuating incidence curves, which may be indicative of inconsistency in reporting. May this criticism lead to an even more conscientious recording of all persons diagnosed with cancer. Thus, it may not happen that owing to incomplete reports the treatment success would appear worse than it actually is. Cancer belongs to the diseases with a strong social dimension: people from lower social class get cancer more frequently, are diagnosed at a later stage and have more problems in obtain- ing an optimum therapy. They fall ill more frequently because of unhealthy lifestyle as well as working and living conditions that are detrimental to their health. A low general education level and low social environment represent an obstacle to timely diagnosis and accessibility of optimal treatment. Referring to the book on cancer patient survival, why to mention these self-evi- dent though often neglected circumstances? Hence, because many will see in this book but one thing: the percentages of the cured patients in Slovenia as compared to the relevant per- centages in other European countries and in the USA. Although this comparison is valuable, it should be interpreted with considerable degree of caution. It should be kept in mind that our registry covers the whole territory of Slovenia, thus also its most remote and neglected regions. A comparison between such a population registry and databases provided by the EUROCARE study or the SEER Program of the National Cancer Institute can in the best case be only of an indicative value. As for a European study based on reports from selected regions of selec- ted countries, it can be said with great certainty that its coverage of poor and socially deprived territories of Europe is insufficient. The representativeness of data for the USA is even more doubtful, since all their statistics are mere presumption, considering that a large segment of their population is left without basic healthcare and thus also lost to any analyses. Therefore, the most important message of this book is not the unreliable comparison with Europe and the USA, but the obvious advances made in Slovenia. In 15 years, 5-year survival of adult cancer patients has increased from 39.6% to 51.8%, and of children from 70.6% to 82.7%. Cancer, which appeared to be an impenetrable wall in the past, is slowly falling down. It will not col- lapse at once like the Berlin Wall, but we can see that it is not invincible. A thought of cancer leaves no one indifferent, may it be a patient, a relative, a friend, a physician or a nurse. Let me therefore end this foreword with thanks to all the named and anonymous co-workers of this book for offering us such a valuable enticement. Matja` Zwitter FOREWORD 9 Survival of cancer patients, diagnosed in 1991–2005 in Slovenia Rak.qxd 22.7.2009 12:38 Page 9 Rak ni ena sama bolezen, pa~ pa ve~ sto razli~nih, ki lahko vzniknejo v vseh tkivih in organih ~love{kega organizma. Razlikujejo se po pogostosti, imajo pa tudi razli~ne, bolj ali manj zna- ne nevarnostne dejavnike, med katerimi so javnozdravstveno najpomembnej{i tisti, ki so bodisi posledica `ivljenjskih navad in razvad bodisi naravnega procesa staranja. Politi~ne in ekonom- ske spremembe, ki smo jim bili pri~a v zadnjem desetletju prej{njega stoletja, so vplivale na `ivljenjski slog pa tudi na organizacijo zdravstvenega varstva. Ker je laten~na doba pri raku ve~i- noma dalj{a od 20 let, lahko pri~akujemo, da se bo mnogo posledic teh sprememb pokazalo {ele v prihodnosti. Tudi `ivljenjska doba prebivalstva se dalj{a, poleg tega pa je {tevil~nej{a povoj- na generacija `e v letih, v katerih je pojavljanje rakave bolezni pogostej{e, zato je pri~akovati, da bo breme te bolezni pri nas vse ve~je. Rak je zato pomemben javnozdravstveni, socialni in ekonomski problem sodobne dru`be in obvladovanju te bolezni bo treba posve~ati vse ve~ pozor- nosti. Uspe{nost in u~inkovitost prizadevanja zdravstvene politike in slu`b zdravstvenega varstva za obvladovanje raka je mogo~e objektivno ovrednotiti le z ustreznimi podatki o bremenu te bolez- ni in njegovem spreminjanju v ~asu. Samo podatki o tem, koliko sredstev je namenjenih raznim programom, namre~ {e ne potrjujejo, da so ta sredstva u~inkovito porabljena in da imajo za posledico bolj{e zdravje prebivalstva. Breme raka opisujejo osnovni kazalci, kot so incidenca, umrljivost, prevalenca in pre`ivetje. Zbiranje podatkov o bolnikih z rakom ima v Sloveniji dolgoletno tradicijo, saj imamo na Onko- lo{kem in{titutu Ljubljana enega najstarej{ih populacijskih registrov raka v Evropi, ki zagotavlja podatke o incidenci, prevalenci in pre`ivetju. Podatke o umrljivosti za rakom zbira In{titut za varovanje zdravja in jih redno po{ilja banki podatkov Svetovne zdravstvene organizacije. Vsi ti podatki pa ne prikazujejo le bremena rakavih bolezni v dr`avi, ampak so tudi izhodi{~e za ocenjevanje uspe{nosti onkolo{ke primarne in sekundarne preventive, diagnostike, zdravljenja, rehabilitacije in paliativne oskrbe ter za na~rtovanje zmogljivosti in sredstev (osebja, medicin- ske opreme, posteljnih zmogljivosti …), ki so potrebni za obvladovanje rakavih bolezni na vseh omenjenih podro~jih. Osnovni kazalec bremena raka po svetu, ki je na voljo za najve~je {tevilo dr`av, je umrljivost za rakom. Ta je po eni strani odvisna od {tevila novih bolnikov, incidence, po drugi strani pa od pre`ivetja bolnikov. Samo pre`ivetje ni odvisno od incidence, saj upo{teva samo tiste, ki so `e zboleli, zato posredno ka`e na uspe{nost zdravljenja. Populacijsko pre`ivetje bolnikov z ra- kom, kot ga prikazujejo registri raka, je sestavljen kazalec, v katerem se zrcalijo tako zna~ilnosti bolnikov kot tudi organizacija, dostopnost, kakovost in u~inkovitost sistema zdravstvenega vars- tva; ve~inoma se precej razlikuje od pre`ivetja skupin bolnikov z dolo~eno boleznijo, zdravljenih v posameznih bolni{nicah, kakor obi~ajno svoje rezultate prikazujejo kliniki. Na populacijsko pre`ivetje vpliva npr. stadij bolezni ob diagnozi, ki je odvisen od ~asa od prvih sumljivih zna- kov do postavitve diagnoze; ta ~as pa je tem kraj{i, ~im bolj je prebivalstvo zdravstveno ozave{~eno, kdaj naj se ob te`avi z zdravjem odlo~i za pregled pri zdravniku, ~im bolj je zdravnik prvega stika usposobljen, da sploh pomisli na mo`nost resne bolezni, ~im ve~ja je dostopnost diag- nosti~nih preiskav in ~im kraj{e so zanje ~akalne vrste. Razpolo`ljivost presejalnih programov za tiste rakave bolezni, pri katerih je dobrobit programov neizpodbitno dokazana, dodatno ve~a mo`nost ozdravitve ali vsaj bolj{ega pre`ivetja. Ko je diagnoza postavljena, pa je uspeh zdrav- ljenja odvisen od vrste rakave bolezni, bolnikovih zna~ilnosti (starosti, spremljajo~ih bolezni, splo{ne telesne zmogljivosti), in tudi od usposobljenosti zdravstvenega tima, to je izku{enosti UVOD 10 Pre`ivetje bolnikov z rakom, zbolelih v letih 1991–2005 v Sloveniji Rak.qxd 22.7.2009 12:38 Page 10 Cancer is not a single disease but rather a few hundreds of different disorders that may origi- nate from in all tissues and organs of the human body. They differ with respect to their frequency as well as to more or less known risk factors, among which those resulting from unhealthy lifestyles or natural ageing are most relevant in terms of public health. Political and economic changes witnessed in the last decade of the previous century have influenced the population's lifestyle as well as the organization of the healthcare. The latency period in cancer being generally longer than 20 years, it may be expected that many consequences of these changes will become appar- ent only in the future. Moreover, the population's life expectancy is increasing and the more numerous after-war generation has reached an age when the occurrence of cancer is more fre- quent, and therefore it may be expected that the burden of this disease in our country will further increase. This renders cancer an important public-health, social and economic problem of the modern society, and ever more attention should be devoted to the control of this disease. The effectiveness and efficiency of the endeavours of health policy and healthcare services as regards cancer control can be objectively evaluated only by means of relevant data on cancer burden and its changes with time. Bare information on the amount of funds intended for dif- ferent programs alone does not prove that these resources were used effectively, thus resulting in better health of the population. Cancer burden can be described with basic indicators such as incidence, mortality, prevalence and survival. The collection of data on cancer patients has a long-standing tradition in Slovenia, as the IO Ljubljana manages one of the oldest population-based cancer registries in Europe, which provides data on incidence, prevalence and survival. Cancer mortality data are collect- ed by the Institute of Public Health and regularly sent to the data bank of the World Health Organization. These data not only show the cancer burden in the country, but also serve as a basis for evaluation of the effectiveness of oncological primary and secondary prevention, diagno- sis, treatment, rehabilitation and palliative care, as well as for planning the capacities and resources (personnel, medical equipment, bed fond …), needed for cancer control in the mentioned areas of activity. Cancer mortality is the basic indicator of cancer burden in the world, which is available for most countries. This depends on the one hand on the number of new patients, i. e. incidence, and on patients' survival on the other. Survival alone does not depend on incidence, since it refers only to those who have already been diagnosed, thus indirectly reflecting the success of treatment. Population-based survival of cancer patients, as shown by cancer registries, is a com- plex indicator, which reflects patients' characteristics as well as the organization, accessibility, quality and efficiency of healthcare system; generally, it greatly differs from the survival of patient groups with a particular disease, treated in individual hospitals, as commonly presented by cli- nicians. The population survival is influenced e. g. by stage of the disease at diagnosis, which depends on the time from first suspicious symptoms to diagnosis, this time being the short- er, the better is public awareness about which health problems require medical attention, the more skilled is the physician who first sees the patient and considers the possibility of a severe illness, the greater the accessibility of diagnostic procedures and the shorter the waiting time. The availability of screening programs for those cancers in which the benefit of such programs is clearly demonstrated, further improves the chances of cure or at least better survival. After the diagnosis has been established, treatment success depends on the type of cancer, patient's characteristics (age, comorbidity, general performance status), as well as on the competence INTRODUCTION 11 Survival of cancer patients, diagnosed in 1991–2005 in Slovenia Rak.qxd 22.7.2009 12:38 Page 11 in kakovosti kirurga onkologa ter vseh, ki sodelujejo v multidisciplinarni obravnavi; tam, kjer se zdravljenje za~ne, v~asih takega tima sploh ni. Z javnozdravstvenega vidika k populacijske- mu pre`ivetju prispeva manj dostopnost najnovej{ih in najdra`jih zdravil. Vse te dejavnike, ki odlo~ajo o populacijskem pre`ivetju, mora upo{tevati, kdor interpretira rezultate raziskav o pre- `ivetju v kak{ni dr`avi, {e bolj pa, kdor primerja pre`ivetje po dr`avah. Sedanja publikacija je `e tretje obse`nej{e poro~ilo RRS o pre`ivetju slovenskih bolnikov z ra- kom. Obravnava tiste, ki so zboleli in bili zdravljeni v samostojni dr`avi Sloveniji. Ka`e napredek, ki so ga zagotovili slovenska onkologija in slovensko zdravstveno varstvo skupaj s celotno dru`- bo v 15 letih; o dose`enem in mo`nostih za {e bolj{e rezultate pi{ejo kolegice in kolegi, ki se dnevno ukvarjajo s specifi~nim zdravljenjem bolnikov z rakom na OI Ljubljana in klinikah UKC Ljubljana. Najve~ja evropska raziskava o pre`ivetju bolnikov z rakom v Evropi se kratko imenuje EUROCARE. Podatke dobiva iz evropskih registrov raka. Doslej je objavila {tiri poro~ila in drugo `e vsebuje tudi podatke RRS. Prvo je obravnavalo 800.000 bolnikov, ki so v letih 1978–1985 zboleli v 12 evrop- skih dr`avah in o katerih je prispevalo podatke 30 populacijskih registrov raka, za ~etrto pa je podatke o 2.699.086 bolnikih, ki jim je bila diagnoza postavljena v letih 1995–1999, dalo 83 re- gistrov raka iz 23 evropskih dr`av; za dodatne analize obdobnega pre`ivetja bolnikov, zbolelih v letih 2000–2002, pa je prispevalo podatke 47 oz. 31 registrov, med njimi tudi slovenski. Vsi, ki sodelujemo v raziskavah o pre`ivetju bolnikov z rakom v Evropi, se zavedamo, da ima na{e sodelovanje ve~ metodolo{kih pomanjkljivosti: registracija in sledenje bolnikov nista povsod enako popolna in kakovostna, definicije vseh rakavih bolezni pri registraciji bolnikov niso enot- ne, pa tudi nekateri rezultati niso reprezentativni za vse dr`ave, saj nekateri registri pokrivajo podro~ja celih dr`av, nekateri pa le posamezne regije. Ne glede na to pa so izsledki raziskave EUROCARE pomembni predvsem zato, ker vsem sodelujo~im ka`ejo, ali so na pravi poti; marsikje so jih `e izkoristili za to, da so izbolj{ali sistem organizacije zdravstvenega varstva, saj je slabo pre`ivetje zastavilo {tevilna, ne le strokovna, pa~ pa tudi ostra politi~na vpra{anja. 12 Pre`ivetje bolnikov z rakom, zbolelih v letih 1991–2005 v Sloveniji REGISTRIRANJE RAKA V SLOVENIJI IN SPREMLJANJE BOLNIKOV RRS je eden najstarej{ih populacijskih registrov raka v Evropi. Leta 1950 ga je ustanovila in do leta 1975 vodila pokojna profesorica dr. Bo`ena Ravnihar. Njeno delo je prevzela profeso- rica dr. Vera Pompe Kirn, ki je do upokojitve leta 2003 skrbela za nadaljnjo uveljavljanje RRS v doma~em in mednarodnem merilu. Od leta 2003 je RRS skupaj z Enoto za epidemiologi- jo v enotni slu`bi Epidemiologija in register raka. V njej so poleg RRS {e bolni{ni~ni register OI Ljubljana, ki posreduje RRS velik del podatkov in omogo~a podrobnej{i pregled nad bol- niki, zdravljenimi v na{i ustanovi ne glede na to, kje imajo stalno prebivali{~e. V zadnjem desetletju smo vzpostavili {e nov dr`avni register za vodenje in spremljanje organiziranega presejalnega programa za raka materni~nega vratu (ZORA), od leta 2007 pa izgrajujemo informacijski sistem DORA, ki bo informacijska podpora organiziranemu presejalnemu programu za raka dojk. Tudi obstoj teh novih registrov prispeva k popolnosti in kakovosti podatkov RRS, po drugi strani pa podatki RRS prispevajo k vrednotenju u~inkovitosti presejalnih programov. Prijavljanje raka je v Republiki Sloveniji obvezno in z zakonom predpisano `e od ustanovitve RRS (Ur. l. SRS, {t. 10/50, {t. 29/50, {t. 14/65, {t. 1/80, {t. 45/82, {t. 42/85; Ur. l. RS, {t. 9/92 in {t. 65/00). Osnovni vir podatkov so prijavnice rakave bolezni, ki jih po{iljajo iz vseh bolni- {nic in diagnosti~nih centrov v Sloveniji, iz ordinacij osnovnega zdravstvenega varstva pa le izjemoma, ~e bolnik ni napoten na nadaljnje preiskave in/ali zdravljenje. Dodatni vir podatkov so zdravni{ka poro~ila o vzroku smrti in obdukcijski zapisniki z diagnozo maligne bolezni. Rak.qxd 22.7.2009 12:38 Page 12 of health team, i. e. on the experience and skills of the oncological surgeon and all those involved in the multidisciplinary treatment approach; sometimes, in the institutions where first treatment is started, no such team is available at all. From the public health point of view, population-based survival is less influenced by the availability of the latest and most expensive drugs. When inter- preting the results of survival studies for a particular country, and particularly when comparing survival by countries, all these factors influencing the population-based survival should be taken into account. The current publication is already the third extensive report by the CRS on the survival of Slovenian cancer patients, who were diagnosed and treated in the independent State of Slovenia. Presented are advances made by the Slovenian oncology and health care along with the whole society in fifteen years; the results achieved and the possibilities for further improvement are discussed by colleagues, daily involved in the specific treatment of cancer patients at the IO Ljubljana and in the departments of the UMC Ljubljana. The largest European study of the survival of cancer patients in Europe has a short name EURO- CARE. Data are obtained from the European cancer registries. So far, four EUROCARE reports have been published, and the second one already includes the CRS's data. The first report cov- ered 800,000 patients diagnosed in the period 1978–1985 in 12 European countries; the data were contributed by 30 population-based cancer registries. For the fourth report, the data on 2,699,086 patients diagnosed in the period 1995–1999 were obtained from 83 cancer registries from 23 European countries; additional data for further survival period analyses of patients diagnosed in the years 2002–2002 were contributed by 47 or 31 registries respectively, among them also by CRS. All of us taking part in the research of cancer patient survival in Europe are aware that our studies have a few methodological deficiencies: everywhere, registration and follow-up are not equally complete and of the same quality; in patient registration, the definitions of all cancer diseases are not uniform, and certain results are not representative for all countries since some registries cover the whole country while others present only individual regions. Nevertheless, the results of EUROCARE study are important primarily because they help the participants check whether they are on the right track; many have already used them to improve their organ- ization of healthcare after the poor survival posed a number of not only professional but also political questions. 13 Survival of cancer patients, diagnosed in 1991–2005 in Slovenia CANCER REGISTRATION AND FOLLOW UP OF PATIENTS IN SLOVENIA CRS is one of the oldest population based cancer registries in Europe. It was founded in 1950 by the late Professor Bo`ena Ravnihar, MD, PhD, who headed it till 1975. She was succee- ded by Professor Vera Pompe-Kirn, who contributed a lot to the further development of the Registry as well as its recognition at the national and international level all until her retire- ment in 2003. Since 2003, the CRS together with the Unit of Epidemiology is merged in a single Epidemiology and Cancer Registry service. Besides the CRS, the new service also comprises the hospital-based Cancer Registry of the OI Ljubljana, which contributes a considerable part of information to the CRS and facilitates a more detailed overview of patients treated at the IO Ljubljana, irrespective of their permanent residence. In the last decade, we have established a new national registry in charge of coordinating and monitoring the organised cervical can- cer screening programme (ZORA), while an information system DORA to support organized breast screening program has been underway since 2007.While the existence of these two new registries contributes to a higher quality and completeness of CRS's data, the latter contribute to the evaluation of the effectiveness of screening programs. Notification of cancer has been compulsory in Slovenia since the foundation of the CRS and prescribed by law (Official Gazette of SRS, No 10/50, 29/50, 14/65, 1/80, 45/82 and 42/85; Rak.qxd 22.7.2009 12:38 Page 13 Podatki, ki se zbirajo o novih primerih rakave bolezni, so naslednji: • identifikacijski podatki: enotna mati~na {tevilka ob~ana (EM[O), ime in priimek, dekli{ki pri- imek, rojstni kraj in naslov stalnega prebivali{~a; • podatki o bolezni: anatomsko mesto raka, histolo{ka oz. citolo{ka diagnoza, stadij po TNM ali drugi ustrezni klasifikaciji, opredelitev stadija po vseh preiskavah, na~in postavitve diag- noze; • podatki o zdravljenju: bolni{nica, oddelek, {tevilka popisa, vzrok sprejema, datum sprejema, datum ugotovitve sedanjega raka, predhodno zdravljenje sedanjega raka, na~in zdravljenja med sedanjo hospitalizacijo, datum pri~etega zdravljenja, zaporedna {tevilka sedanjega raka, predhodno ugotovljen kak{en drug rak; • podatki ob odpustu oz. smrti: datum odpusta oz. smrti, stanje ob odpustu, morebitna obduk- cija, ali je predvidena kontrola oz. je bil bolnik preme{~en. Za izra~un pre`ivetja bolnikov, kar je ena izmed osnovnih nalog RRS, potrebujemo vitalno sta- nje bolnikov. Ta podatek {tirikrat letno dobimo iz Centralnega registra prebivalstva za vse osebe iz RRS, za katere imamo podatek, da so {e `ive. Oseba je lahko `iva, mrtva ali izgubljena. Pri izgubljenih osebah upo{tevamo kot datum izgube datum zadnje prijave oz. datum izgube, ki nam ga posreduje Centralni register prebivalstva, odvisno od tega, kateri datum je kasnej{i. Od leta 1983, odkar se v Sloveniji uporablja enotna mati~na {tevilka ob~ana, je v RRS odstotek izgubljenih manj{i od 1 %; pri bolnikih, registriranih v desetletju 1996–2005, pa je bil 0,1 %. 14 Pre`ivetje bolnikov z rakom, zbolelih v letih 1991–2005 v Sloveniji PRIPRAV A PODATKOV ZA RA^UNALNI[KO OBDELAVO V RRS posebej usposobljene medicinske sestre kodirajo podatke, prispele na prijavnicah, v skla- du z mednarodnimi in v RRS dogovorjenimi pravili. Za razvr{~anje neoplazem po umestitvi RRS od leta 1997 uporablja deseto revizijo Medna- rodne klasifikacije bolezni in sorodnih zdravstvenih problemov za statisti~ne namene, do takrat pa je uporabljal osmo. Prav pri uvr{~anju med maligne bolezni je treba opozoriti {e na klasifika- cijo za morfologijo neoplazem, za katero uporabljamo morfolo{ki del Mednarodne klasifikacije bolezni za onkologijo, od poro~ila za leto 2001 njeno tretjo izdajo. V tej izdaji je spet nekaj sprememb, tudi, katere histolo{ke vrste sodijo med maligne. Po tretji reviziji so med maligne uvr{~ene kroni~ne mieloproliferativne bolezni in mielodisplasti~ni sindromi (sedaj v topografski {ifri C96.7). V skladu z novimi pravili tudi mejno malignih ovarijskih tumorjev ne uvr{~amo ve~ v kategorijo C56, pa~ pa v D39.1. Za opredelitev stadija v registrih ve~inoma uporabljamo poenostavljeno opredelitev stadijev, ki upo{teva vse preiskovalne metode, vklju~no z operacijo; ~e bolnik ni bil poprej zdravljen, tudi obdukcijo. Uporabljamo in navajamo jo zato, ker so podatki o stadiju bolezni po klasifi- kaciji TNM na prijavnicah pogosto pomanjkljivi. Poenostavljena opredelitev stadijev pri solidnih tumorjih praviloma sledi klasifikaciji TNM. V omejeni stadij je razvr{~ena bolezen, kjer je tumor ozna~en kot T1 in T2 (razen pri dojki, malignem melanomu in {~itnici, pri katerih so vklju- ~eni tudi tumorji T3, in materni~nem vratu, telesu in sarkomih, pri katerih so vklju~eni le tumorji T1) in pri kateri niso prizadete podro~ne bezgavke in ni zasevkov v oddaljenih orga- nih (N0, M0). V stadiju regionalne raz{iritve je bolezen, pri kateri je tumor opredeljen kot T3 in T4 (razen v omenjenih izjemah) in/ali so prizadete tudi podro~ne bezgavke (N1), zasevkov v oddaljenih bezgavkah in organih pa ni (M0). V stadiju oddaljene raz{iritve pa je tista bolezen, pri kateri so zasevki `e v oddaljenih bezgavkah ali organih (M1). Maligni limfomi so oprede- ljeni po klasifikaciji Ann-Arbor. Rak.qxd 22.7.2009 12:38 Page 14 Official Gazette of RS, No 9/92 and 65/00). The main sources of data are notifications gath- ered from all hospitals and diagnostic centres in Slovenia, exceptionally also from primary health care centres in case the patient has not been referred for further diagnostic investigations and/or treatment. Additional sources of information are death certificates and autopsy protocols stat- ing cancer diagnosis. The following data are collect on new cancer cases: • Identity data: a uniform personal ID number, name and surname, maiden name, place of birth and address of permanent residence; • Particulars of disease: anatomic cancer site, histological or cytological diagnosis, stage by TNM or other suitable classification, staging after all examinations performed, method of estab- lishing diagnosis; • Treatment information: hospital, department, patient record number, reason for admission, date of admission, date of present cancer diagnosis, any former treatment of the present cancer, method of treatment during present admission, date of the beginning of treatment, sequen- tial number of present cancer, previous evidence of any other cancer; • Information on discharge or death: date of discharge or death, status on discharge, possible autop- sy, any foreseen follow up or patient's transfer. Calculation of patient survival, this being one of the primary tasks of CRS, requires the patient's vital status. This data is obtained quarterly from the Central Population Registry for all par- sons registered in the CRS data base as alive. A person may be alive, dead or lost to follow-up. In lost persons, the date of last notification or the date of loss obtained from the Central Population Registry, whichever first, is considered as date of loss. From 1983, since the uni- form personal ID number has been used in Slovenia, in CRS the percentage of the lost to follow-up is below 1%, in patients registered in the decade between 1996–2005 being 0.1%. 15 Survival of cancer patients, diagnosed in 1991–2005 in Slovenia PREPARATION OF DAT A FOR COMPUTER PROCESSING In CRS specially trained nurses code the data retrieved from notifications in accordance with the internationally and internally agreed rules. Since 1997, cancer sites are coded according to the 10 th revision of the International Statistical Classification of Diseases and Related health Problems (ICD-10); before, the 8 th revision was used (ICD-8). When classifying tumours as malignant, the behaviour digit of the morpho- logy code of the third edition of International Classification of Diseases for Oncology has been used since the report for 2001 on. In this edition, some changes were introduced in terms of morphology and behaviour code. According to this classification, chronic myeloproliferative disorders and myelodisplastic syndromes are classified as malignant (currently C96.7 topog- raphy code), while ovarian tumours of borderline malignancy are currently coded as D39.1 (and not C56). A simplified definition of stages is generally used for stage classification by registries, taking into account all investigation methods, including surgery; in case the patient was not treated before death, the autopsy record is considered as well. The simplified stage definition is used because the data on stage according to TNM Classification System are often lacking, in can- cer notification forms. In solid tumors, the simplified stage definition generally follows the TNM classification. Localised stage includes all cancers where the tumour has been classified as T1 and T2 (except in breast, malignant melanoma and thyroid cancer, where T3 is also included, and uterine cervix, uterine corpus and sarcomas, where T1 only is included), where neither regional node involvement nor distant metastases are found (N0, M0). The regional stage includes tumours classified as T3 and T4 (exceptions already mentioned) and/or regional node metastases (N1), Rak.qxd 22.7.2009 12:38 Page 15 Kakovost podatkov registrov raka osvetljujejo naslednji kazalci: odstotni dele` mikroskopsko (histolo{ko ali citolo{ko) potrjenih primerov in odstotni dele` primerov, registriranih samo iz zdravni{kih poro~il o vzroku smrti. Vrednosti teh kazalcev v treh opazovanih obdobjih so pri- kazane v Tabeli 1. Popolnost registracije ka`e dele` vseh novih primerov raka na podro~ju, ki ga pokriva register in ki so vklju~eni v podatkovno zbirko registra. Neposredno jo je mogo~e meriti samo s po- sebnimi raziskavami, namenjenimi oceni popolnosti, npr. s ponovnim pregledom odpustnih diagnoz in popisov bolezni v bolni{nicah ali ambulantah na dolo~enem obmo~ju. V Sloveni- ji takih raziskav zaenkrat {e nismo opravili, veliko pa nam k popolnosti zajema pomagajo kolegi kliniki, ki jih zanima pre`ivetje pri njih zdravljenih bolnikov in nam po{ljejo podatke o svoji skupini bolnikov, med katerimi velikokrat najdemo take, ki jih v podatkovni zbirki RRS {e ni. Popolnost je ve~ja tam, kjer imamo registri dostop do zdravni{kih poro~il o vzroku smrti. Tako v Sloveniji za umrle za rakom, ki jih {e nismo registrirali, dodatno poizvedujemo. S tem se izbolj{a popolnost registracije rakov s slabo napovedjo izida, ne pa manj usodnih. V Sloveniji predvideva- mo, da je registracija manj popolna pri nemelanomskem ko`nem raku in pri tistih malignomih, ki se zdravijo samo ambulantno. Podoben problem imajo tudi drugi populacijski registri raka v Evropi. Popolnost registracije merimo z razmerjem med umrljivostjo in incidenco ter s stabilnostjo inci- dence v ~asu. To pomeni, da med posameznimi leti ni velikih nihanj incidence in da ni velikih razlik v odstotnem dele`u primerov, ki jih register zabele`i po tem, ko `e zaklju~i obdelavo podat- kov za dolo~eno leto. Razmerja med umrljivostjo in incidenco za posamezno petletno obdobje so prikazana v Tabeli 2, {tevilo naknadno prijavljenih primerov za vsa leta registracije pa je objav- ljeno v letnih poro~ilih RRS. 16 Pre`ivetje bolnikov z rakom, zbolelih v letih 1991–2005 v Sloveniji KAKOVOST PODATKOV REGISTRA IN POPOLNOST REGISTRACIJE IZBOR BOLNIKOV, VKLJU^ENIH VA N A L I Z O PRE@IVETJA V analizo smo vklju~ili bolnike s stalnim prebivali{~em v Sloveniji, ki jim je bil rak ugotovljen v letih 1991 do 2005. Za bolj{e spremljanje trendov inciden~nih in umrljivostnih stopenj in za oceno desetletnega relativnega pre`ivetja so v slikah dodani {e podatki o bolnicah in bol- nikih, ki jim je bila diagnoza postavljena v letih 1986–1990. Bolniki, ki jih obravnavamo, so lahko imeli eno ali ve~ primarnih rakavih bolezni. ^e je imel bolnik ve~ kot eno rakavo bole- zen, je vsak primer rakave bolezni obravnavan v tistem poglavju, ki prikazuje pre`ivetje po organskem sistemu, ki ga je rak prizadel. Pri vseh analizah smo upo{tevali stanje baze RRS na dan 1. junija 2008, zato se lahko inci- denca iz na{e analize po posameznih letih razlikuje od podatkov, kot jo objavlja RRS v letnih poro~ilih, saj okrog 4 % bolnikov registriramo {ele po izdaji letnih poro~il. Bolnike smo sprem- ljali do 31. marca 2008. Iz analize pre`ivetja smo izlo~ili 2675 oseb, ki smo jih v RRS registrirali samo na podlagi zdravni{kih poro~il o vzrokih smrti, saj za te ne poznamo datuma ugotovitve Obdobje / Period Vsi registrirani / Dele` Dele` ugotovljenih Dele` registriranih samo All registered mikroskopsko z drugimi iz zdravni{kih poro~il potrjenih (%) / preiskavami (%) / o vzroku smrti (%) / % of microscopically % of diagnosed % registred from death confirmed by other investigations certificats only 1991–1995 35.166 92,4 4,0 3,6 1996–2000 42.425 93,1 5,1 1,9 2001–2005 50.815 93,6 5,2 1,2 Tabela 1: Incidenca raka v treh opazovanih petletnih obdobjih glede na na~in postavitve diagnoze. Table 1: Cancer incidence in three 5-year observation periods by method for establishing diagnosis. Rak.qxd 22.7.2009 12:38 Page 16 without presence of metastases in distant lymph nodes or organs (M0). The disease with metas- tases in distant lymph nodes or organs is classified as the remote stage (M1). Malignant lymphomas are classified according to Ann-Arbor System. 17 Survival of cancer patients, diagnosed in 1991–2005 in Slovenia DAT A QUALITY AND COMPLETENESS OF REGISTRATION The quality of information can be assessed by the following parameters: the percentage of micro- scopically (histologically or cytologically) confirmed cases and the percentage of cancer cases registered on the basis of death certificates only. The values of these parameters in the three observation periods are presented in Table 1. The completeness of registration shows the proportion of all new cancer cases in the region covered by the registry, which are included in the registry's data base. It can be measured direct- ly only by means of special surveys for the evaluation of completeness, e. g. by reviewing patient record in the hospitals or outpatient clinics in a particular region. In Slovenia, no such sur- veys have been carried out so far. However, a considerable contribution towards the completeness of registration is made by our colleagues – clinicians, who send us the data on their groups of patients in order to get information about their survival and among them we often find cases that have not been entered in the CRS database yet. The registration is more complete where the registries have access to death certificates, and can send out additional inquiries about disease for the deceased that have not been entered into the database yet. This improves the completeness of registration of cancers with poor prog- nosis, but not also of less fatal ones. It is presumed that in Slovenia registration is less complete in non-melanoma skin cancer and in malignomas that are treated on the out-patient basis only. The completeness of registration is measured by the ratio between mortality and incidence, and by stability of incidence in time, which means that there are no major fluctuations in the incidence between individual years, and neither great differences in the percentage of cases reg- istered only after the data for a particular year have already been processed. The ratios between the mortality and incidence for individual 5-year periods are presented in Table 2; the num- bers of subsequently reported cases for all registration years are published in the annual reports of the CRS. SELECTION OF PATIENTS INCLUDED IN THE SURVIV AL ANALYSIS The analysis includes patients with permanent residence in Slovenia diagnosed with cancer in the years 1991–2005. In figures, data on patients diagnosed in the period 1986–1990 were added for better presentation of trends in the incidence and mortality rates as well as for the evaluation of 10-year relative survival. The analysed patients might have had one or more pri- mary cancers. If the patient had more than one cancer, each of them is dealt with in the chapter presenting the survival by organ system affected. Tabela 2: [tevilo umrlih in zbolelih za rakom ter razmerje med umrljivostjo in incidenco v treh opazovanih petletnih obdobjih. Table 2: The number of the deceased and diagnosed with cancer and the ratio between the mortality and inci- dence in three 5-year observation periods. Obdobje / Period [tevilo umrlih / [tevilo novih primerov / Umrljivost/incidenca / Number of deceased Number of new cases Mortality/incidence 1991–1995 17.690 35.166 0,50 1996–2000 23.572 42.425 0,56 2001–2005 25.054 50.815 0,49 Rak.qxd 22.7.2009 12:38 Page 17 bolezni. Praviloma se iz analiz pre`ivetja izklju~ijo tudi primeri raka, pri katerih je datum ugotovi- tve enak datumu smrti, torej je ~as pre`ivetja enak ni~. Izmed 1793 tak{nih primerov so v 1553 z obdukcijo ugotovili, da so imeli raka. Prav tako nismo vklju~ili podatkov o 117 bolnikih, za katere ne poznamo vitalnega stanja (oz. so bili izgubljeni iz evidence) (Tabela 3). 18 Pre`ivetje bolnikov z rakom, zbolelih v letih 1991–2005 v Sloveniji IZRA^UN PRE@IVETJA V biostatistiki definiramo pre`ivetje kot ~as med dvema dogodkoma, najpogosteje med datu- mom diagnoze in datumom smrti. Pri skupinah bolnikov je pre`ivetje dele` bolnikov, ki so po izbranem obdobju od postavitve diagnoze {e `ivi. Pre`ivetje bolnikov z rakom obi~ajno opa- zujemo po enem, treh, petih in desetih letih po diagnozi. Mo`nosti in metod za izra~un pre`ivetja je ve~. Praviloma pa se v vsaki analizi pre`ivetja poja- vijo bolniki, pri katerih trajanja `ivljenja po diagnozi ni mogo~e izmeriti, saj za njih vemo le, da so `iveli dolo~en ~as po diagnozi, podatka o ~asu smrti pa ne poznamo. Tak{nim podat- kom pravimo krnjeni podatki. Razlogov za krnjenje je ve~: najpogosteje je posledica tega, da so ob koncu {tudije nekateri bolniki {e `ivi, v~asih pa posameznika tudi pred~asno izgubimo iz evidence, na primer zaradi selitve v tujino. V vsakem primeru je zaradi krnjenih opazovanj potreben poseben pristop pri ocenjevanju dele`a pre`ivelih. Osnovna in hkrati najpreprostej{a mera pre`ivetja je tako imenovano opazovano pre`ivetje. Med razli~nimi metodami, ki so na voljo za izra~un opazovanega pre`ivetja, se danes najve~krat upo- rablja Kaplan-Meierjeva metoda. Ta metoda je zaradi svoje natan~nosti posebej primerna za analize z majhnim {tevilom podatkov, vendar pa jo v ~asu zmogljivih ra~unalnikov uporablja- mo tudi pri ve~jih vzorcih, saj je natan~nost {e vedno velika, metoda je uveljavljena, ra~unanje pa enostavno. Za oceno opazovanega pre`ivetja smo jo uporabili tudi v tej knjigi. V klini~nih raziskavah, v katerih nas obi~ajno zanimajo samo smrti, ki so posledica natan~no dolo~ene bolezni, vse umrle zaradi drugih vzrokov v analizi obravnavamo kot krnjene (t. i. vzro~- no specifi~no pre`ivetje). Tak pristop bi bil smiseln tudi v populacijskih raziskavah, vendar pa se v praksi izka`e, da je v njih vklju~eno {tevilo bolnikov praviloma preveliko, da bi za vsakega preverjali natan~en vzrok smrti; uradni vzroki smrti, ki jih v Sloveniji zbira In{titut za varova- nje zdravja RS, so za take posebne namene pogosto premalo natan~ni. Zaradi tega in zaradi neprimerljivosti opazovanih pre`ivetij med razli~nimi populacijami se danes v populacijskih raziskavah Tabela 3: [tevilo oseb, ki smo jih izlo~ili iz analize pre`ivetja. Table 3: The number of persons excluded from the survival analysis. Obdobje / Period Registrirani samo iz zdravni{kih Ugotovljeni Ugotovljeni Izgubljeni / poro~il o vzrokih smrti / na obdukciji / na dan smrti / Lost Registered from death Diagnosed Diagnosed on the certificates only at autopsy date of death 1991–1995 1263 492 95 59 1996–2000 792 548 59 35 2001–2005 620 513 86 23 V posameznih poglavjih obravnavamo odrasle bolnike s 30 izbranimi primarnimi mesti raka in z vsemi mesti raka skupaj. Po starosti smo jih razvrstili v tri ve~je skupine: 20–49, 50–74 in 75 let in ve~. Pri vseh primerih raka skupaj nismo upo{tevali ko`nega (C44), saj gre za bole- zen, ki je prakti~no popolnoma ozdravljiva in zaradi nje v zadnjih desetletjih skoraj nih~e ve~ ne umre. Ker je prijavljanje ko`nega raka povsod po Evropi pomanjkljivo, dele` neregistrira- nega pa je zelo razli~en, tudi v mednarodnih primerjavah ko`nega raka ne upo{tevajo pri izra~unu pre`ivetja vseh bolnikov z rakom. Rak.qxd 22.7.2009 12:38 Page 18 In all the analyses, the status of CRS database on 1 June 2008 was taken into account, and therefore the incidence in our analysis by individual years may differ from the data published in CRS annual reports, as some 4% of patients were registered only after the annual reports had already been published. The patients were followed up until 31 March 2008. 2675 per- sons, registered only on the basis of autopsy reports, were excluded from the analysis because of the unknown date of diagnosis. Generally, the cases where the date of diagnosis is the same as the date of death are also excluded from analyses since the duration of survival in these cases is equal to zero. In 1553 out of 1793 such cases autopsy revealed cancer. The data of 117 patients with unknown vital status (or the lost ones) were not included either. Individual chapters are dedicated to 30 selected primary cancer sites in adult patients and cumu- latively to all cancers. They were distributed into three major categories by age: 20–49, 50–74 and 75 years plus older. Skin cancer (C44) was not considered among all cancers together, since this is a disease that is practically fully curable and of which hardly anyone has died in the last decades. As everywhere in Europe, the reporting of skin cancer is incomplete and the proportion of unregistered cases is greatly varying, in comparative international studies too skin cancer is not considered in the survival statistics of all cancer patients. 19 Survival of cancer patients, diagnosed in 1991–2005 in Slovenia CALCULATION OF SURVIV AL In biostatistics, survival is defined as the time between two events, mostly between the date of diagnosis and the date of death. In groups of patients, the survival represents the propor- tion of patients still alive after a selected period of time from diagnosis. Survival of cancer patients is generally observed after one, three, five and ten years from diagnosis. There are more possibilities and methods for the calculation of survival available. In every sur- vival analysis, however, there are patients in whom the duration of survival after diagnosis cannot be determined, since it is only known that they lived a certain period of time from diagnosis while the time of their death is unknown. Such data are referred to as censored data. The rea- sons for their occurrence are multifold: most frequently they are attributable to the fact that by the end of the study, some patients are still alive while others may be prematurely lost from evidence, e.g. because of moving abroad. In any case, such incomplete observations require a special approach to the evaluation of survival rates. A basic and at the same time most simple measure of survival is the so-called observed sur- vival. Among various methods available for calculating the observed survival, currently the most frequently used is Kaplan-Meier's method. High accuracy renders this method particularly suit- able for analyses with a limited number of data; however, thanks to powerful computers available nowadays, it is also used in larger samples, since its accuracy is still high while the method is well established and calculation simple. For the needs of this publication too, observed sur- vival was calculated according to this method. In clinical studies, where our interest is generally focused on deaths due to a particular dis- ease, in the analysis all deaths due to other causes are treated as censored (the so-called cause-specific survival). Such approach would seem reasonable also in population studies, how- ever, in practice it turns out that the number of patients entered into such studies is too large to allow the exact cause of death to be established for each individual patient; the data on offi- cial causes of death that are collected by the Institute of Public Health of the Republic of Slovenia, are often insufficiently accurate for such purposes. Therefore, and because of the incompara- bility of the observed survival between different populations, currently relative survival rather than observed one is used in population studies. The calculation of relative survival does not require information on the cause of death, but nevertheless, the method yields a result that is Rak.qxd 22.7.2009 12:38 Page 19 namesto opazovanega uporablja relativno pre`ivetje. Za izra~un relativnega pre`ivetja ne potrebujemo vzrokov smrti, kljub temu pa je metoda zastavljena tako, da je rezultat dober prib- li`ek pre`ivetja bolnikov kot v primeru, da bi upo{tevali kot vzrok smrti samo prou~evanega raka. Relativno pre`ivetje je razmerje med opazovanim in pri~akovanim pre`ivetjem, t. j. pre`ivet- jem, ki ga glede na spol in starost v dolo~enem obdobju pri~akujemo v celotni populaciji, iz katere prihajajo bolniki. Pri~akovano pre`ivetje se izra~una na podlagi podatkov o splo{ni umrljivosti, ki se v obliki tablic umrljivosti za posamezno dr`avo rutinsko objavljajo v okviru demograf- ske statistike. Za izra~un relativnega pre`ivetja v tej knjigi smo uporabili slovenske letne popolne momentne tablice umrljivosti. V praksi je relativno pre`ivetje bolnikov z rakom praviloma manj{e od 100 %. V redkih pri- merih, ko je relativno pre`ivetje enako 100%, pa lahko zaklju~imo, da je pre`ivetje skupine bolnikov z rakom enako pre`ivetju splo{ne populacije in torej bolezen sama ni skraj{ala pri- ~akovane `ivljenjske dobe. Teoreti~no je izra~unano relativno pre`ivetje lahko tudi ve~je od 100 %, kar pomeni, da imajo bolniki bolj{e pre`ivetje kot celotno prebivalstvo. To se lahko zgodi v pri- meru, ~e bolni privzamejo bolj zdrave `ivljenjske navade, ali pa ~e njihove pridru`ene bolezni temeljiteje obravnavajo kot v povpre~ju v splo{ni populaciji. Tak{nega, teoreti~no mo`nega pri- mera, med slovenskih bolniki z rakom nismo zasledili. Za izra~un relativnega pre`ivetja poznamo ve~ metod. Pri kohortni metodi sledimo skupini bolnikov dolo~en ~as, obi~ajno pet let. Vsaka oseba, vklju~ena v analizo, mora imeti torej mo`- nost pre`iveti pet let. Pre`ivetje izra~unamo kot dele` bolnikov, `ivih po dolo~enih obdobjih, obi~ajno po enem, treh in petih letih po diagnozi. Pri popolni metodi vklju~imo v izra~un tudi bolnike, ki so zboleli kasneje in smo jih ob koncu {tudije sledili manj kot pet let. Bolniki, ki smo jih sledili kraj{i ~as, prispevajo v izra~un popolnega relativnega pre`ivetja samo toliko ~asa, kot smo jih dejansko lahko sledili. Tako skupina zbolelih tri leta pred zaklju~kom {tudije pris- peva k eno- in triletnemu popolnemu relativnemu pre`ivetju, k petletnemu pa ne. Posebna oblika popolnega relativnega pre`ivetja je obdobno relativno pre`ivetje. Pri metodi obdobnega pre`ivetja vklju~imo v izra~un enoletnega pre`ivetja samo tiste bolnike, ki so zbo- leli v zadnjem letu, v izra~un dveletnega pre`ivetja samo tiste bolnike, ki so zboleli dve leti nazaj in so pre`iveli prvo leto ter ustrezno v izra~un petletnega pre`ivetja samo tiste bolnike, ki so zboleli pred petimi leti in so po diagnozi `iveli vsaj {tiri leta. Za nazornej{i prikaz razlike med kohortnim, popolnim in obdobnim relativnim pre`ivetjem si poglejmo primer analize relativnega pre`ivetja, ki jo `elimo narediti za bolnike z rakom, za katere imamo podatke o vitalnem stanju na dan 31. 12. 2008. Kohortno petletno relativno pre- `ivetje lahko izra~unamo le za bolnike, ki so zboleli do konca leta 2003, saj je samo to skupino mogo~e slediti vsaj pet let. V analizo popolnega petletnega relativnega pre`ivetja lahko vklju- ~imo tudi vse bolnike, ki so zboleli do konca leta 2007 in jih spremljamo do 31. 12. 2008; na ta dan je njihov ~as opazovanja krnjen, razen seveda pri tistih, ki so do takrat `e umrli. Tako bolniki, zboleli leta 2007, prispevajo le k izra~unu enoletnega pre`ivetja, samo bolniki, ki so zboleli do konca leta 2003, pa imajo mo`nost prispevati k izra~unu popolnega petletnega rela- tivnega pre`ivetja. V analizo obdobnega petletnega relativnega pre`ivetja ravno tako vklju~imo bolnike, zbolele v obdobju 2003–2007. Vendar se metoda bistveno razlikuje od prej{nje v tem, da bolniki, ki so zboleli leta 2003, prispevajo le k izra~unu petletnega pre`ivetja, medtem ko teh podatkov (za razliko od popolnega pre`ivetja) ne upo{tevamo pri izra~unu enoletnega pre`ivetja. Obdob- no enoletno relativno pre`ivetje tako izra~unamo iz skupine bolnikov, zbolelih v letu 2007, dveletno pre`ivetje iz skupine zbolelih leta 2006 itd. Zaradi vsakoletnega napredka medicine in s tem bolj{e napovedi izida bolezni pri bolnikih, ki so zboleli zadnja leta, so obdobna pet- letna relativna pre`ivetja obi~ajno ve~ja od popolnih pre`ivetij, ta pa bolj{a od kohortnih pre`ivetij. 20 Pre`ivetje bolnikov z rakom, zbolelih v letih 1991–2005 v Sloveniji Rak.qxd 22.7.2009 12:38 Page 20 a good approximation of patients' survival in the case that the observed cancer would be con- sidered as the only cause of death. Relative survival is a ratio between the observed and the expected survival, i. e. the survival expec- ted with respect to gender and age in certain time period in the whole population the patients come from. The expected survival is calculated from general mortality data, published routinely in the form of mortality tables for an individual country within the framework of its vital sta- tistics The relative survival for the needs of this publication was calculated using the Slovenian annual complete yearly period life tables. In practice, the relative survival of cancer patients is generally less than 100%. In rare cases, when the relative survival is equal to 100%, it can be concluded that the survival in cancer patient group is comparable with survival in general population, which means that the disease itself has not shortened the expected lifespan. Theoretically, the calculated relative survival may even exceed 100%, meaning that patients have better survival than the whole population. This may happen if the sick adopt a healthier lifestyle, or if their concomitant diseases are treated more consistently than in general population on average. No such theoretically possible case has been noted in the Slovenian cancer patient population. Relative survival can be calculated by different methods. In the cohort method, a group of patients is followed up for a certain period of time, generally for five years. Thus, every person includ- ed in the analysis should have the possibility to survive five years. Survival is calculated as the proportion of patients alive after certain periods of time, generally after one, three and five years from diagnosis. In complete method, patients diagnosed later on and followed up for less than five years by the end of the observation period are also included. The patients followed up for a shorter period of time are considered in the calculation of complete relative survival only for the time when they were actually followed. Thus, a group diagnosed three years before the com- pletion of study, contributes to one- and three-year complete relative survival but not also to five-year survival. A special form of complete relative survival is period relative survival. In the method of peri- od survival, only the patients diagnosed in the last year are included in the calculation of one-year survival, while the calculation of two-year survival includes only the patients diagnosed two years before and have survived the first year; accordingly, the calculation of five-year survival includes only the patients diagnosed five years ago and still alive at least four years from diag- nosis. For better demonstrating the differences between cohort, complete and period relative sur- vival, a case of relative survival analysis carried out in cancer patients with data on their vital status on 31 December 2008 is presented. Cohort 5-year survival can only be calculated for patients diagnosed by the end of 2003, since only that group can be followed up at least five years. An analysis of complete 5-year relative survival can also include all patients diagnosed by the end of 2007 and followed up until 31 December 2008, their follow-up period being censored by that date, except in the patients that have already died. Thus, patients diagnosed in 2007 are considered only in the calculation of one-year survival, while only the patients diag- nosed by the end of 2003 have the chance to be considered in the calculation of complete 5-year relative survival. Likewise, an analysis of period 5-year relative survival includes patients diagnosed in the peri- od 2003–2007. However, this method significantly differs from the former in that the patients diagnosed in 2003 are considered only in the calculation of 5-year survival, but (for the difference from complete survival) not in the calculation of one-year survival. Thus, peri- od one-year relative survival is calculated from the group of patients diagnosed in 2007, two-year survival from the group of those diagnosed in 2006, etc. Because of the continuous advances in medicine, and associated with that better prognosis of the outcome of disease in patients 21 Survival of cancer patients, diagnosed in 1991–2005 in Slovenia Rak.qxd 22.7.2009 12:38 Page 21 Pri prikazu in razlagi rezultatov obdobnega relativnega pre`ivetja je dolo~ena zadr`anost vse- eno na mestu, saj gre, kot je razvidno iz opisanega postopka, v tem primeru zgolj za napoved pre`ivetja bolnikov – bolniki, zboleli leta 2007, so konec leta 2008 lahko pre`iveli le leto dni. Tako z obdobnim relativnim pre`ivetjem na opisan na~in le ocenimo, kak{no bi bilo njihovo petletno relativno pre`ivetje. V na{i knjigi smo za izra~un vseh relativnih pre`ivetij uporabili metodo popolnega relativnega pre`ivetja. Bolniki, vklju~eni v analize, so zboleli do konca leta 2005, sledili pa smo jih do 31. 3. 2008. Za izra~un smo uporabili programsko kodo relsurv za okolje R. V {tudiji EUROCARE-4, ki jo povzemamo za primerjavo povpre~nih slovenskih, evropskih in ameri{kih bolnikov, zbole- lih v obdobju 2000–2002, ki so jim sledili do konca leta 2003, pa so uporabili metodo obdobnega pre`ivetja tudi pri na{ih, slovenskih podatkih. 22 Pre`ivetje bolnikov z rakom, zbolelih v letih 1991–2005 v Sloveniji PRIKAZ REZUL T ATOV Vsako poglavje obravnava eno od rakavih bolezni pri odraslih glede na organ, v katerem je nasta- la. Na koncu so prikazani vsi raki skupaj, razen ko`nega, pri odraslih, nazadnje pa {e rak pri otrocih in mladostnikih. V za~etku vsakega poglavja je navedeno {tevilo vseh zbolelih v 15-letnem obdobju, na Sliki 1 pa prikazujemo najosnovnej{a kazalca bremena bolezni, inciden~ne in umrljivostne stopnje dolo- ~ene rakave bolezni pri obeh spolih skupaj in njihove ~asovne trende v 20 letih, 1986–2005. Poleg grobih prikazujemo tudi starostno standardizirane stopnje. Za standardizacijo smo upo- rabili neposredno metodo, za standard pa starostno strukturo prebivalcev Slovenije sredi leta 1986. Iz razlike med grobimi in standardiziranimi inciden~nimi stopnjami lahko ocenimo, kolik{en dele` sprememb gre pripisati staranju slovenskega prebivalstva, koliko pa gre na ra~un vseh drugih nevarnostnih dejavnikov. Spremembe umrljivostnih stopenj zrcalijo spremembe incidence in u~inkovitosti zdravljenja. Povpre~ne letne odstotne spremembe smo ocenili z matemati~nimi modeli segmentne linijske regresije. Za modeliranje smo uporabili statisti~ni program Join- point, ki zaporedne ve~letne to~kovne podatke o incidenci ali umrljivosti opi{e z eno ali ve~ regresijskimi premicami; iz regresijskega koeficienta vsake od premic pa lahko izra~unamo pov- pre~no letno spremembo za obdobje, ki ga posamezna premica (segment) predstavlja. Trend inciden~nih in umrljivostnih stopenj, ki ga prikazujemo na za~etku vsakega poglavja, se nana{a na vse bolnike z obravnavanim rakom vseh starosti, vklju~no s tistimi, ki jim je bila diagnoza postavljena {ele ob smrti. Vse nadaljnje analize pa smo omejili samo na bolnike, ki jim diagnoza ni bila postavljena {ele ob smrti, saj ti ne prispevajo ni~esar k oceni pre`ivetja, ker sta datum diagnoze in smrti enaka; bolnike smo razdelili na odrasle (stare 20 let in ve~) in na otroke in mladostnike (stare 0–19 let). Prikazu trendov sledi opis {tevila v analizo vklju~enih in izklju~enih bolnikov. Kjer je bilo smi- selno, navajamo odstotke bolnikov z natan~neje opredeljenim mestom vznika raka v posameznem organu, pa dele` mikroskopsko potrjenih primerov in najpogostej{e histolo{ke vrste malignoma. Starost bolnikov ob diagnozi in stadij bolezni v treh obdobjih, 1991–1995, 1996–2000 in 2001–2005, sta prikazana v Tabeli 1 in Tabeli 2. Pri vsaki rakavi bolezni v besedilu navajamo tudi odsto- tek bolnikov, ki so bili po podatkih RRS specifi~no zdravljeni, kak{no je bilo prvo zdravljenje in v katerih slovenskih bolni{nicah se je za~elo. Relativno eno-, tri-, pet- in desetletno pre`ivetje bolnikov obeh spolov skupaj, ki jim je bila diagnoza postavljena v {tirih petletnih obdobjih, prikazuje Slika 2. V Tabeli 3 pa je prikazano opazovano in relativno eno-, tri- in petletno pre`ivetje, lo~eno po spolu. Slika 3 ka`e petlet- no relativno pre`ivetje po stadiju, Slika 4 pa po starosti. V obeh slikah je za primerjavo dodano {e pre`ivetje vseh bolnikov skupaj. Rak.qxd 22.7.2009 12:38 Page 22 diagnosed in recent years, the period 5-year survivals generally turn out to be better than com- plete survivals, and the latter better than cohort survivals. But, the results of period relative survival should nevertheless be presented and interpreted with a certain degree of caution, since it is evident from the procedure described, that in this case the anticipated survival is but esti- mated; by the end of 2008, patients diagnosed in 2007 might have survived one year only. Using the described period relative survival method, we can assess what would be their 5-year sur- vival. In our publication, all relative survivals were calculated by means of the complete relative sur- vival method. Patients included in the analyses were diagnosed until the end of 2005 and followed up till 31 March 2008. For calculation, the relsurv program code for R environment was used. In EUROCARE-4 study, which was used as a reference to compare the survival of average Slovenian, European and American patients diagnosed in the period 2000–2002 and followed up until the end of 2003, the method of period survival was also applied to the Slovenian data. 23 Survival of cancer patients, diagnosed in 1991–2005 in Slovenia THE PRESENT ATION OF RESUL TS Every chapter is devoted to one of the cancer diseases in adults, with respect to the organ of origin. In the end, all cancers (except cutaneous) in adults are presented together, and finally also cancers in children and adolescents. Every chapter starts with the number of patients diagnosed in the 15-year period studied, while Figure 1 presents the basic indicators of disease burden, the incidence and mortality rates of a particular cancer disease in both genders together and their time trends in the course of 20 years, from 1986 to 2005. Besides the crude rates also the age-standardized rates are presented. Standardization was done by means of the direct method, using the age structure of Slovenia's population in the middle of 1986 as standard. From the difference between the crude and stan- dardized incidence rates we can assess the proportion of changes that should be ascribed to population ageing and the proportion due to other risk factors. The changes in mortality rates reflect the changes in incidence and treatment success. Average annual percentage changes were calculated using the mathematical model of segmental linear regression. Statistical programme Joinpoint was used as a modelling tool presenting sequential long-term data on incidence or mortality as one or more regression lines; from the regression coefficient of each line we can calculate an average annual change for the period represented by an individual line (segment). The trend in incidence and mortality rates, presented in the beginning of every chapter, refers to all patients of all ages, who have that particular cancer, including those diagnosed only after death. All further analyses were limited to patients diagnosed during their lifetime, as those diagnosed only after death do not contribute anything to the evaluation of survival, because their dates of diagnosis and death are the same. After trend presentation, the numbers of patients included and excluded from the analysis are given. The percentages of patients with precisely defined cancer site in a particular organ, the proportion of microscopically confirmed cases and the most common histological types of malig- nomas are stated when appropriate. Age of patients at diagnosis and stage of the disease in three time periods, i.e. 1991–1995, 1996–2000 and 2001–2005 are presented in Table 1 and Table 2. Each description of cancer disease also contains the data on the percentage of patients receiving specific treatment, the type of their primary treatment and the hospital where it was started. Relative 1-, 3-, 5- and 10-year survivals of patients of both genders together, diagnosed in the four 5-year periods, are presented in Figure 2. The observed and relative 1-, 3- and 5-year sur- vivals for each gender separately are presented in Table 3. 5-year relative survival by stage is Rak.qxd 22.7.2009 12:38 Page 23 VIRI Literature Pre`ivetje dodatno osvetljujeta {e dva podatka, zapisana ob koncu uvodnega dela: pogojno pet- letno relativno pre`ivetje in pre`ivetje bolnikov, pri katerem je prou~evani rak edina rakava bolezen. Pogojno pre`ivetje je petletno relativno pre`ivetje tistih bolnikov, ki so pre`iveli prvo leto po postavitvi diagnoze. Praviloma je ve~je od tistega, ki ga ra~unamo od datuma diagnoze. Pri neka- terih rakavih boleznih pri~akujemo {e druge in naslednje primarne rake; bolniki, pri katerih je bila prou~evana rakava bolezen edini rak, imajo praviloma ve~je pre`ivetje. Ob koncu uvodnega dela prikazujemo petletno relativno pre`ivetje slovenskih bolnikov, bol- nikov v Evropi in v nekaterih obmo~jih ZDA. Vrednosti so povzete po raziskavi EUROCARE-4, v kateri so zdru`ili podatke 31 registrov raka iz 15 evropskih dr`av ter podatke iz ZDA, ki jih posreduje program SEER ameri{kega Dr`avnega in{tituta za raka (13 registrov raka). Vsi bolni- ki so zboleli v obdobju 2000–2002, stari so 15 let in ve~, za izra~un pa je bila uporabljena metoda obdobnega relativnega pre`ivetja. Zaradi razli~ne starostne razporeditve bolnikov z rakom v po- sameznih podro~jih so v raziskavi EUROCARE-4 obdobno relativno pre`ivetje tudi starostno standardizirali. V na{i knjigi pri ve~ini anatomskih mest prikazujemo starostno standardizi- rane vrednosti iz te raziskave. Pri sedmih anatomskih mestih, kjer je bilo v Sloveniji malo primerov (ustno in spodnje `relo, jetra, trebu{na slinavka, modo, mo`gani in akutna limfoblastna lev- kemija), je starostna standardizacija tako spremenila {tevil~ne vrednosti, da ne ustrezajo dejanskemu stanju, zato objavljamo pravilnej{e, nestandardizirane vrednosti. Analizi podatkov, ki smo jo pripravili v RRS, sledi komentar strokovnjakov klinikov, ki se dnev- no ukvarjajo s specifi~nim zdravljenjem bolnikov z rakom na OI Ljubljana in klinikah UKC Ljubljana. Razpravljajo o spremembah v metodah diagnostike in zdravljenja, ki so lahko vpli- vale na pre`ivetje slovenskih bolnikov, in opozarjajo na pomanjkljivosti, ki bi morda, ~e bi jih odpravili, {e izbolj{ale pre`ivetje na{ih bolnikov. Brenner H, Gefeller O. An alternative approach to monitoring cancer patient survival. Cancer 1996; 78: 2004–10. Ederer F, Axtell LM, Cutler SJ. The relative survival rate: a statistical methodology. Natl Cancer Inst Monogr 1961; 6: 101–21. EUROCARE-1 do EUROCARE-4: vsi prispevki dosegljivi na: http://www.eurocare.it/. Incidenca raka v Sloveniji (1986–2005). Ljubljana: Onkolo{ki in{titut, Register raka za Slovenijo, 1989–2008. In{titut za varovanje zdravja RS. Mednarodna klasifikacija bolezni in sorodnih zdravstvenih problemov za statisti~ne namene. 10. revizija (International Statistical Classification of Diseaseses and Related health Problems). Ljubljana: In{titut za varovanje zdravja, 1995. Kaplan EL, Meier P. Non parametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–81. Kim HJ, Fay MP , Feuer EJ, Midthune DN. Permutation tests for joinpoint regression with applications to cancer rates. Stat Med 2000; 19: 335–51 (correction: 2001; 20: 655). Parkin DM, Whelan SL, Ferlay J, Teppo L, Thomas DB, eds. Cancer incidence in five continents. Vol 8. Lyon: International Agency for Research on Cancer, 2002 (IARC Sci Publ 155). Pohar M, Stare J. Relative survival analysis in R. Computer Methods and Programs in Biomedicine 2006; 81: 272–8. Pompe-Kirn V, Zakotnik B, Volk N, Benuli~ T , [krk J. Pre`ivetje bolnikov z rakom v Sloveniji 1963–1990 (Cancer Patients' Survival in Slovenia 1963–1990). Ljubljana: Onkolo{ki in{titut, Register raka za Slovenijo, 1995. Pompe-Kirn V, Zakotnik B, Zadnik V. Pre`ivetje bolnikov z rakom v Sloveniji 1983–1997 (Cancer Patients' Survival in Slovenia 1983–1997). Ljubljana: Onkolo{ki in{titut, Register raka za Slovenijo, 2003. Primic-@akelj M, Pompe-Kirn V, [krlec F, [elb-[emerl J. Can we rely on cancer mortality data? Checking the validity of cervical cancer mortality data for Slovenia = So podatki o umrljivosti za rakom verodostojni – analiza podatkov o umrljivosti zaradi raka materni~nega vratu. Radiol Oncol 2001; 35: 243–7. R Development Core Team, R. A Language and Environment for Statistical Computing, R Foundation for Statistical Computing, Vienna, Austria, 2005. Available at: http://www.R-project.org. World Health Organisation. International Calssification of Diseases for Oncology. Geneva: World Health Organisation, 2000. @agar T . Lifetables for Slovenia 1982–2004. Rostock: Max Planck, 2005. 94 str. http://www.lifetable.de/cgi-bin/ Country.plx?Country=Slovenia. 24 Pre`ivetje bolnikov z rakom, zbolelih v letih 1991–2005 v Sloveniji Rak.qxd 22.7.2009 12:38 Page 24 shown in Figure 3 and by age in Figure 4. In both figures the survival of all patients together is added for comparison. The survival is additionally pointed out by the data given at the end of the introductory part: conditional 5-year relative survival and the survival of patients with the studied cancer as the only cancer. Conditional survival is the 5-year relative survival of patients surviving the first year from diagnosis. As a rule, it is greater than that calculated from the date of diagnosis. In certain cancers, a second and further primary cancers may be expected; patients with the stud- ied cancer as the only primary cancer will generally have better survival. By the end of the introductory part we present the 5-year relative survival of patients in Slovenia, in Europe and in certain regions of the USA. The results are summarized from the EURO- CARE-4 study, where the data from 31 cancer registries of 15 European countries are pooled with the data from the USA reported by the SEER program of American National Cancer Institute (13 registries). All the patients were diagnosed in the period 2000–2002, they were aged 15 years or more and their survival was calculated according to the period relative sur- vival method. Owing to different age distribution of cancer patients in individual areas, in EUROCARE-4 study the period relative survival was also age-standardized. In this publica- tion, age-standardized values are presented for most cancer sites. In seven cancer sites with only few cases in Slovenia (oropharynx and hypopharynx, liver, pancreas, testis, brain and acute lymphoblastic leukemia), age standardization changed the values so much that they did not correspond to the actual situation, and therefore more correct, non-standardized values are pub- lished instead. The data analyses prepared in the CRS are followed by commentaries of expert-clinicians daily dealing with specific treatment of cancer patients at the IO Ljubljana as well as at various depart- ments of the UMC Ljubljana. They discuss the changes in diagnostic and therapeutic methods that might have influenced the survival of the Slovenian patients, and point out the drawbacks, which – if eliminated – may further improve the survival of our patients. 25 Survival of cancer patients, diagnosed in 1991–2005 in Slovenia Rak.qxd 22.7.2009 12:38 Page 25 RAK PRI ODRASLIH 26 Pre`ivetje bolnikov z rakom, zbolelih v letih 1991–2005 v Sloveniji Rak.qxd 22.7.2009 12:38 Page 26 CANCER IN ADULTS 27 Survival of cancer patients, diagnosed in 1991–2005 in Slovenia Rak.qxd 22.7.2009 12:38 Page 27 V obdobju 1991–2005 je za rakom ustnega `rela zbolelo 1834 ljudi, od tega 1629 mo{kih in 205 `ensk. Kot je razvidno s Slike 1, se tako grobe kot starostno standardizirane inciden~ne in umrljivostne stopnje od leta 1991 zmanj{ujejo. Groba inciden~na stopnja se zmanj{uje povpre~- no za 0,4 % letno, groba umrljivostna stopnja pa povpre~no za 1,0 % letno. Starostno standardizirani stopnji se zmanj{ujeta {e nekoliko hitreje, saj v zadnjih letih zboli ve~ starej{ih bolnikov (Ta- bela 1). USTNO @RELO MKB 10: C01, C05, C09, C10 28 0 1 2 3 4 5 6 7 8 1986 1990 1995 2000 2005 Leto / Year Incidenca – groba stopnja / Incidence – crude rate Incidenca – SSS* / Incidence – ASR** Umrljivost – groba stopnja / Mortality – crude rate Umrljivost – SSS* / Mortality – ASR** Stopnja na 100.000 / Rate per 100,000 * SSS – starostno standardizirana stopnja (standard – slovenska populacija leta 1986) ** ASR – age standardized rate (standard Slovenian population in 1986) Slika 1: Groba in starostno standardizirana inciden~na in umrljivostna stopnja raka ustnega `rela, Slovenija 1986–2005. Figure 1: Crude and age-standardized incidence and mortality rate of oropharyngeal cancer, Slovenia 1986–2005. V analizo pre`ivetja je vklju~enih 1818 primerov; 15 bolnikov (0,8 %) nismo upo{tevali, ker jim je bila diagnoza postavljena po smrti, enega, mlaj{ega od 20 let, pa obravnavamo v poglav- ju o pre`ivetju pri otrocih in mladostnikih. Pri polovici bolnikov je rak nastal prav v ustnem `relu, pri 24 % v tonzilah, po 13 % pa jih je imelo raka na bazi jezika ali na nebu. Manj kot 1 % bolnikov v vsakem obdobju ni imel mikroskopsko potrjene bolezni. Skoraj vsi primeri mikroskopsko potrjene bolezni (95 %) so bili plo{~atoceli~ni karcinomi. T abela 1: [tevilo bolnikov z rakom ustnega `rela po spolu in obdobju postavitve diagnoze ter njihovi dele`i po starosti. T able 1: Number of oropharyngeal cancer patients by sex and period of diagnosis with their proportions by age. Mo{ki / Males @enske / Females Obdobje / {tevilo / 20–49 let / 50–74 let / 75+ let / {tevilo / 20–49 let / 50–74 let / 75+ let / Period number years (%) years (%) years (%) number years (%) years (%) years (%) 1991–1995 553 25,1 72,9 2,0 57 12,3 71,9 15,8 1996–2000 563 23,3 73,2 3,6 63 27,0 60,3 12,7 2001–2005 501 21,6 72,7 5,8 81 21,0 61,7 17,3 EPIDEMIOLOGIJA Rak.qxd 22.7.2009 12:38 Page 28 In the period 1991–2005, a total of 1834 persons were diagnosed with oropharyngeal cancer, of these 1629 males and 205 females. As evident from Figure 1, since 1991, crude as well age-stan- dardized incidence and mortality rates have been decreasing. The estimated annual percentage decrease in crude incidence rate was 0.4% and in crude mortality rate 1.0%. Age-standardized rates have been decreasing even faster, as more elderly patients have been diagnosed in recent years (Table 1). The survival analysis included 1818 cases; 15 patients (0.8%) diagnosed only after death were not considered in the analysis, one patient under 20 years of age is presented in the chapter on the survival of children and adolescents. In half of the patients cancer occurred in the orophar- ynx, in 24% in the tonsils, while cancer in the tongue base and the oral palate occurred in 13% each. Approximately 1% of patients in each time period did not have microscopically confirmed dis- ease. Practically all microscopically confirmed cancers (95%) were planocellular carcinomas. Age of the majority of patients at diagnosis ranged between 50 and 74 years. In males, the pro- portion of those aged 75 years or older was low all the time while in females it reached 17% in the recent period. In both genders, 21% of patients developed the disease before the age of 50 (Table 1). The proportion of patients in individual age groups did not change signifi- cantly with time. In all three time-periods, the majority of patients were diagnosed with regional disease; in the period 2001–2005 there were 79% such patients in both genders (Table 2). The remaining majo- rity of patients had the disease diagnosed at a localized stage. A minimum proportion of patients, in whom stage at diagnosis was not determined, is encouraging. The proportion of patients in individual stages did not change significantly with time. In the period 2001–2005, 6% of patients did not receive specific treatment. In all the observed 15-year period the proportion of untreated patients has remained practically unchanged. In the period 2001–2005, 91% of patients with specific treatment received radiotherapy. Radiotherapy alone was used in 36% of patients, one third received radiotherapy in combination with sur- gery and 21% in combination with chemotherapy, while 11% of the irradiated patients had surgery combined with chemotherapy. There were 8% of patients treated by surgery alone. In the period 2001–2005, practically all patients started their treatment in one of the three lead- ing Slovenian health institutions: 56% at the IO Ljubljana, 30% in the UMC Ljubljana, and 14% in the UMC Maribor. The relative survival of patients with oropharyngeal cancer has been increasing; in 15 years, the 5-year relative survival increased by 5% (Figure 2), in males more than in females, although the 5-year relative survival in females was considerably better (Table 3). The relevance of stage OROPHARYNX ICD 10: C01, C05, C09, C10 29 EPIDEMIOLOGY Tabela 2: [tevilo bolnikov z rakom ustnega `rela po spolu in obdobju postavitve diagnoze ter njihovi dele`i po stadiju. T able 2: Number of oropharyngeal cancer patients by sex and period of diagnosis with their proportions by stage. Mo{ki / Males @enske / Females Obdobje / {tevilo / omejen / raz{irjen / razsejan / neznan / {tevilo / omejen / raz{irjen / razsejan / neznan / Period number localized regional distant unknown number localized regional distant unknown (%) (%) (%) (%) (%) (%) (%) (%) 1991–1995 553 15,9 80,1 2,9 1,1 57 19,3 75,4 1,8 3,5 1996–2000 563 17,2 79,4 2,3 1,1 63 19,0 79,4 1,6 0,0 2001–2005 501 17,4 78,8 3,2 0,6 81 18,5 79,0 2,5 0,0 Rak.qxd 22.7.2009 12:38 Page 29 Najve~ji dele` zbolelih je bil ob diagnozi star med 50 in 74 let. Dele` starih 75 let in ve~ je pri mo{kih ves ~as majhen, pri `enskah pa v zadnjem obdobju dosega 17 %. Pri obeh spolih pred 50. letom zboli 21 % bolnikov (Tabela 1). Dele`i bolnikov v posameznih starostnih skupinah se s ~asom niso bistveno spreminjali. V vseh treh obdobjih je imelo najve~ bolnikov ob diagnozi raz{irjeno bolezen; v obdobju 2001–2005 je bilo takih bolnikov pri obeh spolih 79 % (Tabela 2). Ve~ini preostalih bolnikov je bila bole- zen odkrita v omejenem stadiju. Razveseljuje pa dejstvo, da le pri majhnem dele`u bolnikov stadij ob diagnozi ni bil dolo~en. Dele`i posameznih stadijev se s ~asom niso bistveno spre- minjali. 30 USTNO @RELO 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Slika 2: Deset-, pet-, tri- in enoletno relativno pre`ivetje bolnikov z rakom ustnega `rela po obdobju postavitve diagnoze. Figure 2: 10-, 5-, 3- and 1-year relative survival of oropharyngeal cancer patients by period of diagnosis. Tabela 3: Opazovano in relativno pre`ivetje bolnikov z rakom ustnega `rela po spolu in obdobju postavitve diagnoze s 95-odstotnim intervalom zaupanja (IZ). Table 3: Observed and relative survival of oropharyngeal cancer patients by sex and period of diagnosis with 95% confidence interval (CI). Opazovano pre`ivetje / Observed survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 55,9 (51,9–60,2) 29,3 (25,7–33,3) 21,2 (18,0–24,9) 68,4 (57,4–81,6) 47,4 (36,0–62,3) 38,6 (27,8–53,5) 1996–2000 59,0 (55,0–63,2) 30,7 (27,1–34,8) 24,0 (20,7–27,8) 63,5 (52,7–76,6) 55,6 (44,5–69,3) 46,0 (35,2–60,1) 2001–2005 64,1 (60,0–68,4) 38,0 (33,9–42,6) 24,9 (20,8–29,8) 75,3 (66,5–85,3) 56,4 (46,5–68,4) 42,0 (31,2–56,6) Relativno pre`ivetje / Relative survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 57,1 (52,8–61,5) 31,4 (27,1–35,8) 23,9 (19,7–28,1) 70,1 (56,6–83,6) 51,0 (35,0–67,1) 43,7 (26,8–60,7) 1996–2000 60,3 (56,0–64,6) 32,9 (28,6–37,3) 27,0 (22,7–31,3) 64,5 (51,2–77,7) 58,3 (43,9–72,7) 50,0 (34,7–65,3) 2001–2005 65,5 (61,1–69,9) 40,8 (35,9–45,7) 28,3 (22,8–33,9) 76,8 (66,6–87,0) 60,1 (47,3–72,9) 46,9 (30,6–63,1) Rak.qxd 22.7.2009 12:38 Page 30 at diagnosis is shown in Figure 3. In the last period, 5-year relative survival of patients with locali- zed stage was 42%, while in those with regional stage at diagnosis it was 30%. Due to a small number of patients with disseminated disease, the evaluation of their survival is rather unreli- able. In recent years, the greatest improvement in the survival was observed in patients with regional disease. Age is a prognostic factor as well, since the relative survival in patients over 50 years of age is considerably lower than in those diagnosed before the age of 50 years (Figure 4). The 5-year relative survival of all patients diagnosed in the period 2001–2005 was 31% (Figure 2); patients surviving the first year may expect to survive five years in 46%. In comparison with other cancer patients, those with cancers of the head/neck will more frequently develop a second primary cancer. Five-year relative survival of patients with oropharynx as the only primary can- cer site was 40%. According to the results of EUROCARE-4 study for patients diagnosed in 2000–2002, the survival of Slovenian patients with oropharyngeal cancer is statistically significantly below the European average (Figure 5). 31 OROPHARYNX 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 Omejen / Localized Raz{irjen / Regional Razsejan / Distant Vsi / All Slika 3: Petletno relativno pre`ivetje bolnikov z rakom ustnega `rela po stadiju in obdobju postavitve diagnoze. Figure 3: 5-year relative survival of oropharyngeal cancer patients by stage and period of diagnosis. 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 20–49 let / years 50–74 let / years 75+ let / years Vsi / All Slika 4: Petletno relativno pre`ivetje bolnikov z rakom ustnega `rela po starosti in obdobju postavitve diagnoze. Figure 4: 5-year relative survival of oropharyngeal cancer patients by age and period of diagnosis. Rak.qxd 22.7.2009 12:38 Page 31 V letih 2001–2005 ni bilo specifi~no zdravljenih 6 % bolnikov. Dele` nezdravljenih bolnikov ostaja v opazovanem 15-letnem obdobju skoraj enak. Med specifi~no zdravljenimi je bilo v le- tih 2001–2005 obsevanih 91 % bolnikov. Samo obsevanih je bilo 36 % bolnikov, pri tretjini je bilo obsevanje kombinirano z operacijo, pri 21 % pa s kemoterapijo; 11 % obsevanih bolnikov je poleg operacije v okviru prvega zdravljenja prejelo {e kemoterapijo. Samo operiranih je bilo 8 % bolnikov. V obdobju 2001–2005 so prakti~no vsi bolniki zdravljenje za~eli v eni od treh vodilnih slo- venskih zdravstvenih ustanov: 56 % na OI Ljubljana, 30 % v UKC Ljubljana in 14 % v UKC Maribor. Relativno pre`ivetje bolnikov z rakom ustnega `rela se postopno pove~uje; v 15 letih se je pet- letno relativno pre`ivetje pove~alo za 5 % (Slika 2), pri mo{kih bolj kot pri `enskah, ~eprav je petletno relativno pre`ivetje `ensk precej bolj{e (Tabela 3). Kako pomemben je stadij ob diag- nozi, ka`e Slika 3; petletno relativno pre`ivetje bolnikov z omejenim stadijem je v zadnjem obdobju 42 %, z raz{irjenim stadijem bolezni ob diagnozi pa 30 %. Bolnikov z razsejanim sta- dijem je malo, tako da je ocenjevanje njihovega pre`ivetja precej nezanesljivo. V zadnjih letih se je najbolj izbolj{alo pre`ivetje bolnikov z raz{irjeno boleznijo. Napovedni dejavnik je tudi starost, saj je relativno pre`ivetje starej{ih od 50 let precej manj{e od pre`ivetja zbolelih pred 50. letom starosti (Slika 4). Petletno relativno pre`ivetje vseh zbolelih v obdobju 2001–2005 je bilo 31 % (Slika 2), tisti, ki pre`ivijo prvo leto, pa lahko pri~akujejo 46-odstotno petletno relativno pre`ivetje. Pogosteje kot drugi bolniki z rakom zbolijo bolniki z rakom na podro~ju glave in vratu {e za drugim pri- marnim rakom. Bolniki, pri katerih je bil rak ustnega `rela edini rak, so imeli petletno relativno pre`ivetje 40 %. Rezultati {tudije EUROCARE-4 za zbolele v obdobju 2000–2002 ka`ejo, da je pre`ivetje sloven- skih bolnikov z rakom ustnega `rela statisti~no zna~ilno manj{e od evropskega povpre~ja (Slika 5). 32 USTNO @RELO KLINI^NI KOMENT AR Lojze [mid Primo` Strojan Branko Zakotnik Na raz{irjenost raka ustnega `rela vpliva predvsem raz{irjenost kajenja; med slovenskimi mo{- kimi se zmanj{uje, ~emur sledi zmanj{evanje incidence tega raka; porast incidence pri `enskah gre pripisati spremenjenim kadilskim navadam med njimi. Dele` mikroskopsko potrjene bolez- ni je bil v opazovanem obdobju ves ~as visok: pomeni dobro opredeljeno in ute~eno diagnosti~no pot pri obravnavi bolnikov z rakom zgornjega dela dihal in prebavil v Sloveniji. @al pa je dele` napredovalih stadijev raka {e vedno izjemno visok, okoli 80 %, in se v opazovanem obdobju ni prav ni~ spremenil, kar je svojevrsten kazalec zdravstvene ozave{~enosti v dr`avi. Skrajno neugodnemu izhodi{~u navkljub pa je mo~ opaziti vztrajno tendenco zni`evanja umr- ljivosti zaradi tega raka in predvsem dejstvo, da se je pre`ivetje bolnikov z raz{irjeno obliko raka ustnega `rela v opazovanem 20-letnem obdobju skoraj podvojilo! Ugoden zasuk v pre`ivetju bolnikov obeh spolov in vseh starostnih skupin je bil dose`en z uvedbo sistemskega zdravljenja te vrste raka v rutinsko obravnavo, tako operabilnih tumorjev (pooperativna so~asna radioke- moterapija od leta 2000) kot tudi neoperabilnih tumorjev (radikalna so~asna radiokemoterapija v drugi polovici 90-ih let preteklega stoletja). K oblikovanju obstoje~ih na~el zdravljenja napredo- valega raka tega podro~ja so pomembno prispevale tudi prospektivne randomizirane raziskave, izvedene na OI Ljubljana in na Kliniki za otorinolaringologijo in cervikofacialno kirurgijo UKC Ljubljana. Manj spodbudni so rezultati zdravljenja omejene in razsejane oblike raka ustnega `rela. V pr- vem primeru, ki predstavlja okoli 15 % vseh bolnikov s to vrsto raka, se pre`ivetje v opazovanem obdobju ni izbolj{alo. Glede na to, da se obstoje~i na~ini zdravljenja v tej skupini v zadnjih 15 letih Rak.qxd 22.7.2009 12:38 Page 32 The prevalence of oropharyngeal cancer is mainly influenced by the prevalence of smoking; among the Slovenian males the latter is decreasing, which is reflected in the decreasing inci- dence of that cancer, while an increase in the incidence among women could be attributed to their changed smoking habits. The proportion of microscopically confirmed disease was high throughout the observation period: it is indicative of a well defined and implemented diag- nostics in the management of cancer patients of the upper respiratory and digestive tracts in Slovenia. Unfortunately, however, the proportion of advanced cancers is still outstandingly high (about 80%) and has not changed at all during the observation period, which can be regarded as a unique indicator of health-related awareness in the country. Despite that extremely unfavourable situation, there is an apparent decreasing trend in the mor- tality due to this cancer as well as the fact that during the observed 20-year period the survival of patients with advanced stages of oropharyngeal cancer has almost doubled! A favourable shift in the survival of patients of both genders and all age groups was achieved by introduc- ing chemotherapy into the routine management of this type of cancer, so for operable tumors (postoperative and concomitant radiochemotherapy since 2000) as well as for inoperable tumors (radical concomitant radiochemotherapy – in the second half of the 90's of the past century). An important part in the establishment of the current principles in the treatment of advanced oropharyngeal cancer should be attributed to prospective randomised studies carried out at the IO Ljubljana and at the Department of Otorhinolaryngology and Cervicofacial surgery of the UMC Ljubljana. Treatment results in the case of localized and disseminated oropharyngeal cancer are less encour- aging. In the former, which represents approximately 15% of all oropharyngeal cancers, the survival in the observed period has not changed. Considering that in the last 15 years the existing treatment approach for this group has not changed, the result was expected. No improvement 33 OROPHARYNX CLINICAL COMMENT ARY Lojze [mid Primo` Strojan Branko Zakotnik 01 02 0 30 40 50 60 70 80 90 100 % Slovensko povpre~je / 2000–2002 (EUROCARE-4) Slovenian average Evropsko povpre~je / 2000–2002 (EUROCARE-4) European average Povpre~je ZDA / 2000–2002 (SEER-13) USA average Slika 5: Petletno relativno pre`ivetje bolnikov z rakom ustnega `rela* (povpre~je in 95-odstotni interval zaupanja), zbolelih v letih 2000–2002 v Sloveniji, Evropi in nekaterih obmo~jih v ZDA. Figure 5: 5-year relative survival of oropharyngeal* cancer patients (average and 95% confidence interval) diag- nosed in the period 2000–2002 in Slovenia, Europe and in some regions of the USA. * Nabor MKB10 kod v {tudiji EUROCARE-4 je nekoliko druga~en kot smo ga uporabili pri ostalih analizah predstavljenih v tem poglavju: v {tudiji EURCARE-4 so iz analize izvzete maligne neoplazme jezika (MKB10: C01) in maligne neoplazme neba (MKB10: C05). * The ICD10 code selection in EUROCARE-4 study is slightly different in comparison to the selection applied in other analysis in this chapter: in EUROCARE-4 study the malignant neoplasm of base of tongue (ICD10: C01) and malignant neoplasm of palate (ICD10: C05) are excluded. Rak.qxd 22.7.2009 12:38 Page 33 niso spremenili, je rezultat pri~akovan. Pre`ivetje bolnikov z razsejano obliko raka ustnega `re- la se prav tako ni izbolj{alo in je ostalo vse prej kot spodbudno. To je posledica dejstva, da zato obliko raka ni (bilo) uspe{nega zdravljenja, pa tudi zaradi majhnega {tevila bolnikov (okoli 5 %), ki ne omogo~a razpoznati manj{ih sprememb v pre`ivetju bolnikov, zdravljenih z drugimi ali novimi pristopi in na~ini. Pri iskanju vzrokov za slab{e rezultate zdravljenja raka ustnega `rela v Sloveniji v primerjavi z zahodnoevropskimi dr`avami in ZDA ne velja prezreti vloge HPV. S temi virusi naj bi bilo na zahodu oku`enih med 40–60 % bolnikov z rakom ustnega `rela, ki predstavljajo s klini~- nega in molekularnega stali{~a jasno lo~eno skupino tumorjev z ugodnej{o prognozo kot v skupini HPV negativnih tumorjev. @al sta v Sloveniji {e vedno prevladujo~a dejavnika tveganja raka ustnega dela `rela ~ezmerno pitje alkoholnih pija~ in kajenje. Pomembne razlike v pre`ivetju med spoloma, ki gredo v prid `enskam, ugotavljamo pri vseh stadijih, starostnih skupinah in znotraj vseh treh opazovanih obdobij. Budihna M, [oba E, [mid L, Zakotnik B, Strojan P , ^ema`ar M, et al. Inoperable oropharyngeal carcinoma treated with concomitant irradiation, mitomycin C and bleomycin – long term results. Neoplasma 2005; 52: 165–74. Fakhry C, Westra WH, Li S, Cmelak A, Ridge JA, Pinto H, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 2008; 100: 261–9. Strojan P , Karner K, [mid L, [oba E, Fajdiga I, Jan~ar B, et al. Concomitant chemoradiotherapy with mitomycin C and cisplatin in advanced unresectable carcinoma of the head and neck: Phase I–II clinical study. Int J Radiat Oncol Biol Phys 2008; 72: 365–72. [mid L, Budihna M, Zakotnik B, [oba E, Strojan P, Fajdiga I, et al. Postoperative concomitant irradiation and chemotherapy with mitomycin C and bleomycin for advanced head-and-neck carcinoma. Int J Radiat Oncol Biol Phys 2003; 56: 1055–62. [mid L, Le{ni~ar H, Zakotnik B, [oba E, Budihna M, Furlan L, et al. Radiotherapy, combined with simul- taneous chemotherapy with mitomycin C and bleomycin for inoperable head and neck cancer-preliminary report. Int J Radiat Oncol Biol Phys 1995; 32: 769–75. Zakotnik B, [mid L, Budihna M, Le{ni~ar H, [oba E, Furlan L, et al. Concomitant radiotherapy with mitomycin C and bleomycin compared with radiotherapy alone in inoperable head and neck cancer: final report. Int J Radiat Oncol Biol Phys 1998; 41: 1121–7. Zakotnik B, Budihna M, [mid L, [oba E, Strojan P , Fajdiga I, et al. Patterns of failure in patients with locally advanced head and neck cancer treated postoperatively with irradiation or concomitant irradiation with Mitomycin C and Bleomycin. Int J Radiat Oncol Biol Phys 2007; 67: 685–90. 34 USTNO @RELO VIRI Literature Rak.qxd 22.7.2009 12:38 Page 34 has either been achieved in the survival of patients with advanced stage of oropharyngeal can- cer, which remains rather discouraging. This is attributable to the fact that there was no effective treatment available for this type of cancer, and also to the small number of patients (approx- imately 5%), which does not enable the detection of minor changes in the survival of patients treated by other or innovative treatment approaches and methods. Further on, the role of HPV infection must not be overlooked when searching for the reasons of less effective treatment of hypopharingeal cancer in Slovenia in comparison to western European countries and the USA. In the west, probably about 40 to 60% of patients with hypopharingeal cancer are HPV positive. They represent a clearly different group from clinical as well as from molecular point of view and their prognosis is better than that of HPV negative patients. Unfortunately, in Slovenia the prevailing risk factors for hypopharingeal cancer are still alco- hol abuse and tobacco smoking. Significant differences in the survival between genders, which are in favour of women, are appa- rent in all stages, age groups and within all the three observation periods. 35 OROPHARYNX Rak.qxd 22.7.2009 12:38 Page 35 V obdobju 1991–2005 je za rakom ustne votline zbolelo 1374 ljudi, od tega 1126 mo{kih in 208 `ensk. Kot je razvidno s Slike 1, se razen grobe inciden~ne stopnje druge mere od leta 1991 zmanj{ujejo. Groba inciden~na stopnja se po~asi ve~a, povpre~no za 0,5 % letno, starostno stan- dardizirana pa se manj{a povpre~no za 1 % letno. Groba umrljivostna stopnja se manj{a povpre~no za 3,6 % letno, starostno standardizirana pa za 5 %. USTNA VOTLINA MKB 10: C02, C03, C04, C06 36 Mo{ki / Males @enske / Females Obdobje / {tevilo / 20–49 let / 50–74 let / 75+ let / {tevilo / 20–49 let / 50–74 let / 75+ let / Period number years (%) years (%) years (%) number years (%) years (%) years (%) 1991–1995 398 21,1 75,4 3,5 52 19,2 63,5 17,3 1996–2000 349 21,5 71,9 6,6 88 19,3 59,1 21,6 2001–2005 372 22,8 69,1 8,1 101 16,8 62,4 20,8 T abela 1: [tevilo bolnikov z rakom ustne votline po spolu in obdobju postavitve diagnoze ter njihovi dele`i po starosti. Table 1: Number of oral cavity cancer patients by sex and period of diagnosis with their proportions by age. 0 1 2 3 4 5 6 1986 1990 1995 2000 2005 Leto / Year Incidenca – groba stopnja / Incidence – crude rate Incidenca – SSS* / Incidence – ASR** Umrljivost – groba stopnja / Mortality – crude rate Umrljivost – SSS* / Mortality – ASR** Stopnja na 100.000 / Rate per 100,000 * SSS – starostno standardizirana stopnja (standard – slovenska populacija leta 1986) ** ASR – age standardized rate (standard Slovenian population in 1986) Slika 1: Groba in starostno standardizirana inciden~na in umrljivostna stopnja raka ustne votline, Slovenija 1986–2005. Figure 1: Crude and age-standardized incidence and mortality rate of oral cavity cancer, Slovenia 1986–2005. V analizo pre`ivetja je vklju~enih 1360 primerov; 13 bolnikov (0,9 %) nismo upo{tevali, ker jim je bila diagnoza postavljena po smrti, bolnico, ki je bila ob diagnozi mlaj{a od 20 let, pa obravnavamo v poglavju o pre`ivetju pri otrocih in mladostnikih. Pri 40 % bolnikov je rak nastal na ustnem dnu, pri 33 % na jeziku, pri 7 % na dlesnih, pri 20 % pa mesto nastanka ni bilo natan~- neje opredeljeno. Manj kot 1 % bolnikov v vsakem obdobju ni imelo mikroskopsko potrjene bolezni. Skoraj vsi mikroskopsko potrjeni malignomi (95 %) so bili plo{~atoceli~ni karcinomi. EPIDEMIOLOGIJA Rak.qxd 22.7.2009 12:38 Page 36 In the period 1991–2005, a total of 1374 persons were diagnosed with cancer of the oral cavi- ty, of these 1126 males and 208 females. As evident from Figure 1, since 1991 all rates but crude incidence rate have been decreasing. The estimated annual percentage increase in crude incidence rate was 0.5%, while age-standardized rate decreased by 1%. The estimated annu- al percentage decrease in crude mortality rate was 3.6% and in age-standardized 5%. The survival analysis included 1360 cases; 13 patients (0.9%) diagnosed only after death were not considered in the analysis, one female patient under 20 years of age at diagnosis is pre- sented in the chapter on the survival of children and adolescents. In 40% of the patients cancer occurred in the oral base, 33% in the tongue, 7% in the gum, while in 20% the origin of can- cer has not been clearly defined. Approximately 1% of patients in each time period did not have microscopically confirmed dis- ease. Practically all microscopically confirmed cancers (95%) were planocellular carcinomas. Age of the majority of patients at diagnosis ranged between 50 and 74 years. In males, the pro- portion of those aged 75 years or older was low all the time while in females it reached 21% in the recent period. In both genders approximately 20% of patients developed the disease before the age of 50 (Table 1). The proportion of patients in individual age groups did not change significantly with time. In all three time-periods, the majority of patients were diagnosed with regional disease; in the period 2001–2005 there were 64% such patients among males and 55% among females (Table 2). The remaining majority of patients had the disease diagnosed at a localized stage. In the 15-year period, the proportion of localized stage has increased, particularly in females, on the account of a smaller proportion of regional disease. In the years 2001–2005, 3% of patients did not receive specific treatment. In the observed 15-year period, the proportion of untreated patients has decreased by one third. Among the patients receiv- ing specific treatment in the period 2001–2005, 40% were treated by surgery and radiotherapy, 30% underwent surgery alone, and 15% received radiotherapy alone, while 10% of the patients had surgery and radiotherapy combined with chemotherapy. Other combinations of treatments were rare. Compared to the period 1991–1995, in the recent period the proportion of patients treated by surgery alone has increased significantly in comparison with those treated by radiotherapy alone. In the period 2001–2005, almost all patients started their treatment in one of the three lead- ing Slovenian health institutions: 53% in the UMC Ljubljana, 32% at the IO Ljubljana, and 14% in the UMC Maribor. The relative survival of patients with cancers of the oral cavity has been increasing: in 15 years, the 5-year relative survival increased by 14% (Figure 2). In comparison with males, the 5-year ORAL CAVITY ICD 10: C02, C03, C04, C06 37 Tabela 2: [tevilo bolnikov z rakom ustne votline po spolu in obdobju postavitve diagnoze ter njihovi dele`i po stadiju. Table 2: Number of oral cavity cancer patients by sex and period of diagnosis with their proportions by stage. Mo{ki / Males @enske / Females Obdobje / {tevilo / omejen / raz{irjen / razsejan / neznan / {tevilo / omejen / raz{irjen / razsejan / neznan / Period number localized regional distant unknown number localized regional distant unknown (%) (%) (%) (%) (%) (%) (%) (%) 1991–1995 398 26,6 68,8 2,5 2,0 52 30,8 65,4 1,9 1,9 1996–2000 349 30,1 67,0 1,7 1,1 88 51,1 47,7 0,0 1,1 2001–2005 372 33,1 64,2 1,3 1,3 101 41,6 55,4 2,0 1,0 EPIDEMIOLOGY Rak.qxd 22.7.2009 12:38 Page 37 Najve~ bolnikov je bilo ob diagnozi starih med 50 in 74 let. Dele` starih 75 let in ve~ je pri mo{kih ves ~as majhen, pri `enskah pa v zadnjem obdobju dosega 21 %. Pri obeh spolih pred 50. letom zboli okoli 20 % bolnikov (Tabela 1). Dele`i v posameznih starostnih skupinah se s ~asom niso bistveno spreminjali. V vseh treh obdobjih je imelo najve~ bolnikov ob diagnozi raz{irjeno bolezen; v obdobju 2001–2005 je bilo pri mo{kih 64 % takih bolnikov, pri `enskah pa 55 % (Tabela 2). Pri ve~ini preostalih bolnikov je bila bolezen odkrita v omejenem stadiju. V 15-letnem obdobju se je dele` omeje- nega stadija pove~eval, predvsem pri `enskah, na ra~un manj{ega dele`a raz{irjenega stadija. V letih 2001–2005 niso bili specifi~no zdravljeni 3 % bolnikov. Dele` nezdravljenih bolnikov se je v opazovanem 15-letnem obdobju zmanj{al za tretjino. Med specifi~no zdravljenimi je 38 USTNA VOTLINA 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Slika 2: Deset-, pet-, tri- in enoletno relativno pre`ivetje bolnikov z rakom ustne votline po obdobju postavitve diagnoze. Figure 2: 10-, 5-, 3- and 1-year relative survival of oral cavity cancer patients by period of diagnosis. Tabela 3: Opazovano in relativno pre`ivetje bolnikov z rakom ustne votline po spolu in obdobju postavitve diagnoze s 95-odstotnim intervalom zaupanja (IZ). Table 3: Observed and relative survival of oral cavity cancer patients by sex and period of diagnosis with 95% confidence interval (CI). Opazovano pre`ivetje / Observed survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 61,1 (56,4–66,0) 37,9 (33,5–43,0) 27,9 (23,8–32,7) 78,8 (68,5–90,8) 57,7 (45,7–72,8) 46,2 (34,4–61,9) 1996–2000 62,8 (57,9–68,0) 43,0 (38,1–48,5) 31,2 (26,7–36,5) 86,4 (79,5–93,8) 68,2 (59,1–78,6) 51,1 (41,7–62,7) 2001–2005 69,4 (64,8–74,2) 46,0 (41,2–51,4) 38,9 (33,9–44,6) 88,1 (82,0–94,7) 65,5 (56,7–75,7) 53,7 (43,4–66,4) Relativno pre`ivetje / Relative survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 62,5 (57,4–67,6) 40,8 (35,3–46,3) 31,7 (26,3–37,2) 80,9 (68,7–93,2) 62,5 (46,1–78,8) 53,0 (34,9–71,1) 1996–2000 64,3 (58,9–69,7) 46,5 (40,5–52,4) 35,8 (29,8–41,8) 88,8 (81,1–96,5) 74,2 (62,8–85,6) 59,1 (45,7–72,4) 2001–2005 71,0 (66,0–76,0) 49,6 (43,8–55,4) 44,4 (37,9–50,9) 90,2 (83,5–96,9) 70,6 (59,7–81,6) 60,8 (46,4–75,2) Rak.qxd 22.7.2009 12:38 Page 38 relative survival of females is much better (Table 3). The relevance of stage at diagnosis is shown in Figure 3. In the last period, 5-year relative survival of patients with localized stage was 69%, while in those with regional stage at diagnosis it was 38%. Due to a small number of patients with disseminated disease, the evaluation of their survival is rather unreliable. In recent years, the greatest increase in the survival was observed in patients with localized and regional di- sease. Age is a prognostic factor as well, since the relative survival of patients at an age between 50 to 74 years and of those aged 75 years or older is lower than in those diagnosed before the age of 50 years (Figure 4). The 5-year relative survival rate of all patients diagnosed in the period 2001–2005 was 48% (Figure 2); patients surviving the first year may expect to survive five years in 63%. In com- parison with the rest of cancer patients, those with cancers of the head/neck will more frequently develop a second primary cancer. Patients with oral cavity as the only primary cancer site had 57% 5-year relative survival rate. 39 ORAL CAVITY 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 Omejen / Localized Raz{irjen / Regional Razsejan / Distant Vsi / All Slika 3: Petletno relativno pre`ivetje bolnikov z rakom ustne votline po stadiju in obdobju postavitve diagnoze. Figure 3: 5-year relative survival of oral cavity cancer patients by stage and period of diagnosis. 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 20–49 let / years 50–74 let / years 75+ let / years Vsi / All Slika 4: Petletno relativno pre`ivetje bolnikov z rakom ustne votline po starosti in obdobju postavitve diagnoze. Figure 4: 5-year relative survival of oral cavity cancer patients by age and period of diagnosis. Rak.qxd 22.7.2009 12:38 Page 39 bilo v letih 2001–2005 40 % bolnikov operiranih in obsevanih, 30 % je bilo samo operiranih, 15 % pa samo obsevanih; pri 10 % je bila operaciji in obsevanju dodana {e kemoterapija. Osta- le kombinacije so bile uporabljene redko. V primerjavi z obdobjem 1991–1995 se je v zadnjem obdobju bistveno pove~al dele` samo operiranih v primerjavi s samo obsevanimi. V obdobju 2001–2005 so skoraj vsi bolniki zdravljenje za~eli v eni od treh vodilnih slovenskih zdravstvenih ustanov: 53 % v UKC Ljubljana, 32 % na OI Ljubljana in 14 % v UKC Maribor. Relativno pre`ivetje bolnikov z rakom v ustni votlini se pove~uje; v 15 letih se je petletno rela- tivno pre`ivetje pove~alo za 14 % (Slika 2). Petletno relativno pre`ivetje `ensk je v primerjavi z mo{kimi precej bolj{e (Tabela 3). Kako pomemben je stadij ob diagnozi, ka`e Slika 3: pet- letno relativno pre`ivetje bolnikov z omejenim stadijem je v zadnjem obdobju 69 %, medtem ko je petletno relativno pre`ivetje bolnikov z raz{irjenim stadijem bolezni ob diagnozi 38 %. Bolnikov z razsejanim stadijem je malo, tako da je ocenjevanje njihovega pre`ivetja precej neza- nesljivo. V zadnjih letih se je pove~alo pre`ivetje bolnikov z omejenim in raz{irjenim stadijem bolezni. Napovedni dejavnik je tudi starost, saj je relativno pre`ivetje starih 50–74 let in sta- rih 75 let in ve~ podobno, a slab{e kot pri zbolelih pred 50. letom starosti (Slika 4). Petletno relativno pre`ivetje vseh zbolelih v obdobju 2001–2005 je bilo 48-odstotno (Slika 2); bolniki, ki pre`ivijo prvo leto, pa lahko pri~akujejo 63-odstotno petletno relativno pre`ivetje. Pogosteje kot ostali bolniki z rakom zbolijo bolniki z rakom na podro~ju glave in vratu {e za drugim primarnim rakom. Bolniki, pri katerih je bil rak v ustni votlini edini rak, so imeli 57-od- stotno petletno relativno pre`ivetje. Rezultati {tudije EUROCARE-4 za zbolele v obdobju 2000–2002 ka`ejo, da je pre`ivetje sloven- skih bolnikov z rakom ustne votline statisti~no zna~ilno manj{e od evropskega povpre~ja (Slika 5). 40 USTNA VOTLINA KLINI^NI KOMENT AR Lojze [mid Primo` Strojan Branko Zakotnik Zadnja leta se je {tevilo bolnic z rakom v ustni votlini podvojilo, tako da v zadnjem obdobju predstavljajo `e petino vseh obolelih za to vrsto raka. Vzrok gre iskati v spremenjenih kadil- skih in morda tudi pivskih navadah `ensk v zadnjih desetletjih. Dele` mikroskopsko opredeljenih rakov je izjemno velik, kar zaradi lahke dostopnosti tumor- jev v ustni votlini ne presene~a. V zadnjem petletnem obdobju je tudi ugodnej{a razporeditev stadijev bolezni ob diagnozi: dele` omejene oblike se je vztrajno pove~eval in je dosegel v ob- dobju 2001–2005 `e tretjino vseh novih primerov raka v ustni votlini. To se je odra`alo tudi pri na~inu zdravljenja. V obdobju 1991–1995 je bilo samo z operacijo zdravljenih 13 % bol- nikov, v letih 2001–2005 pa je bilo operiranih `e 30 % vseh obravnavanih bolnikov. Nasprotno se je dele` samo obsevanih bolnikov v tem ~asu pri~akovano zmanj{al, s 36 % na 15 %. Pre`ivetje bolnikov z rakom v ustni votlini se je v celotnem 15-letnem obdobju pove~evalo, umrljivost pa se je zmanj{evala, kar je gotovo posledica `e omenjenih ugodnih sprememb v zasto- panosti posameznih stadijev bolezni. Dodatno je v skupini omejenih tumorjev k uspehu prispeval napredek na podro~ju kirurgije in radioterapije (izbolj{anje postopkov na~rtovanja in priprave bolnikov na obsevanje, uvedba naprednej{ih obsevalnih tehnik), v skupini raz{irjenih tumor- jev pa poleg slednjega predvsem vklju~itev sistemskega zdravljenja (so~asna radiokemoterapija) v na~rt zdravljenja tako operabilnih kot tudi neoperabilnih primerov raka v ustni votlini. Bol- nikov z razsejano obliko bolezni je bilo na sre~o malo: uspe{nega zdravljenja v tej skupini ni (bilo) na voljo, njena {tevil~nost pa ne dovoljuje zanesljivega statisti~nega vrednotenja. Pre`ivetje je bilo v vseh obdobjih, starostnih skupinah in v vseh stadijih boleznih odvisno od spola; dlje so `ivele bolnice. Domnevamo, da je v na{i populaciji dele` prognosti~no ugodnej{ih tumorjev, katerih nastanek je povezan z oku`bo s HPV, nizek; `al sta prevladujo~a dejavnika tveganja raka ustne votline ~ezmerno u`ivanje alikoholnih pija~ in kajenje. Rak.qxd 22.7.2009 12:38 Page 40 According to the results of EUROCARE-4 study for patients diagnosed in 2000–2002, the survival of Slovenian patients with cancer of the oral cavity is statistically significantly below the European average (Figure 5). 41 ORAL CAVITY CLINICAL COMMENT ARY Lojze [mid Primo` Strojan Branko Zakotnik 01 02 0 30 40 50 60 70 80 90 100 % Slovensko povpre~je / 2000–2002 (EUROCARE-4) Slovenian average Evropsko povpre~je / 2000–2002 (EUROCARE-4) European average Povpre~je ZDA / 2000–2002 (SEER-13) USA average Slika 5: Petletno relativno pre`ivetje bolnikov z rakom ustne votline* (povpre~je in 95-odstotni interval zaupanja), zbolelih v letih 2000–2002 v Sloveniji, Evropi in nekaterih obmo~jih v ZDA. Figure 5: 5-year relative survival of oral cavity cancer patients* (average and 95% confidence interval) diagnosed in the period 2000–2002 in Slovenia, Europe and in some regions of the USA. In the recent years the number of female patients with cancers of the oral cavity nearly dou- bled, so in the last time-period they represent one fifth of all patients with this type of cancer. The reason should be sought in the changed smoking and perhaps also drinking habits of women in last decades. The proportion of microscopically confirmed cancers is extremely high, which is not surprising, considering the easy accessibility of the oral cavity. In the last 5-year period, the distribution of disease stages at diagnosis was more favourable too: the proportion of localized disease had been steadily increasing, and represented a third of all newly diagnosed oral cancer cases in the period 2001–2005. This was also reflected in the treatment modality. In the period 1991–1995, 13% of patients were treated by surgery alone, whereas in the period 2001–2005 as many as 30% of the treated patients underwent surgery. Contrary to that, in the same period the pro- portion of patients treated by radiotherapy alone expectedly decreased from 36% to 15%. Throughout the 15-year period, the survival rates of patients with cancer of the oral cavity were increasing while their mortality rates were decreasing, which can probably be attributed to the already mentioned favourable changes in the stage distribution of the disease. Further success in the group of localized tumors was brought about by advances in the area of surgery and radio- therapy (improved procedures for planning and preparation of patients for radiotherapy, introduction of advanced irradiation techniques), while in the group of regional tumors – apart * Nabor MKB10 kod v {tudiji EUROCARE-4 je nekoliko druga~en kot smo ga uporabili pri ostalih analizah predstavljenih v tem poglavju: v {tudiji EURCARE-4 so iz analize izvzete maligne neoplazme drugih in neopredeljenih delov jezika (MKB10: C02), vklju~ene pa so maligne neoplazme neba (MKB10: C05). * The ICD10 code selection in EUROCARE-4 study is slightly different in comparison to the selection applied in other analysis in this chapter: in EUROCARE-4 study the malignant neoplasm of other and unspecified parts of tongue (ICD10: C01) are excluded while malignant neoplasm of palate (ICD10: C05) are included. Rak.qxd 22.7.2009 12:38 Page 41 Fakhry C, Westra WH, Li S, Cmelak A, Ridge JA, Pinto H, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 2008; 100: 261–9. Strojan P , Karner K, [mid L, [oba E, Fajdiga I, Jan~ar B, et al. Concomitant chemoradiotherapy with mitomycin C and cisplatin in advanced unresectable carcinoma of the head and neck: Phase I–II clinical study. Int J Radiat Oncol Biol Phys 2008; 72: 365–72. [mid L, Budihna M, Zakotnik B, [oba E, Strojan P, Fajdiga I, et al. Postoperative concomitant irradiation and chemotherapy with mitomycin C and bleomycin for advanced head-and-neck carcinoma. Int J Radiat Oncol Biol Phys 2003; 56: 1055–62. [mid L, Le{ni~ar H, Zakotnik B, [oba E, Budihna M, Furlan L, et al. Radiotherapy, combined with simulta- neous chemotherapy with mitomycin C and bleomycin for inoperable head and neck cancer-preliminary report. Int J Radiat Oncol Biol Phys 1995; 32: 769–75. Zakotnik B, [mid L, Budihna M, Le{ni~ar H, [oba E, Furlan L, et al. Concomitant radiotherapy with mitomycin C and bleomycin compared with radiotherapy alone in inoperable head and neck cancer: final report. Int J Radiat Oncol Biol Phys 1998; 41: 1121–7. Zakotnik B, Budihna M, [mid L, [oba E, Strojan P , Fajdiga I, et al. Patterns of failure in patients with locally advanced head and neck cancer treated postoperatively with irradiation or concomitant irradiation with Mitomycin C and Bleomycin. Int J Radiat Oncol Biol Phys 2007; 67: 685–90. 42 USTNA VOTLINA VIRI Literature Rak.qxd 22.7.2009 12:38 Page 42 from the latter – the success should also be attributed to the addition of chemotherapy (con- comitant radiochemotherapy) into the treatment schedule of operable as well as inoperable cancers of the oral cavity. Fortunately, there were few patients with disseminated disease: no success- ful treatment has been available for this group of patients, however, their small number does not allow a reliable statistical evaluation. In all time periods, age groups and stages of the disease survival depended on gender: thus, female patients lived longer. We assume that the proportion of prognosticaly more favorable tumors caused by HPV infection in Slovenian patients is smaller than in western Europe; unfor- tunately, the prevailing risk factors are alcohol abuse and tobacco smoking. 43 ORAL CAVITY Rak.qxd 22.7.2009 12:38 Page 43 V obdobju 1991–2005 je za rakom spodnjega `rela zbolelo 759 ljudi, od tega 709 mo{kih in 50 `ensk. Kot je razvidno s Slike 1, se trendi inciden~nih in umrljivostnih stopenj med seboj nekoliko razlikujejo. Obe inciden~ni stopnji se pove~ujeta, groba v povpre~ju za 1,6 % letno, ravno tako groba umrljivostna stopnja povpre~no za 0,2 % letno, medtem ko se starostno stan- dardizirana umrljivostna stopnja zmanj{uje za 1,4 % letno. SPODNJE @RELO MKB 10: C12, C13 44 V analizo pre`ivetja je vklju~enih 749 primerov; 10 bolnikov (1,3 %) nismo upo{tevali, ker jim je bila diagnoza postavljena po smrti. Od bolnikov, vklju~enih v analizo, je imelo 54% raka piriformnega sinusa, 46 % pa raka drugih delov spodnjega `rela. Manj kot 1 % bolnikov v vsakem obdobju ni imel mikroskopsko potrjene bolezni. Skoraj vsi mikroskopsko potrjeni malignomi (97 %) so bili plo{~atoceli~ni karcinomi. Najve~ji dele` bolnikov je bil ob diagnozi v starostni skupini od 50 do 74 let. Dele` starih 75 let in ve~ je pri mo{kih ves ~as majhen, pri `enskah pa se je v zadnjem obdobju pove~al na 23 % (Tabela 1). Pri mo{kih se s ~asom manj{a dele` tistih, ki zbolijo mlaj{i od 50 let, ve~a pa dele` 0 1 2 3 4 1986 1990 1995 2000 2005 Leto / Year Incidenca – groba stopnja / Incidence – crude rate Incidenca – SSS* / Incidence – ASR** Umrljivost – groba stopnja / Mortality – crude rate Umrljivost – SSS* / Mortality – ASR** Stopnja na 100.000 / Rate per 100,000 * SSS – starostno standardizirana stopnja (standard – slovenska populacija leta 1986) ** ASR – age standardized rate (standard Slovenian population in 1986) Slika 1: Groba in starostno standardizirana inciden~na in umrljivostna stopnja raka spodnjega `rela, Slovenija 1986–2005. Figure 1: Crude and age-standardized incidence and mortality rate of hypopharyngeal cancer, Slovenia 1986–2005. Mo{ki / Males @enske / Females Obdobje / {tevilo / 20–49 let / 50–74 let / 75+ let / {tevilo / 20–49 let / 50–74 let / 75+ let / Period number years (%) years (%) years (%) number years (%) years (%) years (%) 1991–1995 217 25,8 71,4 2,8 13 15,4 84,6 0,0 1996–2000 238 23,5 74,4 2,1 13 53,8 38,5 7,7 2001–2005 246 13,4 80,9 5,7 22 18,2 59,1 22,7 T abela 1: [tevilo bolnikov z rakom spodnjega `rela po spolu in obdobju postavitve diagnoze ter njihovi dele`i po starosti. T able 1: Number of hypopharyngeal cancer patients by sex and period of diagnosis with their proportions by age. EPIDEMIOLOGIJA Rak.qxd 22.7.2009 12:38 Page 44 In the period 1991–2005, a total of 759 persons were diagnosed with hypopharyngeal cancer, of these 709 males and 50 females. As evident from Figure 1, the trends in incidence and mor- tality rates slightly differ from each other. Both incidence and crude mortality rates have been increasing; the estimated annual percentage increase in crude incidence rate was 1.6%, while in crude mortality rate it was 0.2%. The age standardized mortality rate was decreasing by 1.4% annually on average. The survival analysis included 749 cases; 10 patients (1.3%) diagnosed only after death were not considered in the analysis. Among the patients included in the analysis 54% had cancer of the pyriform sinus and 46% cancers of other parts of the hypopharynx. Less than 1% of patients in each time period did not have microscopically confirmed disease. Practically all microscopically confirmed malignomas (97%) were planocellular carcino- mas. The largest proportion of patients was diagnosed at an age between 50–74 years. In males, the proportion of those aged 75 years or older was low all the time while in females it increased to 23% in the recent period (Table 1). In males, the proportion of patients under 50 years of age at diagnosis is decreasing with time, while the proportion of those diagnosed after the age of 50 and 74 is increasing (Table 1). The evaluation of time-trend in females is unreliable because of the small number of patients. In all three time-periods, the majority of patients were diagnosed with regional disease; in the period 2001–2005 there were 83% such patients among males and 86% among females (Table 2). The remaining majority of patients had the disease diagnosed at a localized stage. The pro- portion of localized stage has been increasing throughout the observation period, prevailingly on the account of smaller proportion of regional disease. In the years 2001–2005, 7% of patients did not receive specific treatment. In the observed 15-year period the proportion of untreated patients has decreased by 2%. Among the patients receiv- ing specific treatment in the period 2001–2005, 29% were either irradiated or treated by surgery plus radiotherapy, while 18% of patients also received chemotherapy in addition to the men- tioned treatment modalities. In the 15-year period, the proportion of patients receiving chemotherapy in addition to the standard treatment by radiotherapy or radiotherapy plus sur- gery has undergone a four-fold increase. In the period 2001–2005, almost all patients started their treatment in one of the three lead- ing Slovenian health institutions: 52% at the IO Ljubljana, 33% in the UMC Ljubljana and 15% in the UMC Maribor. HYPOPHARYNX ICD 10: C12, C13 45 Tabela 2: [tevilo bolnikov z rakom spodnjega `rela po spolu in obdobju postavitve diagnoze ter njihovi dele`i po stadiju. Table 2: Number of hypopharyngeal cancer patients by sex and period of diagnosis with their proportions by stage. Mo{ki / Males @enske / Females Obdobje / {tevilo / omejen / raz{irjen / razsejan / neznan / {tevilo / omejen / raz{irjen / razsejan / neznan / Period number localized regional distant unknown number localized regional distant unknown (%) (%) (%) (%) (%) (%) (%) (%) 1991–1995 217 6,0 86,6 5,5 1,8 13 0,0 84,6 15,4 0,0 1996–2000 238 7,6 87,8 4,2 0,4 13 0,0 100,0 0,0 0,0 2001–2005 246 13,0 82,9 2,8 1,2 22 13,6 86,4 0,0 0,0 EPIDEMIOLOGY Rak.qxd 22.7.2009 12:38 Page 45 zbolelih po 50. in po 74. letu starosti. Ocenjevanje ~asovnega trenda pri `enskah je nezane- sljivo, saj je {tevilo bolnic majhno. V vseh treh obdobjih je imelo najve~ bolnikov ob diagnozi raz{irjeno bolezen; v obdobju 2001–2005 je imelo tako bolezen 83 % mo{kih in 86 % `ensk (Tabela 2). Pri ve~ini ostalih bolnikov je bila bolezen odkrita v omejenem stadiju. Dele` bolnikov z omejenim stadijem se ves ~as opazova- nja ve~a, predvsem na ra~un manj{ega dele`a raz{irjenega stadija. V letih 2001–2005 ni bilo specifi~no zdravljenih 7 % bolnikov. Dele` nezdravljenih bolnikov se je v opazovanem 15-letnem obdobju zmanj{al za 2 %. Med specifi~no zdravljenimi je bilo v letih 2001–2005 po 29 % obsevanih ali operiranih in obsevanih, 18 % pa je dobilo poleg tega {e kemoterapijo. Ostale kombinacije zdravljenj so bile uporabljene redko. Dele` bolnikov, ki 46 SPODNJE @RELO 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Slika 2: Deset-, pet-, tri- in enoletno relativno pre`ivetje bolnikov z rakom spodnjega `rela po obdobju postavitve diagnoze. Figure 2: 10-, 5-, 3- and 1-year relative survival of hypopharyngeal cancer patients by period of diagnosis. Tabela 3: Opazovano in relativno pre`ivetje bolnikov z rakom spodnjega `rela po spolu in obdobju postavitve diagnoze s 95-odstotnim intervalom zaupanja (IZ). Table 3: Observed and relative survival of hypopharyngeal cancer patients by sex and period of diagnosis with 95% confidence interval (CI). Opazovano pre`ivetje / Observed survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 52,5 (46,3–59,6) 29,0 (23,6–35,7) 18,0 (13,5–23,9) 53,8 (32,6–89,1) 38,5 (19,3–76,5) 30,8 (13,6–69,5) 1996–2000 55,9 (49,9–62,6) 26,1 (21,0–32,3) 17,2 (13,0–22,8) 61,5 (40,0–94,6) 38,5 (19,3–76,5) 15,4 (4,3–55,0) 2001–2005 61,4 (55,6–67,8) 30,7 (25,4–37,0) 21,9 (16,9–28,3) 54,5 (37,2–79,9) 31,8 (17,3–58,7) 19,1 (7,4–48,9) Relativno pre`ivetje / Relative survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 53,7 (46,5–61,0) 31,1 (23,9–38,3) 20,3 (13,7–27,0) 54,4 (18,8–90,0) 39,7 (0,4–79,0) 32,6 (0,0–73,7) 1996–2000 57,1 (50,3–63,9) 27,8 (21,2–34,5) 19,3 (13,1–25,6) 62,1 (28,8–95,5) 39,7 (0,4–78,9) 16,3 (0,0–58,2) 2001–2005 62,8 (56,2–69,3) 33,0 (26,1–39,8) 24,9 (17,5–32,2) 55,4 (29,7–81,2) 33,6 (5,3–62,0) 21,0 (0,0–53,9) Rak.qxd 22.7.2009 12:38 Page 46 The 5-year relative survival of patients with cancers of the hypopharynx has undergone a slow increase; in 15 years it has increased by 3% (Figure 2). In comparison with females, the 5-year relative survival of males is slightly better, however, the results in females being rather unreli- able due to small number of patients (Table 3). The relevance of stage at diagnosis is shown in Figure 3. In the last period, 5-year relative survival of patients with localized stage was 39%, while in those with regional stage at diagnosis it was 23%. Due to a small number of patients with disseminated disease, the evaluation of their survival is unreliable. In recent years, a con- siderable improvement in the survival was observed in patients with localized disease, whereas no significant improvement was noted in those with regional and disseminated disease. The survival of patients in our analysis did not depend on age at diagnosis (Figure 4). The 5-year relative survival rate of all patients diagnosed in the period 2001–2005 was 25% (Figure 2); patients surviving the first year may expect to survive five years in 39%. Patients with hypopharynx as the only primary cancer site had 26% 5-year relative survival rate. 47 HYPOPHARYNX 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 Omejen / Localized Raz{irjen / Regional Razsejan / Distant Vsi / All Slika 3: Petletno relativno pre`ivetje bolnikov z rakom spodnjega `rela po stadiju in obdobju postavitve diagnoze. Figure 3: 5-year relative survival of hypopharyngeal cancer patients by stage and period of diagnosis. 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 20–49 let / years 50–74 let / years 75+ let / years Vsi / All Slika 4: Petletno relativno pre`ivetje bolnikov z rakom spodnjega `rela po starosti in obdobju postavitve diagnoze. Figure 4: 5-year relative survival of hypopharyngeal cancer patients by age and period of diagnosis. Rak.qxd 22.7.2009 12:38 Page 47 jim je bila h klasi~nemu zdravljenju samo z obsevanjem ali z obsevanjem in operacijo dodana {e kemoterapija, se je v 15 letih pove~al za {tirikrat. V obdobju 2001–2005 so skoraj vsi bolniki, ki so bili zdravljeni, zdravljenje pri~eli v eni od treh vodilnih slovenskih zdravstvenih ustanov: 52 % na OI Ljubljana, 33 % v UKC Ljubljana in 15 % v UKC Maribor. Petletno relativno pre`ivetje bolnikov z rakom v spodnjem `relu se le po~asi pove~uje; v 15 le- tih se je pove~alo za 3 % (Slika 2). Petletno relativno pre`ivetje mo{kih je v primerjavi z `enskami nekoliko bolj{e, vendar so rezultati pri `enskah nezanesljivi, saj je zbolelih malo (Tabela 3). Kako pomemben je stadij ob diagnozi, ka`e Slika 3: petletno relativno pre`ivetje bolnikov z ome- jenim stadijem je v zadnjem obdobju 39 %, medtem ko je pri bolnikih z raz{irjenim stadijem bolezni ob diagnozi petletno relativno pre`ivetje 23 %. Bolnikov z razsejanim stadijem je malo, tako da je ocenjevanje njihovega pre`ivetja nezanesljivo. V zadnjih letih se je precej izbolj{alo pre`ivetje bolnikov z omejenim stadijem bolezni, medtem ko pri bolnikih z raz{irjeno in raz- sejano boleznijo ni bistvenega napredka. Pre`ivetje bolnikov, vklju~enih v na{o analizo, ni bilo odvisno od starosti ob diagnozi (Slika 4). Petletno relativno pre`ivetje vseh zbolelih v obdobju 2001–2005 je bilo 25 % (Slika 2); bolniki, ki pre`ivijo prvo leto, pa lahko pri~akujejo 39-odstotno petletno relativno pre`ivetje. Pre`ivetje bolnikov, pri katerih je bil rak spodnjega `rela edini rak, so imeli petletno relativno pre`ivet- je 26 %. Rezultati {tudije EUROCARE-4 za zbolele v obdobju 2000–2002 ka`ejo, da je pre`ivetje sloven- skih bolnikov z rakom spodnjega `rela statisti~no nezna~ilno manj{e od evropskega povpre~ja (Slika 5). 48 SPODNJE @RELO KLINI^NI KOMENT AR Lojze [mid Primo` Strojan Branko Zakotnik Dele` bolnikov z mikroskopsko potrjeno boleznijo je primerno visok in potrjuje ustreznost orga- nizacije dela zdravstvene dejavnosti, ki obravnava to sorazmerno redko vrsto raka. Pre`ivetje in umrljivost bolnikov z rakom spodnjega dela `rela vseh stadijev bolezni skupaj v preu- ~evanem 15-letnem obdobju ne ka`e ve~je dinamike. Izjema je omejena oblika raka, kjer je napredek o~iten. Predpostavljamo, da je odraz spremenjenih terapevtskih konceptov, ki so se razvili v 90. letih preteklega stoletja: o~iten je namre~ upad dele`a bolnikov, zdravljenih samo z operacijo in obsevanjem ali celo samo z obsevanjem, in jasen porast {tevila bolnikov, pri katerih smo obsevanju (sledilo je operaciji ali je bilo temeljno zdravljenje) priklju~ili so~asno kemo- terapijo. @al je skupina z omejeno obliko bolezni ob diagnozi majhna, le okoli 13 % vseh primerov raka v spodnjem `relu. Pri ve~inski, raz{irjeni obliki raka spodnjega `rela ostaja pre`ivetje {e vedno nesprejemljivo nizko, pri redkih bolnikih z razsejano obliko bolezni pa o dolgotrajnem pre`ivetju niti ne moremo govoriti. Ob dejstvu, da u~inkovitega zdravljenja za sistemsko raz{irjeno bolezen ni, slednji izsled- ki ne presene~ajo. Nekoliko presene~a spoznanje, da tudi uvedba kemoterapije v zdravljenje raz{irjene oblike bolezni ob diagnozi ni privedla do bolj{ih rezultatov zdravljenja. Zavedajo~ se biolo{kih zna~ilnosti poteka raka spodnjega `rela z mo~no izra`eno te`njo k sistemski raz- {iritvi, za katero pa, kot je bilo `e omenjeno, ni u~inkovitega zdravljenja, pa tak rezultat ni presenetljiv. Morda bodo izbolj{anje prinesli novej{i terapevtski koncepti, ki dajejo {e ve~ji pouda- rek sistemsko delujo~im tar~nim zdravilom. Te u~inkovine poleg `e uveljavljenega kombiniranja z obsevanjem, katerega temeljni namen je pove~anje ob~utljivosti tumorskih celic na ionizira- jo~e `arke (t. i. radiosenzibilizacija), vstopajo v zdravljenje `e v uvodnem, indukcijskem delu prav zato, da bi uni~ile morebitne mikrozasevke v organizmu. Spol pri raku spodnjega `rela v nasprotju z drugimi raki na podro~ju zgornjega dela prebavne cevi in dihalnih poti nima zna~ilne napovedne vrednosti. Rak.qxd 22.7.2009 12:38 Page 48 The proportion of patients with microscopically confirmed disease is correspondingly high and confirms that the organization of work in the healthcare sector dealing with this relatively rare type of cancer is adequate. In the 15-year observation period, no major changes have been observed in the survival and mortality rates of patients with cancer of the hypopharynx of all stages. An exception is the localized disease, where improvement is quite evident. Presumably, this can be attributed to the changed therapeutic approaches developed in the 90's: there is an obvious decrease in the proportion of patient treated by either surgery or radiotherapy alone, and a clear increase in the number of patients where radiotherapy (following surgery or used as a primary treatment) has been supplemented by concomitant chemotherapy. Unfortunately, the group with locali- zed disease at diagnosis represents only around 13% of all cancers of the hypopharynx. Survival in the prevailing, regional stage of the hypopharyngeal cancer still remains unacceptably low, while in few patients with the disseminated disease any long-term survival is out of ques- tion. In view of the fact that there is no effective treatment available for advanced disease, such results are not surprising. Slightly unexpected though is the finding that even the introduc- ing of chemotherapy into the treatment of patients with regional disease at diagnosis has not resulted in more favorable treatment outcomes. However, being aware of the biological char- acteristics of the course of hypopharyngeal cancer with strong tendency to metastasizing, which is known to lack any effective treatment, even such result should not come as a surprise. Perhaps an improvement will be brought about by new therapeutic approaches assigning greater role to systemic treatment with target drugs. These drugs – apart from the already established combi- nations with radiotherapy intended to enhance the sensitivity of tumor cells to ionizing irradiation 49 HYPOPHARYNX CLINICAL COMMENT ARY Lojze [mid Primo` Strojan Branko Zakotnik 01 02 0 30 40 50 60 70 80 90 100 % Slovensko povpre~je / 2000–2002 (EUROCARE-4) Slovenian average Evropsko povpre~je / 2000–2002 (EUROCARE-4) European average Povpre~je ZDA / 2000–2002 (SEER-13) USA average Slika 5: Petletno relativno pre`ivetje bolnikov z rakom spodnjega `rela (povpre~je in 95-odstotni interval zaupanja), zbolelih v letih 2000–2002 v Sloveniji, Evropi in nekaterih obmo~jih v ZDA. Figure 5: 5-year relative survival of hypopharyngeal cancer patients (average and 95% confidence interval) diag- nosed in the period 2000–2002 in Slovenia, Europe and in some regions of the USA. According to the results of EUROCARE-4 study for patients diagnosed in 2000–2002, the survival of Slovenian patients with hypopharyngeal cancer is statistically significantly below the European average (Figure 5). Rak.qxd 22.7.2009 12:38 Page 49 Strojan P , Karner K, [mid L, [oba E, Fajdiga I, Jan~ar B, et al. Concomitant chemoradiotherapy with mitomycin C and cisplatin in advanced unresectable carcinoma of the head and neck: Phase I–II clinical study. Int J Radiat Oncol Biol Phys 2008; 72: 365–72. [mid L, Budihna M, Zakotnik B, [oba E, Strojan P, Fajdiga I, et al. Postoperative concomitant irradiation and chemotherapy with mitomycin C and bleomycin for advanced head-and-neck carcinoma. Int J Radiat Oncol Biol Phys 2003; 56: 1055–62. [mid L, Le{ni~ar H, Zakotnik B, [oba E, Budihna M, Furlan L, et al. Radiotherapy, combined with simul- taneous chemotherapy with mitomycin C and bleomycin for inoperable head and neck cancer-preliminary report. Int J Radiat Oncol Biol Phys 1995; 32: 769–75. Zakotnik B, Budihna M, [mid L, [oba E, Strojan P , Fajdiga I, et al. Patterns of failure in patients with locally advanced head and neck cancer treated postoperatively with irradiation or concomitant irradiation with Mitomycin C and Bleomycin. Int J Radiat Oncol Biol Phys 2007; 67: 685–90. Zakotnik B, [mid L, Budihna M, Le{ni~ar H, [oba E, Furlan L, et al. Concomitant radiotherapy with mitomy- cin C and bleomycin compared with radiotherapy alone in inoperable head and neck cancer: final report. Int J Radiat Oncol Biol Phys 1998; 41: 1121–7. 50 SPODNJE @RELO VIRI Literature Rak.qxd 22.7.2009 12:38 Page 50 (radiosensibilization) – are used already in the initial, induction therapy, in order to destroy possible micrometastases in the body. For the difference from other cancers of the upper respiratory and digestive tract in the case of hypopharynx, gender does not have a significant prognostic value. 51 HYPOPHARYNX Rak.qxd 22.7.2009 12:38 Page 51 V obdobju 1991–2005 je za rakom po`iralnika zbolelo 1398 ljudi, od tega 1155 mo{kih in 243 `ensk. Kot je razvidno s Slike 1, je groba inciden~na stopnja ustaljena, groba umrljivost- na stopnja pa se manj{a povpre~no za 1,0% letno. Starostno standardizirane inciden~ne in umrljivostne stopnje pa se od leta 1991 zmanj{ujejo (inciden~ne za 1,3 %, umrljivostne pa za povpre~no 2,6 % letno), saj v zadnjih letih zboli ve~ starej{ih bolnikov (Tabela 1). Manj natan~- no opredeljevanje vzroka smrti in slab izid bolezni sta verjetno glavna razloga za v nekaterih letih ve~jo umrljivostno stopnjo od inciden~ne. PO@IRALNIK MKB 10: C15 52 V analizo pre`ivetja je vklju~enih 1307 primerov; 91 bolnikov (6,5 %) nismo upo{tevali, ker jim je bila diagnoza postavljena po smrti. Med vsemi bolniki jih 57 % ni imelo natan~neje opre- deljenega mesta nastanka malignoma, v zadnjem obdobju 28%. Med zbolelimi v zadnjem obdobju, ki so imeli opredeljeno mesto, je imelo 37 % bolnikov tumor v spodnji tretjini po`i- ralnika, 26 % v srednji tretjini in 23 % v zgornji tretjini po`iralnika; 4 % tumorjev se je ob diagnozi razra{~alo prek ve~ delov po`iralnika. 0 1 2 3 4 5 6 7 1986 1990 1995 2000 2005 Leto / Year Incidenca – groba stopnja / Incidence – crude rate Incidenca – SSS* / Incidence – ASR** Umrljivost – groba stopnja / Mortality – crude rate Umrljivost – SSS* / Mortality – ASR** Stopnja na 100.000 / Rate per 100,000 * SSS – starostno standardizirana stopnja (standard – slovenska populacija leta 1986) ** ASR – age standardized rate (standard Slovenian population in 1986) Slika 1: Groba in starostno standardizirana inciden~na in umrljivostna stopnja raka po`iralnika, Slovenija 1986–2005. Figure 1: Crude and age-standardized incidence and mortality rate of esophageal cancer, Slovenia 1986–2005. Mo{ki / Males @enske / Females Obdobje / {tevilo / 20–49 let / 50–74 let / 75+ let / {tevilo / 20–49 let / 50–74 let / 75+ let / Period number years (%) years (%) years (%) number years (%) years (%) years (%) 1991–1995 363 10,5 78,2 11,3 61 3,3 55,7 41,0 1996–2000 359 11,4 79,4 9,2 75 9,3 56,0 34,7 2001–2005 370 10,0 74,6 15,4 79 5,1 54,4 40,5 T abela 1: [tevilo bolnikov z rakom po`iralnika po spolu in obdobju postavitve diagnoze ter njihovi dele`i po starosti. Table 1: Number of esophageal cancer patients by sex and period of diagnosis with their proportions by age. EPIDEMIOLOGIJA Rak.qxd 22.7.2009 12:38 Page 52 In the period 1991–2005, a total of 1398 persons were diagnosed with cancer of the esopha- gus, of these 1155 males and 243 females. As evident from Figure 1, the crude incidence rate is stable, while crude mortality rate is decreasing with an estimated annual percentage change of 1.0%. Age-standardized incidence and mortality rates have been decreasing (1.3% estimated annual percentage decrease in incidence rate and 2.6% in mortality rate) since 1991, as more elderly patients have been diagnosed in recent years (Table 1). Mortality rate exceeds incidence rate in some years, which can be explained most probably by less accurate definition of the cau- ses of death and poor prognosis of the disease. The survival analysis included 1307 cases; 91 patients (6.5%) diagnosed only after death were not considered in the analysis. Among all patients, 57% did not have the origin of maligno- ma more precisely defined, in the last period the proportion of such patients being 28%. Among those diagnosed in the last period and who had the site precisely defined, there were 37% of patients with tumors of the lower third of the esophagus, 26% with the middle third and 23% with tumors of the upper third of the esophagus; at the time of diagnosis, 4% of tumors were found to spread over more segments of the esophagus. In the period 2001–2005, 93% of cancers were microscopically verified. In comparison with the period 1991–1995, the proportion of microscopically confirmed disease has increased by 5%. In all three observation periods the majority of patients had planocellular carcinoma (70%). The number of patients with adenocarcinomas is increasing every year: thus, in the peri- od 2001–2005 their proportion represented already 14% (in the period 1991–1995 only 7%). At the time of diagnosis most patients were aged 50–74 years. Approximately three-fourths of male and slightly over a half of female patients belonged to this age group; approximately 40% of females were aged 75 years or older, and less than 10% of patients were younger than 50 years (Table 1). The proportion of patients in individual age groups did not change sig- nificantly with time. In all three time-periods, the majority of patients were diagnosed with regional disease; in the period 2001–2005 there were 38% males and 44% females (Table 2). A greater proportion of disseminated stage in both genders evidenced in the last period is mainly on the account of a smaller proportion of patients with localized stage; in almost 15% of patients the stage at diagnosis was not determined. In the years 2001–2005, 37% of patients did not receive specific treatment. In comparison with the period 1991–1995, the proportion of untreated patients has decreased by 6%. In the peri- od 2001–2005, 62% of patients with specific treatment received radiotherapy. In almost a half of them irradiation was combined with chemotherapy, while 10% of irradiated patients were ESOPHAGUS ICD 10: C15 53 Tabela 2: [tevilo bolnikov z rakom po`iralnika po spolu in obdobju postavitve diagnoze ter njihovi dele`i po stadiju. Table 2: Number of esophageal cancer patients by sex and period of diagnosis with their proportions by stage. Mo{ki / Males @enske / Females Obdobje / {tevilo / omejen / raz{irjen / razsejan / neznan / {tevilo / omejen / raz{irjen / razsejan / neznan / Period number localized regional distant unknown number localized regional distant unknown (%) (%) (%) (%) (%) (%) (%) (%) 1991–1995 363 28,4 43,0 16,3 12,4 61 19,7 42,6 14,8 23,0 1996–2000 359 32,9 35,9 15,3 15,9 75 37,3 30,7 13,3 18,7 2001–2005 370 20,3 38,4 27,6 13,8 79 22,8 44,3 15,2 17,7 EPIDEMIOLOGY Rak.qxd 22.7.2009 12:38 Page 53 V obdobju 2001–2005 je bilo 93 % primerov raka mikroskopsko potrjenih. Dele` mikroskop- sko potrjenih primerov se je v primerjavi z obdobjem 1991–1995 pove~al za 5 %. V vseh treh obdobjih je imelo najve~ bolnikov plo{~atoceli~ni karcinom (70 %). Vsako leto je ve~je {tevi- lo bolnikov z adenokarcinomom: v obdobju 2001–2005 je bil njihov dele` `e 14% (le 7% v obdobju 1991–1995). Najve~ji dele` zbolelih je bilo ob diagnozi starih med 50 in 74 let. Med mo{kimi je v tej sta- rostni skupini pribli`no tri ~etrtine zbolelih, med `enskami pa nekaj ve~ kot polovica. Okrog 40 % `ensk je ob diagnozi starih 75 let in ve~, pred 50. letom pa zboli manj kot 10 % bolnikov (Tabela 1). Dele`i v posameznih starostnih skupinah se s ~asom niso bistveno spreminjali. 54 PO@IRALNIK 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Slika 2: Deset-, pet-, tri- in enoletno relativno pre`ivetje bolnikov z rakom po`iralnika po obdobju postavitve diagnoze. Figure 2: 10-, 5-, 3- and 1-year relative survival of esophageal cancer patients by period of diagnosis. Tabela 3: Opazovano in relativno pre`ivetje bolnikov z rakom po`iralnika po spolu in obdobju postavitve diagnoze s 95-odstotnim intervalom zaupanja (IZ). Table 3: Observed and relative survival of esophageal cancer patients by sex and period of diagnosis with 95% confidence interval (CI). Opazovano pre`ivetje / Observed survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 20,7 (16,9–25,3) 6,1 (4,0–9,1) 5,0 (3,2–7,8) 29,5 (20,0–43,5) 13,1 (6,9–25,0) 9,8 (4,6–21,0) 1996–2000 25,9 (21,7–30,9) 6,1 (4,1–9,2) 4,2 (2,5–6,9) 22,7 (14,9–34,4) 6,7 (2,9–15,5) 6,7 (2,9–15,5) 2001–2005 28,6 (24,4–33,6) 9,3 (6,8–12,8) 6,3 (4,1–9,7) 30,4 (21,8–42,4) 14,9 (8,7–25,4) 13,2 (7,4–23,7) Relativno pre`ivetje / Relative survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 21,5 (16,7–26,2) 6,8 (3,4–10,2) 5,9 (2,6–9,3) 31,1 (16,4–45,8) 15,5 (1,4–29,6) 12,7 (0,0–27,2) 1996–2000 26,8 (21,6–31,9) 6,8 (3,4–10,2) 5,0 (1,8–8,2) 23,8 (11,5–36,2) 7,7 (0,0–18,0) 8,5 (0,0–19,8) 2001–2005 29,7 (24,5–34,9) 10,5 (6,5–14,4) 7,8 (3,6–11,9) 31,9 (19,3–44,6) 17,3 (5,1–29,6) 17,3 (3,6–30,9) Rak.qxd 22.7.2009 12:38 Page 54 also treated by surgery and chemotherapy. There were 21% of all patients treated by surgery and 7% by chemotherapy as single-modality treatment. In the period 2001–2005, practically all patients started their treatment in one of the three lead- ing Slovenian health institutions: 64% at the IO Ljubljana, 27% in the UMC Ljubljana and 9% in the UMC Maribor. The relative survival rate of patients with esophageal cancer has been increasing very slowly: in 15 years, the 5-year relative survival rate increased by 2% only (Figure 2), in females slight- ly more than in males (Table 3). The relevance of stage at diagnosis is shown in Figure 3. In the last period, 5-year relative survival of patients with localized stage has exceeded 20%. However, 5-year survival of patients with regional and disseminated stages is still lower than 10%. Age is a prognostic factor as well, since the relative survival is the lowest in patients aged 75 years or older, while the survival of those diagnosed at an age between 50 and 74 years has been lag- ging slightly behind the relative survival of those diagnosed before the age of 50 throughout the observation period (Figure 4). 55 ESOPHAGUS 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 Omejen / Localized Raz{irjen / Regional Razsejan / Distant Vsi / All Slika 3: Petletno relativno pre`ivetje bolnikov z rakom po`iralnika po stadiju in obdobju postavitve diagnoze. Figure 3: 5-year relative survival of esophageal cancer patients by stage and period of diagnosis. 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 20–49 let / years 50–74 let / years 75+ let / years Vsi / All Slika 4: Petletno relativno pre`ivetje bolnikov z rakom po`iralnika po starosti in obdobju postavitve diagnoze. Figure 4: 5-year relative survival of esophageal cancer patients by age and period of diagnosis. Rak.qxd 22.7.2009 12:38 Page 55 V vseh treh obdobjih je imelo najve~ bolnikov ob diagnozi raz{irjeno bolezen; v obdobju 2001–2005 38 % mo{kih in 44 % `ensk (Tabela 2). Ve~ji dele` razsejanega stadija v zadnjem obdobju pri obeh spolih gre na ra~un manj{ega dele`a bolnikov z omejenim stadijem; skoraj 15 % bolni- kov ob diagnozi ni imelo dolo~enega stadija. V letih 2001–2005 ni bilo specifi~no zdravljenih 37% bolnikov. Dele` nezdravljenih se je v primerjavi z obdobjem 1991–1995 zmanj{al za 6 %. Med specifi~no zdravljenimi jo bilo v le- tih 2001–2005 obsevanih 62 % bolnikov. Pri skoraj polovici je bilo obsevanje kombinirano {e s kemoterapijo, 10 % med vsemi obsevanimi pa je bilo operiranih in zdravljenih {e s kemote- rapijo. Samo operiranih je bilo 21 % vseh bolnikov, le kemoterapijo pa jih je prejelo 7 %. V obdobju 2001–2005 so prakti~no vsi bolniki, ki so bili zdravljeni, zdravljenje pri~eli v eni od treh vodilnih slovenskih zdravstvenih ustanov: 64 % na OI Ljubljana, 27 % v UKC Ljub- ljana in 9 % v UKC Maribor. Pre`ivetje bolnikov z rakom po`iralnika se pove~uje zelo po~asi; v 15 letih se je petletno rela- tivno pre`ivetje pove~alo le za 2 % (Slika 2), nekoliko bolj pri `enskah (Tabela 3). Kako pomemben je stadij ob diagnozi, ka`e Slika 3: petletno relativno pre`ivetje bolnikov z omejenim stadijem je v zadnjem obdobju preseglo 20 %. Petletno relativno pre`ivetje bolnikov z raz{irjenim in razse- janim stadijem pa je {e vedno manj{e od 10 %. Napovedni dejavnik je tudi starost, saj je relativno pre`ivetje najslab{e pri starej{ih od 75 let, pre`ivetje pri zbolelih med 50. in 74. letom pa ves ~as opazovanja rahlo zaostaja za relativnim pre`ivetjem pri zbolelih pred 50. letom starosti (Slika 4). Petletno relativno pre`ivetje vseh zbolelih v obdobju 2001–2005 je bilo 9 % (Slika 2); bolni- ki, ki pre`ivijo prvo leto, pa lahko pri~akujejo 30-odstotno petletno relativno pre`ivetje. Rezultati {tudije EUROCARE-4 za zbolele v obdobju 2000–2002 ka`ejo, da je pre`ivetje sloven- skih bolnikov z rakom po`iralnika statisti~no zna~ilno manj{e od evropskega povpre~ja (Slika 5). 56 PO@IRALNIK KLINI^NI KOMENT AR Miha Sok Pre`ivetje bolnikov z rakom po`iralnika v treh obdobjih od leta 1991 do leta 2005 ostaja sla- bo. Minimalni trend izbolj{anja pre`ivetja gre na ra~un bolj{ega pre`ivetja pri bolnikih, mlaj{ih od 50 let, in pri bolnikih z rakom v omejenem stadiju. To je skupina bolnikov, ki smo jih zdra- vili kirur{ko. Zgodnja diagnostika je tako {e vedno najpomembnej{a, a velikih premikov na tem podro~ju `al ni. V zadnjem obdobju je bilo v primerjavi s prej{njimi obdobji registriranih celo manj bolnikov z omejeno obliko in ve~ bolnikov z razsejano obliko. Manj omejenega raka ka`e po eni strani na zelo maligno naravo raka po`iralnika, po drugi strani pa na natan~nej{o diagnosti- ko v zadnjem obdobju. Sodobna diagnostika pa {e vedno ni optimalna, saj sta sicer najprimernej{i preiskavi za zamejitev bolezni, CT prsnega ko{a in zgornjega trebuha ter endoskopska ultra- zvo~na preiskava, neto~ni kar v 60 % oz. 30 %. Omejene oblike raka po`iralnika so pravzaprav izjemne, {e posebej ~e vemo, da rak po`iralnika v stadiju T1 metastazira v bezgavke `e v 30 %, praviloma pa dobimo v ambulanto bolnike s stadijem T2. Manj omejenih oblik se ka`e tudi v manj{em {tevilu resekcij. Tako smo v obdobju od 1991–1995 operirali kar 42 % vseh bolni- kov z rakom po`iralnika, v obdobju od 2001–2005 pa le 21 %. Bolj{e pre`ivetje bolnikov z omejeno obliko, ki smo jih operirali, pa gre tudi na ra~un manj{e pooperacijske smrtnosti. V razisko- valnem projektu Kirurgija raka prebavil smo od leta 2003–2007 bele`ili manj kot 2-odstotno pooperacijsko smrtnost. Kirur{ko zdravljenje {e vedno ostaja metoda izbire. Pri tem se vedno vpra{amo, ali lahko nare- dimo radikalno resekcijo, a tudi, ali bolnika sploh smemo operirati. Radikalno resekcijo lahko naredimo zelo redko, saj so po`iralnik in podro~ne bezgavke za kirurga slabo dostopen organ. Pogosto je tudi aktualno vpra{anje, ali sploh smemo operirati, ker gre najve~krat za starej{e bol- nike s {tevilnimi pridru`enimi boleznimi in slabo telesno zmogljivostjo. Protokoli kombiniranega Rak.qxd 22.7.2009 12:38 Page 56 The 5-year relative survival rate of all patients diagnosed in the period 2001–2005 was 9% (Figure 2); patients surviving the first year may expect to survive five years in 30%. According to the results of EUROCARE-4 study for patients diagnosed in 2000–2002, sur- vival of Slovenian patients with esophageal cancer is statistically significantly below the European average (Figure 5). 57 ESOPHAGUS CLINICAL COMMENT ARY Miha Sok 01 02 0 30 40 50 60 70 80 90 100 % Slovensko povpre~je / 2000–2002 (EUROCARE-4) Slovenian average Evropsko povpre~je / 2000–2002 (EUROCARE-4) European average Povpre~je ZDA / 2000–2002 (SEER-13) USA average Slika 5: Petletno relativno pre`ivetje bolnikov z rakom po`iralnika (povpre~je in 95-odstotni interval zaupanja), zbolelih v letih 2000–2002 v Sloveniji, Evropi in nekaterih obmo~jih v ZDA. Figure 5: 5-year relative survival of esophageal cancer patients (average and 95% confidence interval) diagnosed in the period 2000–2002 in Slovenia, Europe and in some regions of the USA. In the three observation periods, from 1991 to 2005, the survival of patients with esophageal cancer remains poor. A trend of slight improvement in the survival is attributable to better sur- vival of patients under 50 years of age and in those with localized stage. These are the patients that were treated surgically. Therefore, early diagnosis is still most important, but unfortunately no relevant advances in this area have been achieved. In comparison with the previous peri- ods, among the patients registered in the last period there were even fewer with localized than with disseminated form of the disease. On the one hand, smaller proportion of localized di- sease reflects the highly malignant nature of esophageal cancer, and on the other, more accurate diagnostics available in the last period. However, the current diagnostic protocol is still not optimal, since the most suitable methods for staging of the disease, i. e. CT scan of the chest and upper abdomen and endoscopic ultrasonography, turn out inaccurate in as many as 60% and 30% of cases respectively. The localized forms of esophageal cancer are actually exceptional, particularly in view of the fact that stage T1 esophageal cancer metastasizes into the lymph nodes already in 30% of cases, while as a rule the patients seen in our outpatient clinic present with stage T2. Smaller proportion of localized disease is also reflected in a small- er number of cancer resections. Thus, in the period 1991–1995, as many as 42% of all esophageal cancer patients were treated by surgery, whereas in the period 2001–2005 there were only 21% of them. Better survival of patients with localized disease, who underwent surgery, is also attribu- table to lower postoperative lethality rates. The study on surgery of gastrointestinal cancer in the period 2003–2007 revealed a postoperative lethality rate of less than 2%. Surgery still remains the method of choice. Nevertheless, there is always a question whether we can perform a radical resection and whether we can operate on the patient at all. Radical Rak.qxd 22.7.2009 12:38 Page 57 zdravljenje z radioterapijo, kemoterapijo in kirurgijo se zadnjih deset let niso spremenili. ^akamo na nova zdravila, na u~inkovitej{e sheme, ki bodo nudile ve~je upanje za ozdravitev. Chang HK, Young TK, Sang-Hoon J, Sook-Whan S, Joo HK. Lymphadenectomy extent is closely related to long-term survival in esophageal cancer. Eur J Cardiothorac Surg 2007; 31: 154–60. Graham AJ, Shrive FM, Ghali WA, Manns BJ, Grondin SC, Finley RJ, et al. Defining the Optimal Treatment of Locally Advanced Esophageal Cancer: A Systematic Review and Decision Analysis. Ann Thorac Surg 2007; 83: 1257–64. Imdahl I, Bognar G, Schulte-Mönting J, Schöffe U, Farthmann EH, Ihling C. Predictive factors for response to neoadjuvant therapy in patients with oesophageal cancer. Eur J Cardiothorac Surg 2002; 21: 657–63. Satoshi Y, Kawahara K, Maekawa T , Shiraishi T , Shirakusa T . Minimally Invasive Esophagectomy for Stage I and II Esophageal Cancer. Ann Thorac Surg 2005; 80: 2070–5. 58 PO@IRALNIK KLINI^NI KOMENT AR Franc Anderluh Karcinom po`iralnika je, `al, tako pri nas kot tudi drugje po svetu {e vedno bolezen z zelo sla- bo napovedjo izida. Incidenca adenokarcinoma se pove~uje zaradi spremenjenih `ivljenjskih navad. Ugotavljamo, da bolniki kljub ve~ji ozave{~enosti pomo~ pri zdravniku `al {e vedno i{~e- jo prepozno, saj v zadnjem opazovanem obdobju, pri obeh spolih, nara{~a dele` bolnikov, pri katerih so ob postavitvi diagnoze prisotni tudi `e oddaljeni zasevki, njihovo zdravljenje pa je praviloma lahko le simptomatsko. Razveseljuje dejstvo, da se v zadnjem obdobju izbolj{uje pre- `ivetje bolnikov z omejenim in raz{irjenim rakom (na ta ra~un tudi pre`ivetje vseh bolnikov z rakom po`iralnika), pri katerih je mo`no kurativno zdravljenje. ^eprav je dele` bolnikov, ki so bili dele`ni kombiniranega zdravljenja z obsevanjem, kemo- terapijo in operacijo v zadnjih letih glede na obdobje 1996–2000 nekoliko manj{i, pa se pre`ivetje teh bolnikov izbolj{uje, kar verjetno lahko pripi{emo bolj natan~nemu na~rtovanju obsevanja in vedno manj{i ob- in pooperativni smrtnosti. Pri teh bolnikih smo namre~ vpeljali trodimen- zionalno na~rtovanje obsevanja, ki nam omogo~a natan~nej{e obsevanje tumorja in podro~nih bezgavk ter bolj{o za{~ito zdravih organov. Kljub temu so rezultati zdravljenja, `al, {e vedno dale~ nezadovoljivi. V svetu potekajo {tevilne klini~ne raziskave, s katerimi posku{ajo izbolj- {ati pre`ivetje predvsem z dodatkom novih citostatikov `e uveljavljenim kurativnim terapevtskim shemam, vendar pa zaenkrat zdravljenje s 5-FU v nepretrgani infuziji in s cisplatinom, ki ga izvajamo tudi pri nas, {e vedno ostaja standardno. Poleg tega ugotavljamo, da so bili v zadnjem opazovanem obdobju prakti~no vsi slovenski bol- niki, ki so bili zaradi karcinoma po`iralnika dele`ni kakr{nega koli zdravljenja, obravnavani na OI Ljubljana in/ali v UKC Ljubljana in/ali v UKC Maribor, kar je verjetno edino smisel- no, saj gre za ustanove, ki imajo z zdravljenjem tovrstnih bolnikov najve~ izku{enj, zato so bolniki dejansko lahko dele`ni multidisciplinarne obravnave. Bosset JF, Lorchel F, Mantion G, Buffet J, Crehange G, Bosset M, et al. Radiation and chemoradiation for esophageal adenocarcinoma. J Surg Oncol 2005; 92: 239–45. Kaklamanos IG, Walker GR, Ferry K, Franceschi D, Livingston AS. Neoadjuvant treatment for resectable cancer of the esophagus and the gastroesophageal junction: A meta-analysis of randomized clinical trials. Ann Surg Oncol 2003; 10: 754–61. Stahl M, Stuschke M, Lehmann N, Meyer HJ, Walz MK, Seebwe S, et al. Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus. J Clin Oncol 2005; 23: 2310–7. VIRI Literature VIRI Literature Rak.qxd 22.7.2009 12:38 Page 58 resection is feasible only very rarely as the esophagus and regional lymph nodes are not easi- ly accessible to surgery. Another question that turns up frequently is whether we may perform surgery at all, since these are generally older patients with several concomitant diseases and a poor general condition. The protocols of combined treatment with radiotherapy, chemothe- rapy and surgery have not changed over the last decade. We expect new medications and more effective treatment schedules that would hold more promise of cure. 59 ESOPHAGUS CLINICAL COMMENT ARY Franc Anderluh Unfortunately, in Slovenia as elsewhere in the world, carcinoma of the esophagus still remains a disease with rather poor prognosis. The incidence of adenocarcinoma is increasing due to changed lifestyles. It turns out that – despite of raising awareness – the patients still seek medi- cal help too late. Namely, in the last observation period the proportion of patients presenting with distant metastases at diagnosis, when treatment options are reduced to symptomatic treat- ment only, has been increasing in both genders. It is encouraging to note that in the last period the survival of patients with localized and locoregionally advanced disease (and thus also the survival of all esophageal cancer patients), in whom curative treatment is still feasible, has improved. Although in last years the proportion of patients treated with a combination of radiotherapy, chemotherapy and surgery has slightly decreased as compared to the period 1996–2000, the survival of these patients has been improving, which can probably be attributed to a more pre- cise irradiation planning as well as to steadily decreasing peri- and postoperative lethality rates. Namely, in these patients we introduced a 3-D irradiation planning system, which facilitates more accurate irradiation of the tumor and regional lymph nodes and also provides a better protection of healthy organs. Nevertheless, the treatment results are unfortunately still far from satisfactory. Several clinical studies are underway worldwide, which are aimed at improving the patient survival particularly by introducing new cytotostatic drugs into the already estab- lished curative therapeutic schedules. However, the treatment with 5-FU in a continued infusion with cis-platinum, which is used also in our institution, still remains a standard treatment approach. Furthermore, it has been established that in the last observation period practically all patients receiving any kind of treatment for carcinoma of the esophagus were treated either at the IO Ljubljana and/or UMC Ljubljana and/or UMC Maribor, which seems only reasonable, since these are the institutions with most experience in the treatment of such patients, and thus able to offer the patients a multidisciplinary treatment approach. Rak.qxd 22.7.2009 12:38 Page 59 V obdobju 1991–2005 je za `elod~nim rakom zbolelo 7345 ljudi, 4435 mo{kih in 2910 `ensk. Kot je razvidno s Slike 1, je bila v opazovanem obdobju groba inciden~na stopnja stabilna, dru- ge stopnje so se zmanj{evale, predvsem obe starostno standardizirani meri; inciden~na stopnja se je zmanj{evala za povpre~no 1,8 % letno, umrljivostna pa za povpre~no 3,9 % letno. @ELODEC MKB 10: C16 60 V analizo pre`ivetja je vklju~enih 6833 primerov; 508 (6,9 %) jih nismo upo{tevali, ker jim je bila diagnoza postavljena po smrti, 4 mlaj{e od 20 let obravnavamo v poglavju o pre`ivetju pri otrocih in mladostnikih. V obdobju 2001–2005 je imelo 1447 primerov (od 2278) natan~ne- je opredeljeno mesto vznika tumorja v `elodcu. Najpogosteje je bil to antrum (31 %), sledijo kardija (21 %), korpus (20 %), mala krivina (7 %), velika krivina in pilorus s po 2 %; pri 17 % je bila bolezen tako raz{irjena, da mesta nastanka ni bilo mogo~e dolo~iti. Dele`i opredelje- nih mest vznika tumorja se v zadnjih desetih letih niso bistveno spreminjali. Odstotek mikroskopsko potrjenih primerov se je pove~al z 92 % v letih 1991–1995 na 96 % v letih 2001–2005. V vseh treh obdobjih je bilo ve~ kot tri ~etrtine `leznih karcinomov, v zadnjem 0 5 10 15 20 25 30 1986 1990 1995 2000 2005 Leto / Year Incidenca – groba stopnja / Incidence – crude rate Incidenca – SSS* / Incidence – ASR** Umrljivost – groba stopnja / Mortality – crude rate Umrljivost – SSS* / Mortality – ASR** Stopnja na 100.000 / Rate per 100,000 * SSS – starostno standardizirana stopnja (standard – slovenska populacija leta 1986) ** ASR – age standardized rate (standard Slovenian population in 1986) Slika 1: Groba in starostno standardizirana inciden~na in umrljivostna stopnja `elod~nega raka, Slovenija 1986–2005. Figure 1: Crude and age-standardized incidence and mortality rate of stomach cancer, Slovenia 1986–2005. Mo{ki / Males @enske / Females Obdobje / {tevilo / 20–49 let / 50–74 let / 75+ let / {tevilo / 20–49 let / 50–74 let / 75+ let / Period number years (%) years (%) years (%) number years (%) years (%) years (%) 1991–1995 1364 8,9 68,4 22,7 911 9,2 56,1 34,7 1996–2000 1387 8,6 66,8 24,7 893 11,4 55,2 33,4 2001–2005 1397 8,3 63,7 28,0 881 9,5 47,4 43,0 T abela 1: [tevilo bolnikov z `elod~nim rakom po spolu in obdobju postavitve diagnoze ter njihovi dele`i po starosti. Table 1: Number of stomach cancer patients by sex and period of diagnosis with their proportions by age. EPIDEMIOLOGIJA Rak.qxd 22.7.2009 12:38 Page 60 In the period 1991–2005, a total of 7345 persons were diagnosed with cancer of the stomach, of these 4435 males and 2910 females. As evident from Figure 1, in the observed time peri- od the crude incidence rate was stable, while other rates have been decreasing, especially the age-standardized rates; the estimated annual percentage decrease in age-standardized incidence rate was 1.8% and 3.9% in age-standardized mortality rate. The survival analysis included 6833 cases; 508 patients (6.9%) diagnosed only after death were not considered in the analysis, 4 patients less than 20 years of age are presented in the chap- ter on the survival of children and adolescents. In the period 2001–2005, 1447 patients (out of total 2278) had the site of tumor origin in the stomach more precisely defined. This was most frequently the antrum (31%), followed by cardia (21%), corpus (20%), lesser curvature (7%), greater curvature and pylorus (2% each); in 17% the disease was so advanced that the site of origin could not be determined. The proportion of undefined site of origin has not been changing much in the last years. The percentage of microscopically confirmed cases increased from 92% in the period 1991–1995 to 96% in the period 2001–2005. In all three time-periods, more than three-quarters of cancers were adenocarcinomas; in the last period they represented 88% of the total, their proportion increasing mainly on the account of undefined carcinomas, while in all three periods other defined histological types represent less than 1%. Among adenocarcinomas, according to Lauren's clas- sification, there were 34% adenocarcinomas of intestinal and 16% of diffuse type. In fifteen years, the proportion of younger patients (20–49 years) has not changed significantly while the proportion of patients aged 75 years or older, particularly among females, has been increasing (Table 1). In all three time-periods, almost three quarters of patients were diagnosed with regional or disseminated disease (Table 2). The stage of disease at diagnosis is probably the main reason that in the period 2001–2005 40% (1,375) patients did not receive specific treatment, which was 10% less that in the first peri- od; more than three fourths of these patients were diagnosed with disseminated disease or their stage was not determined at all. In the period 2001–2005, 55% (1,248) of all patients included in the analysis underwent sur- gery, i. e. 91% of all that received specific treatment in this period. In the 15-year period, the proportion of patients treated by surgery alone has decreased from 85% to 68%; the propor- tion of those treated additionally with a combination of irradiation and chemotherapy (15% in the period 2001–2005) or chemotherapy alone (7%) has been gradually increasing; 7% were treated by chemotherapy as single modality treatment and 3% with other combinations. STOMACH ICD 10: C16 61 Tabela 2: [tevilo bolnikov z `elod~nim rakom po spolu in obdobju postavitve diagnoze ter njihovi dele`i po stadiju. Table 2: Number of stomach cancer patients by sex and period of diagnosis with their proportions by stage. Mo{ki / Males @enske / Females Obdobje / {tevilo / omejen / raz{irjen / razsejan / neznan / {tevilo / omejen / raz{irjen / razsejan / neznan / Period number localized regional distant unknown number localized regional distant unknown (%) (%) (%) (%) (%) (%) (%) (%) 1991–1995 1364 19,6 37,6 30,1 12,7 911 21,4 33,3 30,4 14,9 1996–2000 1387 20,5 37,7 32,4 9,4 893 22,3 34,6 31,2 11,9 2001–2005 1397 19,3 40,4 33,9 6,4 881 24,0 37,3 27,7 11,0 EPIDEMIOLOGY Rak.qxd 22.7.2009 12:38 Page 61 obdobju 88 %; njihov dele` se ve~a predvsem na ra~un zmanj{evanja dele`a neopredeljenih kar- cinomov, drugih opredeljenih histolo{kih vrst je v vseh obdobjih manj kot 1 %. Med `leznimi karcinomi `elodca jih je bilo glede na klasifikacijo po Laurenu 34 % intestinalnega tipa in 16 % difuznega tipa. V petnajstih letih se dele` mlaj{ih bolnikov (20–49 let) ni bistveno spremenil, pove~uje pa se dele` bolnikov, starej{ih od 75 let, zlasti med `enskami (Tabela 1). V vseh treh obdobjih so ime- le ob diagnozi skoraj tri ~etrtine bolnic in bolnikov raz{irjeno ali razsejano bolezen (Tabela 2). Raz{irjenost bolezni ob diagnozi je verjetno najpomembnej{i vzrok, da tudi v obdobju 2001–2005 ni bilo specifi~no zdravljenih 40 % (1375) bolnikov, kar pa je 10 % manj kot v prvem obdobju; 62 @ELODEC 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Slika 2: Deset-, pet-, tri- in enoletno relativno pre`ivetje bolnikov z `elod~nim rakom po obdobju postavitve diagnoze. Figure 2: 10-, 5-, 3- and 1-year relative survival of stomach cancer patients by period of diagnosis. Tabela 3: Opazovano in relativno pre`ivetje bolnikov z `elod~nim rakom po spolu in obdobju postavitve diagnoze s 95-odstotnim intervalom zaupanja (IZ). Table 3: Observed and relative survival of stomach cancer patients by sex and period of diagnosis with 95% confidence interval (CI). Opazovano pre`ivetje / Observed survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 34,4 (32,0–37,0) 18,8 (16,8–21,0) 14,3 (12,6–16,3) 34,9 (31,9–38,1) 18,8 (16,4–21,5) 14,5 (12,4–17,0) 1996–2000 37,1 (34,6–39,7) 19,4 (17,4–21,6) 15,9 (14,1–18,0) 38,2 (35,1–41,5) 23,2 (20,6–26,1) 19,9 (17,5–22,7) 2001–2005 42,4 (39,9–45,1) 24,4 (22,3–26,8) 19,9 (17,7–22,3) 43,5 (40,3–46,9) 28,6 (25,7–31,8) 24,4 (21,6–27,7) Relativno pre`ivetje / Relative survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 36,2 (33,5–39,0) 22,0 (19,4–24,6) 18,7 (16,1–21,3) 36,5 (33,1–39,9) 21,6 (18,4–24,7) 18,3 (15,2–21,5) 1996–2000 39,1 (36,3–41,8) 22,8 (20,2–25,4) 20,9 (18,2–23,6) 39,9 (36,4–43,3) 26,4 (23,1–29,8) 24,8 (21,3–28,3) 2001–2005 44,7 (41,9–47,6) 28,8 (26,0–31,6) 26,4 (23,2–29,6) 45,4 (41,8–48,9) 32,8 (29,1–36,4) 31,0 (26,9–35,1) Rak.qxd 22.7.2009 12:38 Page 62 In the period 2001–2005, near to 40% of patients started their treatment in the UMC Ljubljana (similar as in the previous years), 21% in the UMC Maribor, 13% at the IO Ljubljana and 6% in the GH Celje; the remaining 20% were operated on in the general hospitals of Jesenice (4%), Novo mesto (4%), Murska Sobota (4%), Slovenj Gradec (3%), Nova Gorica (2%), Izola (2%) and Ptuj (1%). The relative survival has been gradually increasing, particularly in the last period; in 15 years, the 5-year relative survival increased by 9% (Figure 2), by 13% in females and 8% in males (Table 3). The relevance of stage at diagnosis is shown in Figure 3. Compared to the peri- od 1991–1995, in the last period the 5-year relative survival of patients with localized stage was already above 70%, thus having increased by 20%, while the 5-year relative survival of patients with regional disease has increased by 11%. Age is a prognostic factor as well, since in the last period all the patients under 50 years of age had 10% higher relative survival than those aged 75 years or older (Figure 4). 63 STOMACH 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 Omejen / Localized Raz{irjen / Regional Razsejan / Distant Vsi / All Slika 3: Petletno relativno pre`ivetje bolnikov z `elod~nim rakom po stadiju in obdobju postavitve diagnoze. Figure 3: 5-year relative survival of stomach cancer patients by stage and period of diagnosis. 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 20–49 let / years 50–74 let / years 75+ let / years Vsi / All Slika 4: Petletno relativno pre`ivetje bolnikov z `elod~nim rakom po starosti in obdobju postavitve diagnoze. Figure 4: 5-year relative survival of stomach cancer patients by age and period of diagnosis. Rak.qxd 22.7.2009 12:38 Page 63 pri ve~ kot treh ~etrtinah nezdravljenih bolnic in bolnikov je {lo za razsejano bolezen ali pa stadij sploh ni bil dolo~en. V letih 2001–2005 je bilo operiranih 55 % (1248) od vseh v anali- zo vklju~enih primerov oz. 91 % od vseh, ki so bili v tem obdobju specifi~no zdravljeni. Dele` samo operiranih se je v petnajstletnem obdobju zmanj{al s 85 % na 68 %, postopno se ve~a dele` dodatno zdravljenih z obsevanjem in kemoterapijo v kombinaciji (15 % v letih 2001–2005) ali samo s kemoterapijo (7 %), 7 % je bilo zdravljenih samo s kemoterapijo, 3 % pa z drugimi kom- binacijami. V letih 2001–2005 je blizu 40 % bolnikov zdravljenje pri~elo v UKC Ljubljana (podobno tudi v prej{njih letih), 21 % v UKC Maribor, 13 % na OI Ljubljana in 6 % v SB Celje, preostalih 20 % pa je bilo operiranih v bolni{nicah Jesenice (4 %), Novo mesto (4 %), Murska Sobota (4 %), Slovenj Gradec (3 %), Nova Gorica (2 %), Izola (2 %) in Ptuj (1 %). Relativno pre`ivetje se postopno pove~uje, predvsem v zadnjem obdobju; v 15 letih se je pet- letno relativno pre`ivetje pove~alo za 9 % (Slika 2), za 13 % pri `enskah in za 8 % pri mo{kih (Tabela 3). Kako pomemben je stadij ob diagnozi, ka`e Slika 3: v zadnjem obdobju je petletno relativno pre`ivetje bolnikov z omejenim stadijem `e ve~ kot 70-odstotno in se je v primerjavi z obdobjem 1991–1995 pove~alo za 20 %, za 11 % se je pove~alo tudi petletno relativno pre- `ivetje bolnikov z raz{irjeno boleznijo. Napovedni dejavnik je tudi starost, saj so v zadnjem obdobju mlaj{i od 50 let imeli za 10 % ve~je relativno pre`ivetje kot stari 75 let in ve~ (Slika 4). Petletno relativno pre`ivetje vseh zbolelih v obdobju 2001–2005 je bilo 28 % (Slika 2); bolni- ki, ki pre`ivijo prvo leto, pa lahko pri~akujejo 60-odstotno relativno petletno pre`ivetje. Rezultati {tudije EUROCARE-4 za zbolele v obdobju 2000–2002 ka`ejo, da je pre`ivetje slo- venskih bolnikov z `elod~nim rakom skoraj enako evropskemu povpre~ju (Slika 5). 64 @ELODEC KLINI^NI KOMENT AR Stane Rep{e Razvoj in stanje kirur{kega zdravljenja `elod~nega raka v Sloveniji v letih 1983–1997 je bilo opisano v zadnji izdaji monografije Pre`ivetje bolnikov z rakom v Sloveniji leta 2003. Ali je takrat- no mnenje, da se bodo strokovna prizadevanja na podro~ju `elod~nega raka po letu 1980 (strokovni sestanki, nacionalne ankete, multidisciplinarni timi, delavnice in simpoziji, publi- kacije) pokazala z bolj{imi rezultati pre`ivetja na dr`avni ravni {ele v sedanjem obdobju, pravilno? V obdobju, ki je sedaj analizirano in prikazano s petletnim pre`ivetjem, smo se kirurgi v Slo- veniji dr`ali doktrinarnih na~el za obravnavo bolnikov z `elod~nim rakom, ki smo jih izdelali v za~etku devetdesetih let in so bila objavljena v publikaciji Priporo~ila za zdravljenje bolnikov z rakom prebavil leta 1997. Resekcija, radikalna in/ali paliativna, je imela absolutno prednost, ne glede na starost bolnika. Vrsta operacije – distalna subtotalna resekcija oz. totalna gastrek- tomija s sistemati~no limfadenektomijo vseh bezgavk 1. in 2. skupine (D2 limfadenektomija) – je bila odvisna od mesta procesa na `elodcu (tretjine) in od histolo{kega tipa po Laurenu. D2 lim- fadenektomija je bila sestavni del radikalne operacije ne glede na kategorijo T . Neoadjuvantna kemoterapija in/ali radioterapija pri napredovalem stadiju (T3, T4) sta bili bolj izjema kot pra- vilo, prav tako tudi adjuvantno onkolo{ko zdravljenje. Po letu 2000 se je doktrina zdravljenja `elod~nega raka pri nas za~ela ponovno postopoma spre- minjati v smislu bolj individualizirane kirurgije – »tailored surgery« (mukozektomija pri tumorjih T1N0, samo D1 limfadenektomija pri tumorjih T1Nx) in neoadjuvantne radiokemoterapije pri tumorjih v kategorijah nad T2bNxMx. Sprva posamezni primeri so postajali vse {tevilnej{i. Kirurgija, ki je bila edino zdravljenje v obdobju 1996–2000 pri 83 % bolnikov, se je v obdob- ju 2001–2005 zmanj{ala na 68 %, pove~al pa se je odstotek kombiniranega zdravljenja. Tudi dele` bolnikov, ki jih ni bilo mogo~e operirati in so bili zdravljeni samo s kemoterapijo, se je pove~al s 3 % v prvem obdobju na 7 % v tretjem. Rezultati ankete, ki smo jo naredili med kirur{kimi Rak.qxd 22.7.2009 12:38 Page 64 The 5-year relative survival of all patients diagnosed in the period 2001–2005 was 28% (Figure 2); patients surviving the first year may expect to survive five years in 60%. According to the results of EUROCARE-4 study for patients diagnosed in 2000–2002, the survival of Slovenian patients is nearly equal to the European average (Figure 5). 65 STOMACH CLINICAL COMMENT ARY Stane Rep{e The development and the state-of-the-art of surgical treatment for stomach cancer in Slovenia in the period 1983–1997 was presented in the last edition of the monograph Cancer Patients Survival in Slovenia issued in 2003. How correct were we then by presuming that the results of endeavors in the area of stomach cancer after the year 1980 (expert meetings, national sur- veys, multidisciplinary teams, workshops and symposia, publications) would be reflected in better survival rates at the national level only in the current period? In the period, which is subject to the current analysis and is presented by 5-year survival, the surgeons in Slovenia followed the doctrinaire principles of stomach cancer patient treatment, which were adopted in the beginning of 90's and published in 1997 under the title Recommendations for a Comprehensive Treatment of Patients with Cancers of Digestive Organs. Resection, either rad- ical and/or palliative, was the treatment of choice, irrespective of the patient's age. The type of resection – distal subtotal resection or total gastrectomy with systematic lymphadenecto- my of all groups 1 and 2 lymph nodes (D2 lymphadenectomy) depended on the site of process in the stomach (thirds) as well as on histological type by Lauren. D2 lymphadenectomy was an integral part of radical surgery, regardless the T category. At an advanced stage (T3, T4), neoadjuvant chemotherapy and/or radiotherapy were the exception rather than the rule, and so was also adjuvant oncological therapy. After the year 2000, the principle of stomach cancer treatment in Slovenia again started to change gradually in terms of a more individualized surgery, the so-called »tailored surgery« (mucosectomy in T1N0 tumors, D1 lymphadenectomy alone in T1Nx tumors) and neoadju- vant radiochemotherapy in categories above T2bNxMx. Initially, this approach was used in individual cases only, but later on it became more and more frequent. In the period 1996–2000, 01 02 0 30 40 50 60 70 80 90 100 % Slovensko povpre~je / 2000–2002 (EUROCARE-4) Slovenian average Evropsko povpre~je / 2000–2002 (EUROCARE-4) European average Povpre~je ZDA / 2000–2002 (SEER-13) USA average Slika 5: Petletno relativno pre`ivetje bolnikov z `elod~nim rakom (povpre~je in 95-odstotni interval zaupanja), zbolelih v letih 2000–2002 v Sloveniji, Evropi in nekaterih obmo~jih v ZDA. Figure 5: 5-year relative survival of stomach cancer patients (average and 95% confidence interval) diagnosed in the period 2000–2002 in Slovenia, Europe and in some regions of the USA. Rak.qxd 22.7.2009 12:38 Page 65 oddelki slovenskih bolni{nic, ka`ejo, da se je pooperacijska smrtnost reseciranih bolnikov posto- poma zmanj{evala; leta 1994 je bila 6 %, leta 2004 pa 4 %. Kot smo napovedali, se napredek na{ih skupnih prizadevanj na dr`avni ravni ka`e {ele v tem obdobju. Petletno relativno pre`ivetje bolnikov z `elod~nim rakom v Sloveniji se je postopoma pove~evalo: od 17 % v obdobju 1986–1990 in 19 % v obdobju 1991–1995 na 23 % v obdob- ju 1996–2000 in 28 % v obdobju 2001–2005. Bolj{i rezultati klini~nih serij iz UKC v Ljubljani in v Mariboru, kjer je t. i. resektabilnost bistve- no ve~ja, pooperativna smrtnost manj{a in petletno pre`ivetje ve~je od slovenskega povpre~ja, so zagotovilo, da bo tudi naslednje obdobje prineslo izbolj{anje, {e posebej, ~e bomo uspeli regio- nalizirati kirur{ko zdravljenje `elod~nega raka. Tretjino bolnikov, ki so sedaj operirani v 9 regionalnih bolni{nicah (okrog 80 do 100 bolnikov), bi lahko operirali v treh najve~jih bol- ni{nicah, v Ljubljani, Mariboru in Celju, morda {e v treh regijskih, v Novi Gorici, Izoli in Novem mestu. To bi se gotovo pokazalo s pove~anjem sedanjega, {e vedno slabega, populacijskega pre- `ivetja. Juvan R, Omejc M, Jelenc F, Rep{e S. Rezultati operacijskega zdravljenja `elodca v obdobju 1993–2002. In: Omejc M, Rep{e S, eds. Kirurgija `elodca – standardi in novosti: zbornik simpozija. Ljubljana, Kirur{ka klinika, 2005; 210–6. Omejc M, Rep{e S. Rak `elodca v Sloveniji 2004. In: Omejc M, Rep{e S, eds. Kirurgija `elodca – standardi in novosti: zbornik simpozija. Ljubljana, Kirur{ka klinika, 2005; 128–33. Potr~ S, Horvat M, Ivanez A, Hazabend M. Kaj smo se nau~ili pri kirur{kem zdravljenju adenokarcinoma `elodca: primerjava dveh obdobij. In: Omejc M, Rep{e S, eds. Kirurgija `elodca – standardi in novosti: zbornik sim- pozija. Ljubljana, Kirur{ka klinika, 2005; 197–09. Rep{e S, Juvan R. Kirurgija raka `elodca v Sloveniji. In: Rep{e, ed. Kirurgija `elodca: zbornik simpozija. Ljub- ljana, Kirur{ka {ola, Kirur{ke klinike, 1995; 101–12. Rep{e S, Omejc M, Juvan R, Jelenc F. Napredovali rak `elodca – standardna resekcija danes. In: Omejc M, Rep{e S, eds. Kirurgija `elodca – standardi in novosti: zbornik simpozija. Ljubljana, Kirur{ka klinika, 2005; 154–60. Rep{e S, @itko T , Kocijan~i~ B, Lamovec J, Golouh R, Jelenc F , et al. Rak `elodca. In: Rep{e S, ed. Priporo~ila za celostno obravnavo bolnikov z rakom prebavil. Ljubljana: Ministrstvo za zdravstvo R Slovenije, 1997; 13–21. 66 @ELODEC KLINI^NI KOMENT AR Irena Oblak ^eprav se incidenca `elod~nega raka po svetu in v Sloveniji zmanj{uje, sodi ta bolezen med najpogostej{e vzroke smrti zaradi raka. Zanimivo je, da se v zadnjih letih pove~uje incidenca karcinoma, ki vznikne na kardiji, predvsem v razvitih zahodnih dr`avah. @e ob diagnozi ima ve~ kot dve tretjini bolnikov raz{irjeno ali metastatsko bolezen. Po podatkih iz literature je pri 40–50 % bolnikih ob postavitvi diagnoze bolezen ocenjena kot neresekta- bilna, njihovo srednje pre`ivetje pa je 6 mesecev do 1 leta. V primeru, da je operacija izvedljiva, je osnovno zdravljenje radikalna resekcija tumorja s pripadajo~imi podro~nimi bezgavkami. Na `alost se bolezen ponovi kar v 75 % primerih, od tega pri 40–65 % primerov lokalno in/ali podro~no. Leta 2001 smo v Sloveniji uvedli dopolnilno zdravljenje s pooperativno radiokemoterapijo (fluo- ropirimidini ± cisplatin), ki izbolj{a pre`ivetje bolnikov po radikalni resekciji `elod~nega raka stadijev Ib–IV brez oddaljenih zasevkov. V na{i skupini bolnikov smo dosegli odli~en lokalni nadzor, saj se kar pri 81 % bolnikov bolezen po petih letih ni ponovila ne lokalno ne podro~no. Petletno pre`ivetje brez ponovitve bolezni je bilo pri na{ih bolnikih 51 %, za bolezen specifi~- no pre`ivetje 51 % in skupno 49 %. Kot je `e splo{no znano, tudi v na{i raziskavi ugotavljamo, da imajo bolniki z ve~jimi tumorji in tisti s tumorji, ki so vzniknili na kardiji `elodca, slab{o napoved izida bolezni. VIRI Literature Rak.qxd 22.7.2009 12:38 Page 66 83% of patients were treated by surgery alone, whereas in the period 2001–2005 their proportion deceased to 68% while the percentage of combined treatment increased. The proportion of inope- rable patients treated by chemotherapy alone increased from 3% in the first observation period to 7% in the third. The results of the survey carried out in all surgical departments in Slovenia show that postoperative lethality rates of the resected patients gradually decreased, from 6% in 1994 to 4% in 2004. Consistent with our projections, the progress resulting from our joint endeavors at the nation- al level is evident only in the last observed period. The 5-year relative survival of patients with stomach cancer in Slovenia has gradually increased: from 17% in the period 1986–1990 and 19% in the period 1991–1995 to 23% in the period 1996–2000 and 28% in the period 2001–2005. Better results of the clinical series of the UMC Ljubljana and UMC Maribor, where resectabi- lity is significantly higher, postoperative lethality lower and 5-year survival above the Slovenian average, justify the expectation that the following period too will bring further improvement, particularly if we manage to reorganize the surgical treatment for stomach cancer. A third of the patients that currently undergo surgical treatment in nine regional hospitals (approximately 80 to 100 patients) could have surgery in three major hospitals – in Ljubljana, Maribor and Celje, and perhaps also in three regional hospitals – in Nova Gorica, Izola and Novo mesto. Undoubtedly, this would result in an increase in the currently still poor population survival. 67 STOMACH CLINICAL COMMENT ARY Irena Oblak Although the incidence of stomach cancer in Slovenia has been decreasing, this disease still remains among the most frequent cancer-related causes of deaths. It is interesting, however, that in recent years the incidence of carcinoma stemming from the cardia has been increasing particularly in the developed countries of the West. More than two thirds of patients will have regional or metastatic disease already at the time of diagnosis. In as many as 40–50% of patients the disease is assessed as nonresectable at diag- nosis; the median survival of these patients is 6 months to 1 year. In the case of resectable disease the basic treatment comprises a radical resection of the tumor with relevant regional lymph nodes. Unfortunately, the disease will recur in as many as 75% of cases, 40–65% of these recur- rences being local and/or regional. In 2001, an adjuvant treatment with postoperative radiochemotherapy (fluoropirimidins with or without cisplatin) was introduced in Slovenia. This treatment regimen improves the sur- vival of patients after radical resection for stomach cancer stage Ib–IV without distant metastases. In our group of patients, an excellent local response has been achieved, as in 81% of patients the disease did not recur, neither locally nor regionally. The 5-year recurrence-free survival in our patient's group was 51%, the disease specific survival 51% and the overall survival 49%. As elsewhere, also our patients with larger tumors and those with tumors arising at cardia have worse prognosis. Recently, the use of preoperative systemic chemotherapy and/or radiochemotherapy has become increasingly more frequent. In the last two years in Slovenia too we started to treat patients with operable stomach cancer by preoperative systemic chemotherapy according to ECF sched- ule (epidoxorubicin, cisplatin and 5-fluorouracil in continuous infusion), which is followed by surgery and afterwards by the same schedule as maintenance chemotherapy. When tumors were not resectable, the patients received radiochemotherapy prior to surgery. Such preoperative treat- ment is aimed at reducing the tumor mass and increasing the possibility of radical resection. Study results show that such treatment approach facilitates surgical removal of the tumor and regional lymph nodes (R0 resection) in more than 80% of patients, while a complete patho- logic response and tumor disappearance is achieved in 20–30% of cases. Rak.qxd 22.7.2009 12:38 Page 67 V zadnjem ~asu se vse bolj uveljavlja predoperativno zdravljenje s sistemsko terapijo in/ali radio- kemoterapijo. Tudi v Sloveniji smo v zadnjih dveh letih pri~eli zdraviti bolnike z operabilnim rakom `elodca s predoperativno sistemsko kemoterapijo po shemi ECF (epidoksorubicin, cis- platin in 5-FU v trajni infuziji), ki ji sledi operacija in nato ista vzdr`evalna kemoterapija. ^e tumorji niso bili resektabilni, so bili bolniki pred operacijo zdravljeni z radiokemoterapijo. Namen predoperativnega zdravljenja je zmanj{ati tumor in pove~ati mo`nost za radikalno operacijo. Po izsledkih raziskav ta na~in zdravljenja omogo~a popolno kirur{ko odstranitev tumorja in podro~nih bezgavk (resekcija R0) pri ve~ kot 80 % bolnikov, pri 20–30 % pa `e s tem postop- kom tumor v celoti uni~imo. Izbolj{anje pre`ivetja bolnikov z `elod~nim rakom v zadnjih letih pripisujemo tako izbolj{ani kirur{ki tehniki, kot tudi dodatnemu zdravljenju s kemo- in/ali radioterapijo. Tudi pri bolni- kih z oddaljenimi zasevki in tistih, pri katerih tumor kljub intenzivnemu zdravljenju ostane neoperabilen, s paliativnim zdravljenjem (operacijo, radioterapijo in/ali sistemskim zdravlje- njem) izbolj{amo kakovost `ivljenja, pove~amo pa lahko tudi pre`ivetje. Ajani JA, Mansfield PF, Janjan N, Morris J, Pisters PW, Lynch PM, et al. Multi-Institutional trial of preope- rative chemoradiotherapy in patients with potentially resectable gastric carcinoma. J Clin Oncol 2004; 22: 2774–80. Cunningham D, Allum WH, Stenning SP, Thomson JN, Van de Velde CJ, Nicolson M, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl Med 2006; 355: 11–20. Gunderson LL, Sosin H. Adenocarcinoma of the stomach: Areas of failure in a reoperation series (second or symptomatic look); clinicopathological correlation and implications for adjuvant therapy. Int J Radiat Oncol Biol Phys 1982; 8: 1–11. Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, et al. Chemotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001; 345: 725–30. Oblak I, Velenik V, Anderluh F, Strojan P . Results of adjuvant radiochemotherapy for gastric adenocarcinoma in Slovenia. Eur J Surg Oncol 2007; 33: 982–7. 68 @ELODEC VIRI Literature Rak.qxd 22.7.2009 12:38 Page 68 The improved survival of patients with stomach cancer in recent years is attributable to more advanced surgical techniques as well as to the use of adjuvant chemo and/or radiotherapy. Thus, even in patients with distant metastases and in those whose tumors remain inoperable despite intensive therapy, palliative therapy (surgery, radiotherapy and/or systemic therapy) is able to improve their quality of life and even increase their survival. 69 STOMACH Rak.qxd 22.7.2009 12:38 Page 69 V obdobju 1991–2005 je za rakom debelega ~revesa zbolelo 8208 ljudi, od tega 4326 mo{kih in 3882 `ensk. Kot je razvidno s Slike 1, se groba in starostno standardizirana inciden~na stop- nja od leta 1991 pove~ujeta, groba stopnja povpre~no za 4,9 % letno, starostno standardizirana pa za 2,8 %. Groba umrljivostna stopnja se od leta 1996 ve~a v povpre~ju za 2,6 % letno, sta- rostno standardizirana pa v povpre~ju za 0,5 % letno. DEBELO ^REVO MKB 10: C18 70 0 5 10 15 20 25 30 35 40 1986 1990 1995 2000 2005 Leto / Year Incidenca – groba stopnja / Incidence – crude rate Incidenca – SSS* / Incidence – ASR** Umrljivost – groba stopnja / Mortality – crude rate Umrljivost – SSS* / Mortality – ASR** Stopnja na 100.000 / Rate per 100,000 * SSS – starostno standardizirana stopnja (standard – slovenska populacija leta 1986) ** ASR – age standardized rate (standard Slovenian population in 1986) Slika 1: Groba in starostno standardizirana inciden~na in umrljivostna stopnja raka debelega ~revesa, Slovenija 1986–2005. Figure 1: Crude and age-standardized incidence and mortality rate of colon cancer, Slovenia 1986–2005. V analizo pre`ivetja je vklju~enih 7934 primerov; 274 bolnikov (3,3 %) nismo upo{tevali, ker jim je bila diagnoza postavljena po smrti. V obdobju 2001–2005 je imela ve~ina bolnikov (97 %) natan~neje opredeljeno mesto vznika tumorja v debelem ~revesu. Najpogosteje je bilo to esa- sto debelo ~revo (44 %), sledijo slepo ~revo (15 %), ascendentni kolon (13 %), jetrni zavoj in pre~no debelo ~revo, vsak z 8 %, vrani~ni zavoj (7 %), descendentni kolon (6 %) in slepi~ z 1 %. Odstotek mikroskopsko potrjenih primerov se je z 92 % v letih 1991–1995 pove~al na 96 % v letih 2001–2005. V vseh treh obdobjih je bilo ve~ kot tri ~etrtine `leznih karcinomov, v zadnjem Mo{ki / Males @enske / Females Obdobje / {tevilo / 20–49 let / 50–74 let / 75+ let / {tevilo / 20–49 let / 50–74 let / 75+ let / Period number years (%) years (%) years (%) number years (%) years (%) years (%) 1991–1995 1018 8,4 69,5 22,0 995 8,4 62,7 28,8 1996–2000 1413 9,1 69,3 21,6 1252 8,0 57,3 34,7 2001–2005 1767 6,2 69,2 24,6 1489 5,9 56,1 37,9 Tabela 1: [tevilo bolnikov z rakom debelega ~revesa po spolu in obdobju postavitve diagnoze ter njihovi dele`i po starosti. Table 1: Number of colon cancer patients by sex and period of diagnosis with their proportions by age. EPIDEMIOLOGIJA Rak.qxd 22.7.2009 12:38 Page 70 In the period 1991–2005, a total of 8208 persons were diagnosed with colon cancer, of these 4326 males and 3882 females. As evident from Figure 1, since 1991 the crude and age stan- dardized incidence rates have been increasing (4.9% estimated annual percentage increase in crude and 2.8% in age-standardized rate). From 1996 on, crude mortality rate has been increa- sing by 2.6% yearly, while in the same period, age-standardized mortality rate has been decreasing by 0.5% on average. The survival analysis included 7934 cases; 274 patients (3.3%) diagnosed only after death were not considered in the analysis. In the period 2001–2005, the majority of patients (97%) had the site of tumor origin in the colon more precisely defined. The most frequent site was the sig- moid colon (44%), followed by the caecum (15%), ascending colon (13%), hepatic flexure and transverse colon (8% each), spleen flexure (7%), descending colon (6%) and the appendix (1%). The percentage of microscopically confirmed cases increased from 92% in the period 1991–1995 to 96% in the period 2001–2005. In all three time-periods, more than three-quarters of cancers were adenocarcinomas, in the last period they represented 97% of the total, their proportion increasing mainly on the account of decrease in undefined carcinomas, while in all three peri- ods other defined histological types represent less than 1%. Age of the majority of patients at diagnosis ranged between 50 and 74 years. Less than 10% of patients developed the disease before the age of 50 (Table 1). Particularly in females, the proportion of patients aged 75 years or older is increasing with time, while the proportion of those aged 50–74 years is decreasing (Table 1). In all three time-periods, the majority of patients were diagnosed with regional disease; in the period 2001–2005 there were 60% such patients. In approximately 10% of patients the di- sease was diagnosed in the localized stage, while in more than 20% it was found to be disseminated. The proportions of individual stages have not changed significantly with time; an increase in the proportion of patients with regional stage is attributable to the decrease in the proportion of cancers with undefined stage in all periods (Table 2). In the period 2001–2005, 13% of patients did not receive specific treatment. The proportion of untreated patients was slightly decreasing throughout the period of analysis; among those diagnosed in the years 1991–1995 there were 20% of patients without specific treatment. Practically all patients among the specifically treated in the period 2001–2005 underwent sur- gery; only 5% of patients with advanced disease at diagnosis were not treated by surgery. In 63% of patients primary treatment consisted of surgery alone, while 32% had surgery plus chemotherapy. In the period 2001–2005, 34% of patients started their treatment in the UMC Ljubljana, 17% in the UMC Maribor, 8% in GH Celje, 7% in GH Jesenice, 6% in GH Murska COLON ICD 10: C18 71 Tabela 2: [tevilo bolnikov z rakom debelega ~revesa po spolu in obdobju postavitve diagnoze ter njihovi dele`i po stadiju. Table 2: Number of colon cancer patients by sex and period of diagnosis with their proportions by stage. Mo{ki / Males @enske / Females Obdobje / {tevilo / omejen / raz{irjen / razsejan / neznan / {tevilo / omejen / raz{irjen / razsejan / neznan / Period number localized regional distant unknown number localized regional distant unknown (%) (%) (%) (%) (%) (%) (%) (%) 1991–1995 1018 13,5 51,6 28,0 7,0 995 11,8 57,4 22,4 8,4 1996–2000 1413 10,5 59,1 26,3 4,2 1252 13,3 58,4 22,9 5,4 2001–2005 1767 11,6 60,0 26,0 2,4 1489 11,8 61,4 23,1 3,8 EPIDEMIOLOGY Rak.qxd 22.7.2009 12:38 Page 71 obdobju 97 %; njihov dele` se ve~a predvsem na ra~un zmanj{anja dele`a neopredeljenih kar- cinomov. Drugih opredeljenih histolo{kih vrst je v vseh obdobjih manj kot 1 %. Starost najve~jega dele`a zbolelih je bila ob diagnozi 50–74 let. Pred 50. letom zboli manj kot 10 % bolnikov (Tabela 1). Predvsem pri `enskah se s ~asom ve~a dele` starih 75 let in ve~, manj- {a pa dele` starih 50–74 let. V vseh treh obdobjih je imelo najve~ bolnikov ob diagnozi raz{irjeno bolezen; v obdobju 2001–2005 je bilo takih 60 % bolnikov. Pri pribli`no 10 % bolnikov je bila bolezen odkrita v omejenem stadiju, pri ve~ kot 20 % pa v razsejanem. Dele`i posameznih stadijev se s ~asom niso bistve- no spreminjali; ve~anje dele`a bolnikov z raz{irjenim stadijem gre predvsem na ra~un manj{anja dele`a bolnikov z neopredeljenim stadijem v vseh obdobjih (Tabela 2). 72 DEBELO ^REVO 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Slika 2: Deset-, pet-, tri- in enoletno relativno pre`ivetje bolnikov z rakom debelega ~revesa po obdobju postavitve diagnoze. Figure 2: 10-, 5-, 3- and 1-year relative survival of colon cancer patients by period of diagnosis. Tabela 3: Opazovano in relativno pre`ivetje bolnikov z rakom debelega ~revesa po spolu in obdobju postavitve diagnoze s 95-odstotnim intervalom zaupanja (IZ). Table 3: Observed and relative survival of colon cancer patients by sex and period of diagnosis with 95% con- fidence interval (CI). Opazovano pre`ivetje / Observed survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 59,5 (56,6–62,6) 39,2 (36,3–42,3) 29,8 (27,1–32,7) 62,2 (59,3–65,3) 43,8 (40,8–47,0) 36,1 (33,2–39,2) 1996–2000 62,8 (60,4–65,4) 44,9 (42,3–47,5) 36,7 (34,3–39,3) 64,1 (61,5–66,8) 47,4 (44,7–50,2) 40,3 (37,6–43,1) 2001–2005 69,7 (67,6–71,8) 52,1 (49,8–54,5) 44,7 (42,3–47,3) 71,0 (68,7–73,3) 53,4 (50,9–56,0) 46,2 (43,5–49,0) Relativno pre`ivetje / Relative survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 62,7 (59,4–65,9) 45,8 (42,2–49,5) 38,8 (35,0–42,6) 64,6 (61,4–67,8) 49,3 (45,7–52,9) 44,1 (40,3–47,9) 1996–2000 66,0 (63,3–68,7) 52,2 (49,1–55,3) 47,5 (44,2–50,9) 66,8 (63,9–69,6) 53,7 (50,5–56,9) 49,8 (46,3–53,3) 2001–2005 73,1 (70,8–75,4) 60,7 (57,9–63,5) 58,3 (55,0–61,7) 73,8 (71,4–76,2) 60,4 (57,5–63,4) 57,1 (53,6–60,5) Rak.qxd 22.7.2009 12:38 Page 72 Sobota and 5% in GH Nova Gorica, while 18% of patients were admitted to almost all other Slovenian hospitals. The relative survival rate of patients with colon cancer has been increasing: in 15 years, the 5-year relative survival increased by 16% (Figure 2), in males slightly more than in females (Table 3). The relevance of stage at diagnosis is shown in Figure 3. In the last period, the 5-year relative survival of patients with localized stage has reached near to 96%. The 5-year relative survival of patients with regional stage of the disease is near to 72%, whereas patients with dis- seminated disease had only a rate of 8%. Age is a prognostic factor as well, since the relative survival is the lowest in patients aged 75 years or older, while survival in the age group 50–74 years was lagging behind the relative survival of those diagnosed before the age of 50 throughout the observation period (Figure 4). The relative 5-year survival rate of all patients diagnosed in the period 2001–2005 was 58% (Figure 2); patients surviving the first year may expect to survive five years in 77%. 73 COLON 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 Omejen / Localized Raz{irjen / Regional Razsejan / Distant Vsi / All Slika 3: Petletno relativno pre`ivetje bolnikov z rakom debelega ~revesa po stadiju in obdobju postavitve diagnoze. Figure 3: 5-year relative survival of colon cancer patients by stage and period of diagnosis. 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 20–49 let / years 50–74 let / years 75+ let / years Vsi / All Slika 4: Petletno relativno pre`ivetje bolnikov z rakom debelega ~revesa po starosti in obdobju postavitve diagnoze. Figure 4: 5-year relative survival of colon cancer patients by age and period of diagnosis. Rak.qxd 22.7.2009 12:38 Page 73 V obdobju 2001–2005 ni bilo specifi~no zdravljenih 13 % bolnikov. Dele` nezdravljenih bolnikov se je skozi vse obdobje analize po~asi zmanj{eval; med bolniki, zbolelimi v obdobju 1991–1995, jih je bilo brez specifi~nega zdravljenja {e 20 %. Med specifi~no zdravljenimi so bili v letih 2001–2005 prakti~no vsi bolniki operirani; brez kirur{kega zdravljenja je ostalo 5 % bolnikov z napredo- valo boleznijo ob diagnozi. Pri 63 % bolnikov je bilo prvo zdravljenje zaklju~eno z operacijo, 32 % pa jih je poleg operacije prejelo {e kemoterapijo. V obdobju 2001–2005 se je 34 % bolnikov pri~elo zdraviti v UKC Ljubljana, 17 % v UKC Mari- bor, 8 % v SB Celje, 7 % v SB Jesenice, 6 % v SB Murska Sobota in 5 % v SB Nova Gorica, 18 % bolnikov je za~elo zdravljenje v skoraj vseh drugih slovenskih bolni{nicah. Relativno pre`ivetje bolnikov z rakom debelega ~revesa se postopno pove~uje; v 15 letih se je petletno relativno pre`ivetje pove~alo za 16 % (Slika 2), pri mo{kih nekoliko ve~ kot pri `en- skah (Tabela 3). Kako pomemben je stadij ob diagnozi, ka`e Slika 3: petletno relativno pre`ivetje bolnikov z omejenim stadijem se je v zadnjem obdobju pribli`alo 96 %. Petletno relativno pre- `ivetje bolnikov z raz{irjenim stadijem se pribli`uje 72%, pri bolnikih z razsejano boleznijo ob diagnozi pa je petletno relativno pre`ivetje le 8 %. Napovedni dejavnik je tudi starost, saj je relativno pre`ivetje najmanj{e pri starih 75 let in ve~, pre`ivetje ob diagnozi starih 50–74 let pa ves ~as opazovanja zaostaja za relativnim pre`ivetjem zbolelih pred 50 letom starosti (Slika 4). Petletno relativno pre`ivetje vseh zbolelih v obdobju 2001–2005 je bilo 58 % (Slika 2); bolni- ki, ki pre`ivijo prvo leto, pa lahko pri~akujejo 77-odstotno petletno relativno pre`ivetje. Rezultati {tudije EUROCARE-4 za zbolele v obdobju 2000–2002 ka`ejo, da je pre`ivetje slo- venskih bolnikov z rakom debelega ~revesa statisti~no zna~ilno manj{e od evropskega povpre~ja (Slika 5). 74 DEBELO ^REVO KLINI^NI KOMENT AR Stane Rep{e Razvoj in stanje kirur{kega zdravljenja raka debelega ~revesa v Sloveniji v obdobju 1983 do 1997 je bilo opisano v zadnji izdaji Pre`ivetje bolnikov z rakom v Sloveniji leta 2003. Takrat smo meni- li, da se bodo posledice prizadevanja na podro~ju raka debelega ~revesa po letu 1980 (strokovni sestanki, nacionalne ankete, multidisciplinarni timi, delavnice in simpoziji, publikacije) poka- zale z bolj{imi rezultati pre`ivetja na dr`avni ravni {ele v sedanjem obdobju. V obdobju, ki je sedaj analizirano in je prikazano s petletnim pre`ivetjem, smo kirurgi v Slo- veniji spo{tovali doktrinarna na~ela obravnave bolnikov z rakom debelega ~revesa, ki smo jih izdelali v za~etku 90. let in so bila objavljena v publikaciji Priporo~ila za celostno obravnavo bol- nikov z rakom prebavil leta 1997. Standardna resekcija obolelega dela ~revesa in raz{irjena resekcija z radikularno ligaturo `il ter limfadenektomijo je bila kirur{ki standard. Pooperativna adjuvant- na kemoterapija pri stadiju III je bila splo{no sprejeta, pri stadiju II pa je bila dovoljena samo v okviru klini~nih raziskav. Vseh kirur{kih podatkov za raka debelega ~revesa in za raka danke ni mogo~e dobro prikaza- ti lo~eno. V nadaljevanju prikazujemo podatke za obe mesti raka skupaj. Po podatkih ankete Rak debelega ~revesa in danke v Sloveniji 2005 je bilo zdravljenih na vseh kirur{kih oddelkih v Slo- veniji 1121 bolnikov: 449 (40 %) v Ljubljani, 233 (20 %) v Mariboru in Celju ter 452 (40 %) na kirur{kih oddelkih drugih bolni{nic. Operiranih je bilo 1102 od 1121 (operabilnost 98 %), reseciranih pa 1014 od 1102 (resektabilnost 92 %). ^e primerjamo podatke te ankete s podatki enake ankete iz leta 1995 (803 bolniki), vidimo, da je bila operabilnost enaka (98 %), resektabilnost pa manj{a, samo 82 %. Tudi dele` bolni- kov po kraju zdravljenja je bil skoraj enak: Ljubljana 43 %, Maribor in Celje 22 %, vse preostale bolni{nice pa 36 %. Pooperacijska smrtnost reseciranih bolnikov se je v zadnjem obdobju neko- liko pove~ala (leta 1995 3 %, leta 2005 5 %), kar pa je zaradi 10 % ve~je resektabilnosti razumljivo. Rak.qxd 22.7.2009 12:38 Page 74 According to the results of EUROCARE-4 study for patients diagnosed in 2000–2002, sur- vival of Slovenian patients with colon cancer is statistically significantly below the European average (Figure 5). 75 COLON CLINICAL COMMENT ARY Stane Rep{e 01 02 0 30 40 50 60 70 80 90 100 % Slovensko povpre~je / 2000–2002 (EUROCARE-4) Slovenian average Evropsko povpre~je / 2000–2002 (EUROCARE-4) European average Povpre~je ZDA / 2000–2002 (SEER-13) USA average Slika 5: Petletno relativno pre`ivetje bolnikov z rakom debelega ~revesa (povpre~je in 95-odstotni interval zaupanja), zbolelih v letih 2000–2002 v Sloveniji, Evropi in nekaterih obmo~jih v ZDA. Figure 5: 5-year relative survival of colon cancer patients (average and 95% confidence interval) diagnosed in the period 2000–2002 in Slovenia, Europe and in some regions of the USA. The development and the state-of-the-art of surgical treatment for colon cancer in Slovenia in the period 1983–1997 was presented in the last edition of the publication Cancer Patients Survival in Slovenia issued in 2003. Then we presumed that the results of endeavors in the area of colon cancer after the year 1980 (expert meetings, national surveys, multidisciplinary teams, workshops and symposia, publications) would be reflected in better survival rates at the national level only in the current period. In the period, which is subject to the current analysis and is presented by 5-year survival, the surgeons in Slovenia followed the doctrinary principles of colon cancer patient treatment, which were adopted in the 90's and published in 1997 under the title Recommendations for a Comprehensive Treatment of Patients with Cancers of Digestive Organs. Thus, standard resection of the affec- ted part of the colon and extended resection with radicular artery ligation and lymphadenectomy represented a surgical standard. While in stages III and IV postoperative adjuvant chemother- apy was commonly accepted, in stage II it was approved only within the framework of clinical trials. It is not possible to present all the surgical data for colon cancer and rectal cancer separately. Therefore, in this commentary the data for both sites are presented together. According to the survey on the colorectal cancer in Slovenia in 2005, there were 1121 patients treated in all sur- gical departments in Slovenia: 449 (40%) in UMC Ljubljana, 233 (20%) in UMC Maribor and GH Celje, and 452 (40%) at surgical departments of other hospitals. Out of the total of 1121 patients, 1102 underwent surgery (98% operability), 1014 of 1102 had a resection (92% resectability). When comparing the data of this survey with the data of the same survey carried out in 1995 (803 patients), the operability turns out to be equal (98%) while the resectability was lower, Rak.qxd 22.7.2009 12:38 Page 75 Rezultati na{ih skupnih prizadevanj na dr`avni ravni v zadnjih dveh desetletjih prej{njega sto- letja so se dejansko pokazali v sedanjem obdobju, saj se je populacijsko petletno relativno pre`ivetje bolnikov v 10 letih pove~alo za 16 %. Rezultati v posamezni ustanovi so lahko pri tem bistve- no bolj{i od dr`avnega povpre~ja. Tako je v seriji 1478 reseciranih bolnikov z rakom debelega ~revesa in danke v UKC Ljubljana iz obdobja 1991–2000 opazovano petletno pre`ivetje vseh reseciranih (R0, R1, R2) bolnikov 55 % (Kaplan-Meier); pri reseciranih R0 zaradi raka debe- lega ~revesa 66 % in pri raku danke 59 %. Ker tudi populacijski podatki ka`ejo, da petletno relativno pre`ivetje bolnikov z omejenim stadi- jem po letu 1996 presega 80 %, lahko pri~akujemo nadaljnje izbolj{evanje pre`ivetja na dr`avni ravni, ~e se bo s presejalnim programom SVIT ve~ primerov bolezni odkrilo v omejenem stadiju. Markovi~ S, [tabuc B, Zakotnik B, Benuli~ T, ^ali} M, @akelj B, et al. Rak debelega ~revesa in danke. In: Rep{e S, ed. Priporo~ila za celostno obravnavo bolnikov z rakom prebavil. Ljubljana: Ministrstvo za zdravstvo R Slovenije, 1997; 23–32. Rep{e S, Jelenc F, [tor Z, Omejc M, Juvan R. Kirurgija raka debelega ~revesa in danke v Sloveniji v obdob- ju 1995 do 2005. In: Rep{e S, [tor Z, eds. Kirurgija raka debelega ~revesa in danke – standardi in novosti: zbornik simpozija. Ljubljana, Kirur{ka klinika, 2006; 3–13. Rep{e S, [tor Z, Juvan R. Kirurgija raka {irokega ~revesa in danke v Sloveniji. In: Rep{e S, ed. Kirurgija `elodca: zbornik simpozija. Ljubljana, Kirur{ka {ola, Kirur{ke klinike, 1996; 118–26. [tor Z, Jelenc F, Juvan R, Omejc M, Bunc M, Rep{e S. Improved Outcome of Patients with Colorectal Cancer: The Ljubljana University Medical Centre Experience. Dig Surg 2008; 25: 158–63. [tor Z, Rep{e S. Kirurgija raka debelega ~revesa in danke v Sloveniji – rezultati ankete 2005. In: Rep{e S, [tor Z, eds. Kirurgija raka debelega ~revesa in danke – standardi in novosti: zbornik simpozija. Ljubljana, Kirur{ka klinika, 2006; 95–103. 76 DEBELO ^REVO KLINI^NI KOMENT AR Janja Ocvirk Presejalnega programa za raka debelega ~revesa v obdobju 1991–2005 v Sloveniji ni bilo, kakor tudi ne dejavnosti za ozave{~anje prebivalstva, kar se zrcali v velikem {tevilu bolezni, odkrite v napredovalem stadiju. Samo 10–13 % bolnikov je bilo odkritih z boleznijo v omejenem sta- diju, kar je veliko manj kot v drugih evropskih dr`avah, veliko ve~ pa je bolnikov z raz{irjeno (50–60 %) in razsejano boleznijo (22–28 %). V vseh petletnih obdobjih dele` omejene bolez- ni ostaja enako majhen in dele` razsejane bolezni enako velik, manj pa je bolnikov, za katere stadij ni znan, kar lahko pripi{emo bolj{im diagnosti~nim postopkom. Temu pripisujemo tudi ve~ji dele` mikroskopsko potrjenih primerov raka. Kolonoskopija z biopsijo je uveljavljena `e od 80. let, izbolj{ale pa so se preiskave za natan~nej{o opredelitev raz{irjenosti bolezni: UZ, CT in MR. Bolnike z rakom debelega ~revesa so operirali in jih {e operirajo v vseh slovenskih bolni{nicah, vendar pa jih najve~ operirajo v UKC Ljubljana, nekaj ve~ kot 30 %, sledita UKC Maribor in SB Celje. Skupaj je bila v treh najve~jih centrih za abdominalno kirurgijo operi- rana ve~ kot polovica bolnikov. Incidenca raka debelega ~revesa se iz leta v leto ve~a v vseh starostnih skupinah, vendar naj- ve~ med bolniki, starimi 75 let in ve~, katerih dele` se zato ve~a. Spodbuden je podatek, da se umrljivost ve~a veliko manj kot incidenca. Petletno relativno pre`ivetje bolnikov se ve~a v vseh obdobjih `e od leta 1991; tako pre`ivet- je vseh bolnikov kakor tudi bolnikov z omejeno in raz{irjeno boleznijo. Za vse ve~je pre`ivetje vseh na{tetih skupin so pomembni tako bolj{a diagnostika, bolj{e in standardizirane operativne tehnike in dodatno sistemsko zdravljenje. Pri bolnikih z raz{irjeno boleznijo, ki so bili poleg operativnega zdravljenja dele`ni {e adjuvantne kemoterapije, pa ve~anje pre`ivetja pripisujemo tudi tej, saj se je dele` tako zdravljenih mo~no pove~al. V obdobju 1991–1995 se je samo 8 % bolnikov po operaciji tudi dodatno zdravilo s kemoterapijo, medtem ko se je ta dele` v obdobju 2001–2005 VIRI Literature Rak.qxd 22.7.2009 12:38 Page 76 being 82% only. The proportion of patients by place of treatment was similar: Ljubljana 43%, Maribor and Celje 22%, and all other hospitals 36%. In the last period, postoperative mor- tality of the resected patients has slightly increased (in 1995 it was 3% and in 2005, 5%), which is understandable, considering the 10% greater resectability. The results of our joint endeavors at the national level, achieved in the last two decades of the previous century, have become apparent in the present period, since in a 10-year period, the population-based relative 5-year relative survival increased by 16%. Results of an individual insti- tution may be significantly better than the national average. Thus, in the series of 1478 patients with colon and rectum cancer resected in the UMC Ljubljana, in the period 1991–2000, the observed 5-year survival rate of all the resected patients (R0, R1, R2) was 55% (Kaplan-Meier); in the R0 group resected for colon cancer it was 66% and in rectal cancer patients it was 59%. As population data show that 5-year relative survival of patients with localized disease after 1996 exceeds 80%, we can expect further improvement in survival at the national level, particular- ly if by means of SVIT screening program more cases of the disease will be diagnosed at a localized stage. 77 COLON CLINICAL COMMENT ARY Janja Ocvirk In the period 1991–2005 there was no screening program for colon cancer in Slovenia and nei- ther any awareness-raising activity in this respect, which is reflected in a high number of cases diagnosed at an advanced stage. In only 10–13% of patients the disease was diagnosed at a local- ized stage, which is far less than in other European countries; accordingly, the proportion of patients with regional (50–60%) and disseminated disease (22–28%) was much greater. In all 5-year time-periods, the proportion of localized disease remains equally low and the propor- tion of disseminated disease equally high, while the number of patients with undefined stage is lower, which is attributable to better diagnostic procedures. The same applies to the higher proportion of microscopically confirmed cancers. Colonoscopy with biopsy has been estab- lished since the 80's, however, the methods for more precise staging of the disease have improved; thus ultrasonography is used along with computer tomography and magnetic resonance. Patients with colon cancer used to be and still are treated surgically in all Slovenian hospitals, howev- er, most of them (more than 30%) undergo surgery in the UMC Ljubljana; following in descending order are UMC Maribor and GH Celje. Altogether, more than a half of these patients were operated on in the three largest centers for abdominal surgery. The incidence of colon cancer has been increasing every year in all age groups, however most steeply in patients aged 75 or older, whose proportion is therefore getting larger. It is encoura- ging to note that the mortality rate is increasing less than the incidence. The 5-year relative survival of patients has been improving in all time periods since 1991; this applies to the survival of all patients as well as of those with localized and regional disease. The increasingly better survival of all these groups can be ascribed to better diagnostics, more advanced and standardized surgical techniques and to adjuvant systemic therapy. In patients with regional disease treated by surgery in combination with adjuvant chemotherapy the increas- ing survival rates should be actually attributed to the latter treatment modality, since the proportion of thus treated patients has markedly increased. In the period 1991–1995, only 8% of patients were treated by adjuvant chemotherapy after surgery, whereas in the period 2001–2005 this proportion increased to almost 32%, thanks to the generally recognized knowledge on the effec- tiveness of adjuvant therapy, up-to-dated recommendations for such treatment and, last but not least, to a better multidisciplinary approach to patient treatment. The effectiveness of such treatment is also reflected in better survival of these patients. Rak.qxd 22.7.2009 12:38 Page 77 pove~al na skoraj 32 %, kar lahko pripi{emo spoznanjem o u~inkovitosti adjuvantne terapije, posodobljenim priporo~ilom za tovrstno zdravljenje in seveda bolj{i multidisciplinarni obrav- navi bolnika. U~inkovitost takega zdravljenja se ka`e tudi v ve~jem pre`ivetju teh bolnikov. Petletno pre`ivetje bolnikov z razsejano boleznijo se je za~elo ve~ati {ele po letu 2001, ko smo v zdravljenje vpeljali prvo izmed skupine novih zdravil – irinotekan, kateremu so v nadaljnjih letih sledili {e kapecitabin, oksaliplatin, cetuksimab in bevacizumab, vendar se bo vpliv zad- njih treh bolj opazil {ele v naslednjem obdobju. Luzar B, Cerar A, [tabuc B, eds. Tumorji debelega ~revesa in danke. Ljubljani: In{titut za patologijo, Medi- cinska fakulteta; 2008. Ocvirk J. Novosti v zdravljenju metastatskega raka debelega ~revesa in danke. Onkologija 2006; 10: 24–6. Ocvirk J. Sistemsko zdravljenje bolnikov z rakom debelega ~revesa in danke. In: Rep{e S, [tor Z, eds. Kirurgija raka debelega ~revesa in danke – standardi in novosti: zbornik simpozija. Ljubljana, Kirur{ka klinika, 2006; 170–8. Ocvirk J. Sistemsko zdravljenje inoperabilnih jetrnih zasevkov raka debelega ~revesa in danke. In: Rep{e S, Stani- savljevi} D, eds. Kirurgija jeter in vranice: zbornik simpozija. Ljubljana: Kirur{ka klinika, 2004; 107–16. Ocvirk J. Zdravljenje bolnikov z rakom debelega ~revesa. In: Kop~avar Gu~ek N, Petek D, eds. Kakovostna obravnava bolnika v dru`inski medicini: zbornik predavanj. Ljubljana: Zdru`enje zdravnikov dru`inske medi- cine, 2006; 111–5. Program SVIT: www.program-svit.si. Reber{ek M, Hlebanja Z, Ocvirk J. Priporo~ila za adjuvantno zdravljenje bolnikov z rakom debelega ~revesa. Onkologija 2007; 11: 26–7. Reber{ek M, Hlebanja Z, Ocvirk J. Priporo~ila za sistemsko zdravljenje bolnikov z napredovalim rakom debelega ~revesa in danke. Onkologija 2007; 11: 28–31. 78 DEBELO ^REVO VIRI Literature Rak.qxd 22.7.2009 12:38 Page 78 The 5-year survival of patients with disseminated disease has started to improve only after the year 2001, when the first in the group of new cancer drugs – irinotecan was introduced into therapy, followed over the years by capecitabin, oxaliplatin, cetuximab and bevacizumab. However, the impact of the latter drugs will be noticeable only in the next observation period. 79 COLON Rak.qxd 22.7.2009 12:38 Page 79 V obdobju 1991–2005 je za rakom danke zbolelo 7309 ljudi, od tega 4121 mo{kih in 3188 `ensk. Kot je razvidno s Slike 1, se groba in starostno standardizirana inciden~na stopnja od leta 1991 pove~ujeta, groba stopnja se ve~a hitreje, povpre~no za 2,9 % letno, kot starostno standardizi- rana (0,9 %). Groba umrljivostna stopnja se je v letih 1991–2005 pove~evala za 0,9 % letno, starostno standardizirana umrljivostna stopnja pa se je manj{ala v povpre~ju za 1,2 % letno. DANKA MKB10: C19–C21 80 0 5 10 15 20 25 30 35 40 45 50 1986 1990 1995 2000 2005 Leto / Year Incidenca – groba stopnja / Incidence – crude rate Incidenca – SSS* / Incidence – ASR** Umrljivost – groba stopnja / Mortality – crude rate Umrljivost – SSS* / Mortality – ASR** Stopnja na 100.000 / Rate per 100,000 * SSS – starostno standardizirana stopnja (standard – slovenska populacija leta 1986) ** ASR – age standardized rate (standard Slovenian population in 1986) Slika 1: Groba in starostno standardizirana inciden~na in umrljivostna stopnja raka danke, Slovenija 1986–2005. Figure 1: Crude and age-standardized incidence and mortality rate of rectal cancer, Slovenia 1986–2005. Mo{ki / Males @enske / Females Obdobje / {tevilo / 20–49 let / 50–74 let / 75+ let / {tevilo / 20–49 let / 50–74 let / 75+ let / Period number years (%) years (%) years (%) number years (%) years (%) years (%) 1991–1995 1122 8,8 69,2 22,0 927 8,0 63,9 28,2 1996–2000 1304 6,5 73,4 20,1 1004 7,4 62,5 30,1 2001–2005 1595 7,4 70,4 22,2 1114 5,9 56,0 38,1 Tabela 1: [tevilo bolnikov z rakom danke po spolu in obdobju postavitve diagnoze ter njihovi dele`i po starosti. Table 1: Number of rectal cancer patients by sex and period of diagnosis with their proportions by age. V analizo pre`ivetja je vklju~enih 7066 primerov; 243 bolnikov (3,3 %) nismo upo{tevali, ker jim je bila diagnoza postavljena po smrti, 1 mlaj{i od 20 let pa je vklju~en v poglavje o pre`i- vetju pri otrocih in mladostnikih. V zadnjem obdobju je imelo 78 % bolnikov tumor ampule danke, 19 % tumor rektosigmoidne zveze in 3 % tumor zadnjika ali zadnji~nega kanala. V obdobju 2001–2005 je bilo 97 % primerov raka mikroskopsko potrjenih. Dele` mikroskop- sko potrjenih se je v primerjavi z obdobjem 1991–1995 pove~al za 5 %. Ve~ina mikroskopsko potrjenih malignomov je bila adenokarcinomov, drugih histolo{kih vrst je bilo manj kot 2 %. EPIDEMIOLOGIJA Rak.qxd 22.7.2009 12:38 Page 80 In the period 1991–2005, a total of 7309 persons were diagnosed with cancer of the rectum, of these 4121 males and 3188 females. As evident from Figure 1, since 1991 the crude and age standardized incidence rates have been increasing, the crude rate more rapidly than the age-standardized rate (2.9% vs. 0.9% estimated annual percentage increase, respectively). In the period 1991–2005 the crude mortality rate was increasing by 0.9%, while the age-stan- dardized mortality rate was decreasing by an estimated annual percentage change of 1.2%. The survival analysis included 7066 cases; 243 patients (3.3%) diagnosed only after death were not considered in the analysis, 1 patient younger than 20 years is included in the chapter on the survival of children and adolescents. In the last period, 78% of patients had tumor situa- ted in the rectal ampulla, 19% in the rectosigmoid junction and 3% in the anus or anal canal. In the period 2001–2005, 97% of rectal cancers were microscopically verified. In comparison with the period 1991–1995 the proportion of microscopically confirmed cases has increased by 5%. The majority of microscopically confirmed malignomas were adenocarcinomas; other histological types represented less than 2% of cases. Age of the majority of patients at diagnosis ranged between 50–74 years. Less than 10% of patients developed the disease before the age of 50 (Table 1). Except for the increased pro- portion of females in the oldest age group, the proportion of patients in individual age groups did not change significantly with time. In all three time-periods, the majority of patients were diagnosed with regional disease; in the period 2001–2005 there were 57% such patients. Approximately 20% of patients were diag- nosed either with localized or disseminated stage. The proportion of patients with individual stages has not changed significantly with time, however the proportion of patients with unde- fined stage has been decreasing (Table 2). In the period 2001–2005, 15% of patients did not receive specific treatment. The proportion of untreated patients was gradually decreasing throughout the observation periods; among those diagnosed in the period 1991–1995 there were 23% of patients without specific treatment. Practically all patients among the specifically treated in the period 2001–2005 underwent sur- gery; only 7% of patients with advanced disease at diagnosis were not treated by surgery. In 42% of patients primary treatment consisted of surgery alone, 30% were additionally treated by irradiation and chemotherapy, 14% had surgery combined with chemotherapy, while 6% received only radiotherapy. In the period 2001–2005, 25% of patients started their treatment at the IO Ljubljana, 21% in the UMC Ljubljana, 10% in the UMC Maribor, 5% each in GH Celje and GH Novo mesto, while less than 5% of patients were admitted to almost all other Slovenian general hospitals. RECTUM ICD 10: C19–C21 81 Tabela 2: [tevilo bolnikov z rakom danke po spolu in obdobju postavitve diagnoze ter njihovi dele`i po stadiju. Table 2: Number of rectal cancer patients by sex and period of diagnosis with their proportions by stage. Mo{ki / Males @enske / Females Obdobje / {tevilo / omejen / raz{irjen / razsejan / neznan / {tevilo / omejen / raz{irjen / razsejan / neznan / Period number localized regional distant unknown number localized regional distant unknown (%) (%) (%) (%) (%) (%) (%) (%) 1991–1995 1122 19,3 50,9 20,6 9,3 927 17,0 51,6 19,6 11,8 1996–2000 1304 17,5 53,4 22,8 6,4 1004 21,6 52,7 18,1 7,6 2001–2005 1595 17,1 58,1 21,4 3,4 1114 18,4 56,1 19,9 5,6 EPIDEMIOLOGY Rak.qxd 22.7.2009 12:38 Page 81 Starost najve~jega dele`a zbolelih je bila ob diagnozi 50–74 let. Pred 50. letom zboli manj kot 10 % bolnikov (Tabela 1). Razen pove~anega dele`a najstarej{ih `ensk se dele`i v posameznih starostnih skupinah s ~asom niso bistveno spreminjali. V vseh treh obdobjih je imelo ob diagnozi najve~ bolnikov raz{irjeno bolezen; v obdobju 2001–2005 jih je bilo 57 %. Z omejenim in razsejanim stadijem je bilo diagnosticiranih pribli`no po 20 % bolnikov. Dele`i bolnikov s posameznimi stadiji se s ~asom niso bistveno spreminjali, se pa manj- {a dele` bolnikov, pri katerih stadij ni bil opredeljen (Tabela 2). V obdobju 2001–2005 se ni specifi~no zdravilo 15 % bolnikov. Dele` nezdravljenih bolnikov se je v vseh obdobjih po~asi zmanj{eval; med bolniki, zbolelimi v letih 1991–1995, se jih ni specifi~no zdravilo 23 %. Med specifi~no zdravljenimi so bili v letih 2001–2005 prakti~no vsi 82 DANKA 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Slika 2: Deset-, pet-, tri- in enoletno relativno pre`ivetje bolnikov z rakom danke po obdobju postavitve diagnoze. Figure 2: 10-, 5-, 3- and 1-year relative survival of rectal cancer patients by period of diagnosis. Tabela 3: Opazovano in relativno pre`ivetje bolnikov z rakom danke po spolu in obdobju postavitve diagnoze s 95-odstotnim intervalom zaupanja (IZ). Table 3: Observed and relative survival of rectal cancer patients by sex and period of diagnosis with 95% confidence interval (CI). Opazovano pre`ivetje / Observed survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 66,9 (64,2–69,7) 40,4 (37,6–43,4) 29,9 (27,3–32,7) 65,8 (62,8–68,9) 41,3 (38,3–44,6) 31,9 (29,1–35,1) 1996–2000 68,8 (66,3–71,4) 45,2 (42,6–48,0) 34,4 (31,9–37,1) 69,8 (67,0–72,7) 49,0 (46,0–52,2) 38,9 (36,0–42,1) 2001–2005 71,9 (69,7–74,2) 50,9 (48,5–53,5) 42,2 (39,7–45,0) 71,1 (68,5–73,8) 49,3 (46,4–52,3) 40,2 (37,2–43,5) Relativno pre`ivetje / Relative survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 70,4 (67,4–73,3) 47,0 (43,5–50,5) 38,5 (34,9–42,1) 68,5 (65,2–71,7) 46,7 (43,0–50,4) 39,2 (35,3–43,1) 1996–2000 72,1 (69,4–74,8) 52,2 (49,0–55,4) 44,1 (40,6–47,5) 72,4 (69,4–75,4) 54,7 (51,1–58,3) 47,1 (43,3–50,9) 2001–2005 75,2 (72,9–77,6) 58,7 (55,8–61,7) 54,3 (50,8–57,8) 73,8 (71,0–76,6) 55,5 (52,1–58,9) 49,5 (45,5–53,6) Rak.qxd 22.7.2009 12:38 Page 82 Within the primary treatment, many patients – after having received initial preoperative chemo and/or radiotherapy at the IO Ljubljana – underwent surgery at their local hospitals. In the period 2001–2005 the majority of surgical procedures in rectal cancer patients were performed in the UMC Ljubljana (34%). The percentage of surgeries for rectal cancer performed in the UMC Maribor was a half of that (17%); 8% of patients were operated on at the IO Ljubljana and 7% each in the general hospitals of Celje, Novo mesto and Murska Sobota. In the 5-year period, over a 100 patients were operated on in the general hospitals of Jesenice and Slovenj Gradec (5% of all such patients). Four percents of all patients underwent surgery in the gen- eral hospitals of Nova Gorica and Izola, while individual patients were also operated on elsewhere. The relative survival rate of patients with rectal cancer has been gradually increasing: in 15 years, the 5-year relative survival increased by 13% (Figure 2), in males slightly more than in females (Table 3). The relevance of stage at diagnosis is shown in Figure 3. In the last period, 5-year relative survival of patients with localized stage has reached near to 90%. The 5-year relative survival of patients with regional stage of the disease is near to 60%, whereas patients with 83 RECTUM 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 Omejen / Localized Raz{irjen / Regional Razsejan / Distant Vsi / All Slika 3: Petletno relativno pre`ivetje bolnikov z rakom danke po stadiju in obdobju postavitve diagnoze. Figure 3: 5-year relative survival of rectal cancer patients by stage and period of diagnosis. 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 20–49 let / years 50–74 let / years 75+ let / years Vsi / All Slika 4: Petletno relativno pre`ivetje bolnikov z rakom danke po starosti in obdobju postavitve diagnoze. Figure 4: 5-year relative survival of rectal cancer patients by age and period of diagnosis. Rak.qxd 22.7.2009 12:38 Page 83 bolniki operirani; operiranih ni bilo 7 % bolnikov z napredovalo boleznijo ob diagnozi. Pri 42 % primerov se je prvo zdravljenje zaklju~ilo z operacijo, 30 % jih je bilo dodatno {e obsevanih in zdravljenih s kemoterapijo, 14 % jih je poleg operacije prejelo kemoterapijo, 6 % pa samo radio- terapijo. V obdobju 2001–2005 se je 25 % bolnikov za~elo zdraviti na OI Ljubljana, 21 % v UKC Ljub- ljana, 10 % v UKC Maribor, po 5 % pa v SB Celje in SB Novo mesto; manj kot 5 % bolnikov so za~eli zdraviti v skoraj vseh drugih slovenskih splo{nih bolni{nicah. V okviru prvega zdrav- ljenja se je veliko bolnikov, ki so se za~eli zdraviti s predoperativno kemo- in/ali radioterapijo na OI Ljubljana, na kirur{ki poseg vrnilo v mati~no bolni{nico. Najve~ kirur{kih posegov pri bolnikih z rakom danke so v obdobju 2001–2005 naredili v UKC Ljubljana (34 %). Polovico manj kirur{kih posegov pri bolnikih s tumorji danke so naredili v UKC Maribor (17 % vseh operacij), 8 % so jih operirali na OI Ljubljana, po 7 % pa v splo{nih bolni{nicah v Celju, Novem mestu in Murski Soboti. Ve~ kot 100 bolnikov v petletnem obdobju (po 5 % med vsemi) so operirali {e v SB Jesenice in SB Slovenj Gradec. V SB Nova Gorica in v SB Izola so operira- li 4 % vseh bolnikov, posamezni bolniki pa so bili operirani tudi drugod. Relativno pre`ivetje bolnikov z rakom danke se postopno pove~uje; v 15 letih se je petletno relativno pre`ivetje pove~alo za 13 % (Slika 2), pri mo{kih malo ve~ kot pri `enskah (Tabe- la 3). Kako pomemben je stadij ob diagnozi, ka`e Slika 3: petletno relativno pre`ivetje bolnikov z omejenim stadijem se je v zadnjem obdobju pribli`alo 90 %. Petletno relativno pre`ivetje bol- nikov z raz{irjenim stadijem se pribli`uje 60 %, pri bolnikih z razsejano boleznijo ob diagnozi pa je petletno relativno pre`ivetje le 7 %. Napovedni dejavnik je tudi starost, saj je relativno pre`i- vetje najslab{e pri starih 75 let in ve~, pre`ivetje zbolelih med 50–74 leti pa ves ~as opazovanja nekoliko zaostaja za relativnim pre`ivetjem zbolelih pred 50. letom (Slika 4). Petletno relativno pre`ivetje vseh zbolelih v obdobju 2001–2005 je bilo 52 % (Slika 2); bolni- ki, ki pre`ivijo prvo leto, pa lahko pri~akujejo 68-odstotno petletno relativno pre`ivetje. Rezultati {tudije EUROCARE-4 za zbolele v obdobju 2000–2002 ka`ejo, da je pre`ivetje slo- venskih bolnikov z rakom danke statisti~no zna~ilno manj{e od evropskega povpre~ja (Slika 5). 84 DANKA KLINI^NI KOMENT AR Ibrahim Edhemovi} Iz prilo`enih podatkov je razvidno, da se je pre`ivetje bolnikov z rakom danke v Sloveniji v zad- njem opazovanem obdobju izbolj{alo, vendar ne v zadovoljivem obsegu. Za to sta dva temeljna razloga: napredovali stadij ob diagnozi in razpr{eno kirur{ko zdravljenje po vseh kirur{kih oddel- kih v Sloveniji. Skoraj tri ~etrtine bolnikov ima `e ob diagnozi raz{irjeni ali razsejani stadij – tak{ni bolniki imajo slab{o napoved izida oz. slab{e pre`ivetje. Pri~akujemo, da bo letos za~eti presejalni pro- gram za zgodnje odkrivanje raka debelega ~revesa in danke (SVIT) pove~al dele` bolnikov z ni`jimi stadiji ob diagnosticiranju in s tem tudi pove~al pre`ivetje. Rezultati zdravljenja raka danke so izrazito odvisni od samega kirurga, oz. od njegove stro- kovne izpopolnjenosti in izku{enj, ki jih lahko nabere le z ustreznim dodatnim izobra`evanjem in velikim {tevilom operacij. V Sloveniji adjuvantno in neoadjuvantno zdravljenje izvajajo izklju~- no zdravniki na OI Ljubljana, zato ni razpr{enosti, s tem sta tudi zagotovljena kakovost in nadzor. Kar se ti~e kirurgije, pa opa`amo, da bolnike z rakom danke operirajo v skoraj vseh bolni{ni- cah v Sloveniji – tudi na oddelkih, kjer na leto opravijo 10 ali manj operacij. ^e bi te operacije {teli na posameznega kirurga, bi bile {tevilke {e manj{e. Kirurgi, ki niso dodatno izobra`eni s podro~ja kirurgije raka danke in naredijo malo operacij, ne morejo kakovostno izvesti ope- racije (totalna mezorektalna ekscizija), kar pa je temeljni pogoj za dobre rezultate zdravljenja. Drugi razlog, zaradi katerih je treba bolnike koncentrirati v ve~jih centrih, je la`ja dostopnost do preiskave MRI, ki je danes nepogre{ljiva za pravilno na~rtovanje predoperativnega zdravljenja Rak.qxd 22.7.2009 12:38 Page 84 disseminated disease at diagnosis have only a rate of 7%. Age is a prognostic factor as well, since the relative survival is the lowest in patients aged 75 years or older, while the survival of those diagnosed between 50–74 years of age was lagging behind the relative survival of the patients diagnosed before the age of 50 throughout the observation period (Figure 4). The 5-year relative survival of all patients diagnosed in the period 2001–2005 was 52% (Figure 2); patients surviving the first year may expect to survive five years in 68%. According to the results of EUROCARE-4 study for patients diagnosed in 2000–2002, sur- vival of Slovenian patients with rectal cancer is statistically significantly below the European average (Figure 5). 85 RECTUM CLINICAL COMMENT ARY Ibrahim Edhemovi} 01 02 0 30 40 50 60 70 80 90 100 % Slovensko povpre~je / 2000–2002 (EUROCARE-4) Slovenian average Evropsko povpre~je / 2000–2002 (EUROCARE-4) European average Povpre~je ZDA / 2000–2002 (SEER-13) USA average Slika 5: Petletno relativno pre`ivetje bolnikov z rakom danke (povpre~je in 95-odstotni interval zaupanja), zbolelih v letih 2000–2002 v Sloveniji, Evropi in nekaterih obmo~jih v ZDA. Figure 5: 5-year relative survival of rectal cancer patients (average and 95% confidence interval) diagnosed in the period 2000–2002 in Slovenia, Europe and in some regions of the USA. The data presented indicate, that in the last observation period the survival of rectal cancer patients in Slovenia has improved, though not to a sufficient extent. There are two basic rea- sons for that: advanced stage at diagnosis and surgical treatment, which is dispersed practically through all surgical departments in Slovenia. Almost three fourths of patients present with regional or disseminated disease at diagnosis, and such patients have worse prognosis. It is expected that the screening program for early colo- rectal cancer detection (SVIT) launched this year will contribute to a greater proportion of patients with lower stages and thus also to a better survival. The results of rectal cancer treatment very much depend on the surgeon, i. e. on his profes- sional skills and experience, which can only be obtained through additional training and sufficient number of surgeries performed. In Slovenia, adjuvant and neoadjuvant therapy is performed exclusively by specialized doctors at IO Ljubljana, which ensures that there is no dispersion and that adequate quality and supervision are maintained. However, as regards surgery we note that rectal cancer patients are operated on in almost all hospitals throughout Slovenia, thus also in departments with a turnover of less than 10 such surgeries per year. If these procedures Rak.qxd 22.7.2009 12:38 Page 85 in operacije same. Poleg tega v ve~jih centrih posve~ajo posebno pozornost prehranskemu zdrav- ljenju v pred- in pooperativnem obdobju, kar zaradi pozitivnega vpliva na imunsko stanje bolnika izbolj{uje tudi pre`ivetje. Poseben pomen ima tudi obdelava preparata po Quirkejevem pro- tokolu na oddelkih za patologijo, ki jo opravljajo skoraj izklju~no na oddelku za patologijo na OI Ljubljana, drugje pa le izjemoma. V prihodnje bi bilo treba po bolni{nicah poleg pre`ivet- ja registrirati tudi {tevilo lokalnih in oddaljenih ponovitev ter razmerje med kontinuitetnimi in nekontinuitetnimi operacijami. Ti parametri so merljivi in predstavljajo osnovo za oceno kakovosti zdravljenja raka danke. Na ta na~in bi lahko ugotovili, katere ustanove ne izpolnju- jejo minimalnih standardov kakovosti zdravljenja in bi morale bolnike preusmeriti v ustanove, kjer je ve~ja verjetnost ozdravitve. Bolj{e pre`ivetje v zadnjem opazovanem obdobju je lahko posledica ve~jega dele`a bolnikov, ki so bili neoadjuvantno zdravljeni. K temu je prispevalo tudi sodobno sistemsko pooperativ- no zdravljenje. Zavedati pa se moramo, da brez odli~ne kirurgije tudi vrhunska kemoterapija in radioterapija ne moreta bistveno izbolj{ati pre`ivetja. Beets-Tan RG, Lettinga T, Beets GL. Pre-operative imaging of rectal cancer and its impact on surgical per- formance and treatment outcome. Eur J Surg Oncol 2005; 31: 681–8. Nagtegaal ID, van de Velde CJ, van der Worp E, Kapiteijn E, Quirke P , van Krieken JH. Cooperative Clinical Investigators of the Dutch Colorectal Cancer Group. Macroscopic evaluation of rectal cancer resection specimen: clinical significance of the pathologist in quality control. J Clin Oncol 2002; 20: 1729–34. Peeters KC, van de Velde CJ. Surgical quality assurance in rectal cancer treatment: the key to improved outcome. Eur J Surg Oncol 2005; 31: 630–5. Weimann A, Braga M, Harsanyi L, Laviano A, Ljungqvist O, Soeters P , et al. ESPEN Guidelines on Enteral Nutrition: Surgery including organ transplantation. Clin Nutr 2006; 25: 224–44. 86 DANKA KLINI^NI KOMENT AR Vaneja Velenik Rak danke je bolezen, ki jo opredeljujeta velika zbolevnost in umrljivost. Incidenca je v stal- nem porastu. Rezultati zdravljenja raka danke v Sloveniji se izbolj{ujejo, {e vedno pa so slab{i kot v razvitih evropskih dr`avah. Eden glavnih razlogov za to je, da ima ob diagnozi kar 70 % bolnikov lokalno in/ali podro~no raz{irjeno bolezen (tj. stadij II ali III). Ti bolniki potrebuje- jo odlo~no multimodalno zdravljenje, saj je napoved izida bolezni pri njih slab{a kot pri tistih, pri katerih je tumor omejen na sluznico ali mi{i~no plast danke. Presejalni program za zgod- nje odkrivanje raka debelega ~revesa in danke (SVIT) se je pri~el sredi leta 2008; z ve~jim dele`em bolnikov z rakom danke, odkritim v za~etnem stadiju, pri~akujemo v naslednjem petletnem obdobju tudi ve~anje pre`ivetja. Standardno zdravljenje lokalno ali podro~no napredovalega raka danke je predoperativna radio- terapija ali radiokemoterapija s 5-FU. V primerjavi s pooperativno radiokemoterapijo je manj toksi~na, zagotavlja bolj{i lokalni nadzor bolezni in ve~ji dele` bolnikov z ohranjenim anal- nim sfinktrom. Na~rtovanje obsevanja je natan~nej{e s pomo~jo CT in ra~unalni{kega sistema z algoritmom 3D. Tako je tveganje akutnih toksi~nih sopojavov manj{e, verjetnost, da bodo bolniki dokon~ali predvideno zdravljenje, pa ve~ja. Dele` predoperativno zdravljenih bolnikov se je ve~al od leta 2000 pa vse do leta 2006, ko so tudi iz vseh obmo~nih bolni{nic pri~eli bol- nike po{iljati na predoperativno radiokemoterapijo na OI Ljubljana. Poleg tega smo v letu 2004 pri~eli kot radiosenzibilizator uporabljati kapecitabin, ki po na~inu delovanja in ob dvakrat dnev- nem peroralnem jemanju ves ~as obsevanja posnema kontinuirano infuzijo 5-FU, zdravljenje pa je za bolnika prijaznej{e in varnej{e. Kljub trendu, da se kirurgija raka danke centralizira v ve~jih kirur{kih oddelkih, tega raka {e vedno operirajo v skoraj vseh slovenskih bolni{nicah. Rezultati zdravljenja bi bili verjetno bolj- {i, ~e bi bolnike operiralo omejeno {tevilo strokovno usposobljenih in v onkolo{ki kirurgiji VIRI Literature Rak.qxd 22.7.2009 12:38 Page 86 were scored by individual surgeons the number would be even lower. Surgeons that are not additionally qualified in the area of rectal cancer surgery and themselves perform but few oper- ations, are not able to carry out a quality surgical intervention such as the total mesorectal excision, which is a prerequisite for favorable treatment outcome. Next reason why the patients should be referred to bigger centers is in better accessibility of MR imaging, which is nowadays indis- pensable for correct planning of preoperative treatment and surgery. Moreover, in bigger centers due attention is paid to dietetic therapy in the preoperative as well as postoperative period, which – through its favorable impact on the patients' immune response – contributes to their better survival. Next, the importance of histological sample processing according to the Quirke's protocol should be pointed out too, the method being practiced almost exclusively at the Pathology Department of the IO Ljubljana and only exceptionally elsewhere. In the future, besides the survival statistics, the data on the number of local and distant recurrences and the ratio between continuity and discontinuity surgeries should be registered as well. These parameters are measu- rable and provide a basis for the quality assessment of rectal cancer treatment. In this way it could be established which institutions fail to meet the minimum standards for quality treat- ment, and the patients be referred to the institutions where the chances for their cure would be greater. Better survival in the last observation period may be attributed to a greater proportion of patients receiving neoadjuvant therapy. Besides, the survival results were also favorably influenced by up-to-date postoperative systemic therapy. However, we should keep in mind that without excel- lent surgery even the state-of-the-art chemotherapy and radiotherapy are unable to significantly improve the survival rates. 87 RECTUM CLINICAL COMMENT ARY Vaneja Velenik Rectal cancer is a disease that is characterized by high incidence and mortality rates. The inci- dence is constantly increasing. The results of rectal cancer treatment in Slovenia have been improving, however they are still below those in the developed European countries. One of the main reasons lies in the fact that as many as 70% of patients present with locally and/or regionally advanced disease at diagnosis (i. e., stage II or III). These patients require an aggres- sive multimodality treatment since their prognosis is worse than in those with tumors limited to the mucosa or muscular layer of the rectum. A screening program for early colorectal can- cer detection (SVIT) was launched in the middle of 2008; it is expected that a greater proportion of rectal cancer patients detected at an earlier stage of the disease will contribute to a better survival in the next five-year period. Standard therapy for locally or regionally advanced rectal cancer consists of preoperative radio- therapy or radiochemotherapy with 5-FU. In comparison with postoperative radiotherapy, the former is less toxic and provides better local control of the disease as well as a greater number of patients with preserved anal sphincter. Using CT scan and 3D computer vision algorithms, irradiation planning has become more accurate. Thus the risk of acute toxic side effects is lower and the probability that patients may complete the anticipated therapy is accordingly higher. The proportion of preoperatively treated patients had been increasing from 2000 all until 2006, when all peripheral hospitals started to refer their patients for radiochemotherapy to the IO Ljubljana. Furthermore, in 2004 we started to use capecitabin as radiosensitizer; with twice daily oral application, this drug imitates the effects of 5-FU in continuous infusion through- out the course of irradiation while the treatment for the patient is safer and easier to tolerate. Despite the tendency to centralize surgery for rectal cancer in bigger surgical departments, these procedures are still carried out in almost all Slovenian hospitals. The treatment results would probably be better if the patients were operated on by a limited number of adequately quali- fied surgeons with skills and experience in oncological surgery. The mortality of our patients is Rak.qxd 22.7.2009 12:38 Page 87 izku{enih kirurgov. Zaradi sistemskega razsoja bolezni je umrljivost na{ih bolnikov {e vedno velika. V iskanju mo`nosti za izbolj{anje pre`ivetja uvajamo v predoperativno zdravljenje nove kombinacije citostatikov in tar~nih zdravil. Luzar B, Cerar A, [tabuc B, eds. Tumorji debelega ~revesa in danke. Ljubljani: In{titut za patologijo, Medi- cinska fakulteta; 2008. Program SVIT: www.program-svit.si. Velenik V, Anderluh F, Oblak I, Strojan P , Zakotnik B. Capecitabine as a radiosensitizing agent in neoadjuvant treatment of locally advanced resectable rectal cancer: prospective phase II trial. Croat Med J 2006; 47: 693–700. 88 DANKA VIRI Literature Rak.qxd 22.7.2009 12:38 Page 88 still high due to systemic dissemination of the disease. In an attempt to improve their survival, new combinations of cytostatics and target medications are being introduced into preopera- tive treatment schedules. 89 RECTUM Rak.qxd 22.7.2009 12:38 Page 89 V obdobju 1991–2005 je za jetrnoceli~nim rakom zbolelo 893 ljudi, 698 mo{kih in 195 `ensk. Kot je razvidno s Slike 1, se tako groba kot starostno standardizirana inciden~na stopnja od leta 1991 ve~ata; groba stopnja za povpre~no 7,1 % letno, starostno standardizirana pa za 5,3 % letno. Trend umrljivostnih stopenj je te`ko ovrednotiti, saj je leta 1997 o~itno pri{lo do spre- membe v kodiranju vzrokov smrti; do takrat so med primarni jetrnoceli~ni rak uvr{~ali tudi jetrne metastaze, zato ~asovnega trenda umrljivosti ni mogo~e pravilno interpretirati. JETRA, jetrnoceli~ni rak MKB 10: C22.0 90 0 1 2 3 4 5 1986 1990 1995 2000 2005 Leto / Year Incidenca – groba stopnja / Incidence – crude rate Incidenca – SSS* / Incidence – ASR** Umrljivost – groba stopnja / Mortality – crude rate Umrljivost – SSS* / Mortality – ASR** Stopnja na 100.000 / Rate per 100,000 * SSS – starostno standardizirana stopnja (standard – slovenska populacija leta 1986) ** ASR – age standardized rate (standard Slovenian population in 1986) Slika 1: Groba in starostno standardizirana inciden~na in umrljivostna stopnja jeternoceli~nega karcinoma, Slovenija 1986–2005. Figure 1: Crude and age-standardized incidence and mortality rate of hepatocellular carcinoma, Slovenia 1986–2005. Mo{ki / Males @enske / Females Obdobje / {tevilo / 20–49 let / 50–74 let / 75+ let / {tevilo / 20–49 let / 50–74 let / 75+ let / Period number years (%) years (%) years (%) number years (%) years (%) years (%) 1991–1995 137 13,9 78,1 8,0 37 10,8 73,0 16,2 1996–2000 189 7,9 80,4 11,6 71 7,0 73,2 19,7 2001–2005 283 7,4 74,2 18,4 74 9,5 56,8 33,8 Tabela 1: [tevilo bolnikov z jeternoceli~nim karcinomom po spolu in obdobju postavitve diagnoze ter njihovi dele`i po starosti. T able 1: Number of hepatocellular carcinoma patients by sex and period of diagnosis with their proportions by age. V analizo pre`ivetja je vklju~enih 791 primerov; 102 bolnikov (11 %) nismo upo{tevali, ker jim je bila diagnoza postavljena po smrti. V obdobju 2001–2005 je bilo 70 % primerov raka mikroskopsko potrjenih. Dele` mikroskop- sko potrjenih primerov se je v primerjavi z obdobjem 1991–1995 zmanj{al za 19 %. EPIDEMIOLOGIJA Rak.qxd 22.7.2009 12:39 Page 90 In the period 1991–2005, a total of 893 persons were diagnosed with hepatocellular carcino- ma, of these 698 males and 195 females. As evident from Figure 1, since 1991 the crude and age standardized incidence rates have been increasing, the crude rate by 7.1% and the age-stan- dardized by 5.3% annually on average. The trend in mortality rates is difficult to assess since in 1997 obviously a change occurred in the cause-of-death coding system; until then liver metas- tases had also been included among primary liver cancer, and therefore time trends in mortality cannot be interpreted correctly. The survival analysis included 791 cases; 102 patients (11%) diagnosed only after death were not considered in the analysis. In the period 2001–2005, 70% of cancers were microscopically verified. In comparison with the period 1991–1995, the proportion of microscopically confirmed cancers has decreased by 19%. Age of the majority of patients at diagnosis ranged between 50 and 74 years. In the last peri- od, approximately three-fourths of male- and slightly over a half of female patients belonged to this age group (Table 1). An increased proportion of patients aged 75 or more can be observed in the last period. In all three time-periods, the majority of patients were diagnosed with localized disease; in the period 2001–2005 there were 53% males and 41% females (Table 2); in almost 15% of patients stage at diagnosis was not determined. In the years 2001–2005, 71% of patients did not receive specific treatment. In comparison with the period 1991–1995, the proportion of untreated patients has not changed significantly. Among the patients receiving specific treatment in the period 2001–2005, 49% underwent surgery; in 37% of them surgery was the only treatment while 12% also received chemotherapy; chemothera- py alone was used in 37% of patients; 9% of patients were treated by radiotherapy and 3% received chemotherapy besides irradiation treatment. In the period 2001–2005, almost all patients started their treatment in one of the three lead- ing Slovenian health institutions: 59% in the UMC Ljubljana, 23% in the UMC Maribor and 17% at the IO Ljubljana. The trend in the survival of patients with liver cancer is difficult to assess as the number of patients in individual time-periods is small; in the last periods the 5-year relative survival LIVER, hepatocellular carcinoma ICD 10: C22.0 91 Tabela 2: [tevilo bolnikov z jeternoceli~nim karcinomom po spolu in obdobju postavitve diagnoze ter njihovi dele`i po stadiju. T able 2: Number of hepatocellular carcinoma patients by sex and period of diagnosis with their proportions by stage. Mo{ki / Males @enske / Females Obdobje / {tevilo / omejen / raz{irjen / razsejan / neznan / {tevilo / omejen / raz{irjen / razsejan / neznan / Period number localized regional distant unknown number localized regional distant unknown (%) (%) (%) (%) (%) (%) (%) (%) 1991–1995 137 57,7 13,9 22,6 5,8 37 27,0 27,0 29,7 16,2 1996–2000 189 55,6 18,0 17,5 9,0 71 46,5 18,3 19,7 15,5 2001–2005 283 52,7 14,1 20,1 13,1 74 40,5 21,6 21,6 16,2 EPIDEMIOLOGY Rak.qxd 22.7.2009 12:39 Page 91 Najve~ zbolelih je ob diagnozi starih med 50 in 74 let. Med mo{kimi je v tej starostni skupi- ni pribli`no tri ~etrtine zbolelih, med `enskami pa v zadnjem obdobju nekaj ve~ kot polovica (Tabela 1). V zadnjih letih opa`amo pove~anje dele`a starih 75 let in ve~. V vseh treh obdobjih je imelo najve~ bolnikov ob diagnozi omejeno bolezen; v obdobju 2001–2005 53 % mo{kih in 41 % `ensk (Tabela 2); skoraj 15 % bolnikov stadija ob diagnozi ni imelo dolo- ~enega. V letih 2001–2005 ni bilo specifi~no zdravljenih 71 % bolnikov. Dele` nezdravljenih se v pri- merjavi z obdobjem 1991–1995 ni bistveno spremenil. Med specifi~no zdravljenimi je bilo v letih 2001–2005 operiranih 49 % bolnikov; pri 37 % je bil to edini na~in zdravljenja, 12 % je 92 JETRA, JETRNOCELI^NI RAK 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Slika 2: Deset-, pet-, tri- in enoletno relativno pre`ivetje bolnikov z jeternoceli~nim karcinomom po obdobju postavitve diagnoze. Figure 2: 10-, 5-, 3- and 1-year relative survival of hepatocellular carcinoma patients by period of diagnosis. Tabela 3: Opazovano in relativno pre`ivetje bolnikov z jeternoceli~nim karcinomom po spolu in obdobju postavitve diagnoze s 95-odstotnim intervalom zaupanja (IZ). Table 3: Observed and relative survival of hepatocellular carcinoma patients by sex and period of diagnosis with 95% confidence interval (CI). Opazovano pre`ivetje / Observed survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 19,0 (13,4–26,8) 8,8 (5,1–15,0) 6,6 (3,5–12,4) 18,9 (9,7–36,9) 10,8 (4,3–27,3) 5,4 (1,4–20,8) 1996–2000 20,6 (15,6–27,3) 5,3 (2,9–9,7) 1,6 (0,5–4,9) 21,1 (13,5–33,1) 5,6 (2,2–14,6) 2,8 (0,7–11,0) 2001–2005 25,8 (21,2–31,4) 8,6 (5,8–12,6) 4,8 (2,3–10,1) 23,0 (15,1–34,9) 10,8 (5,6–20,8) 3,8 (0,8–19,0) Relativno pre`ivetje / Relative survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 19,6 (11,5–27,7) 9,5 (2,7–16,4) 7,9 (0,9–14,8) 19,5 (1,0–37,9) 11,7 (0,0–29,5) 6,4 (0,0–24,6) 1996–2000 21,4 (14,5–28,3) 5,9 (1,0–10,9) 1,9 (0,0–5,9) 21,7 (9,4–34,0) 6,2 (0,0–15,9) 3,3 (0,0–12,8) 2001–2005 26,8 (21,0–32,7) 9,7 (5,1–14,2) 5,9 (0,0–12,5) 23,7 (11,4–36,0) 12,0 (0,9–23,0) 4,5 (0,0–22,6) Rak.qxd 22.7.2009 12:39 Page 92 rate is slightly lower than 15 years ago (Figure 2); there were no major differences between genders (Table 3). The survival of patients with localized stage is slightly better while in the remaining stages the rates are unstable due to the small number of cases (Figure 3). The sur- vival of patients younger than 50 years is slightly better than the survival of older patients (Figure 4). The 5-year relative survival rate of all patients diagnosed in the period 2001–2005 was 5.4% (Figure 2); patients surviving the first year may expect to survive five years in 20%. According to the results of EUROCARE-4 study for patients diagnosed in 2000–2002, the survival of Slovenian patients with primary liver cancer is below (statistically not significant) the European average (Figure 5). 93 LIVER, HEPATOCELLULAR CARCINOMA 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 Omejen / Localized Raz{irjen / Regional Razsejan / Distant Vsi / All Slika 3: Petletno relativno pre`ivetje bolnikov z jeternoceli~nim karcinomom po stadiju in obdobju postavitve diagnoze. Figure 3: 5-year relative survival of hepatocellular carcinoma patients by stage and period of diagnosis. 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 20–49 let / years 50–74 let / years 75+ let / years Vsi / All Slika 4: Petletno relativno pre`ivetje bolnikov z jeternoceli~nim karcinomom po starosti in obdobju postavitve diagnoze. Figure 4: 5-year relative survival of hepatocellular carcinoma patients by age and period of diagnosis. Rak.qxd 22.7.2009 12:39 Page 93 prejelo {e kemoterapijo; samo kemoterapijo je prejelo 37 % bolnikov. Obsevanih je bilo 9 % bol- nikov, 3 % pa je poleg radioterapije prejelo {e kemoterapijo. V obdobju 2001–2005 so prakti~no vsi bolniki, ki so bili zdravljeni, zdravljenje pri~eli v eni od treh vodilnih slovenskih zdravstvenih ustanov: 59 % v UKC Ljubljana, 23 % v UKC Mari- bor in 17 % na OI Ljubljana. Trend pre`ivetja bolnikov z jetrnoceli~nim rakom je te`ko vrednotiti, saj je {tevilo bolnikov v po- sameznih obdobjih majhno; v zadnjem obdobju je vrednost petletnega relativnega pre`ivetja nekoliko manj{a kot 15 let prej (Slika 2). Med spoloma ne bele`imo ve~jih razlik v pre`ivet- ju (Tabela 2). Pre`ivetje bolnikov z omejenim stadijem je nekoliko ve~je, pri ostalih stadijih pa so vrednosti nestabilne zaradi majhnega {tevila primerov (Slika 3). Pre`ivetje mlaj{ih od 50 let je nekoliko bolj{e od tistega pri starej{ih (Slika 4). Petletno relativno pre`ivetje vseh zbolelih v obdobju 2001–2005 je bilo 5,4 % (Slika 2); bol- niki, ki pre`ivijo prvo leto, pa lahko pri~akujejo 20-odstotno petletno relativno pre`ivetje. Rezultati {tudije EUROCARE-4 za zbolele v obdobju 2000–2002 ka`ejo, da je grobo petletno relativno pre`ivetje slovenskih bolnikov statisti~no nezna~ilno manj{e od evropskega povpre~- ja (Slika 5). 94 JETRA, JETRNOCELI^NI RAK KLINI^NI KOMENT AR Eldar M. Gad`ijev ^eprav se inciden~na stopnja jetrnoceli~nega raka po letu 2002 ne pove~uje ve~, predvideva- mo, da {e ni dosegla pri~akovane incidence, ki je povezana s predvidenim velikim odstotkom oku`enih z virusom hepatitisa C. Vsekakor smo {e pri~a u~inkom aktivnosti gastroenterologov za zgodnje odkrivanje jetrnoceli~nega raka pri bolnikih z jetrno cirozo. Uveljavitev doktrine, da pri bolniku s cirozo, pri katerem je z ultrazvo~no preiskavo vidna `ari{~na jetrna spremem- ba in imajo vrednost alfa fetoproteina (AFP) nad 400, ni potrebna citolo{ka ali histopatolo{ka potrditev za diagnozo raka, pa je vplivala na izrazito manj{i odstotek histolo{ko potrjene bolez- ni v obdobju od 2001–2005 v primerjavi s prej{njimi obdobji. Dolo~anje zamejitve jetrne bolezni in stadija tumorja po Child-Pughu oziroma Okudi se je dokon~no uveljavilo tudi pri nas; med kirurgi pa se je uveljavila nova, japonska zamejitev TNM. Pomemben prispevek k obravnavi bolnikov z jetrno cirozo in jetrnoceli~nim rakom je v Slo- veniji dala skupina, ki se ukvarja s presaditvami jeter, ki ob upo{tevanju Milanskih meril za dolo~itev bolnikov, primernih za presaditev (tumor pod 5 cm v premeru ali najve~ trije tumor- ji, manj{i od 3cm v premeru brez invazije v `ile), uvr{~a bolnike z jetrnoceli~nim rakom na program za zaenkrat naju~inkovitej{i na~in zdravljenja bolezni. Zaradi organizacije oskrbe bolnikov z jetrnoceli~nim rakom se v zadnjem obdobju ka`e zna- ~ilen premik prvega specifi~nega zdravljenja v oba klini~na centra, pri ~emer pa ostaja {e vedno preve~ bolnikov brez zdravljenja (71 %). V celotnem opazovanem obdobju je na~in zdravljenja prete`no kirur{ki; po letu 1996 se je zmanj- {al odstotek kombiniranega zdravljenja s predoperativno kemoembolizacijo. [e vedno pa je nekaj bolnikov letno, ki pridejo do operacije jetrnoceli~nega raka po zmanj{evanju tumorja s trans- hepati~no arterijsko kemoembolizacijo (TACE), pri kateri se v zadnjem obdobju uporabljata mikrosfere in doksorubicin namesto prej{njega lipiodola in mitomicina. Porast drugih na~inov zdravljenja v zadnjem opazovanem obdobju 2001–2005 gre na ra~un uveljavitve radiofrekven~- ne ablacije kot intersticijske metode za uni~evanje tumorskega tkiva, ki ga izvajamo lahko tudi perkutano pod nadzorom ultrazvoka in ima svoje posebne indikacije (recidiv bolezni, neope- rabilnost tumorja). Pre`ivetje bolnikov z jetrnoceli~nim rakom je {e vedno majhno (triletno komaj dosega 10 % in petletno 5 % pri obeh spolih skupaj), kar gre zagotovo v veliki meri na ra~un velikega odstotka Rak.qxd 22.7.2009 12:39 Page 94 Although since 2002 the incidence rate of hepatocellular carcinoma has stopped increasing, we presume that it still has not reached the expected value associated with the anticipated high percentage of hepatitis-C infected persons. Presently, we may still observe the effects of the activity of gastroenterologists for early detection of hepatocellular cancer in patients with liver cirrhosis. Implementation of the doctrine, according to which no cytological or histopatho- logical confirmation of cancer diagnosis is required in patients with cirrhosis, an US-imaged focal hepatic lesion and AFT (alpha-fetoprotein) values above 400, resulted in a considerably lower percentage of histologically confirmed disease in the period 2001–2005 as compared with the former periods. Staging of liver disease and tumor stage according to Child-Pugh score or Okuda staging sys- tem has finally been adopted also in Slovenia. Surgeons, on the other hand, started using the new Japanese TNM staging system. A relevant contribution towards the management of patients with liver cirrhosis and hepato- cellular cancer in Slovenia was made by a group involved in liver transplantations: in accordance with the Milan criteria for determining suitable transplantation candidates (single tumor ≤5cm in diameter or ≤ 3 tumors each ≤ 3 cm in diameter without vascular invasion) patients with hepa- tocellular carcinoma have been considered suitable for this, currently most effective method of treatment. In order to provide organized care for patients with hepatocellular carcinoma, in the last peri- od there has been a significant shift towards having the primary specific treatment performed in both university medical centers, but nevertheless, still too many patients are left without treatment (71%). Throughout the observation period the prevailing treatment approach was surgery with a sig- nificant downward trend in the percentage of combined treatments with preoperative chemoembolization and subsequent surgery being noted after the year 1996. Still, there are a few patients yearly operated on for hepatocellular carcinoma after debulking treatment with trans- hepatic chemoembolization (TACE); in recent period, the latter method has been performed 95 LIVER, HEPATOCELLULAR CARCINOMA CLINICAL COMMENT ARY Eldar M. Gad`ijev 01 02 0 30 40 50 60 70 80 90 100 % Slovensko povpre~je / 2000–2002 (EUROCARE-4) Slovenian average Evropsko povpre~je / 2000–2002 (EUROCARE-4) European average Povpre~je ZDA / 2000–2002 (SEER-13) USA average Slika 5: Petletno relativno pre`ivetje bolnikov z jeternoceli~nim karcinomom (povpre~je in 95-odstotni interval zaupanja), zbolelih v letih 2000–2002 v Sloveniji, Evropi in nekaterih obmo~jih v ZDA. Figure 5: 5-year relative survival of hepatocellular carcinoma patients (average and 95% confidence interval) diagnosed in the period 2000–2002 in Slovenia, Europe and in some regions of the USA. Rak.qxd 22.7.2009 12:39 Page 95 nezdravljenih bolnikov. Zaskrbljujo~e je, da se ta odstotek v opazovanih treh petletnih obdob- jih ni zmanj{al in ostaja 71 %! Kljub uspe{ni akciji gastroenterologov pri odkrivanju zgodnej{ih primerov raka ob kontrolah bolnikov z jetrno cirozo pa je prosvetljenost prebivalstva {e ved- no preslaba in ob pove~ani incidenci verjetno tudi aktivnosti na primarni ravni niso ustrezne. Temu v prid govori tudi podatek o porazdelitvi po stadiju bolezni ob diagnozi, kjer je odsto- tek raz{irjene in razsejane bolezni {e vedno enak ali ve~ji od omejenega stadija predvsem pri `enskah, pri ~emer se v opazovanih treh petletnih obdobjih razmerje ni bistveno spreminjalo. [e vedno visok odstotek neznanega stadija ob diagnozi pa ka`e lahko tudi na premajhno natan~- nost ali vestnost pri obravnavi teh bolnikov. Zaradi narave bolezni, ki ima osnovo v motenem delovanju jeter, je tudi petletno relativno pre- `ivetje bolnikov z omejeno boleznijo {e majhno (9 %). Uspe{nost kirur{kega zdravljenja, ki prina{a lahko tudi 50-odstotno petletno pre`ivetje, se zaradi premajhnega {tevila ustrezno zdravlje- nih bolnikov {e ne ka`e dovolj. Izrazito slab{e pre`ivetje bolnikov, starih nad 50 let, ki so sicer v ve~ini, morda lahko razlo`i- mo s trajanjem ciroze in bistveno bolj napredovalo jetrno boleznijo v tej starostni skupini. To se odra`a na eni strani v ve~ji incidenci v tem starostnem obdobju, na drugi strani pa v izrazi- to slab{i napovedi izida, ker nanjo vpliva jetrna bolezen in ne tumor. Upo{tevanja vredno pa je tudi dejstvo, da se jetrnoceli~ni rak v neciroti~nih jetrih (kljub temu, da je nekaj jetrne okva- re prakti~no pri vsakem raku), ki je sicer redkej{i, pojavlja pri mlaj{ih bolnikih, pri katerih je potem tudi predvsem kirur{ko zdravljenje u~inkovitej{e. Poleg uspe{nega odkrivanja lahko pri~akujemo v prihodnje tudi bolj{e rezultate ob uveljavlja- nju presaditve jeter pri zdravljenju jetrnoceli~nega raka, pa tudi napredku laparoskopske kirurgije, pri kateri je poseg manj invaziven in imunsko manj kompromitirajo~. Poleg tega se bodo {e nadalje uveljavljale ablacijske metode, predvsem tudi kot pomo~ pri zadr`evanju tumorske bolez- ni pri premostitvi do presaditve jeter. Zdravljenje jetrnoceli~nega raka ostaja izrazito multidisciplinarno in multimodalno, zato naj {e naprej poteka le v terciarnih klini~nih ustanovah. Cottone M, Turri M, Caltagirone M, Parisi P, Orlando A, Fiorentino G, et al. Screening for hepatocellular carcinoma in patients with Child's A cirrhosis: an 8-year prospective study by ultrasound and alphafeto- protein. J Hepatol 1994; 21: 1029–34. Kudo M, Chung H, Osaki Y. Staging of hepatocellular carcinoma: assessment of the Japanese TNM and AJCC/ UICC TNM systems in a cohort of 13,772 patients in Japan. J Gastroenterol 2003; 38: 207–15. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treat- ment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996; 334: 693–9. Minagawa M, Ikai I, Matsuyama Y, Yamaoka Y, Makuuchi M. Staging of hepatocellular carcinoma: assessment of the Japanese TNM and AJCC/UICC TNM systems in a cohort of 13,772 patients in Japan. Ann Surg 2007; 245: 909–22. 96 JETRA, JETRNOCELI^NI RAK VIRI Literature Rak.qxd 22.7.2009 12:39 Page 96 using microspheres and doxorubicin instead of the previous lipiodol and mitomycin. The increase in other treatment approaches in the last observation period from 2001–2005 is attributable to the implementation of radiofrequency ablation as an interstitial method for destroying tumor tissue, which can be performed percutaneously under US guidance for special indications (recur- rence, inoperable tumors). The survival of patients with hepatocellular carcinoma is still low (3-year survival hardly reach- es 10% while 5-year survival for both genders together amounts to 5%), which is certainly attributable mainly to the high proportion of untreated patients. It raises concern that through- out the three 5-year observation periods this percentage has not decreased and still persists at 71%! Despite the successful action by gastroenterologists to detect cancer at an early stage on follow-up examinations of patients with liver cirrhosis, the awareness of general population is still too low and the activities at the level of primary care also are inadequate. This observa- tion is consistent with the data on the distribution of the disease by stage at diagnosis, where the proportion of regional and disseminated disease is still the same or even greater than the proportion of localized stage, particularly in females, the ratio remaining basically unchanged throughout the three 5-year observation periods. The high proportion of undefined stage at diagnosis may be indicative of an insufficient accuracy or conscientiousness in the treatment of these patients. Owing to the nature of the disease, which originates from a liver disorder, the 5-year relative survival of patients with localized disease is also too low (9%). The effectiveness of surgical treatment, which may result in as high as 50% 5-year survival, still does not yield its full poten- tial because the number of adequately treated patients is too scarce. Markedly worse survival of patients above 50 years of age, which are in majority, could be explained by the duration of cirrhosis and significantly more advanced liver disease in this age group. On the one hand, this is reflected in a higher incidence in this age group and in a con- siderably worse prognosis on the other, since the prognosis is influenced by liver disease rather than by tumor. However, it is noteworthy to remember that hepatocellular cancer in a non-cir- rhotic liver (although some liver damage is present in practically any cancer), albeit scarce, may occur in younger patients, in whom particularly surgical treatment turns out more effective. Apart from efficient detection, better results in the future may be expected with wider use of liver transplantation in the treatment of hepatocellular carcinoma, as well as with advances in laparoscopic surgery, a procedure that is less invasive and has less immune system compromising effects. The use of ablation procedures will be continued too, particularly as an aid to control the tumor growth until liver transplantation. The treatment of hepatocellular carcinoma, which is distinctly multidisciplinary and multi- modal, should remain the domain of the tertiary clinical institutions. 97 LIVER, HEPATOCELLULAR CARCINOMA Rak.qxd 22.7.2009 12:39 Page 97 V obdobju 1991–2005 je za rakom `ol~nika in `ol~nih vodov zbolelo 1860 ljudi, od tega 683 mo{- kih in 1177 `ensk. Kot je razvidno s Slike 1, se tako groba kot starostno standardizirana inciden~na stopnja od leta 1991 pove~ujeta; groba stopnja za 2,6 % povpre~no letno, starostno standardi- zirana pa za 0,6 %. Umrljivostni stopnji se po~asi zmanj{ujeta, groba za 0,1 % povpre~no letno, starostno standardizirana pa za 2,1 %. @OL^NIK IN @OL^NI VODI MKB 10: C23, C24 98 V analizo pre`ivetja je vklju~enih 1722 primerov; 138 bolnikov (8 %) nismo upo{tevali, ker jim je bila diagnoza postavljena po smrti. V prvem obdobju so ve~ bolnikom odkrili tumor `ol~nika (60 %), med tem ko se je v zadnjem ob- dobju razmerje med tumorji `ol~nika in `ol~nih vodov obrnilo v prid slednjih – med leti 2001–2005 je imelo 55 % bolnikov tumor `ol~nih vodov. 0 1 2 3 4 5 6 7 8 9 1986 1990 1995 2000 2005 Leto / Year Incidenca – groba stopnja / Incidence – crude rate Incidenca – SSS* / Incidence – ASR** Umrljivost – groba stopnja / Mortality – crude rate Umrljivost – SSS* / Mortality – ASR** Stopnja na 100.000 / Rate per 100,000 * SSS – starostno standardizirana stopnja (standard – slovenska populacija leta 1986) ** ASR – age standardized rate (standard Slovenian population in 1986) Slika 1: Groba in starostno standardizirana inciden~na in umrljivostna stopnja rakov `ol~nika in `ol~evodov, Slovenija 1986–2005. Figure 1: Crude and age-standardized incidence and mortality rate of gallbladder and bill duct cancer, Slovenia 1986–2005. Mo{ki / Males @enske / Females Obdobje / {tevilo / 20–49 let / 50–74 let / 75+ let / {tevilo / 20–49 let / 50–74 let / 75+ let / Period number years (%) years (%) years (%) number years (%) years (%) years (%) 1991–1995 165 6,7 61,2 32,1 318 5,0 58,5 36,5 1996–2000 221 5,9 68,3 25,8 379 3,2 53,0 43,8 2001–2005 251 6,8 63,3 29,9 388 2,3 44,1 53,6 Tabela 1: [tevilo bolnikov z raki `ol~nika in `ol~evodov po spolu in obdobju postavitve diagnoze ter njihovi dele`i po starosti. Table 1: Number of gallbladder and bill duct cancer patients by sex and period of diagnosis with their proportions by age. EPIDEMIOLOGIJA Rak.qxd 22.7.2009 12:39 Page 98 In the period 1991–2005, a total of 1860 persons were diagnosed with cancer of the gallbladder and bile ducts, of these 683 males and 1177 females. As evident from Figure 1, since 1991 the crude and age standardized incidence rates have been increasing, the crude rate by 2.6% and the age-standardized by 0.6% annually on average. The mortality rates have been gradually decreasing, the crude rate by 0.1% and the age standardized by 2.1% annually on average. The survival analysis included 1722 cases; 138 patients (8%) diagnosed only after death were not considered in the analysis. In the first period more patients were diagnosed with gallbladder cancer (60%), while in the last period this ratio changed in favor of bile ducts cancer; in the years 2001–2005 55% patients were diagnosed with the latter. In the period 2001–2005, 62% of cancers were microscopically verified. In comparison with the period 1991–1995, the proportion of microscopically confirmed cancers has decreased by 12%. Among the microscopically confirmed cancers 77% were adenocarcinomas, 9% cystic, mucinous and serous carcinomas and 14% other carcinomas. Age of the majority of patients at diagnosis ranged between 50 and 74 years. In the last peri- od, approximately 60% of male and slightly less than a half of female patients belonged to this age group (Table 1). In the last period the proportion of females aged 75 years or older has increased to over 50%. In all three time-periods, at the time of diagnosis, the majority of males were diagnosed with regional and females with disseminated disease; in the period 2001–2005 there were 42% males and 36% females (Table 2); in over 13% of patients stage at diagnosis was not determined. In the years 2001–2005, 62% of patients did not receive specific treatment. In comparison with the period 1991–1995, the proportion of untreated patients has decreased by 7%. Among the patients receiving specific treatment in the period 2001–2005, 85% were treated by surgery alone, 9% received additional chemotherapy, and 2% additional radiotherapy; 1% received radio- therapy and chemotherapy in addition to surgery while 2% were treated by radiotherapy alone. In the period 2001–2005, 48% of the treated patients started their treatment in the UMC Ljubljana, 28% in the UMC Maribor, and the remaining 24% in practically all Slovenian gene- ral hospitals; except in the GH Slovenj Gradec and GH Nova Gorica, everywhere else they treated less than 10 patients. GALLBLADDER AND BILE DUCTS ICD 10: C23, C24 99 Tabela 2: [tevilo bolnikov z raki `ol~nika in `ol~evodov po spolu in obdobju postavitve diagnoze ter njihovi dele`i po stadiju. Table 2: Number of gallbladder and bill duct cancer patients by sex and period of diagnosis with their proportions by stage. Mo{ki / Males @enske / Females Obdobje / {tevilo / omejen / raz{irjen / razsejan / neznan / {tevilo / omejen / raz{irjen / razsejan / neznan / Period number localized regional distant unknown number localized regional distant unknown (%) (%) (%) (%) (%) (%) (%) (%) 1991–1995 165 21,8 33,9 30,9 13,3 318 16,0 33,6 38,4 11,9 1996–2000 221 20,8 38,0 25,8 15,4 379 14,0 34,8 34,8 16,4 2001–2005 251 12,7 42,2 31,5 13,5 388 15,5 35,3 36,1 13,1 EPIDEMIOLOGY Rak.qxd 22.7.2009 12:39 Page 99 V obdobju 2001–2005 je bilo 62 % primerov raka mikroskopsko potrjenih. Dele` mikroskop- sko potrjenih se je v primerjavi z obdobjem 1991–1995 zmanj{al za 12 %. Med mikroskopsko potrjenimi je bilo 77 % adenokarcinomov, 9 % cisti~nih, mucinoznih in seroznih neoplazem, 14 % pa drugih karcinomov. Najve~ji dele` zbolelih je ob diagnozi starih 50–74 let. Med mo{kimi je v tej starostni skupi- ni pribli`no 60% zbolelih, med `enskami pa v zadnjem obdobju nekaj manj kot polovica (Tabela 1). Med `enskami se je v zadnjem obdobju dele` starih 75 let in ve~ pove~al na ve~ kot 50 %. 100 @OL^NIK IN @OL^NI VODI 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Slika 2: Deset-, pet-, tri- in enoletno relativno pre`ivetje bolnikov z raki `ol~nika in `ol~evodov po obdobju postavitve diagnoze. Figure 2: 10-, 5-, 3- and 1-year relative survival of gallbladder and bill duct cancer patients by period of diagnosis. Tabela 3: Opazovano in relativno pre`ivetje bolnikov z raki `ol~nika in `ol~evodov po spolu in obdobju postavitve diagnoze s 95-odstotnim intervalom zaupanja (IZ). Table 3: Observed and relative survival of gallbladder and bill duct cancer patients by sex and period of diag- nosis with 95% confidence interval (CI). Opazovano pre`ivetje / Observed survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 23,0 (17,4–30,4) 10,9 (7,1–16,9) 6,7 (3,8–11,8) 14,8 (11,4–19,2) 6,0 (3,9–9,2) 5,0 (3,1–8,1) 1996–2000 32,1 (26,5–38,9) 17,2 (12,9–23,0) 10,9 (7,4–15,8) 18,2 (14,7–22,5) 7,7 (5,4–10,9) 5,8 (3,9–8,7) 2001–2005 31,9 (26,6–38,2) 11,2 (7,9–16,0) 8,8 (5,7–13,5) 20,9 (17,2–25,3) 8,4 (6,0–11,8) 5,2 (3,1–8,8) Relativno pre`ivetje / Relative survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 24,5 (16,6–32,4) 13,2 (6,0–20,4) 8,9 (2,1–15,8) 15,4 (10,8–20,1) 6,9 (3,1–10,6) 6,3 (2,4–10,1) 1996–2000 33,8 (26,7–41,0) 20,1 (13,3–26,8) 14,3 (7,7–20,8) 19,1 (14,6–23,7) 8,8 (5,1–12,5) 7,5 (3,7–11,2) 2001–2005 33,8 (27,1–40,5) 13,4 (7,7–19,1) 11,9 (5,5–18,4) 22,1 (17,3–26,8) 9,9 (6,0–13,9) 7,0 (2,2–11,8) Rak.qxd 22.7.2009 12:39 Page 100 5-year relative survival has been gradually increasing although even in the last period it was under 10% (Figure 2), being slightly higher in males (11%) than in females (7%) (Table 3). The survival in patients with localized stage is slightly higher than in patients with more advanced disease (Figure 3). The survival of patients younger than 50 years is slightly higher than the survival of older patients (Figure 4), however the number of these patients is the lowest. The 5-year relative survival rate of all patients diagnosed in the period 2001–2005 was 9% (Figure 2); patients surviving the first year may expect to survive five years in 31%. According to the results of EUROCARE-4 study for patients diagnosed in 2000–2002, sur- vival of Slovenian patients with gallbladder and bile ducts cancer is below (statistically not significant) the European average (Figure 5). 101 GALLBLADDER AND BILE DUCTS 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 Omejen / Localized Raz{irjen / Regional Razsejan / Distant Vsi / All Slika 3: Petletno relativno pre`ivetje bolnikov z raki `ol~nika in `ol~evodov po stadiju in obdobju postavitve diagnoze. Figure 3: 5-year relative survival of gallbladder and bill duct cancer patients by stage and period of diag- nosis. 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 20–49 let / years 50–74 let / years 75+ let / years Vsi / All Slika 4: Petletno relativno pre`ivetje bolnikov z raki `ol~nika in `ol~evodov po starosti in obdobju postavitve diagnoze. Figure 4: 5-year relative survival of gallbladder and bill duct cancer patients by age and period of diagno- sis. Rak.qxd 22.7.2009 12:39 Page 101 V vseh treh obdobjih je imelo najve~ mo{kih ob diagnozi raz{irjeno bolezen, najve~ `ensk pa razsejano; v obdobju 2001–2005 je bilo takih 42 % mo{kih in 36 % `ensk (Tabela 2); pri nekaj ve~ kot 13 % bolnikov stadija ob diagnozi niso dolo~ili. V letih 2001–2005 ni bilo specifi~no zdravljenih 62 % bolnikov. Dele` nezdravljenih se je v primer- javi z obdobjem 1991–1995 zmanj{al za 7 %. Med specifi~no zdravljenimi je bilo v letih 2001–2005 85 % bolnikov samo operiranih, 9 % je prejelo {e kemoterapijo, 2 % pa je bilo {e obsevanih, 1 % je poleg operacije in radioterapije prejel {e kemoterapijo; samo obsevana sta bila 2 % bolnikov. V obdobju 2001–2005 je 48 % bolnikov, ki so bili zdravljeni, zdravljenje pri~elo v UKC Ljub- ljana, 28 % v UKC Maribor, preostalih 24 % pa prakti~no v vseh slovenskih bolni{nicah; razen v SB Slovenj Gradec in SB Nova Gorica so povsod zdravili manj kot 10 bolnikov. Petletno relativno pre`ivetje se sicer postopno pove~uje, je pa tudi v zadnjem obdobju manj- {e od 10 % (Slika 2); v zadnjem obdobju je malo ve~je pri mo{kih (11 %) kot pri `enskah (7 %) (Tabela 3). Pre`ivetje bolnikov z omejenim stadijem je nekoliko ve~je kot pri bolnikih z bolj napredovalo boleznijo (Slika 3). Pre`ivetje mlaj{ih od 50 let je nekoliko ve~je od tistega pri sta- rej{ih (Slika 4), je pa teh bolnikov najmanj. Petletno relativno pre`ivetje vseh zbolelih v obdobju 2001–2005 je bilo 9 % (Slika 2); bolni- ki, ki pre`ivijo prvo leto, pa lahko pri~akujejo 31-odstotno petletno relativno pre`ivetje. Rezultati {tudije EUROCARE-4 za zbolele v obdobju 2000–2002 ka`ejo, da je pre`ivetje sloven- skih bolnikov z rakom `ol~nika in `ol~nih vodov statisti~no nezna~ilno manj{e od evropskega povpre~ja (Slika 5). 102 @OL^NIK IN @OL^NI VODI KLINI^NI KOMENT AR Eldar M. Gad`ijev Ker sta rak `ol~nika in rak `ol~nih vodov dve razli~ni entiteti, je komentiranje obeh patologij skupaj manj primerno in te`ko opredeljuje zna~ilnosti posameznih bolezni. Simptomatika, odkri- vanje in zdravljenje se namre~ pri raku `ol~nika razlikujejo od tistih pri raku `ol~nih vodov. Poleg tega je kirur{ko zdravljenje raka `ol~nih vodov odvisno od anatomskega mesta in je dru- ga~no pri (glede na jetra) bli`je le`e~ih tumorjih (Klatskinov tumor) kot pri bolj oddaljenih tumorjih. Ob tem je tudi oboperativna smrtnost, ki je pri nas presegala 5 %, pri nekaterih ope- racijah nezanemarljiva, pri operacijah zaradi raka `ol~nika pa je manj{a. Tam je operacija v osnovi manj zahtevna, predvsem pri ni`jih stadijih bolezni. Pri raku `ol~nika se uporablja klasifika- cija TNM, pri raku `ol~nih vodov pa poleg TNM kar nekaj kirur{kih klasifikacij (npr. Bismuth, Strassberg, nizozemska). Pri~ujo~a analiza ka`e, da je v Sloveniji incidenca raka `ol~nika in `ol~nih vodov bolj ali manj enakomerna v opazovanih obdobjih z majhnimi nihanji, a vendar z izrazitej{im porastom v letu 2005. V svetu se incidenca raka `ol~nika in `ol~nih vodov {e ve~a. Nastanek raka `ol~nika je po eni strani povezan z dedno nagnjenostjo; pogostej{i je pri `enskah, pri nenormalnem metaboliz- mu `ol~a z `ol~nimi kamni in vnetjem, pri ~emer pride do inaktivacije tumor supresorskega gena p53 in do nastanka raka. Po drugi strani (prete`no v Aziji) je rak `ol~nika pogostej{i pri prirojeni anomaliji, spojenem `ol~nem in pankreati~nem vodu, kar omogo~a refluks pankrea- ti~nega soka v `ol~nik in razvoj hiperplazije in raka ob mutaciji onkogena K-RAS. Nevarnostni dejavnik raka `ol~nih vodov so {e vnetne ~revesne bolezni, anomalije `ol~nih vodov in oku`- be, predvsem s paraziti. Odstotek mikroskopsko potrjenih primerov je sprejemljiv in se pri~akovano manj{a (v zadnjem petletnem obdobju na 62 %). Ob zna~ilni klini~ni sliki oziroma izvidu morfolo{kih preiskav (ERC, MRI, EUZ) in zna~ilno pove~anem tumorskem ozna~evalcu Ca 19-9 je diagnoza pri raku `ol~nih vodov `e brez mikroskopske potrditve jasna. Poleg tega pa je pridobitev materiala za Rak.qxd 22.7.2009 12:39 Page 102 Cancer of the gallbladder and cancer of the bile ducts being two different entities, comment- ing on both pathologies together is rather inconvenient, as it is difficult to point out their individual characteristics. Symptoms, diagnosis and treatment of gallbladder cancer differ from those of bile duct cancer. Furthermore, surgical treatment for bile duct cancers depends on their location and is different for tumors situated proximally to the liver (Klatskin's tumor) and for those situated distally. The perioperative lethality too – which in our case exceeded 5% – asso- ciated with certain surgical interventions is not negligible, while in surgeries for gallbladder cancer it is lower. The latter procedures are basically less demanding, particularly in patients with earlier stages of the disease. While the TNM classification is used for gallbladder can- cer, in the case of bile duct cancer a number of other surgical classifications are used besides the TNM (Bismuth, Strassberg, Dutch). A characteristic feature of the present analysis is more or less stable incidence of gallbladder and bile duct cancers throughout the observation periods, with minor shifts and a more promi- nent increase in the year 2005. Further increase in the incidence of gallbladder and bile duct cancer is observed worldwide. On the one hand, the development of gallbladder cancer is asso- ciated with hereditary predisposition: female gender, abnormal bile metabolism with gall stones and inflammation resulting in p53 tumor suppressor gene inactivation and the onset of can- cer. On the other hand, (prevailingly in Asia) the onset of gallbladder cancer is associated with a congenital anomalous junction of the bile- and pancreatic ducts, which causes reflux of pan- creatic juice into the gallbladder and the development of hyperplasia and cancer with K-RAS oncogene mutation. Risk factors for bile duct cancer are inflammatory intestinal diseases, bile duct anomalies and infections, particularly infestations with parasites. The proportion of microscopically confirmed cases is within the expected limits and has been decreasing (in the last 5-year period to 62%). With typical clinical picture or morphological findings (ERC, MRI, EUS) and significantly elevated Ca 19-9 tumor marker the diagnosis of bile duct cancer is indisputable without microscopic confirmation. Moreover, in gallbladder cancer the bioptic sample taking is risky because it may cause leakage of bile into the abdomen and thus dissemination of the disease. However, in endoscopic examinations for suspected cancer 103 GALLBLADDER AND BILE DUCTS CLINICAL COMMENT ARY Eldar M. Gad`ijev 01 02 0 30 40 50 60 70 80 90 100 % Slovensko povpre~je / 2000–2002 (EUROCARE-4) Slovenian average Evropsko povpre~je / 2000–2002 (EUROCARE-4) European average Povpre~je ZDA / 2000–2002 (SEER-13) USA average Slika 5: Petletno relativno pre`ivetje bolnikov z raki `ol~nika in `ol~evodov (povpre~je in 95-odstotni interval zaupanja), zbolelih v letih 2000–2002 v Sloveniji, Evropi in nekaterih obmo~jih v ZDA. Figure 5: 5-year relative survival of gallbladder and bill duct cancer patients (average and 95% confidence interval) diagnosed in the period 2000–2002 in Slovenia, Europe and in some regions of the USA. Rak.qxd 22.7.2009 12:39 Page 103 mikroskopsko preiskavo pri raku `ol~nika tvegana, ker lahko povzro~i zatekanje `ol~a v tre- buh in razsoj bolezni. Iskanje malignih celic v `ol~u, predvsem pa krta~ni odvzem celic iz endotela `ol~evoda za citolo{ko preiskavo, pa sta pri endoskopskih posegih ob sumu na raka `ol~nega sistema vendarle smiselna. Rak `ol~nika danes pogosteje odkrijemo v za~etnem stadiju, ko ga najdemo slu~ajno po ope- raciji zaradi `ol~nih kamnov in ima zato bolj{o napoved izida in pre`ivetje. Napredovali rak `ol~nika pa ima tudi, ~e je {e kirur{ko odstranljiv, slabo napoved izida. Po drugi strani pa je zelo redko in te`ko odkriti raka `ol~nih vodov v zgodnjem stadiju. Njegova rast v obliki tumorskih sprememb na preskok (t. i. skip lezij) in {irjenje v steni `ol~nih vodov s pogosto perivaskular- no in perinevralno invazijo opredeljujejo invazivno rast in slabo napoved izida, ~eprav redko metastazira in je tumor sam po sebi majhen. Temu ustrezni so rezultati analize, ki ka`ejo maj- hen odstotek omejene bolezni in velik odstotek raz{irjene in celo razsejane bolezni. Zdravljenje je kirur{ko, kadar je le mo`no; kombinacija s kemoterapijo se uveljavlja v zadnjih letih tudi pri nas. Pri raku `ol~nih vodov pride v~asih v po{tev le endoskopsko ali radiolo{ko intervencijsko dreniranje oziroma postavitev opornice v `ol~ni vod. Pre`ivetje je majhno in se v opazovanih treh petletnih obdobjih ni pove~alo, kar lahko ka`e na slab{e rezultate zdravljenja pri nas, ker je tudi v svetu, tako kot pri nas, le pri 10–20 % bol- nikov bolezen omejena. V razvitih dr`avah je petletno pre`ivetje bolnikov z rakom `ol~nika nekoliko ve~je: okrog 40 % pri tistih z omejenim stadijem, 15 % pri raz{irjeni bolezni in 10 % pri razsejani. Pre`ivetje pri raku `ol~nih vodov je odvisno ne le od stadija bolezni ampak tudi od mesta tumorja (proksimalen, distalen). Pri raku `ol~nih vodov petletno pre`ivetje opisuje- jo po stadijih TNM in se giblje med 8 % pri bolnikih s stadijem III in IV, prek 22 % pri bolnikih s stadijem II, 29 % pri bolnikih s stadijem I in 58 % pri bolnikih s stadijem 0. V prihodnje bi bilo treba za bolj{o primerjavo s podatki iz literature lo~iti obe bolezni; je pa res, da bi bilo ver- jetno potem primerov malo, zato pa tudi ocene manj zanesljive. Bartlett DL, Fong Y, Fortner JG, Brennan MF, Blumgart LH. Long-term results after resection for gallbladder cancer. Implications for staging and management. Ann Surg 1996; 224: 639–46. Bartolasi L, Burgart LJ, Tsiotos GG, Luque-de Leon E, Sarr MG. Adenocarcinoma of the distal bile duct. A clinicopatologic outcome analysis after curative resection. Dig Surg 2000; 17: 36–41. Henson DE, Albores-Saavedra J, Corle D. Carcinoma of the gallbladder. Histologic types, stage of disease, grade, and survival rates. Cancer 1992; 70: 1493–7. Kloek JJ, Ten Kate FJ, Busch OR, Gouma DJ, VanGulik TM. Surgery for extrahepatic cholangiocarcinoma: predictors of survival. HPB 2008; 10: 190–5. Nishio H, Nagino M, Oda K, Ebata T , Arai T , Nimura Y. TNM Classification for perihilar cholangiocarcinoma: comparison between 5th and 6th edition of the AJCC/UICC staging system. Langgenbecks Arch Surg 2005; 390: 319–27. 104 @OL^NIK IN @OL^NI VODI VIRI Literature Rak.qxd 22.7.2009 12:39 Page 104 of the billiard system looking for the presence of malignant cells in bile, and particularly brush biopsy of the bile duct, seem reasonable. Presently, gallbladder cancer is more frequently detected at an initial stage, as an incidental find- ing on surgery for gallstones, and is therefore associated with a better prognosis and survival. However, an advanced gallbladder cancer, even if operable, has a poor prognosis. On the other hand, bile duct cancer is very difficult to detect at an early stage. Its growth in the form of skip lesions (non-contiguous lesions) and spread into bile duct walls with frequent perivascular and perineural invasion are associated with invasive growth and a poor prognosis, regardless the fact that this cancer rarely metastasizes and that the tumor in itself is small. Accordingly, analy- sis results show a small percentage of localized disease and a proportionally greater percentage of regional and even disseminated disease. The treatment of choice is surgery whenever feasible; in recent years a combination with chemotherapy has become more frequently used also in Slovenia. In bile duct cancer some- times an endoscopic or radiological intervention drainage or bile duct stent placement is considered as the only option. The survival is low and has not increased in the three 5-year observation periods, which may be indicative of our worse treatment outcomes, since in Slovenia, as elsewhere in the world, only 10–20% of patients will present with localized disease. In the developed countries, 5-year survival of patients with gallbladder cancer is slightly higher: approximately 40% in those with localized stage, 15% in regional stage and 10% in disseminated disease. The survival in bile duct cancer depends not only on stage of the disease but also on tumor site (proximal or dis- tal). In bile duct cancer 5-year survival is described according to the TNM classification, ranging from 8% in patients with stages III and IV, through 22% in patients with stage II, 29% in those with stage I, to 58% in patients with stage 0. In order to facilitate comparison with the data from literature, in the future it would be necessary to analyze each of the two diseases sepa- rately, however, this may render the analysis results less reliable due to an insufficient number of cases. 105 GALLBLADDER AND BILE DUCTS Rak.qxd 22.7.2009 12:39 Page 105 V obdobju 1991–2005 je za rakom trebu{ne slinavke zbolelo 3323 ljudi, od tega 1582 mo{kih in 1741 `ensk. Kot je razvidno s Slike 1, je razmerje med grobima in starostno standardizira- nima inciden~nima in umrljivostnima stopnjama manj{e od 1 do leta 2003, kar razlagamo z manj natan~nim opredeljevanjem vzrokov smrti in slabo napovedjo izida bolezni. Groba inciden~- na stopnja se ve~a za povpre~no 3,4 % letno, groba umrljivostna stopnja pa za povpre~no 1,9 % letno; nekaj manj se ve~a starostno standardizirana inciden~na stopnja, medtem ko se umrlji- vostna stopnja manj{a za povpre~no 0,2 % letno. TREBU[NA SLINAVKA MKB 10: C25 106 0 2 4 6 8 10 12 14 16 1986 1990 1995 2000 2005 Leto / Year Incidenca – groba stopnja / Incidence – crude rate Incidenca – SSS* / Incidence – ASR** Umrljivost – groba stopnja / Mortality – crude rate Umrljivost – SSS* / Mortality – ASR** Stopnja na 100.000 / Rate per 100,000 * SSS – starostno standardizirana stopnja (standard – slovenska populacija leta 1986) ** ASR – age standardized rate (standard Slovenian population in 1986) Slika 1: Groba in starostno standardizirana inciden~na in umrljivostna stopnja raka trebu{ne slinavke, Slovenija 1986–2005. Figure 1: Crude and age-standardized incidence and mortality rate of pancreatic cancer, Slovenia 1986–2005. Mo{ki / Males @enske / Females Obdobje / {tevilo / 20–49 let / 50–74 let / 75+ let / {tevilo / 20–49 let / 50–74 let / 75+ let / Period number years (%) years (%) years (%) number years (%) years (%) years (%) 1991–1995 429 9,8 68,1 22,1 421 4,3 55,1 40,6 1996–2000 445 10,6 68,5 20,9 517 4,4 56,7 38,9 2001–2005 571 10,9 66,2 22,9 639 6,9 51,6 41,5 Tabela 1: [tevilo bolnikov z rakom trebu{ne slinavke po spolu in obdobju postavitve diagnoze ter njihovi dele`i po starosti. Table 1: Number of pancreatic cancer patients by sex and period of diagnosis with their proportions by age. V analizo pre`ivetja je vklju~enih 3022 primerov; 301 bolnika (9,1 %) nismo upo{tevali, ker jim je bila diagnoza postavljena po smrti. Med vsemi bolniki jih 42 % ni imelo natan~neje opre- deljenega mesta nastanka malignoma, v zadnjem obdobju 38 %. Pri treh ~etrtinah z opredeljenim mestom je tumor nastal v glavi trebu{ne slinavke. V obdobju 2001–2005 je bilo 54 % primerov raka mikroskopsko potrjenih. Dele` mikroskop- sko potrjenih se je v primerjavi z obdobjem 1991–1995 zmanj{al za 3 %. V vseh treh obdobjih je imelo najve~ bolnikov eno od vrst adenokarcinoma (81 %). EPIDEMIOLOGIJA Rak.qxd 22.7.2009 12:39 Page 106 In the period 1991–2005, a total of 3323 persons were diagnosed with cancer of the pancreas, of these 1582 males and 1741 females. As evident from Figure 1, until 2003 the ratio between crude and age standardized incidence and mortality rates had been less than 1, which can be explained by less accurate determination of the causes of death and poor prognosis of the dis- ease, which has been improving very slowly. Thus crude incidence rate has been increasing by 3.4% and crude mortality rate by 1.9% annually on average; a lesser increase has been observed in the age-standardized incidence rate, while age standardized mortality rate is decreas- ing by 0.2% annually on average. The survival analysis included 3022 cases; 301 patients (9.1%) diagnosed only after death were not considered in the analysis. Among all the patients, 42% did not have the site of maligno- ma more precisely defined, in the last period the proportion of such patients being 38%. In three fourths of patients with a defined site, the tumor originated in the pancreatic head. In the period 2001–2005, 54% of cancers were microscopically verified. In comparison with the period 1991–1995 the proportion of microscopically confirmed cases has decreased by 3%. In all three time-periods, the majority of patients had one of types of adenocarcinoma (81%). Age of the majority of patients at diagnosis ranged between 50–74 years. Approximately two thirds of male patients and slightly more than a half of female patients belonged to this age group. More than a third of females were diagnosed at the age of 75 years or older; slightly more males than females were diagnosed before 50 years of age (Table 1). The proportions in individual age groups did not change significantly with time. In all three time-periods, the majority of patients were diagnosed with disseminated disease; in the period 2001–2005 there were 50% of males and 47% of females among such patients (Table 2). The proportion of localized stage has been decreasing in both genders, prevailing- ly on the account of regional and disseminated stages. In the years 2001–2005, almost 70% of patients did not receive specific treatment. In com- parison with the period 1991–1995 the percentage of untreated patients has decreased by 13%. Among the patients receiving specific treatment in the period 2001–2005, 58% were treated by surgery; in 42% this represented the only method of treatment, 16% also received chemotherapy; chemotherapy alone was used in 31% of the patients; 6% received radiothera- py in addition to chemotherapy or were only irradiated; the remaining 5% were treated by other combinations. In the period 2001–2005, almost all patients started their treatment in one of the three lead- ing Slovenian health institutions: 47% in the UMC Ljubljana, 32% at the IO Ljubljana, and 15% in the UMC Maribor. PANCREAS ICD 10: C25 107 Tabela 2: [tevilo bolnikov z rakom trebu{ne slinavke po spolu in obdobju postavitve diagnoze ter njihovi dele`i po stadiju. Table 2: Number of pancreatic cancer patients by sex and period of diagnosis with their proportions by stage. Mo{ki / Males @enske / Females Obdobje / {tevilo / omejen / raz{irjen / razsejan / neznan / {tevilo / omejen / raz{irjen / razsejan / neznan / Period number localized regional distant unknown number localized regional distant unknown (%) (%) (%) (%) (%) (%) (%) (%) 1991–1995 429 15,6 26,3 41,0 17,0 421 11,2 30,4 41,3 17,1 1996–2000 445 9,4 29,2 49,2 12,1 517 12,6 31,7 40,8 14,9 2001–2005 571 6,5 34,3 50,4 8,8 639 8,3 33,6 47,4 10,6 EPIDEMIOLOGY Rak.qxd 22.7.2009 12:39 Page 107 Starost najve~jega dele`a zbolelih je bila ob diagnozi od 50 do 74 let. Med mo{kimi je bilo v tej starostni skupini pribli`no dve tretjini bolnikov, med `enskami pa nekaj ve~ kot polovi- ca. Ve~ kot tretjina `ensk je bila ob diagnozi starih 75 let in ve~, pred 50. letom pa je zbolelo nekaj ve~ mo{kih kot `ensk (Tabela 1). Dele`i v posameznih starostnih skupinah se s ~asom niso bistveno spreminjali. V vseh treh obdobjih je imelo najve~ bolnikov ob diagnozi razsejano bolezen; v obdobju 2001–2005 50 % mo{kih in 47 % `ensk (Tabela 2). Dele` bolnikov z omejenim stadijem se zmanj{uje pri obeh spolih, tako na ra~un raz{irjenega kot razsejanega stadija. 108 TREBU[NA SLINAVKA 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Slika 2: Deset-, pet-, tri- in enoletno relativno pre`ivetje bolnikov z rakom trebu{ne slinavke po obdobju postavitve diagnoze. Figure 2: 10-, 5-, 3- and 1-year relative survival of pancreatic cancer patients by period of diagnosis. Tabela 3: Opazovano in relativno pre`ivetje bolnikov z rakom trebu{ne slinavke po spolu in obdobju postavitve diagnoze s 95-odstotnim intervalom zaupanja (IZ). Table 3: Observed and relative survival of pancreatic cancer patients by sex and period of diagnosis with 95% confidence interval (CI). Opazovano pre`ivetje / Observed survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 10,3 (7,8–13,6) 3,7 (2,3–6,0) 2,6 (1,4–4,6) 11,4 (8,7–14,9) 1,9 (1,0–3,8) 1,2 (0,5–2,8) 1996–2000 11,9 (9,3–15,3) 3,6 (2,2–5,8) 2,7 (1,5–4,7) 11,4 (9,0–14,5) 2,1 (1,2–3,8) 1,7 (0,9–3,3) 2001–2005 16,8 (14,0–20,2) 4,5 (3,1–6,7) 4,1 (2,7–6,2) 16,3 (13,7–19,4) 5,9 (4,3–8,0) 4,0 (2,7–6,1) Relativno pre`ivetje / Relative survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 10,8 (7,3–14,3) 4,3 (1,7–7,0) 3,3 (0,7–6,0) 12,0 (8,3–15,7) 2,2 (0,0–4,4) 1,6 (0,0–3,7) 1996–2000 12,5 (8,9–16,1) 4,1 (1,6–6,6) 3,4 (0,9–6,0) 12,0 (8,7–15,2) 2,4 (0,5–4,4) 2,2 (0,2–4,2) 2001–2005 17,6 (14,1–21,1) 5,2 (2,8–7,7) 5,2 (2,6–7,9) 17,0 (13,7–20,3) 6,8 (4,3–9,2) 5,1 (2,5–7,7) Rak.qxd 22.7.2009 12:39 Page 108 The survival of patients with pancreatic cancer has been increasing very slowly; thus in 15 years, the 5-year relative survival increased only by 3% (Figure 2), slightly more in females (Table 3). The relevance of stage at diagnosis is shown in Figure 3. In the last period, 5-year relative sur- vival of patients with localized stage has exceeded 15%. However, the 5-year relative survival of patients with regional and disseminated stages is still lower than 10%. Age is a prognostic factor as well, since the worst relative survival is observed in patients aged 75 years or older, while the survival in those under 50 years of age is somewhat better, and has actually under- gone the highest increase (Figure 4). The 5-year relative survival of all patients diagnosed in the period 2001–2005 was 5% (Figure 2); patients surviving the first year may expect to survive five years in 28%. According to the results of EUROCARE-4 study for patients diagnosed in 2000–2002, sur- vival of Slovenian patients with pancreatic cancer is nearly equal to the European average (Figure 5). 109 PANCREAS 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 Omejen / Localized Raz{irjen / Regional Razsejan / Distant Vsi / All Slika 3: Petletno relativno pre`ivetje bolnikov z rakom trebu{ne slinavke po stadiju in obdobju postavitve diagnoze. Figure 3: 5-year relative survival of pancreas cancer patients by stage and period of diagnosis. 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 20–49 let / years 50–74 let / years 75+ let / years Vsi / All Slika 4: Petletno relativno pre`ivetje bolnikov z rakom trebu{ne slinavke po starosti in obdobju postavitve diagnoze. Figure 4: 5-year relative survival of pancreatic cancer patients by age and period of diagnosis. Rak.qxd 22.7.2009 12:39 Page 109 V letih 2001–2005 ni bilo specifi~no zdravljenih skoraj 70 % bolnikov. Dele` nezdravljenih se je v primerjavi z obdobjem 1991–1995 zmanj{al za 13 %. Med specifi~no zdravljenimi je bilo v letih 2001–2005 58 % bolnikov operiranih; pri 42 % je bilo to edino zdravljenje, 16 % pa je prejelo {e kemoterapijo; samo s kemoterapijo je bilo zdravljenih 31 % bolnikov; 6 % je poleg kemoterapije prejelo {e radioterapijo ali pa so bili samo obsevani; preostalih 5 % so zdravili z dru- gimi kombinacijami. V obdobju 2001–2005 so skoraj vsi bolniki, ki so bili zdravljeni, zdravljenje pri~eli v eni od treh vodilnih slovenskih zdravstvenih ustanov: 47 % v UKC Ljubljana, 32 % na OI Ljubljana in 15 % v UKC Maribor. Pre`ivetje bolnikov z rakom trebu{ne slinavke se ve~a zelo po~asi; v 15 letih se je petletno rela- tivno pre`ivetje pove~alo le za 3 % (Slika 2), nekoliko bolj pri `enskah (Tabela 3). Kako pomemben je stadij ob diagnozi, ka`e Slika 3: petletno relativno pre`ivetje bolnikov z omejenim stadijem je v zadnjem obdobju preseglo 15 %. Petletno relativno pre`ivetje bolnikov z raz{irjenim in raz- sejanim stadijem pa je {e vedno manj{e od 10 %. Napovedni dejavnik je tudi starost, saj je relativno pre`ivetje najmanj{e pri starih 75 let in ve~, nekoliko ve~je pa pri mlaj{ih od 50 let, pri kate- rih se je s ~asom tudi najbolj pove~alo (Slika 4). Petletno relativno pre`ivetje vseh zbolelih v obdobju 2001–2005 je bilo 5 % (Slika 2); bolni- ki, ki pre`ivijo prvo leto, pa lahko pri~akujejo 28-odstotno petletno relativno pre`ivetje. Rezultati {tudije EUROCARE-4 za zbolele v obdobju 2000–2002 ka`ejo, da je grobo petlet- no relativno pre`ivetje slovenskih bolnikov z rakom trebu{ne slinavke (4,8%) skoraj enako evropskemu povpre~ju (4,7 %). 110 TREBU[NA SLINAVKA KLINI^NI KOMENT AR Mirko Omejc Rak trebu{ne slinavke je zaradi svoje napadalnosti bolezen z veliko umrljivostjo. Klini~no se ka`e z obse`no perinevralno in retroperitonealno infiltracijo, invazijo `ilja, lokalnim recidivom in zgodnjimi lokalnimi in oddaljenimi zasevki. Raziskave v zadnjih letih so pripeljale do {tevilnih novih vpra{anj, a prinesle le malo odgovo- rov nanje. Veliko je novih spoznanj o tej bolezni, malo pa napredka v zdravljenju. Ve~ina bolnikov ima v ~asu diagnoze `e raz{irjeno bolezen. Tudi velik del tistih z domnevno omejeno bolez- nijo umre zaradi raka trebu{ne slinavke. Kljub temu se je pre`ivetje v zadnjem desetletju nekoliko izbolj{alo. V Sloveniji z ve~anjem incidence postopno prihaja do podobnih sprememb v odkrivanju in zdrav- ljenju raka trebu{ne slinavke kot v svetu. Vzporedno z ve~anjem incidence se je ve~alo tudi {tevilo resekcij. Resekcija brez ostanka tumorja (R0) je najpomembnej{i napovedni dejavnik. V zad- njem desetletju se je uveljavila tudi cefali~na duodenopankreatektomija z ohranjenim pilorusom, ki bolnika manj po{koduje ob enakem pre`ivetju kot klasi~na Whipplova operacija. Raz{irje- na limfadenektomija ne izbolj{a pre`ivetja v primerjavi s standardno operacijo. Smrtnost in zapleti po operaciji so obratno sorazmerni s {tevilom resekcij. V centrih z velikim {tevilom operacij se je smrtnost v zadnjem desetletju zmanj{ala pod 5 %, hkrati pa se je tudi pre`ivetje bolnikov v teh centrih pove~alo. V Sloveniji je bila v obdobju 1999–2000 smrtnost po resekciji glave trebu{ne slinavke velika, 16-odstotna. Po letu 2000 opa`amo tudi v Slove- niji centralizacijo specifi~nega zdravljenja na tri ve~je centre, ki se ukvarjajo z onkolo{ko kirurgijo. Tu sta uveljavljena timski pristop in multimodalno zdravljenje. V tem obdobju se je zmanj{al dele` bolnikov, zdravljenih le s kirurgijo, in pove~al dele` tistih, ki so bili {e dodatno zdravlje- ni. Ve~anje pre`ivetja je posebej izrazito v tem obdobju. Ob tem je zanimivo zmanj{anje dele`a omejenega raka in pove~anje dele`a raz{irjenega in razsejanega raka v ~asu diagnoze, kar govo- ri predvsem v prid izbolj{ani diagnostiki v zadnjih letih. Novi diagnosti~ni postopki omogo~ajo Rak.qxd 22.7.2009 12:39 Page 110 Because of its aggressiveness, pancreatic cancer is associated with a high mortality rate. Clinically it manifests itself with perineural and retroperitoneal infiltration, vascular invasion, local recur- rence and early regional and distant metastases. In recent years, research studies have opened a number of new questions, many of which remained unanswered. There are many new findings regarding this disease, though little progress has been achieved in terms of its treatment. The majority of patients will present with an advanced stage at diagnosis. Also a large proportion of those with supposedly localized disease will die from pancreatic cancer. Nevertheless, in the last decade the survival has undergone a slight improvement. By increasing incidence, in Slovenia too – likewise elsewhere in the world – we witness changes in the diagnosis and treatment of pancreatic cancer. Along with the increasing incidence the number of resections has increased too. Radical (R0) resection is the most relevant prognos- tic factor. In the last decade, cephalic duodenopancreatectomy with pylorus preservation has gained in importance; this technique is less mutilating and associated with the same survival rate as the classical Whipple's procedure. In comparison with the standard surgical approach, the extended lymphadenectomy does not improve survival. Postoperative lethality and complications are inversely proportional with the number of resec- tions. In centers with a large number of surgeries performed, in the last decade the lethality rate has dropped under 5% while the survival of patients in those centers has improved. In the period 1999–2000, the cephalic pancreatectomy-related lethality in Slovenia was as high as 16%. After the year 2000, in Slovenia too we witness centralization of the specific treatment in three bigger centers engaged in oncological surgery with an established team approach and multi- modality treatment. In that period, the proportion of patients treated with surgery alone has decreased while the proportion of those treated additionally with other modalities has increased. In the same period an increase in the survival is particularly apparent. Further to that, it is inte- resting to note a decrease in the proportion of localized cancer and an increase in the proportion of regional and disseminated disease at diagnosis, which is indicative of better diagnosis in recent 111 PANCREAS CLINICAL COMMENT ARY Mirko Omejc 01 02 0 30 40 50 60 70 80 90 100 % Slovensko povpre~je / 2000–2002 (EUROCARE-4) Slovenian average Evropsko povpre~je / 2000–2002 (EUROCARE-4) European average Povpre~je ZDA / 2000–2002 (SEER-13) USA average Slika 5: Petletno relativno pre`ivetje bolnikov z rakom trebu{ne slinavke (povpre~je in 95-odstotni interval zaupanja), zbolelih v letih 2000–2002 v Sloveniji, Evropi in nekaterih obmo~jih v ZDA. Figure 5: 5-year relative survival of pancreatic cancer patients (average and 95% confidence interval) diagnosed in the period 2000–2002 in Slovenia, Europe and in some regions of the USA. Rak.qxd 22.7.2009 12:39 Page 111 bolj natan~no dolo~itev stadija in s tem ve~anje {tevila bolnikov z razsejano boleznijo ob diag- nozi. K pove~anju {tevila bolnikov z raz{irjeno in razsejano boleznijo je prispevalo tudi izbolj{anje tehni~nih in diagnosti~nih zmogljivosti, ki omogo~ajo varne in to~ne preiskave tudi pri te`jih bolnikih z zlatenico. Pri mlaj{ih bolnikih z omejenim rakom je izbolj{anje pre`ivetja najbolj izrazito. Starej{i bolni- ki so zaradi pridru`enih bolezni manj primerni za obse`en operativni poseg in dodatno zdravljenje, zato se tu pre`ivetje le malo spreminja. Pri bolnikih z raz{irjenim ali razsejanim tumorjem in obstrukcijsko zlatenico je pogosto mogo~e napraviti le paliativen poseg. Pove~anje pre`ivetja v zadnjem 5-letnem obdobju gre predvsem na ra~un ve~je to~nosti dolo- ~itve bolezenskega stadija, bolj{e izbire bolnikov za operacijo, manj{e zgodnje pooperacijske smrtnosti in dodatnega onkolo{kega zdravljenja, kar je posledica timskega pristopa k obrav- navi bolnikov z rakom trebu{ne slinavke. [e vedno pa ostaja velik del bolnikov, pri katerih do specifi~nega zdravljenja sploh ni pri{lo. Bachmann J, Michalski CW, Martignoni ME, Büchler MW, Friess H. Pancreatic resection for pancreatic cancer. HPB 2006; 8: 346–51. Friess H, Kleef J, Büchler M. Pancreatic cancer. Guest editorial. HPB 2006; 8: 323. Merchant N, Berlin J. Past and future of pancreas cancer: are we ready to move forward together? J Clin Oncol 2008; 26: 3478–80. Omejc M. Rak trebu{ne slinavke v Sloveniji. Anketa kirur{kih oddelkov za leti 1999–2000. In: Pleskovi~ A, ed. Kirurgija trebu{ne slinavke. Ljubljana: Kirur{ke klinike KC, 2002: 135–9. 112 TREBU[NA SLINAVKA VIRI Literature Rak.qxd 22.7.2009 12:39 Page 112 years. New diagnostic procedures and improvements facilitate a more accurate staging and thus also a higher yield of patients with disseminated disease at diagnosis. The higher number of patients with disseminated disease is also attributable to the improved technical and diagnostic facilities, which enable safe and accurate examinations in severe patients with jaundice. The improvement in survival is most apparent in younger patients with localized cancer. Owing to concomitant diseases, older patients are less suitable for extensive surgical procedures and adjuvant therapy, and therefore their survival does not change much. In patients with regio- nal or disseminated tumor and obstructive icterus a palliative intervention is frequently the only option. Improved survival observed in the last 5-year period is prevailingly due to greater accuracy of staging, better selection of patients suitable for surgery, lower early postoperative lethality and additional oncological treatment, which is all a result of team approach to the treatment of patients with pancreatic cancer. However, there are still a large proportion of patients left with- out any specific treatment. 113 PANCREAS Rak.qxd 22.7.2009 12:39 Page 113 V obdobju 1991–2005 je za rakom grla zbolelo 1640 ljudi, od tega 1482 mo{kih in 158 `ensk. Kot je razvidno s Slike 1, se tako grobe kot starostno standardizirane inciden~ne in umrljivost- ne stopnje od leta 1991 zmanj{ujejo. Groba inciden~na stopnja se zmanj{uje povpre~no za 0,3 % letno, groba umrljivostna stopnja pa povpre~no za 2,2 % letno. Starostno standardizirani stop- nji se manj{ata {e nekoliko hitreje, saj v zadnjih letih zboli ve~ starej{ih bolnikov (Tabela 1). GRLO MKB 10: C32 114 0 1 2 3 4 5 6 7 1986 1990 1995 2000 2005 Leto / Year Incidenca – groba stopnja / Incidence – crude rate Incidenca – SSS* / Incidence – ASR** Umrljivost – groba stopnja / Mortality – crude rate Umrljivost – SSS* / Mortality – ASR** Stopnja na 100.000 / Rate per 100,000 * SSS – starostno standardizirana stopnja (standard – slovenska populacija leta 1986) ** ASR – age standardized rate (standard Slovenian population in 1986) Slika 1: Groba in starostno standardizirana inciden~na in umrljivostna stopnja raka grla, Slovenija 1986–2005. Figure 1: Crude and age-standardized incidence and mortality rate of laryngeal cancer, Slovenia 1986–2005. Mo{ki / Males @enske / Females Obdobje / {tevilo / 20–49 let / 50–74 let / 75+ let / {tevilo / 20–49 let / 50–74 let / 75+ let / Period number years (%) years (%) years (%) number years (%) years (%) years (%) 1991–1995 484 17,4 76,2 6,4 46 21,7 69,6 8,7 1996–2000 493 17,6 73,6 8,7 51 13,7 72,5 13,7 2001–2005 479 14,4 74,5 11,1 57 22,8 54,4 22,8 Tabela 1: [tevilo bolnikov z rakom grla po spolu in obdobju postavitve diagnoze ter njihovi dele`i po starosti. Table 1: Number of laryngeal cancer patients by sex and period of diagnosis with their proportions by age. V analizo pre`ivetja je vklju~enih 1610 primerov; 29 bolnikov (1,8 %) nismo upo{tevali, ker jim je bila diagnoza postavljena po smrti, enega, mlaj{ega od 20 let, pa obravnavamo v poglav- ju o pre`ivetju pri otrocih in mladostnikih. Med vsemi bolniki, ki smo jih vklju~ili v analizo, jih je imelo 78 % opredeljeno natan~nej{e mesto nastanka tumorja v grlu: 54 % med njimi je imelo tumor glasilk, 37 % tumor supraglotisa, okrog 1 % tumor subglotisa in grlnega hrustan- ca, 7 % pa je imelo ob diagnozi tako raz{irjen tumor, da natan~nej{ega mesta ni bilo mogo~e opredeliti. Manj kot 1 % bolnikov v vsakem obdobju ni imelo mikroskopsko potrjene bolezni. Prakti~no vsi mikroskopsko potrjeni tumorji (95 %) so bili plo{~atoceli~ni karcinomi. EPIDEMIOLOGIJA Rak.qxd 22.7.2009 12:39 Page 114 In the period 1991–2005, a total of 1640 persons were diagnosed with cancer of the larynx, of these 1482 males and 158 females. As evident from Figure 1, since 1991 crude as well as age-standardized incidence and mortality rates have been decreasing. The estimated annual percentage decrease in crude incidence rate was 0.3%, while in crude mortality rate it was 2.2%. The age-standardized rates have been decreasing even more rapidly as in the recent years the number of patients diagnosed at an advanced age is increasing (Table 1). The survival analysis included 1610 cases; 29 patients (1.8%) diagnosed only after death, were not considered in the analysis, one patient under 20 years of age is presented in the chapter on the survival of children and adolescents. Among all the patients included in the analysis, 78% had the site of tumor origin in the larynx more precisely defined: thus 54% had tumor of the vocal cords, 37% of the supraglottis, approximately 1% of the subglottis and laryngeal car- tilage, while in 7% tumor at the time of diagnosis was so advanced that the exact site of origin could not be precisely defined. Approximately 1% of patients in each time period did not have microscopically confirmed dis- ease. Practically all microscopically confirmed tumors were planocellular carcinomas (95%). The greatest proportion of patients was between 50 and 74 years of age at diagnosis. In both genders, the proportion of those aged 75 years or older has been increasing with time while the proportion of male patients under 50 years of age has undergone a slight decrease; in females however it did not change much (Table 1). Almost all patients had the disease diagnosed at localized or regional stage. The proportions of disseminated and undefined stages are negligible (Table 2). In the years 2001–2005 more than a half of males and approximately a third of females had the disease diagnosed at a locali- zed stage. In males, the ratio between stages remained roughly equal throughout the observation period while in females a decrease in the percentage of patients with localized stage was noted in the recent period. In the period 2001–2005, 5% of patients did not receive specific treatment. In the observed 15-year period the proportion of untreated patients has remained almost unchanged. Among the patients receiving specific treatment in the period 2001–2005, 40% were irradiated, 38% had irradiation combined with surgery while 11% underwent surgery alone. Twelve percents of patients also received chemotherapy besides standard treatment with irradiation and/or sur- gery. The proportions of individual treatment modalities did not change significantly with time. In the period 2001–2005, practically all treated patients started their treatment in one of the three leading Slovenian health institutions: 53% at the IO Ljubljana, 30% in the UMC Ljubljana and 15% in the UMC Maribor. A few patients started their treatment in general hospitals in Celje, Murska Sobota and Novo mesto. LARYNX ICD 10: C32 115 Tabela 2: [tevilo bolnikov z rakom grla po spolu in obdobju postavitve diagnoze ter njihovi dele`i po stadiju. Table 2: Number of laryngeal cancer patients by sex and period of diagnosis with their proportions by stage. Mo{ki / Males @enske / Females Obdobje / {tevilo / omejen / raz{irjen / razsejan / neznan / {tevilo / omejen / raz{irjen / razsejan / neznan / Period number localized regional distant unknown number localized regional distant unknown (%) (%) (%) (%) (%) (%) (%) (%) 1991–1995 484 49,4 48,1 1,4 1,0 46 63,0 34,8 0,0 2,2 1996–2000 493 58,2 40,4 0,8 0,6 51 56,9 43,1 0,0 0,0 2001–2005 479 51,4 47,4 0,8 0,4 57 33,3 61,4 3,5 1,8 EPIDEMIOLOGY Rak.qxd 22.7.2009 12:39 Page 115 Starost najve~jega dele`a zbolelih je bila ob diagnozi med 50–74 let. Dele` starih 75 let in ve~ se pri obeh spolih s ~asom ve~a, medtem ko se dele` mlaj{ih od 50 let pri mo{kih nekoliko manj{a, pri `enskah pa ostaja nespremenjen (Tabela 1). Skoraj vsem bolnikom je bila bolezen odkrita v omejenem ali raz{irjenem stadiju. Dele`i raz- sejanih in neopredeljenih stadijev so zanemarljivi (Tabela 2). V letih 2001–2005 je bila bolezen odkrita v omejenem stadiju pri ve~ kot polovici mo{kih in pri pribli`no tretjini `ensk. Raz- merja med stadiji pri mo{kih ostajajo ves ~as opazovanja pribli`no enaka, pri `enskah pa se je v zadnjem obdobju zmanj{al dele` bolnic z omejenim stadijem. V obdobju 2001–2005 ni bilo specifi~no zdravljenih 5 % bolnikov. Dele` nezdravljenih bol- nikov ostaja v opazovanem 15-letnem obdobju skoraj enak. Med specifi~no zdravljenimi bolniki 116 GRLO 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Slika 2: Deset-, pet-, tri- in enoletno relativno pre`ivetje bolnikov z rakom grla po obdobju postavitve diagnoze. Figure 2: 10-, 5-, 3- and 1-year relative survival of laryngeal cancer patients by period of diagnosis. Tabela 3: Opazovano in relativno pre`ivetje bolnikov z rakom grla po spolu in obdobju postavitve diagnoze s 95-odstotnim intervalom zaupanja (IZ). Table 3: Observed and relative survival of laryngeal cancer patients by sex and period of diagnosis with 95% confidence interval (CI). Opazovano pre`ivetje / Observed survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 81,0 (77,6–84,6) 60,3 (56,1–64,9) 49,2 (44,9–53,8) 76,1 (64,7–89,5) 69,6 (57,5–84,2) 60,9 (48,3–76,7) 1996–2000 78,1 (74,5–81,8) 63,1 (59,0–67,5) 50,9 (46,7–55,5) 88,2 (79,8–97,5) 72,5 (61,3–85,9) 62,7 (50,8–77,5) 2001–2005 83,3 (80,0–86,7) 65,4 (61,2–69,8) 53,9 (49,2–59,0) 75,4 (65,1–87,5) 59,3 (47,7–73,7) 51,0 (38,7–67,2) Relativno pre`ivetje / Relative survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 83,4 (79,7–87,1) 66,1 (61,1–71,0) 57,4 (52,0–62,9) 77,5 (63,9–91,1) 73,7 (58,2–89,3) 67,2 (49,7–84,7) 1996–2000 80,6 (76,7–84,4) 69,5 (64,7–74,4) 60,2 (54,7–65,6) 90,0 (80,5–99,5) 77,2 (63,0–91,4) 69,8 (53,3–86,2) 2001–2005 85,7 (82,2–89,2) 72,0 (67,1–76,8) 63,7 (57,6–69,7) 76,5 (64,3–88,8) 62,4 (47,2–77,5) 55,8 (38,0–73,6) Rak.qxd 22.7.2009 12:39 Page 116 The relative survival of patients with laryngeal cancers has been moderately increasing; in 15 years, it increased by 5% (Figure 2). In comparison with females, the 5-year relative survival of males is slightly better (Table 3). The relevance of stage at diagnosis is shown in Figure 3. In the last period, 5-year relative survival of patients with localized stage was 87%, while in those with regional stage at diagnosis it was 41%. Due to a small number of patients with disseminated disease, the evaluation of their survival is unreliable. In recent years, a considerable improve- ment in the survival was observed in patients with localized disease, whereas no significant improvement was noted in those with regional and disseminated disease. The survival of patients in our analysis did not depend on age at diagnosis (Figure 4). The 5-year relative survival rate of all patients diagnosed in the period 2001–2005 was 63% (Figure 2); patients surviving the first year may expect to survive five years in 74%. In com- parison with the rest of cancer patients, those with cancers of the head/neck will more frequently develop a second primary cancer. Patients in whom larynx was the only primary cancer site had 70% 5-year relative survival rate. 117 LARYNX 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 Omejen / Localized Raz{irjen / Regional Razsejan / Distant Vsi / All Slika 3: Petletno relativno pre`ivetje bolnikov z rakom grla po stadiju in obdobju postavitve diagnoze. Figure 3: 5-year relative survival of laryngeal cancer patients by stage and period of diagnosis. 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 20–49 let / years 50–74 let / years 75+ let / years Vsi / All Slika 4: Petletno relativno pre`ivetje bolnikov z rakom grla po starosti in obdobju postavitve diagnoze. Figure 4: 5-year relative survival of laryngeal cancer patients by age and period of diagnosis. Rak.qxd 22.7.2009 12:39 Page 117 je bilo v letih 2001–2005 40 % obsevanih, 38 % je bilo poleg obsevanja {e operiranih, 11 % pa je bilo samo operiranih. Poleg klasi~nega zdravljenja z obsevanjem in/ali operacijo je 12 % bol- nikov prejelo {e kemoterapijo. Dele`i posameznih na~inov zdravljenja se s ~asom niso bistveno spreminjali. V obdobju 2001–2005 so skoraj vsi bolniki, ki so bili zdravljeni, pri~eli zdravljenje v eni od treh vodilnih slovenskih zdravstvenih ustanov: 53 % na OI Ljubljana, 30 % v UKC Ljubljana in 15 % v UKC Maribor. Nekaj bolnikov se je za~elo z zdraviti {e v SB Celje, SB Murska Sobo- ta in SB Novo mesto. Petletno relativno pre`ivetje bolnikov z rakom grla se zmerno pove~uje; v 15 letih se je petletno relativno pre`ivetje pove~alo za 5 % (Slika 2). Petletno relativno pre`ivetje mo{kih je v primer- javi z `enskami nekoliko bolj{e (Tabela 3). Kako pomemben je stadij ob diagnozi, ka`e Slika 3. Petletno relativno pre`ivetje bolnikov z omejenim stadijem je v zadnjem obdobju 87 %, med- tem ko je pri bolnikih z raz{irjenim stadijem bolezni ob diagnozi 41 %. Bolnikov v razsejanem stadiju je malo, tako da je ocenjevanje njihovega pre`ivetja nezanesljivo. V zadnjih letih se je precej izbolj{alo pre`ivetje bolnikov z omejenim stadijem bolezni, medtem ko pri bolnikih z raz- {irjeno in razsejano boleznijo ni bistvenega napredka. Pre`ivetje bolnikov, vklju~enih v na{o analizo, ni bilo odvisno od starosti ob ugotovitvi bolezni (Slika 4). Petletno relativno pre`ivetje vseh zbolelih v obdobju 2001–2005 je bilo 63 % (Slika 2); bolni- ki, ki pre`ivijo prvo leto, pa lahko pri~akujejo 74-odstotno petletno relativno pre`ivetje. Pogosteje kot drugi bolniki z rakom zbolijo bolniki z rakom na podro~ju glave in vratu {e za drugim pri- marnim rakom. Bolniki z rakom grla kot edinim rakom so imeli petletno relativno pre`ivetje 70 %. Rezultati {tudije EUROCARE-4 za zbolele v obdobju 2000–2002 ka`ejo, da je grobo petlet- no relativno pre`ivetje slovenskih bolnikov z rakom grla statisti~no nezna~ilno ve~je od evropskega povpre~ja (Slika 5). 118 GRLO KLINI^NI KOMENT AR Lojze [mid Primo` Strojan Branko Zakotnik Visok dele` histolo{ko opredeljene bolezni ne presene~a, saj je mikroskopska potrditev bolez- ni pred pri~etkom zdravljenja `e desetletja ena temeljnih zahtev multidisciplinarnega tima strokovnjakov, ki v Sloveniji obravnavajo to vrsto raka. ^eprav je v zadnjem petletnem obdob- ju pri bolnicah opaziti manj primerov z omejeno obliko bolezni (na ra~un raz{irjene oblike), ta »premik« zaradi sorazmerno majhnega {tevila bolnic (okoli 10 % vseh bolnikov z rakom grla) ne vpliva pomembneje na porazdelitev stadijev bolezni ob diagnozi. Razmerje med omejenim in raz{irjenim stadijem tako ostaja skozi celotno 15-letno obdobje stabilno in zna{a pribli`no 50 % : 50 %. Obstoje~e razmerje potrjuje spoznanje, kako pomembna je za posameznika bar- va glasu, kajti sprememba v barvi je pri raku grla obi~ajno prvi znanilec bolezenskega dogajanja v tem delu dihalne poti. Pre`ivetje bolnikov z rakom grla se je ves ~as, iz obdobja v obdobje, ve~alo, stopnja umrljivo- sti pa ustrezno ni`ala. @al pa se opazovano izbolj{anje ka`e izklju~no pri bolnikih z omejeno obliko bolezni, kar se pripisuje napredku v kirurgiji in radioterapiji (izbolj{anje postopkov na~r- tovanja in priprave bolnikov na obsevanje, uvedba naprednej{ih obsevalnih tehnik). V skupini z raz{irjeno obliko bolezni, ki je (bila) tar~na skupina za sodobnej{e kombinirane na~ine zdrav- ljenja, v prvi vrsti radiokemoterapije, ki se je v 90. letih preteklega stoletja uveljavila kot zlati standard v zdravljenju lokalno in podro~no napredovalih rakov glave in vratu, se pre`ivetje bol- nikov ni izbolj{alo. Vzrok velja iskati v spoznanju, da je bil dele` na{ih bolnikov, zdravljenih s kombinacijo obsevanja in kemoterapije (po operaciji ali brez) sorazmerno majhen oziroma vsekakor manj{i kot v primeru drugih rakov podro~ja glave in vratu. Tudi za vpliv prognosti~- no ugodnej{ih tumorjev, nastalih kot posledica oku`be s HPV, domnevamo, da je v slovenski populaciji bolnikov manj{i kot v zahodnih dr`avah; `al sta prevladujo~a dejavnika tveganja raka grla ~ezmerno pitje alikoholnih pija~ in kajenje. Rak.qxd 22.7.2009 12:39 Page 118 According to the results of EUROCARE-4 study for patients diagnosed in 2000–2002, the crude 5-year relative survival of Slovenian patients with laryngeal cancer is above (statistical- ly not significant) the European average (Figure 5). 119 LARYNX CLINICAL COMMENT ARY Lojze [mid Primo` Strojan Branko Zakotnik 01 02 0 30 40 50 60 70 80 90 100 % Slovensko povpre~je / 2000–2002 (EUROCARE-4) Slovenian average Evropsko povpre~je / 2000–2002 (EUROCARE-4) European average Povpre~je ZDA / 2000–2002 (SEER-13) USA average Slika 5: Petletno relativno pre`ivetje bolnikov z rakom grla (povpre~je in 95-odstotni interval zaupanja), zbolelih v letih 2000–2002 v Sloveniji, Evropi in nekaterih obmo~jih v ZDA. Figure 5: 5-year relative survival of laryngeal cancer patients (average and 95% confidence interval) diagnosed in the period 2000–2002 in Slovenia, Europe and in some regions of the USA. The high proportion of histologically verified/confirmed disease is not surprising, since for decades microscopical confirmation of the disease prior to the beginning of therapy has been one of the fundamental requirements of the multidisciplinary team of experts dealing with this type of cancer in Slovenia. Although in the last 5-year period fewer cases with localized disease were observed in women (on the account of regional disease), owing to a relatively small number of female patients (approximately 10% of all laryngeal cancer patients) this shift does not exert a significant influence on stage-distribution at diagnosis. Thus, the ratio between localized and regional stage remains stable throughout the 15-year observation period, being 50% vs. 50%. The present finding confirms the relevance of individual's voice color, which, when changed, is generally the first indicator of a pathological process in that part of the respiratory tract. The survival of laryngeal cancer patients has been steadily improving with every next obser- vation period, and accordingly their mortality rates have been decreasing. Unfortunately, the observed improvement has been limited exclusively to the patients with localized disease, which should be attributed to the advances in surgery and radiotherapy (improved irradiation plan- ning and patient preparation procedures and the implementation of more advanced irradiation techniques). No improvement in the survival was noted in the group with regional disease rep- resenting the target group for more advanced combined treatment modalities, in particular radiochemotherapy, which made the gold standard in the treatment of localized and regiona- lly advanced head and neck cancers. The reason should be sought in the fact that the proportion of our patients treated with a combination of irradiation and chemotherapy (with or without previous surgery) was relatively low or in any case lower than in other head and neck cancers. We assume that the proportion of prognosticaly favurable tumors caused by HPV infection in Slovenian population is smaller than in western Europe; unfortunately, the prevailing risk factors for laryngeal cancer in Slovenia are alcohol abuse and tobacco smoking. Rak.qxd 22.7.2009 12:39 Page 119 (Ne)uspehov pri zdravljenju bolnikov z razsejano obliko bolezni ob diagnozi v razli~nih obdob- jih zaradi malo{tevilnosti teh bolnikov ni mo`no vrednotiti. Vsekakor pa dr`i, da je u~inkovitost zdravljenja, ki je na voljo (predvsem kemoterapija), pri razsejanem raku grla ve~ja kot pri dru- gih, prav tako razsejanih rakih zgornjega dela prebavne cevi in dihalnih poti. Primerjava uspe{nosti zdravljenja med posameznimi starostnimi skupinami ni bila mo`na, ker je bila ve~ina bolnikov z rakom grla v srednji starostni skupini (med 50–74 let). Fakhry C, Westra WH, Li S, Cmelak A, Ridge JA, Pinto H, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 2008; 100: 261–9. Le{ni~ar H, [mid L, Zakotnik B. Early glottic cancer: the influence of primary treatment on voice preservation. Int J Radiat Oncol Biol Phys 1996; 36: 1025–32. Strojan P , Karner K, [mid L, [oba E, Fajdiga I, Jan~ar B, et al. Concomitant chemoradiotherapy with mitomycin C and cisplatin in advanced unresectable carcinoma of the head and neck: Phase I–II clinical study. Int J Radiat Oncol Biol Phys 2008; 72: 365–72. [mid L, Le{ni~ar H, Zakotnik B, [oba E, Budihna M, Furlan L, et al. Radiotherapy, combined with simul- taneous chemotherapy with mitomycin C and bleomycin for inoperable head and neck cancer-preliminary report. Int J Radiat Oncol Biol Phys 1995; 32: 769–75. [mid L, Budihna M, Zakotnik B, [oba E, Strojan P, Fajdiga I, et al. Postoperative concomitant irradiation and chemotherapy with mitomycin C and bleomycin for advanced head-and-neck carcinoma. Int J Radiat Oncol Biol Phys 2003; 56: 1055–62. Zakotnik B, [mid L, Budihna M, Le{ni~ar H, [oba E, Furlan L, et al. Concomitant radiotherapy with mitomycin C and bleomycin compared with radiotherapy alone in inoperable head and neck cancer: final report. Int J Radiat Oncol Biol Phys 1998; 41: 1121–7. Zakotnik B, Budihna M, [mid L, [oba E, Strojan P , Fajdiga I, et al. Patterns of failure in patients with locally advanced head and neck cancer treated postoperatively with irradiation or concomitant irradiation with Mitomycin C and Bleomycin. Int J Radiat Oncol Biol Phys 2007; 67: 685–90. 120 GRLO VIRI Literature Rak.qxd 22.7.2009 12:39 Page 120 Owing to a small number of patients with disseminated disease at diagnosis it is not possible to evaluate their treatment success or failure during different observation periods. It is true, however, that in laryngeal cancer the effectiveness of the available therapy (in particular chemothe- rapy) is greater than in other also disseminated cancers of the upper gastrointestinal and respiratory tract. The fact that the majority of laryngeal cancer patients belonged to the middle-age group (between 50 to 74 years) rendered a comparison of treatment success between different age groups unfea- sible. 121 LARYNX Rak.qxd 22.7.2009 12:39 Page 121 V obdobju 1991–2005 je za plju~nim rakom zbolelo 15.647 ljudi, 12.377 mo{kih in 3270 `ensk. Kot je razvidno s Slike 1, sta se v opazovanem obdobju ve~ali groba inciden~na in umrljivostna stopnja, povpre~no za 2,0 % letno. Ve~ino tega pove~anja lahko pripi{emo staranju prebivalstva, saj sta obe starostno standardizirani stopnji vsa leta prakti~no konstantni. Starostno standar- dizirane stopnje po spolu pa ka`ejo druga~no sliko pri mo{kih in `enskah: pri prvih se obe zmanj{ujeta od sredine devetdesetih let, pri drugih pa ve~ata, kar je posledica razli~nih kadil- skih navad med spoloma. PLJU^A MKB 10: C33, C34 122 Mo{ki / Males @enske / Females Obdobje / {tevilo / 20–49 let / 50–74 let / 75+ let / {tevilo / 20–49 let / 50–74 let / 75+ let / Period number years (%) years (%) years (%) number years (%) years (%) years (%) 1991–1995 3782 9,5 79,3 11,2 753 10,6 72,0 17,4 1996–2000 3943 9,9 76,7 13,3 990 13,8 66,6 19,6 2001–2005 4104 7,1 75,1 17,8 1349 11,6 62,6 25,9 T abela 1: [tevilo bolnikov s plju~nim rakom po spolu in obdobju postavitve diagnoze ter njihovi dele`i po starosti. Table 1: Number of lung cancer patients by sex and period of diagnosis with their proportions by age. 0 10 20 30 40 50 60 70 1986 1990 1995 2000 2005 Leto / Year Incidenca – groba stopnja / Incidence – crude rate Incidenca – SSS* / Incidence – ASR** Umrljivost – groba stopnja / Mortality – crude rate Umrljivost – SSS* / Mortality – ASR** Stopnja na 100.000 / Rate per 100,000 * SSS – starostno standardizirana stopnja (standard – slovenska populacija leta 1986) ** ASR – age standardized rate (standard Slovenian population in 1986) Slika 1: Groba in starostno standardizirana inciden~na in umrljivostna stopnja plju~nega raka, Slovenija 1986–2005. Figure 1: Crude and age-standardized incidence and mortality rate of lung cancer, Slovenia 1986–2005. V analizo pre`ivetja je vklju~enih 14.921 primerov; 722 bolnikov (4,6 %) nismo upo{tevali, ker jim je bila diagnoza postavljena po smrti, 4 mlaj{e od 20 let pa obravnavamo v poglavju o pre- `ivetju pri otrocih in mladostnikih. 85 bolnikov je imelo tumor na sapniku, ostali tumorji pa so vzniknili v sapnicah in plju~ih. Odstotek mikroskopsko potrjenih primerov je v vseh treh obdobjih enak: 93 %. Med mikro- skopsko potrjenimi je imelo v 15-letnem obdobju 34 % bolnikov plo{~atoceli~ni karcinom, 25 % adenokarcinom, 18 % drobnoceli~ni karcinom in 16 % karcinome drugih vrst. Dele` adeno- EPIDEMIOLOGIJA Rak.qxd 22.7.2009 12:39 Page 122 In the period 1991–2005, a total of 15,647 persons were diagnosed with lung cancer, of these 12,377 males and 3270 females. As evident from Figure 1, in the observation period the esti- mated annual percentage increase in crude incidence and mortality rate was 2.0%. This increase can be attributed mainly to population ageing, since both age-standardized rates have remained practically stable throughout the observation period. Age-standardized rates by gender reveal differences between males and females: in the former, both rates have been decreasing since the middle of the 90's, while in the latter they have been increasing as a result of differences in smoking habits between genders. The survival analysis included 14,921 cases; 722 patients (4.6%) diagnosed only after death were not considered in the analysis, four patients under 20 years of age are presented in the chapter on the survival of children and adolescents. 85 patients had tumor of trachea, the rest of tumors originated in the bronchus and lung. The percentage of microscopically confirmed disease remained the same (93%) in all three obser- vation periods. In the 15-year observation period, among the microscopically confirmed cases, planocellular carcinoma was found in 34% of patients, adenocarcinoma in 25%, small-cell car- cinoma in 18% and other types of carcinoma in 16% of patients. The proportion of adenocarcinoma has been increasing all the time; in the last period this histological type represented already 30% of all lung cancers; in comparison with the period 1991–1995, in the period 2001–2005 the number of patients with adenocarcinoma almost doubled. The number of patients with planocellular carcinoma has remained all the time unchanged while the proportion of these patients among all lung cancers has been decreasing; the proportion of small-cell carcinomas has remained almost the same throughout the observation period. More than two thirds of patients of both genders were aged between 50 and 74 years at the time of diagnosis; less than 10% were diagnosed before 50 years of age (Table 1). Proportions in these two age groups have not been changing significantly with time, however, the proportion of those aged 75 years or older has been increasing in both genders, thus in the last period almost a quarter of female patients were aged 75 years or older. Most patients present with disseminated disease at diagnosis. The proportion of these patients has been increasing throughout the observation period, in the last period exceeding 40%. In particular, the proportion of patients with localized disease has been decreasing on the account of a higher proportion of those with disseminated disease; the proportion of patients with undefined stage has remained all the time approximately 4% (Table 2). In the years 2001–2005, 32% of patients did not receive specific treatment. The proportion of untreated patients was decreasing throughout the study period; among those diagnosed in the period 1991–1995 there were 39% of patients without specific treatment. The untreated patients LUNG ICD 10: C33, C34 123 Tabela 2: [tevilo bolnikov s plju~nim rakom po spolu in obdobju postavitve diagnoze ter njihovi dele`i po stadiju. Table 2: Number of lung cancer patients by sex and period of diagnosis with their proportions by stage. Mo{ki / Males @enske / Females Obdobje / {tevilo / omejen / raz{irjen / razsejan / neznan / {tevilo / omejen / raz{irjen / razsejan / neznan / Period number localized regional distant unknown number localized regional distant unknown (%) (%) (%) (%) (%) (%) (%) (%) 1991–1995 3782 27,5 37,1 30,9 4,5 753 26,0 31,1 35,7 7,2 1996–2000 3943 24,5 39,5 32,9 3,0 990 22,4 33,0 40,2 4,3 2001–2005 4104 16,6 38,9 41,0 3,5 1349 17,5 36,2 42,8 3,6 EPIDEMIOLOGY Rak.qxd 22.7.2009 12:39 Page 123 karcinoma se ves ~as pove~uje. V zadnjem obdobju je ta histolo{ka vrsta predstavljala `e 30 % vseh primerov plju~nega raka, {tevilo bolnikov s plju~nim adenokarcinomom pa se je v obdob- ju 2001–2005 glede na obdobje 1991–1995 skoraj podvojilo. [tevilo bolnikov s plo{~atoceli~nim karcinomom ostaja ves ~as enako, zni`uje pa se dele` teh bolnikov med vsemi primeri plju~- nega raka; dele` drobnoceli~nih karcinomov ostaja ves ~as opazovanja skoraj enak. Ve~ kot dve tretjini bolnikov in bolnic je bilo ob diagnozi starih med 50 in 74 let, manj kot 10 % jih je zbolelo pred 50. letom starosti (Tabela 1). Dele`i v teh dveh starostnih skupinah se s ~asom niso bistveno spreminjali, pri obeh spolih pa se pove~uje dele` starih 75 let in ve~; v zadnjem obdobju je bila `e ~etrtina bolnic, starih 75 let in ve~. 124 PLJU^A 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Slika 2: Deset-, pet-, tri- in enoletno relativno pre`ivetje bolnikov s plju~nim rakom po obdobju postavitve diagnoze. Figure 2: 10-, 5-, 3- and 1-year relative survival of lung cancer patients by period of diagnosis. Tabela 3: Opazovano in relativno pre`ivetje bolnikov s plju~nim rakom po spolu in obdobju postavitve diagnoze s 95-odstotnim intervalom zaupanja (IZ). Table 3: Observed and relative survival of lung cancer patients by sex and period of diagnosis with 95% con- fidence interval (CI). Opazovano pre`ivetje / Observed survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 31,2 (29,8–32,7) 10,9 (9,9–11,9) 8,0 (7,2–8,9) 31,2 (28,1–34,7) 13,8 (11,6–16,5) 10,4 (8,4–12,8) 1996–2000 31,5 (30,1–33,0) 11,8 (10,8–12,8) 8,3 (7,5–9,2) 34,3 (31,5–37,4) 12,6 (10,7–14,9) 9,3 (7,6–11,3) 2001–2005 34,1 (32,7–35,6) 13,7 (12,7–14,8) 9,6 (8,6–10,7) 39,3 (36,8–42,0) 16,6 (14,7–18,7) 11,6 (9,9–13,7) Relativno pre`ivetje / Relative survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 32,4 (30,8–34,0) 12,2 (11,0–13,4) 9,8 (8,7–10,9) 32,1 (28,5–35,7) 15,0 (12,1–18,0) 12,0 (9,2–14,8) 1996–2000 32,7 (31,2–34,2) 13,2 (12,1–14,4) 10,2 (9,0–11,3) 35,2 (32,1–38,4) 13,7 (11,2–16,1) 10,7 (8,4–13,0) 2001–2005 35,5 (33,9–37,0) 15,6 (14,3–16,8) 12,0 (10,7–13,3) 40,3 (37,6–43,1) 18,0 (15,7–20,3) 13,5 (11,1–15,9) Rak.qxd 22.7.2009 12:39 Page 124 do not differ significantly from those with specific treatment in terms of stage or age at diag- nosis. Among the patients receiving specific treatment in the period 2001–2005, the majority (31%) were treated by radiotherapy alone, 27% received chemotherapy in addition to irradi- ation while 15% were treated by chemotherapy alone. Within their primary treatment 25% of patients underwent surgery, half of them also receiving chemotherapy and/or radiotherapy. Compared to the period 1991–1995, the proportion of patients treated either by radiotherapy or surgery alone or with a combination of radiotherapy and surgery as single-modality treat- ment has decreased. Contrary to that, there is an increasing number of patients in whom standard radiotherapy and/or surgery has been combined with chemotherapy. In the period 2001–2005, 61% of patients started their treatment at the IO Ljubljana, 19% in the UMC Ljubljana and 10% respectively in the UMC Maribor and at Hospital Golnik. Individual patients started their treatment in general hospitals of Murska Sobota, Topol{ica and Izola. 125 LUNG 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 Omejen / Localized Raz{irjen / Regional Razsejan / Distant Vsi / All Slika 3: Petletno relativno pre`ivetje bolnikov s plju~nim rakom po stadiju in obdobju postavitve diagnoze. Figure 3: 5-year relative survival of lung cancer patients by stage and period of diagnosis. 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 20–49 let / years 50–74 let / years 75+ let / years Vsi / All Slika 4: Petletno relativno pre`ivetje bolnikov s plju~nim rakom po starosti in obdobju postavitve diagnoze. Figure 4: 5-year relative survival of lung cancer patients by age and period of diagnosis. Rak.qxd 22.7.2009 12:39 Page 125 Najve~ bolnikov ima ob diagnozi razsejano bolezen. Dele` teh bolnikov se je ves ~as opazovanja pove~eval. V zadnjem obdobju je presegel 40 %. Na ra~un ve~jega dele`a bolnikov z razseja- nim stadijem se je zmanj{eval predvsem dele` bolnikov z omejenim stadijem; dele` bolnikov brez znanega stadija ostaja ves ~as pribli`no 4 % (Tabela 2). V letih 2001–2005 se ni specifi~no zdravilo 32 % bolnikov. Dele` nezdravljenih bolnikov se je v celotnem obdobju analize zmanj{eval; med bolniki, zbolelimi v obdobju 1991–1995, jih ni bilo specifi~no zdravljenih 39 %. Skupina nezdravljenih se ne razlikuje bistveno glede na sta- dij ali starost ob diagnozi od specifi~no zdravljenih bolnikov. Med specifi~no zdravljenimi je bilo v letih 2001–2005 najve~ bolnikov (31 %) samo obsevanih, pri 27 % je bila radioterapiji dodana {e kemoterapija, 15 % jih je bilo zdravljenih le s kemoterapijo. V sklopu prvega zdrav- ljenja je bilo operiranih 25 % bolnikov, polovici med njimi je bila dodana {e kemoterapija in/ali obsevanje. V primerjavi z obdobjem 1991–1995 se je zmanj{al dele` bolnikov, ki so bili samo obsevani, samo operirani ali pa obsevani in operirani. Nasprotno pa se ve~a {tevilo bolnikov, pri katerih je bila klasi~nemu zdravljenju z obsevanjem in/ali operacijo dodana {e kemoterapija. V obdobju 2001–2005 se je 61 % bolnikov pri~elo zdraviti na OI Ljubljana, 19 % v UKC Ljub- ljana, po 10 % pa v UKC Maribor in Bolni{nici Golnik. Posamezne bolnike so pri~eli zdraviti {e v splo{nih bolni{nicah v Murski Soboti, Topol{ici in Izoli. Petletno relativno pre`ivetje bolnikov s plju~nim rakom se je v 15 letih pove~alo za 2,2 % (Sli- ka 2), pribli`no enako pri obeh spolih (Tabela 3). Relativno dobro je pre`ivetje bolnikov z omejeno boleznijo ob diagnozi: v obdobju 1991–1995 je bilo 26 %, v zadnjem obdobju pa se je pove- ~alo na 41 %. Ve~je je tudi petletno relativno pre`ivetje bolnikov z raz{irjenim stadijem, medtem ko se pre`ivetje bolnikov z razsejanim stadijem bistveno ne spreminja in je {e vedno majhno (Slika 3). Napovedni dejavnik je tudi starost, saj je bilo petletno relativno pre`ivetje bolnikov, ki so v letih 2001–2005 zboleli pred 50. letom starosti, 18 %, tistih, ki so zboleli stari 75 let in ve~, pa manj{e od 5 % (Slika 4). Petletno relativno pre`ivetje vseh zbolelih v obdobju 2001–2005 je bilo 12 % (Slika 2); bolni- ki, ki pre`ivijo prvo leto, pa lahko pri~akujejo 33-odstotno petletno relativno pre`ivetje. Rezultati {tudije EUROCARE-4 za zbolele v obdobju 2000–2002 ka`ejo, da je pre`ivetje slo- venskih bolnikov s plju~nim rakom statisti~no zna~ilno manj{e od evropskega povpre~ja (Slika 5). 126 PLJU^A KLINI^NI KOMENT AR Andrej Debeljak Petletno relativno pre`ivetje bolnikov s plju~nim rakom ka`e rasto~i trend, zamejitev raka je natan~nej{a, eksplorativnih torakotomij je manj. Izbolj{anje pre`ivetja ni posledica zgodnej- {ega odkrivanja bolezni, pa~ pa bolj{e diagnosti~ne in terapevtske oskrbe bolnikov s plju~nim rakom v zadnjih desetletjih. Za obravnavo bolnikov s plju~nim rakom skrbijo timski konzili- ji po slovenskih smernicah. Za prikaz tumorja, pove~anih bezgavk in zasevkov v oddaljene organe se uporablja ra~unal- ni{ka tomografija prsnih organov, glave in zgornjega trebuha. Vse pogostej{a je tudi uporaba preiskav PET CT . Na osnovi slikovnih preiskav se pri bronhoskopiji uporablja bronhialna biop- sija, bronhoskopska plju~na biopsija, vodena z rentgensko ali ultrazvo~no presvetljavo. Bezgavke v mediastinumu so dostopne s pomo~jo endobronhialne in ezofagealne ultrazvo~ne preiska- ve. Za bezgavke v lateralni lo`i aorto-plju~nega okna in ob aorti ascendens pa so {e vedno potrebni kirur{ki diagnosti~ni posegi: prednja mediastinotomija (hiloskopija), VATS ali torakotomija. VATS se uporablja pri neopredeljenih okroglih spremembah, ki bi lahko bile periferni plju~- ni rak. Kadar diagnosti~na bronhoskopija ni uspela potrditi diagnoze, se uporablja transtorakalna igelna biopsija, ne le z rentgensko ali ultrazvo~no presvetljavo, temve~ tudi z natan~nej{o ra~u- nalni{ko tomografijo. Rak.qxd 22.7.2009 12:39 Page 126 In 15 years, the 5-year relative survival of patients with lung cancer increased by 2.2% (Figure 2), the rates being comparable in both genders (Table 3). The survival of patients with localized disease at diagnosis is relatively favorable: in the period 1991–1995 their rate was 26%, where- as in the last period it increased to 41%. A higher 5-year relative survival is also observed in patients with regional stage, while no significant improvement has been noted in those with disseminated disease, which still remains low (Figure 3). Age is a prognostic factor as well, since in the period 2001–2005, the 5-year relative survival of patients less than 50 years of age at diagnosis was 18%, while the rate in those aged 75 years or older was under 5% (Figure 4). The 5-year relative survival of all patients diagnosed in the period 2001–2005 was 12% (Figure 2); patients surviving the first year may expect to survive five years in 33%. According to the results of EUROCARE-4 study for patients diagnosed in 2000–2002, the survival of lung cancer patients in Slovenia is significantly below the European average (Figure 5). 127 LUNG CLINICAL COMMENT ARY Andrej Debeljak 01 02 0 30 40 50 60 70 80 90 100 % Slovensko povpre~je / 2000–2002 (EUROCARE-4) Slovenian average Evropsko povpre~je / 2000–2002 (EUROCARE-4) European average Povpre~je ZDA / 2000–2002 (SEER-13) USA average Slika 5: Petletno relativno pre`ivetje bolnikov s plju~nim rakom (povpre~je in 95-odstotni interval zaupanja), zbolelih v letih 2000–2002 v Sloveniji, Evropi in nekaterih obmo~jih v ZDA. Figure 5: 5-year relative survival of lung cancer patients (average and 95% confidence interval) diagnosed in the period 2000–2002 in Slovenia, Europe and in some regions of the USA. The 5-year relative survival of patients with lung cancer shows an increasing trend, staging of the disease is more accurate and there are fewer explorative thoracotomies performed. Rather than being a consequence of earlier diagnosis, the improved survival in the last decades is attribu- table to a better diagnostic and therapeutic approach to patients with lung cancer. Lung cancer patients are treated by multidisciplinary teams according to the national guidelines. The primary tumor, enlarged lymph nodes and metastases to distant organs are imaged by means of computer tomography of the thoracic organs, head and upper abdomen. The use of PET and CT examinations is becoming more frequent too. Based on imaging methods, bronchoscopy is performed by means of bronchial biopsy and either X-ray- or US-guided bronchoscopic lung biopsy. Mediastinal lymph nodes are accessible by endobronchial and esophageal ultrasonog- raphy. However, surgical diagnostic procedures, such as anterior mediastinotomy (hiloscopy), VATS or thoracotomy, are still required for the examination of lymph nodes in the lateral part of the aortopulmonary window and along the ascending aorta. V ATS is used in undefined round lesions, which might be interpreted as peripheral lung cancer. When diagnosis fails to Rak.qxd 22.7.2009 12:39 Page 127 Slovenski kirurgi so v zadnjih letih uporabljali predvsem lobektomije, manj pulmektomije, raje rokavaste lobektomije. Izjemoma, ob slabi plju~ni funkciji ali visoki starosti, so bile uporab- ljene omejene resekcije. Za plju~ne resekcije so pri~eli uporabljati tudi V ATS. Ob vsaki resekciji so delali limfadenektomijo bezgavk v mediastinumu. Radioterapija se uporablja vse bolj usmerjeno na tumor, zgodaj, v kombinaciji s kemoterapi- jo. Omejene tumorje, pri katerih kirur{ko zdravljenje ni bilo mo`no zaradi spremljajo~ih bolezni ali starosti, so radioterapevti zdravili z obsevanjem ali RFA pod nadzorom ra~unalni{ke tomo- grafije. Najve~ji premiki so se zgodili pri citostatskemu zdravljenju; vse bolj se razli~ne na~ine zdrav- ljenja kombinira. Citostatike dobivajo tudi bolniki z ni`jimi stadiji. Uvajajo se novej{i citostatiki: gemcitabin, docetaksel, pemetreksed ter tar~na zdravila, kot so zaviralci tirozin kinaze (npr. gefitinib, erlotinib) in zaviralci neoangiogeneze (npr. bevacizumab). Pri nedrobnoceli~nem raku 3. in 4. stadija se je poleg najbolj{ega podpornega zdravljenja pri~ela uporabljati paliativna cito- statska kemoterapija. Vse ve~ji poudarek se tudi v Sloveniji daje paliativnemu zdravljenju, ki omogo~i bolnikom bolj kakovostno `ivljenje. Pri centralnih tumorjih se uporablja simptomatsko odstranjevanje tumorske- ga tkiva iz bronhijev in vstavljanje stentov. Poleg protibole~inskega zdravljenja je vse pomembnej{a skrb za bolnike na domu ob sodelovanju bolnika in svojcev pri procesu zdravljenja. Pri tem so pomembne pomo~ patrona`ne slu`be, lai~na pomo~, psiholo{ka podpora, pa tudi skrb za ustrez- no prehrano. Za ugotavljanje zgodnjih oblik plju~nega raka, pri katerih so uspehi zdravljenja bolj{i, bo v pri- hodnje treba pregledovati bolj ogro`ene skupine prebivalstva s spiralno ra~unalni{ko tomografijo z nizkim sevanjem. Debeljak A, Triller N, Kecelj P , Pompe-Kirn V, Rott T , Osolnik K, et al. Smernice za internisti~no obravnavo bolnika s plju~nim rakom. Uradno stali{~e Zdru`enja pulmologov Slovenije, sprejeto na letni konferenci decembra 2001. Zdrav Vestn 2001; 70: 751–70. Zwitter M, ed. Smernice za diagnostiko in zdravljenje bolnikov z rakom plju~. Ljubljana: Onkolo{ki in{titut Ljubljana; 2006. 128 PLJU^A KLINI^NI KOMENT AR Janez Er`en Dandanes se skoraj vsa klini~na in znanstvenoraziskovalna poro~ila in dela, ki govorijo o plju~- nem raku, za~nejo z ugotovitvijo, da je to bolezen, zaradi katere po vsem svetu umira najve~ ljudi, posebno v razvitem delu. Zadnje desetletje na novo vsako leto zboli v Sloveniji za plju~- nim rakom okrog 1000 ljudi, med njimi okrog 800 mo{kih. Tudi pri nas, tako kot v razvitih zahodnih dr`avah, se zbolevnost za plju~nim rakom ve~a pri `enskah hitreje kot pri mo{kih. [tevilo zbolelih `ensk v zadnjem opazovanem obdobju se je v primerjavi s prvim skoraj pod- vojilo. Malo, le nekaj nad 10 % ljudi, ki zbolijo za plju~nim rakom, ne bo umrlo zaradi te bolezni. Na splo{no velja, da je skupno petletno pre`ivetje pri vseh epitelijskih malignih tumorjih okrog 50 % in da ima plju~ni rak med vsemi najslab{o napoved izida. Pri pribli`no polovici bolnikov, ki so bili radikalno operirani zaradi plju~nega raka, se namre~ po dveh letih rak ponovi, le 10–14 % bolnikov s plju~nim rakom pre`ivi pet let. Pre`ivetje bolnikov s plju~nim rakom se je zadnjih 40 let le malo pove~alo. Pre`ivetje je naj- bolj odvisno od stadija bolezni ob diagnozi in za~etku zdravljenja. Bolniki, operirani na na{em klini~nem oddelku s stadijem IA in IB, so imeli petletno pre`ivetje 66 %, s stadijem IIA in IIB 37 %, s stadijem IIIA 22 % in s stadijem IIIB manj kot 10 %. Klini~na ocena, na podlagi kate- re se odlo~amo o vrsti in na~inu zdravljenja, je pogosto napa~na, ve~krat podcenjena kot obratno. VIRI Literature Rak.qxd 22.7.2009 12:39 Page 128 be confirmed by bronchoscopy, transthoracal needle biopsy guided not only by x-ray or US imaging but also by more accurate computer tomography is used. In recent years, surgeons in Slovenia have been using prevailingly lobectomies while pulmec- tomies were used less frequently, preference being given to sleeve lobectomies. Exceptionally, in the case of poor pulmonary function or an advanced age, limited resections have been used. V ATS for pulmonary resections started to be used too. Each resection included lymphadenec- tomy of the mediastinal lymph nodes. Radiotherapy is increasingly more frequently targeted at the primary tumor, and used at an early stage in combination with chemotherapy. Where surgical treatment was not feasible due to concomitant diseases or an advanced age, localized tumors were treated by irradiation or CT-guided RFA. The greatest advances were made in the area of treatment with cytotoxic drugs by combining different therapeutic modalities. Chemotherapy is also administered to the patients with ear- lier stages of the disease. New cytotoxic drugs are being introduced: gemcytabine, docetaxel, pemetrexed and target drugs such as tyrosine kinase inhibitors (e. g. gefitinib, erlotinib) and neoangiogenesis inhibitors (e. g. bevacizumab). In non-small cell cancer of stages III and IV, palliative chemotherapy has been used in addition to the best supportive therapy. In Slovenia too, an increasingly important role is ascribed to palliative therapy, which can improve the quality of patients' life. In centrally situated tumors the treatment consists of symptomatic tumor tissue removal from the bronchi and stent placement. Besides pain-control therapy, care outside the hospital setting in cooperation with patients and their families is gaining in impor- tance. In this respect, the assistance offered by community nursing care, lay caregivers, psychological support as well as care for an adequate diet are considered important. In order to detect lung cancer at its early stages associated with a more favorable treatment outcome, in the future screening of high risk population should be carried out using low-dose spiral computer tomography. 129 LUNG CLINICAL COMMENT ARY Janez Er`en Nowadays practically all clinical and scientific reports and articles on lung cancer start with the fact that lung cancer is a disease associated with the highest mortality rates worldwide, par- ticularly in the developed parts. In the last decade, every year approximately a thousand people will be diagnosed with lung cancer in Slovenia, approximately 800 of these being males. As in other developed countries, in Slovenia the lung cancer incidence in females has been increas- ing more rapidly than in males too. In comparison with the first observation period, the number of women diagnosed in the last observation period is almost two-fold higher. Only few (slight- ly above 10%) people with lung cancer will not die of the disease. It is generally believed that overall 5-year survival rate in all epithelial malignomas is around 50%, among them lung can- cer being the one with the worst prognosis. Thus, in approximately a half of the patients who have undergone radical surgery for lung cancer, the disease will recur within two years, and only 10–14% of them will survive five years. In the last 40 years, the survival of patients with lung cancer has slightly increased. Survival largely depends on the stage of the disease at diagnosis and on the beginning of treatment. Patients with stage IA and IB treated at our department had a 66% 5-year survival rate, while those with stage IIA and IIB 37%, with stage IIIA 22% and with stage IIIB less than 10%. Clinical assessment, which serves as a basis for choosing the treatment modality, is often incorrect and underestimated rather than the opposite. The first weak link is the reliability of stage assess- ment, which is still considered to be the most reliable prognostic factor. There the possibility Rak.qxd 22.7.2009 12:39 Page 129 Prva {ibka to~ka je zanesljivost ocene stadija, ki {e vedno velja za najzanesljivej{i napovedni dejavnik. Pri tem je mo`nost napake ve~plastna. Pri~ne se s podcenjenostjo klini~nega stadi- ja, ker imajo vse klini~ne in slikovne preiskave (RTG, CT , UZ, MRI, PET , scintigrafija kosti itd.) omejeno zmogljivost ob~utljivosti, specifi~nosti in natan~nosti pri zamejevanju bolezni. Pri na~rtovanju najbolj ustreznega zdravljenja bolnikov s plju~nim rakom upo{tevamo dolo- ~ene klini~no-patolo{ke napovedne dejavnike, od katerih sta za zdaj najpomembnej{a stadij bolezni in bolnikova zmogljivost, ki pa pri posameznem bolniku ne moreta zanesljivo napo- vedati poteka bolezni. Verjetnost zmote je velika in nastane pri tretjini bolnikov. Mo`nosti za zmanj{anje umrljivosti zaradi plju~nega raka so zato omejene na optimalno zdravlje- nje, ki naj bo prilagojeno posameznemu bolniku. Ponovitev raka se mnogo pogosteje poka`e z oddaljenimi zasevki kot z lokalno {iritvijo. Kljub temu ostaja znatno podro~je skritega, saj {e vedno tretjina ali ve~ bolnikov po radikalni operaciji z najugodnej{im stadijem IA umre v pe- tih letih po operaciji. Black RJ, Bray F, Ferlay J, Parkin DJ. Cancer incidence and mortality in the European Union: cancer registry data and estimates of national incidence for 1990. Eur J Cancer 1997; 33: 1075–107. Baldini EH, Strauss GM. Women and lung cancer. Waiting to exhale. Chest 1997; 112 Suppl 4: 229–3. Gawrychowski J, Lackowska B, Gabriel A. Prognosis of the surgical treatment of patients with non-small cell lung cancer (NSCLC) – relation to DNA ploidy. Eur J Cardiothorac Surg 2003; 23: 870–77. Litvinov SV, Velders MP , Bakker HA, Fleuren GJ, Warnaar SO. EpCAM: a human epithelial antigen is a ho- mophilic cell-cell adhesion molecule. J Cell Biol 1994; 125: 437–46. Pearson GF. Non-small cell lung cancer. Role of surgery for stages I–III. Chest 1999; 116 Suppl 6: 500–03. Poleri C, Morero JL, Nieva B, Vazquez MF, Rodriguez C, de Titto E, et al. Risk of recurrence in patients with surgically resected stage I non-small cell lung carcinoma: histpathologic and immunohistochemical analy- sis. Chest 2003; 123: 1858–67. Rice D, Kim HW, Sabichi A, Lippman S, Lee JJ, Williams B, et al. The risk of second primary tumors after resection of stage I non-small cell lung cancer. Anal Thorac Surg 2003; 76: 1001–8. 130 PLJU^A KLINI^NI KOMENT AR Matja` Zwitter Plju~ni rak spreminja svojo podobo. V sorazmerno kratkem obdobju petnajstih let vidimo str- mo nara{~anje incidence plju~nega raka pri `enskah, ki sledijo slabemu zgledu mo{kih ne le pri kajenju, pa~ pa tudi pri boleznih, ki jih tobak pospe{uje. O~iten je tudi izrazit porast dele- `a `lezne oblike plju~nega raka, pa hkrati upad plo{~atoceli~nega karcinoma, morda kot posledica kajenja »lahkih« cigaret, ki jih globlje inhaliramo. Tretja sprememba pa je premik na bolje pri pre`ivetju: dobra dva odstotka ve~ pre`ivelih in to ne le v okviru posamezne bolni{nice, pa~ pa v okviru cele dr`ave. To, na prvi pogled skromno izbolj{anje pre`ivetja, je pomembno prav zara- di dejstva, da so v tej statistiki zajeti tudi mnogi bolniki v zelo {ibkem splo{nem stanju in s hudo napredovalo boleznijo, ki jim nismo mogli veliko pomagati niti pred petnajstimi leti in tudi danes ne. Pri bolnikih z zgodnjimi stadiji bolezni (predstavljeni kot omejen in raz{irjen sta- dij) pa je izbolj{anje pre`ivetja {e bistveno ve~je. Krivulje o bolj{em pre`ivetju bolnikov s plju~nim rakom so spodbuda, da smo na pravi poti. Podatki ka`ejo, da se stadiji bolezni niso spremenili. Bolj{e pre`ivetje torej lahko pripi{emo uspe{nej{emu zdravljenju. Kirurgija ni ve~ {ablonska, pa~ pa prilagojena vsakemu posameznemu bolniku. Zdravljenje z obsevanjem je z novo opremo in novim znanjem bistveno natan~nej{e, z manj ne`elenimi sopojavi in z ve~jimi izgledi za lokalno ozdravitev tumorja. Slovenija se je tudi na tem podro~ju v zadnjih letih pribli`ala mednarodnim standardom. Velik premik pa je tudi pri sistemskem zdravljenju, ki je danes osnovno zdravljenje ne le pri drobnoceli~nem raku, pa~ pa tudi pri ostalih vrstah plju~nega raka. Podatki o pre`ivetju bolnikov s plju~nim rakom nam ka`ejo, kam naj v bodo~e usmerimo svo- jo pozornost. V tem kratkem komentarju naj omenim {tiri pomembne naloge. Prva izhaja iz VIRI Literature Rak.qxd 22.7.2009 12:39 Page 130 of error is multifold. It starts with the underestimation of clinical stage, since all the available clinical and imaging examinations (X-ray, CT, US, MRI, PET, bone scintigraphy, etc.) have limited sensitivity, specificity and accuracy with respect to their disease staging potential. In planning the most suitable treatment for lung cancer patients certain clinical-pathological prog- nostic factors are taken into account, among these stage of the disease and patient's performance status being the most important, although they are unable to predict reliably the course of dis- ease in an individual patient. The possibility of error is considerable and occurs in one third of the patients. Therefore, the possibilities for reducing mortality due to lung cancer are limited to an opti- mal treatment, which should be tailored to the individual patient. Rather than with local spread, cancer recurrence much more frequently presents itself with distant metastases. Nevertheless, a large area still remains obscure, since over a third of patients with the most favorable IA stage, having radical surgery, still die within five years from surgical treatment. 131 LUNG CLINICAL COMMENT ARY Matja` Zwitter Lung cancer is changing its features. In a relatively brief period of fifteen years we may wit- ness a steep increase in the incidence of lung cancer in women, who follow the negative example of men not only in smoking habits but also in the diseases caused by tobacco. Furthermore, there is an obvious increase in the proportion of adenocarcinoma with a simultaneous decrease in planocellular carcinoma, possibly as a result of »light« cigarettes smoking associated with deeper inhalation. The third change is a shift towards better survival: there are over two more percents of survivors, and that not only at the level of an individual hospital but also at the level of the whole state. This, at a first glance modest improvement of survival, is important in view of the fact this statistics also includes a large number of patients with very poor gen- eral condition and highly advanced disease, whose prospects for treatment were rather limited fifteen years ago and are currently not much better either. In patients with early stages (locali- zed and regionally advanced) the survival is even better. The improved survival curves of lung cancer patients are encouraging and should be regard- ed as a proof that we are on the right way. The data show that stages of the disease have not changed. Therefore, better survival can be attributed to more effective treatment. Surgery, rather than being standardized, is tailored to every individual patient. Thanks to new equipment and advanced knowledge, radiotherapy has become significantly more accurate, with fewer adverse effects and better chances for a local tumor cure. In this area, Slovenia has approached the inter- national standards in the recent years. A great advance has also been achieved in systemic therapy, which nowadays represents the basic treatment not only for small-cell carcinoma but also for other types of lung cancer. The data on lung cancer patients' survival point out, where to concentrate our future activi- ties. In this brief comment, let me point out four important tasks. The first results from the finding that stage distribution is changing: the proportion of patients with an early, operable lung cancer is not increasing but rather the opposite. A more favorable stage distribution will not happen per se. Instead, we need a systematic approach to early lung cancer detection in high risk groups, such as e. g. those with cured head and neck cancers, along with the com- mitted work of all those that can help to reduce the presently intolerable long interval from first symptoms to diagnosis of lung cancer. The second task would be to implement the advances in lung cancer treatment at the national level. Although this publication does not present the survival curves for individual regions of Slovenia, a detailed review of the data from the Cancer Registry of Slovenia reveals that the north-eastern Slovenia is lagging behind, the survival of patients in this region in the past decade being no better than in the 90's. This should not be understood as a criticism but rather as an encouragement for a detailed analysis and development Rak.qxd 22.7.2009 12:39 Page 131 opa`anja, da se ne spreminja razporeditev po stadijih: dele` bolnikov z zgodnjim, operabilnim plju~nim rakom se ne ve~a, prej nasprotno. Ugodnej{a razporeditev po stadijih ne bo pri{la sama od sebe. Potrebujemo torej sistemati~en pristop pri zgodnjem odkrivanju plju~nega raka pri zelo ogro`enih skupinah bolnikov, na primer tistih z ozdravljenim rakom glave in vratu, ter resno delo vseh, ki lahko prispevajo k skraj{anju danes nedopustno dolgega intervala med prvimi simptomi in diagnozo plju~nega raka. Druga naloga je, da napredek pri zdravljenju plju~ne- ga raka prenesemo na vso dr`avo. Ta knjiga sicer ne prina{a krivulj pre`ivetja po posameznih regijah Slovenije, podroben pregled podatkov RRS pa nam razkrije, da severovzhodna Slove- nija zaostaja in da je pre`ivetje pri njih v zadnjem desetletju enako slabo kot v devetdesetih letih. To naj ne bo kritika, pa~ pa spodbuda k natan~ni analizi in oblikovanju smernic za bodo- ~e delo. Tretja naloga izhaja iz zaskrbljujo~ega poslab{anja pre`ivetja pri starej{ih bolnikih. Je morda res, da ve~ starej{im bolnikom v {ibkem splo{nem stanju, ki bi poprej ostali brez natan~- ne opredelitve narave njihove bolezni, postavimo pravo diagnozo? So ti bolniki zapostavljeni v diagnostiki in zdravljenju, ali pa so morda zdravljeni preve~ agresivno? Tudi tu bo potrebna natan~na analiza, ki naj poka`e na vzrok in hkrati ponudi navodila za bodo~e delo. ^etrta zelo pomembna naloga pa je, da vztrajamo pri zastavljeni protikadilski politiki, ki `e ka`e uspehe pri mo{kih, potrebno pa jo bo nadgraditi za populacijo `ensk in mladih. Zielinski C, Zwitter M. Consensus on medical treatment of non-small-cell lung cancer – update 2004. Lung cancer 2005; 50: 129–37. Zwitter M, Kova~ V, Smrdel U, Strojan P . Gemcitabine, cisplatin and hyperfractionated accelerated radiothe- rapy for locally advanced non-small cell lung cancer. J Thorac Oncol 2006; 1: 662–6. Zwitter M. Nove podobe plju~nega raka. Onkologija 2000; 4: 69–73. Zwitter M. Comments on treatment strategy for locally advanced non-small cell lung cancer. Lung cancer 2002; 38: S33–5. Zwitter M, ^ufer T, Wein W. Gemcitabine and vincristine: an effective outpatient regimen with low myelo- toxicity for stage IV non-smallcell lung cancer. Neoplasma 2001; 48: 200–2. 132 PLJU^A VIRI Literature Rak.qxd 22.7.2009 12:39 Page 132 of guidelines for future work. The third task relates to worse survival of the elderly patients. Could it be that more elderly patients with poor general condition, who would previously be left without exact assessment of the nature of their disease, are nowadays diagnosed correct- ly? Are those patients deprivileged in terms of diagnosis and treatment or are they perhaps treated too aggressively? This calls for a detailed analysis that should point out the true reasons, at the same time providing guidelines for work in the future. Last but not least, the fourth task is to stick with the set anti-smoking policy, which has already yielded positive results in males and needs to be upgraded for the population of females and youth. 133 LUNG Rak.qxd 22.7.2009 12:39 Page 133 V obdobju 1991–2005 je za malignimi tumorji mehkih tkiv zbolelo 816 ljudi, od tega 384 mo{- kih in 432 `ensk. Kot je razvidno s Slike 1, se tako grobe kot starostno standardizirane inciden~ne in umrljivostne stopnje od leta 1991 ve~ajo. Groba inciden~na stopnja se ve~a povpre~no za 4,0 % letno, groba umrljivostna stopnja pa povpre~no za 6,7 % letno. Rast obeh starostno stan- dardiziranih mer je nekoliko manj{a: starostno standardizirana incidenca se ve~a za 2,8%, umrljivost pa za 5,2 % letno. MEHKA TKIV A MKB 10: C38.0, C47–C49 134 0 1 2 3 4 1986 1990 1995 2000 2005 Leto / Year Incidenca – groba stopnja / Incidence – crude rate Incidenca – SSS* / Incidence – ASR** Umrljivost – groba stopnja / Mortality – crude rate Umrljivost – SSS* / Mortality – ASR** Stopnja na 100.000 / Rate per 100,000 * SSS – starostno standardizirana stopnja (standard – slovenska populacija leta 1986) ** ASR – age standardized rate (standard Slovenian population in 1986) Slika 1: Groba in starostno standardizirana inciden~na in umrljivostna stopnja raka mehkih tkiv, Slovenija 1986–2005. Figure 1: Crude and age-standardized incidence and mortality rate of soft tissue cancer, Slovenia 1986–2005. Mo{ki / Males @enske / Females Obdobje / {tevilo / 20–49 let / 50–74 let / 75+ let / {tevilo / 20–49 let / 50–74 let / 75+ let / Period number years (%) years (%) years (%) number years (%) years (%) years (%) 1991–1995 88 38,6 50,0 11,4 102 27,5 59,8 12,7 1996–2000 102 46,1 42,2 11,8 131 29,8 49,6 20,6 2001–2005 148 33,1 53,4 13,5 154 26,6 51,9 21,4 T abela 1: [tevilo bolnikov z rakom mehkih tkiv po spolu in obdobju postavitve diagnoze ter njihovi dele`i po starosti. Table 1: Number of soft tissue cancer patients by sex and period of diagnosis with their proportions by age. V analizo pre`ivetja je vklju~enih 725 primerov; 17 primerov (2,1 %) nismo upo{tevali, ker jim je bila diagnoza postavljena po smrti, 74 mlaj{ih od 20 let pa obravnavamo v poglavju o pre- `ivetju pri otrocih in mladostnikih. V obdobju 2001–2005 sta 2 od 302 bolnikov imela malignom osr~nika, 5 % je imelo malignom perifernih `ivcev in avtonomnega `iv~evja, 29 % malignom potrebu{nice ali retroperitoneja, 66 % pa malignom vezivnega in mehkega tkiva na raznih tele- snih mestih, najve~ (46 %) na spodnjem udu (vklju~no s kolkom). V zadnjem obdobju je bilo mikroskopsko potrjenih 98 % primerov. Dele` mikroskopsko potr- jenih primerov je pribli`no enak v vseh obdobjih opazovanja. Dale~ najve~jo histolo{ko skupino EPIDEMIOLOGIJA Rak.qxd 22.7.2009 12:39 Page 134 In the period 1991–2005, a total of 816 persons were diagnosed with malignant soft tissue tumors, of these 384 males and 432 females. As evident from Figure 1, since 1991 crude as well as age-stan- dardized incidence and mortality rates have been increasing. Thus crude incidence rate has been increasing by 4.0% and crude mortality rate by 6.7% annually on average. The increase in both age-standardized rates is lower: age-standardized incidence rate is increasing by 2.8% and mor- tality rate by 5.2% annually on average. The survival analysis included 725 cases; 17 cases (2.1%) diagnosed only after death, were not considered in the analysis; 74 patients under 20 years of age are presented in the chapter on the survival of children and adolescents. In the period 2001–2005, 2 of 302 patients had malig- noma of the pericardium, 5% had malignoma of the peripheral nerves and autonomous nerves, 29% malignomas of the peritoneum or the retroperitoneum while 66% had malignomas of the connective and soft tissue in different parts of the body, most frequently (46%) in the lower limb (including the hip). In the last period, 98% of cancers were microscopically verified. The proportion of microscopically confirmed cases was basically the same throughout the observation period. Sarcomas repre- sent by far the largest histological group of soft tissue tumors (78% of all soft tissue tumors), germ-cell tumors represent 6% while carcinomas and nerve sheath tumors are represented by 5% each. Other defined histological types represented less than 2% of cases, while in 3% of tumors histological type was not precisely defined. Approximately one fourth of sarcomas were leiomyosarcomas, 20% liposarcomas, 16% fibrohistiocytic sarcomas, 8% synovial sarcomas and 7% fibrosarcomas; 17% of all sarcomas remained undefined. The proportions of all defined sar- comas, except for fibrohistocytic ones, have been increasing with time while the proportion of undefined sarcomas and other soft tissue tumors exhibits a downward trend. More than half of patients are diagnosed at an age between 50 and 74 years, approximately one third are under 50 years of age, and the rest are aged 75 years or older (Table 1). The pro- portion of the oldest patients has been increasing all the time, mainly on the account of a smaller proportion of patients younger than 50 years. In the period 2001–2005, almost half of the patients had disease diagnosed at a regional stage (Table 2). Along with the increasing proportion of regional disease, the proportion of locali- zed disease has been decreasing throughout the observation period. In the last period, only one third of patients were diagnosed with localized disease; particularly in males, the percentage of patients with unknown stage is very high (10%). In the period 2001–2005, 7% of patients did not receive specific treatment. The proportion of untreated patients has not changed significantly throughout the observation period. In the SOFT TISSUE ICD 10: C38.0, C47–C49 135 Tabela 2: [tevilo bolnikov z rakom mehkih tkiv po spolu in obdobju postavitve diagnoze ter njihovi dele`i po stadiju. Table 2: Number of soft tissue cancer patients by sex and period of diagnosis with their proportions by stage. Mo{ki / Males @enske / Females Obdobje / {tevilo / omejen / raz{irjen / razsejan / neznan / {tevilo / omejen / raz{irjen / razsejan / neznan / Period number localized regional distant unknown number localized regional distant unknown (%) (%) (%) (%) (%) (%) (%) (%) 1991–1995 88 46,6 33,0 12,5 8,0 102 55,9 24,5 14,7 4,9 1996–2000 102 48,0 36,3 10,8 4,9 131 48,1 35,9 11,5 4,6 2001–2005 148 33,8 42,6 14,2 9,5 154 35,1 46,1 16,9 1,9 EPIDEMIOLOGY Rak.qxd 22.7.2009 12:39 Page 135 med tumorji mehkih tkiv predstavljajo sarkomi (78 % vseh tumorjev mehkih tkiv), 6 % je tumorjev kli~nih celic, po 5 % pa karcinomov in tumorjev `iv~nih ovojnic. Drugih opredeljenih histo- lo{kih vrst je bilo 2 %, 3 % tumorjev pa ni imelo natan~no opredeljene histolo{ke vrste. Med sarkomi jih je pribli`no ~etrtina leiomiosarkomov, 20% liposarkomov, 16% fibrohistocitnih sarkomov, 8 % sinovijskih sarkomov in 7 % fibrosarkomov. Neopredeljenih je bilo 17 % med vsemi sarkomi. Dele`i vseh opredeljenih sarkomov z izjemo fibrohistocitnih se z leti pove~u- jejo, zmanj{uje pa se dele` neopredeljenih sarkomov in dele` drugih tumorjev mehkih tkiv. Ve~ kot polovica bolnikov je ob diagnozi stara od 50 do 74 let, pribli`no tretjina je mlaj{ih od 50 let, ostali pa so stari 75 let in ve~ (Tabela 1). Dele` najstarej{ih se ves ~as ve~a, ve~inoma na ra~un manj{ega dele`a bolnikov, mlaj{ih od 50 let. 136 MEHKA TKIV A 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Slika 2: Deset-, pet-, tri- in enoletno relativno pre`ivetje bolnikov z rakom mehkih tkiv po obdobju postavitve diagnoze. Figure 2: 10-, 5-, 3- and 1-year relative survival of soft tissue cancer patients by period of diagnosis. Tabela 3: Opazovano in relativno pre`ivetje bolnikov z rakom mehkih tkiv po spolu in obdobju postavitve diagnoze s 95-odstotnim intervalom zaupanja (IZ). Table 3: Observed and relative survival of soft tissue cancer patients by sex and period of diagnosis with 95% confidence interval (CI). Opazovano pre`ivetje / Observed survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 72,7 (64,0–82,7) 48,9 (39,5–60,5) 44,3 (35,1–56,0) 74,5 (66,5–83,5) 56,9 (48,0–67,3) 47,1 (38,3–57,8) 1996–2000 76,5 (68,7–85,2) 57,8 (49,0–68,3) 51,0 (42,1–61,7) 83,2 (77,0–89,9) 61,8 (54,0–70,7) 50,4 (42,5–59,7) 2001–2005 79,1 (72,8–85,9) 57,7 (50,2–66,3) 49,3 (41,3–58,9) 77,9 (71,6–84,8) 58,6 (51,3–67,0) 46,0 (37,8–55,9) Relativno pre`ivetje / Relative survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 75,3 (65,0–85,6) 53,6 (40,8–66,4) 52,5 (38,6–66,3) 76,3 (67,2–85,5) 60,6 (49,5–71,8) 53,0 (40,9–65,1) 1996–2000 78,5 (69,6–87,5) 62,6 (51,4–73,9) 58,3 (46,1–70,5) 85,4 (78,5–92,2) 66,7 (57,1–76,3) 57,3 (46,7–68,0) 2001–2005 81,6 (74,5–88,6) 63,5 (54,0–72,9) 58,3 (47,0–69,6) 79,6 (72,6–86,6) 62,7 (53,7–71,7) 51,8 (40,6–63,0) Rak.qxd 22.7.2009 12:39 Page 136 period 2001–2005, 93% of patients with specific treatment underwent surgery. In over a half of them this was the only treatment modality, 19% were also irradiated, and 16% received chemothera- py in addition to surgery while 11% were treated by surgery, irradiation and chemotherapy. In comparison with the earlier periods, the proportion of patients treated by chemotherapy and the proportion of those treated by surgery alone have been increasing. In the period 2001–2005, almost a half of patients started their treatment at the IO Ljubljana, 17% in the UMC Ljubljana and 10% in the UMC Maribor. Individual patients started their treatment in nine Slovenian general hospitals. Practically all patients (92%), irrespective of the hospital of their initial treatment, were in the course of their primary treatment referred to the IO Ljubljana. Compared to the first period (1991–1995), in the last one the survival of patients with soft tissue malignomas has actually increased; in 15 years, the 5-year relative survival increased by 2% (Figure 2); while in males it increased by 6%, in females the survival rate in the last peri- od slightly decreased (Table 3). The relevance of stage at diagnosis is shown in Figure 3. The 137 SOFT TISSUE 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 Omejen / Localized Raz{irjen / Regional Razsejan / Distant Vsi / All Slika 3: Petletno relativno pre`ivetje bolnikov z rakom mehkih tkiv po stadiju in obdobju postavitve diagnoze. Figure 3: 5-year relative survival of soft tissue cancer patients by stage and period of diagnosis. 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 20–49 let / years 50–74 let / years 75+ let / years Vsi / All Slika 4: Petletno relativno pre`ivetje bolnikov z rakom mehkih tkiv po starosti in obdobju postavitve diagnoze. Figure 4: 5-year relative survival of soft tissue cancer patients by age and period of diagnosis. Rak.qxd 22.7.2009 12:39 Page 137 V obdobju 2001–2005 je bila pri skoraj polovici bolnikov bolezen odkrita v raz{irjenem sta- diju (Tabela 2). Z ve~anjem dele`a raz{irjene bolezni se ves ~as opazovanja manj{a dele` bolnikov z boleznijo, odkrito v omejenem stadiju. V zadnjem obdobju je bila le {e tretjina bolnikov odkri- tih z omejeno boleznijo; predvsem pri mo{kih pa je velik odstotek bolnikov brez opredeljenega stadija ob diagnozi (10 %). V obdobju 2001–2005 ni bilo specifi~no zdravljenih 7 % bolnikov. Dele` nezdravljenih bol- nikov se skozi vse obdobje analize ni bistveno spreminjal. Med specifi~no zdravljenimi je bilo v letih 2001–2005 93 % bolnikov operiranih. Pri dobri polovici je bil to edini na~in zdravlje- nja, 19 % je bilo {e obsevanih, 16 % pa je poleg operacije prejelo {e kemoterapijo; 11 % je bilo zdravljenih z operacijo, obsevanjem in kemoterapijo. V primerjavi z za~etnimi obdobji se ve~a dele` bolnikov, ki so prejeli kemoterapijo, in dele` tistih, ki so bili samo operirani. Skoraj polovica bolnikov je v obdobju 2001–2005 za~ela z zdravljenem na OI Ljubljana, 17 % v UKC Ljubljana ter 10 % v UKC Maribor. Posamezne bolnike so pri~eli zdraviti {e v deve- tih slovenskih splo{nih bolni{nicah. Skoraj vsi bolniki (92 %), ne glede na bolni{nico pri~etka zdravljenja, pa so bili v okviru prvega zdravljenja obravnavani na OI Ljubljana. Relativno pre`ivetje bolnikov z rakom mehkih tkiv se je v zadnjem obdobju v primerjavi s pr- vim (1991–1995) nekoliko pove~alo; v 15 letih se je petletno relativno pre`ivetje pove~alo za 2 % (Slika 2), pri mo{kih se je pove~alo za 6 %, pri `enskah pa se je v zadnjem obdobju celo nekoliko zmanj{alo (Tabela 3). Kako pomemben je stadij ob diagnozi, ka`e Slika 3: petletno relativno pre`ivetje bolnikov z omejenim stadijem je ves ~as opazovanja pribli`no 75 %. Pre- `ivetje bolnikov z raz{irjenim stadijem se z leti ve~a; zboleli v letih 2001–2005 so imeli petletno relativno pre`ivetje 52 %. Bolniki z razsejanim stadijem ob diagnozi imajo 13-odstotno pet- letno relativno pre`ivetje. Napovedni dejavnik je tudi starost, saj imajo mlaj{i od 50 let za pribli`no 15 % ve~je pre`ivetje od bolnikov, ki zbolijo po 50. letu starosti (Slika 4). Petletno relativno pre`ivetje vseh zbolelih v obdobju 2001–2005 je bilo 55 % (Slika 2); bolni- ki, ki pre`ivijo prvo leto, pa lahko pri~akujejo 68-odstotno petletno relativno pre`ivetje. Rezultati {tudije EUROCARE-4 za zbolele v obdobju 2000–2002 ka`ejo, da je pre`ivetje slo- venskih bolnikov s tumorji mehkih tkiv statisti~no nezna~ilno ve~je od evropskega povpre~ja (Slika 5). 138 MEHKA TKIV A KLINI^NI KOMENT AR Branko Zakotnik Ve~ina malignomov mehkih tkiv (83 %) so sarkomi. Ker so ostali malignomi v tej skupini red- ki, princip njihovega zdravljenja pa druga~en kot pri sarkomih, omejujem svoj komentar le na sarkome. Incidenca sarkomov mehkih tkiv se je v 20 letih pove~ala (Slika 1), vendar je to kljub temu {e vedno redka bolezen, saj lahko pri~akujemo, da bo letno zbolelo 70 do 80 bolnikov. Smiselno bi torej bilo, da bi se ti bolniki pri~eli zdraviti v Sloveniji na enem mestu, kjer so na razpola- go vse moderne diagnosti~ne mo`nosti (CT , MRI), usposobljeni citolog in patolog, onkolo{ki kirurg, radioterapevt in internist onkolog, ki kot ~lani multidisciplinarnega konzilija na~rtu- jejo in izvedejo prvo zdravljenje pri tej redki bolezni. Tak{na so vsa mednarodna in slovenska priporo~ila. Podatki pa ka`ejo, da se je odstotek bolnikov, ki so prvi~ obravnavani na OI Ljub- ljana, ki je edina ustanova, ki ima trenutno zagotovljene primerne pogoje za kakovostno zdravljenje, zmanj{al s 50 % v obdobju 1991–1995 na 47 % v obdobju 2001–2005. Pri~akova- li bi, da se bo, glede na objavljena priporo~ila, ta odstotek ve~al. Razloga za pove~evanje incidence ni mo~ ugotoviti. Vsekakor ne gre na ra~un staranja prebi- valstva, saj je razlika med grobo in starostno standardizirano inciden~no stopnjo minimalna. Morda gre na ra~un bolj{e dostopnosti do diagnosti~nih mo`nosti v Sloveniji (UZ, CT , MRI) Rak.qxd 22.7.2009 12:39 Page 138 5-year relative survival of patients with localized stage has been approximately 75% through- out the observation period. The survival of patients with regional disease has been increasing with time, in those diagnosed between the years 2001–2005, 5-year relative survival rate was 52%. Patients with disseminated disease at diagnosis have 13% 5-year relative survival. Age is a prognostic factor as well, since patients younger than 50 years have around 15% higher survival than those diagnosed after 50 years of age (Figure 4). The 5-year relative survival of all patients diagnosed in the period 2001–2005 was 55% (Figure 2); patients surviving the first year may expect to survive five years in 68%. According to the results of EUROCARE-4 study for patients diagnosed in 2000–2002, the survival of patients with soft tissue tumors in Slovenia is above (statistically not significant) the European average (Figure 5). 139 SOFT TISSUE CLINICAL COMMENT ARY Branko Zakotnik 01 02 0 30 40 50 60 70 80 90 100 % Slovensko povpre~je / 2000–2002 (EUROCARE-4) Slovenian average Evropsko povpre~je / 2000–2002 (EUROCARE-4) European average Povpre~je ZDA / 2000–2002 (SEER-13) USA average Slika 5: Petletno relativno pre`ivetje bolnikov z rakom mehkih tkiv (povpre~je in 95-odstotni interval zaupanja), zbolelih v letih 2000–2002 v Sloveniji, Evropi in nekaterih obmo~jih v ZDA. Figure 5: 5-year relative survival of soft tissue cancer patients (average and 95% confidence interval) diagnosed in the period 2000–2002 in Slovenia, Europe and in some regions of the USA. Sarcomas (including nerve sheath tumors) represent the majority of soft tissue malignancies (83%). Other malignomas in this group are rare and the approach to their treatment is dif- ferent than in sarcomas, therefore my comment is limited only to sarcomas. In 20 years, the incidence of soft tissue sarcomas has increased (Figure 1), however the dis- ease is still rare since it may be expected that 70 to 80 patients will be diagnosed with it annually. Therefore, it would be reasonable that these patients would start their treatment in Slovenia in one and the same place, where all the up-to-date diagnostic facilities (CT , MR), skilled cytolo- gists and pathologists, oncological surgeons, radiotherapists and medical oncologists are available; the latter, as members of a multidisciplinary team, plan and carry out the primary treatment in this rare disease. This is consistent with all international and national recommendations. The data however show that the proportion of patients initially treated at the IO Ljubljana, which is the only institution with suitable conditions for quality treatment, has decreased from 50% in the period 1991–1995 to 47% in the period 2001–2005. Considering the published recommendations, it would be expected that this percentage should be increasing. Rak.qxd 22.7.2009 12:39 Page 139 in/ali zaradi vpliva karcinogenov okolja. Vendar bi glede na majhno {tevilo bolnikov, ki letno zboli v Sloveniji, te vplive pri na{ih bolnikih te`ko raziskali. Kako si lahko razlagamo, da ugotovimo vedno ve~ bolnikov z raz{irjeno boleznijo, medtem ko ostaja petletno relativno pre`ivetje enako dobro v primerjavi z evropskimi dr`avami, celo nad evropskim povpre~jem? Z leti ugotavljamo manj bolnikov z omejenim stadijem in ve~ z raz- {irjenim (Tabela 2). Na dolo~itev stadija najbolj vpliva dostopnost sodobnej{e natan~nej{e diagnostike (CT , MRI), ki se je v Sloveniji v zadnjem obdobju izbolj{ala in s katero ugotavljamo selitev stadija navzgor. Z natan~nej{o diagnostiko pa sta lahko bolj{a tudi na~rtovanje zdrav- ljenja in s tem njegov izid. Na ra~un obeh teh dejavnikov smo pri bolnikih z raz{irjenim stadijem dosegli statisti~no pomembno pove~anje relativnega pre`ivetja s 17 % v obdobju 1986–1990 na 52 % v obdobju 2001–2005. Pri omejenem stadiju ostaja petletno relativno pre`ivetje ves ~as opazovanja enako, ve~je od 70 % (Slika 2). Na osnovi tega je te`ko zanesljivo ugotoviti, ali gre samo za selitev stadija navzgor na ra~un bolj{e diagnostike ali pa dejansko bolniki pride- jo do sicer bolje na~rtovanega zdravljenja, vendar kasneje, v bolj napredovalem stadiju. Kljub vsem priporo~ilom, da je pri malignomih mehkih tkiv najpomembnej{e prvo zdravlje- nje v primerno usposobljenem centru z odlo~itvami glede zdravljenja na multidisciplinarnem konziliju, prvo zdravljenje na OI Ljubljana pri~ne le polovica bolnikov. Poleg te polovice bol- nikov zdravimo (s ponovno operacijo in/ali obsevanjem in/ali kemoterapijo) tudi tiste, pri katerih so prvo zdravljenje opravili drugje, a ni bilo opravljeno po smernicah za zdravljenje tumorjev mehkih tkiv. Ker je za kon~ni izid najpomembnej{e pravilno prvo zdravljenje, bi lahko sloven- ske rezultate zdravljenja bolnikov s tumorji mehkih tkiv {e izbolj{ali, ~e bi zdravljenje izvajali pri ve~ini bolnikov v skladu z mednarodnimi in slovenskimi smernicami za zdravljenje sarko- mov mehkih tkiv. Brennan M, Singer S, Maki R, O'Sullivan B. Sarcomas of the soft tissues and bone. In: DeVita VT Jr, Hell- man S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2005: 1581–631. Casali PG, Jost L, Sleijfer S, Verweij J, Blay JY. Soft tissue sarcomas: ESMO Clinical Recommendations for diagnosis, treatment and follow-up. Annals of Oncology 2008; 19 Suppl 2: ii89–ii93. Er`en D. Pomen prvega kirur{kega posega pri bolnikih s sarkomi. Onkologija 2007; 1: 49–52. Er`en D, Novak J, Spiler M, Sen~ar M. Aggressive surgical treatment of retroperitoneal sarcoma: long-term experience of a single institution. Surg Technol Int 2007; 16: 97–106. Nacional Cancer Institute: Adult Soft Tissue Sarcoma Treatment. Dosegljivo na: http://www.cancer.gov/ cancertopics/pdq/treatment/adult-soft-tissue-sarcoma/HealthProfessional/. Novak J. Kirurgija malignih tumorjev mehkih tkiv. In: Smrkolj V, ed. Kirurgija. Ljubljana: Sledi; 1995: 500–8. Onkolo{ki In{titut Ljubljana. Smernice za zdravljenje sarkomov, RSK za onkologijo, 2008. 140 MEHKA TKIV A VIRI Literature Rak.qxd 22.7.2009 12:39 Page 140 The exact reason for an increase in the incidence is not known, but it is certainly not attrib- utable to population ageing, as the difference between the crude and age-standardized incidence rates is minimal. Perhaps it could also be attributed to a better accessibility of diagnostic facili- ties in Slovenia (US, CT, MR) and/or due to the influence of environmental carcinogens. However, considering the small number of patients diagnosed in Slovenia annually, it would be difficult to investigate these influences in our patients. How can we explain that ever more patients are diagnosed with regional disease, while the 5-year relative survival remains just as good in comparison with other European countries, in fact even above the European average? Recently, we find fewer patients with localized stage and more with regionally advanced disease (Table 2). Staging is mainly influenced by the accessibility of modern and more accurate diagnostic procedures (CT , MRI), that is followed by an upward stage migration; in the last period, these diagnostic options have improved in Slovenia. More accurate diagnosis can further improve treatment planning and thus also the outcome of treat- ment. Both these factors contributed to a statistically significant increase in the relative survival of patients with regional stage, from 17% in the period 1986–1990 to 52% in the period 2001–2005. Five-year relative survival in localized stage has remained the same throughout the observa- tion period and exceeds 70% (Figure 2). Based on the above data it is difficult to establish with certainty whether the upward stage migration results from better diagnosis or the patients are diagnosed with more advanced stage, but receive better treatment. Despite all the recommendations claiming that in soft tissue malignomas it is of essential impor- tance that patients start their primary treatment in an adequately equipped center, where the decision about treatment is accepted by a multidisciplinary team counsel, only half of the patients start their treatment at the IO Ljubljana. Apart from this half of the patients, at IO Ljubljana we perform also reoperations and/or irradiation and/or chemotherapy in those who had their primary treatment started elsewhere, however, not in accordance with the guidelines for soft tissue tumor treatment. Since the final outcome crucially depends on the correct choice of pri- mary treatment, the results of soft tissue tumor treatment in Slovenia could be further improved by treatment of the majority of patients according to the international and national guidelines for the treatment of soft tissue sarcomas. 141 SOFT TISSUE Rak.qxd 22.7.2009 12:39 Page 141 V obdobju 1991–2005 je za ko`nim melanomom zbolelo 3508 ljudi, od tega 1608 mo{kih in 1900 `ensk. Kot je razvidno s Slike 1, se ~asovna trenda grobe in starostno standardizirane inci- den~ne stopnje od leta 1991 ve~ata, groba stopnja se ve~a bolj od standardizirane, povpre~no za 6,4 % letno. Umrljivostni stopnji se med letoma 1991 in 2005 nista bistveno spreminjali. KO@A, MELANOM MKB 10: C43 142 0 2 4 6 8 10 12 14 16 18 20 1986 1990 1995 2000 2005 Leto / Year Incidenca – groba stopnja / Incidence – crude rate Incidenca – SSS* / Incidence – ASR** Umrljivost – groba stopnja / Mortality – crude rate Umrljivost – SSS* / Mortality – ASR** Stopnja na 100.000 / Rate per 100,000 * SSS – starostno standardizirana stopnja (standard – slovenska populacija leta 1986) ** ASR – age standardized rate (standard Slovenian population in 1986) Slika 1: Groba in starostno standardizirana inciden~na in umrljivostna stopnja malignega melanoma, Slovenija 1986–2005. Figure 1: Crude and age-standardized incidence and mortality rate of malignant melanoma, Slovenia 1986–2005. V analizo pre`ivetja je vklju~enih 3463 primerov; 20 bolnikov (0,6 %) nismo upo{tevali, ker jim je bila diagnoza postavljena po smrti, 25 mlaj{ih od 20 let pa obravnavamo v poglavju o pre- `ivetju pri otrocih in mladostnikih. V obdobju 2001–2005 so vsi primeri (1526) imeli opredeljen del telesa, kjer je melanom nastal: pri mo{kih najpogosteje na trupu (58 %), sledili so zgornji ud (13 %), spodnji ud (12 %), lobanja (7 %) in obraz (6 %), na vseh drugih mestih je bilo 4 % melanomov. Pri `enskah je melanom najpogosteje nastal na ko`i spodnjega uda (33 %), sledi- li so trup (29 %), zgornji ud (18 %), obraz (11 %), ko`a lobanje (4 %); na vse drugih mestih jih je bilo 4 %. Mo{ki / Males @enske / Females Obdobje / {tevilo / 20–49 let / 50–74 let / 75+ let / {tevilo / 20–49 let / 50–74 let / 75+ let / Period number years (%) years (%) years (%) number years (%) years (%) years (%) 1991–1995 360 36,4 52,2 11,4 459 39,9 49,2 10,9 1996–2000 527 34,9 54,3 10,8 591 35,2 49,1 15,7 2001–2005 704 28,6 58,7 12,8 822 34,1 45,9 20,1 Tabela 1: [tevilo bolnikov z malignim melanomom po spolu in obdobju postavitve diagnoze ter njihovi dele`i po starosti. T able 1: Number of malignant melanoma patients by sex and period of diagnosis with their proportions by age. EPIDEMIOLOGIJA Rak.qxd 22.7.2009 12:39 Page 142 In the period 1991–2005, a total of 3508 persons were diagnosed with skin melanoma, of these 1608 males and 1900 females. As evident from Figure 1, since 1991 the crude and age standardized incidence rates have been increasing, the crude rate more than the age-standardized one, by 6.4% annually on average. In the years 1991–2005, both mortality rates did not change much. The survival analysis included 3463 cases; 20 patients (0.6%) diagnosed only after death, were not considered in the analysis, 25 patients under 20 years of age are presented in the chapter on the survival of children and adolescents. In the period 2001–2005, the site of melanoma origin was determined in all cases (1526): in males the most frequent site was the trunk (58), followed by upper limbs (13%) lower limbs (12%), skull (7%) and face (6%); other sites were found in 4% of cases. In females, the most frequent site was skin of the lower limb (33%), fol- lowed by the skin of trunk (29%), upper limb (18%), face (11%), skin of the skull (4%); all other sites represented 4% of cases. Tumors of all patients included in the analysis were microscopically confirmed; in the first two periods, in almost a half of the cases histological type was not exactly defined, in the last peri- od in 32% (494 cases); among the defined ones (1032), 44% were superficially growing melanomas and 33% nodular melanomas, 6% melanomas of lentigo maligna type and 2% acral lentigi- nous melanomas; all other histological types represented 15%. Approximately half of patients are diagnosed at an age between 50–74 years, a majority of the remaining ones before 50 years of age, while less than 20% of patients are aged 75 years or older at the time of diagnosis (Table 1). Except for the greater proportion of females in the oldest age group, the proportions of patients in individual age groups did not change signifi- cantly with time. In all three time-periods, the majority of patients were diagnosed with localized disease; in the period 2001–2005 there were 76% such male and 81% female patients. The proportions of individual stages did not change significantly with time (Table 2). According to the sim- plified staging used by cancer registries and thus also by the CRS, the category of localized melanoma already includes tumors which have different prognosis with respect to the depth of invasion, tumor thickness and possible ulceration. The data collected by the CRS also include information on the depth of invasion by Clark, and on tumor thickness by Breslow. In 15 years, the average tumor thickness has decreased from 3.37 mm in the years 1991–1995 (measured in 73% cases, i. e. in 599 of 819 cases) to 2.59 mm (thickness determined in 90% of cases, i. e. in 1370 of 1526 cases). In the years 2001–2005, 1.3% of patients did not receive specific treatment. The proportion of untreated patients was gradually decreasing throughout the time of analysis; among those SKIN, MELANOMA MKB 10: C43 143 Tabela 2: [tevilo bolnikov z malignim melanomom po spolu in obdobju postavitve diagnoze ter njihovi dele`i po stadiju. T able 2: Number of malignant melanoma patients by sex and period of diagnosis with their proportions by stage. Mo{ki / Males @enske / Females Obdobje / {tevilo / omejen / raz{irjen / razsejan / neznan / {tevilo / omejen / raz{irjen / razsejan / neznan / Period number localized regional distant unknown number localized regional distant unknown (%) (%) (%) (%) (%) (%) (%) (%) 1991–1995 360 74,2 17,8 4,7 3,3 459 79,5 12,4 3,9 4,1 1996–2000 527 79,7 15,0 3,2 2,1 591 81,4 14,2 2,9 1,5 2001–2005 704 76,3 16,5 4,3 3,0 822 80,5 13,3 3,0 3,2 EPIDEMIOLOGY Rak.qxd 22.7.2009 12:39 Page 143 Vsi tumorji bolnikov, vklju~enih v analizo, so bili mikroskopsko potrjeni; v prvih dveh obdob- jih pri skoraj polovici histolo{ka vrsta ni bila natan~neje opredeljena, v zadnjem pri 32 % (494); med opredeljenimi (1032) je bilo 44 % povr{insko rasto~ih melanomov in 33 % nodularnih mela- nomov, 6 % melanomov lentigo maligna in 2 % akralnih lentigioznih melanomov; vseh ostalih histolo{kih vrst je bilo 15 %. Pribli`no polovica bolnikov zboli v starosti 50–74 let, ve~ina ostalih do 50. leta, manj kot 20 % bolnikov pa je ob postavitvi diagnoze starih 75 let in ve~ (Tabela 1). Razen ve~jega dele`a najstarej{ih `ensk, se dele`i v posameznih starostnih skupinah s ~asom niso bistveno spre- minjali. 144 KO@A, MELANOM 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Slika 2: Deset-, pet-, tri- in enoletno relativno pre`ivetje bolnikov z malignim melanomom po obdobju postavitve diagnoze. Figure 2: 10-, 5-, 3- and 1-year relative survival of malignant melanoma patients by period of diagnosis. Tabela 3: Opazovano in relativno pre`ivetje bolnikov z malignim melanomom po spolu in obdobju postavitve diagnoze s 95-odstotnim intervalom zaupanja (IZ). Table 3: Observed and relative survival of malignant melanoma patients by sex and period of diagnosis with 95% confidence interval (CI). Opazovano pre`ivetje / Observed survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 83,6 (79,9–87,5) 63,3 (58,5–68,5) 54,7 (49,8–60,1) 90,4 (87,8–93,1) 75,4 (71,5–79,4) 66,9 (62,7–71,3) 1996–2000 91,8 (89,5–94,2) 75,5 (71,9–79,3) 65,5 (61,5–69,7) 92,2 (90,1–94,4) 81,0 (78,0–84,3) 74,8 (71,4–78,4) 2001–2005 91,6 (89,6–93,7) 77,3 (74,2–80,5) 67,0 (63,2–70,9) 94,3 (92,7–95,9) 80,8 (78,1–83,6) 74,0 (70,8–77,4) Relativno pre`ivetje / Relative survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 86,1 (82,1–90,1) 69,4 (63,7–75,0) 63,8 (57,5–70,1) 92,1 (89,3–94,9) 79,7 (75,4–84,0) 73,3 (68,4–78,2) 1996–2000 94,5 (92,0–96,9) 82,4 (78,3–86,5) 75,9 (71,1–80,8) 94,2 (92,0–96,4) 86,3 (82,9–89,8) 83,3 (79,3–87,3) 2001–2005 94,6 (92,5–96,7) 85,2 (81,7–88,7) 79,2 (74,5–83,9) 96,4 (94,7–98,0) 86,5 (83,6–89,5) 83,2 (79,4–87,0) Rak.qxd 22.7.2009 12:39 Page 144 diagnosed in the period 1991–1995 there were 2.4% of patients without specific treatment. Almost all patients among the specifically treated in the period 2001–2005 underwent sur- gery; only 7 patients with highly advanced disease at diagnosis were not treated by surgery. In near to 80% of patients primary treatment consisted of surgery alone, 7% of surgically treated patients received interferon and the remaining ones additionally received irradiation combined with or without interferon. Compared to the previous periods, in the period 2001–1995 the proportion of patients receiving interferon in addition to surgery has decreased significantly. In the years 1991–1995, 26% of patients were treated with a combination of surgery and inter- feron. In the period 2001–2005, 36% started their treatment in the UMC Ljubljana, 12% each in the UMC Maribor and at the IO Ljubljana, 9% in the GH Celje and 7% in the GH Novo mesto. Between 1–3% of patients were treated in general hospitals of Jesenice, Nova Gorica, Slovenj Gradec, Murska Sobota and Izola. Nine percent of patients started their treatment in private clinics. 145 SKIN, MELANOMA 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 Omejen / Localized Raz{irjen / Regional Razsejan / Distant Vsi / All Slika 3: Petletno relativno pre`ivetje bolnikov z malignim melanomom po stadiju in obdobju postavitve diagnoze. Figure 3: 5-year relative survival of malignant melanoma patients by stage and period of diagnosis. 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 20–49 let / years 50–74 let / years 75+ let / years Vsi / All Slika 4: Petletno relativno pre`ivetje bolnikov z malignim melanomom po starosti in obdobju postavitve diagnoze. Figure 4: 5-year relative survival of malignant melanoma patients by age and period of diagnosis. Rak.qxd 22.7.2009 12:39 Page 145 V vseh treh obdobjih je imelo najve~ bolnikov ob diagnozi omejeno bolezen; v obdobju 2001–2005 je bilo pri mo{kih takih bolnikov 76 %, pri `enskah pa 81 %. Dele`i posameznih stadijev se s ~a- som niso bistveno spreminjali (Tabela 2). Poenostavljena opredelitev stadijev, kot jo uporabljajo registri raka, tudi slovenski, pri ko`nem melanomu `e v omejenem stadiju zdru`uje tumorje, ki imajo glede na globino invazije, debelino tumorja in morebitno ulceracijo razli~no napoved izida. V RRS zbiramo tudi podatke o globini invazije po Clarku in o debelini tumorja po Bre- slowu. V 15 letih se je povpre~na debelina tumorjev zmanj{ala s 3,37 mm v letih 1991–1995 (opredeljena pri 73 % primerov, to je pri 599 primerih od 819) na 2,59 mm (debelina oprede- ljena pri 90 % primerov, to je pri 1370 primerih od 1526). V letih 2001–2005 ni bilo specifi~no zdravljenih 1,3 % bolnikov. Dele` nezdravljenih bolni- kov se je v obdobjih analize po~asi zmanj{eval; med bolniki, zbolelimi v obdobju 1991–1995, ni bilo specifi~no zdravljenih 2,4 %. Med specifi~no zdravljenimi bolniki so bili v letih 2001–2005 skoraj vsi operirani; brez kirur{kega zdravljenja je ostalo 7 bolnikov z mo~no napredovalo bolez- nijo ob diagnozi. Pri skoraj 80 % je bilo prvo zdravljenje zaklju~eno z operacijo, 7 % operiranih je prejelo interferon, ostali pa so bili {e obsevani in so prejeli interferon ali pa ne. V primerjavi s prej{njima obdobjema se je v letih 2001–2005 bistveno zmanj{al dele` bolnikov, ki so bili poleg operacije zdravljeni {e z interferonom. V letih 1991–1995 je bilo s kombinacijo kirurgije in inter- ferona zdravljenih 26 % bolnikov. V obdobju 2001–2005 je 36 % bolnikov pri~elo zdravljenje v UKC Ljubljana, po 12 % v UKC Maribor in na OI Ljubljana, 9 % v SB Celje in 7 % v SB Novo mesto. Med 3 in 1 % bolnikov se je zdravilo v splo{nih bolni{nicah na Jesenicah, v Novi Gorici, Slovenj Gradcu, Murski Sobo- ti in Izoli. V zasebnih ordinacijah se je pri~elo zdraviti 9 % bolnikov. Relativno pre`ivetje bolnikov s ko`nim melanomom se postopno pove~uje; v 15 letih se je pet- letno relativno pre`ivetje pove~alo za 12% (Slika 2), pri mo{kih nekaj ve~ kot pri `enskah (Tabela 3). Kako pomemben je stadij ob diagnozi, ka`e Slika 3: petletno relativno pre`ivetje bolnikov z omejenim stadijem je v zadnjem obdobju preseglo 90 %. Petletno relativno pre`i- vetje bolnikov z raz{irjenim stadijem se pribli`uje 50 %, bolnikov z razsejanim stadijem pa je malo, tako da je ocenjevanje pre`ivetja precej nezanesljivo. Napovedni dejavnik je tudi starost, saj je relativno pre`ivetje najslab{e pri starih 75 let in ve~, pre`ivetje zbolelih med 50. in 75. le- tom pa ves ~as opazovanja rahlo zaostaja za relativnim pre`ivetjem zbolelih pred 50. letom (Slika 4). Petletno relativno pre`ivetje vseh zbolelih v obdobju 2001–2005 je bilo 81 % (Slika 2); bolni- ki, ki pre`ivijo prvo leto, pa lahko pri~akujejo 85-odstotno petletno relativno pre`ivetje. Rezultati {tudije EUROCARE-4 za zbolele v obdobju 2000–2002 ka`ejo, da je pre`ivetje slo- venskih bolnikov s ko`nim melanomom statisti~no zna~ilno manj{e od evropskega povpre~ja (Slika 5). 146 KO@A, MELANOM KLINI^NI KOMENT AR Marko Ho~evar Pre`ivetje bolnikov z melanomom ostaja {e naprej v najve~ji meri odvisno od stadija bolezni ob postavitvi diagnoze. Stadij ob postavitvi diagnoze je pri melanomu {e bolj kot pri drugih rakih zrcalo ozave{~enosti prebivalstva, saj se melanom ka`e kot ko`na sprememba in je s tem dostopna prostemu o~esu vsakega izmed nas. Glede na izbolj{ano relativno petletno pre`ivet- je v zadnjih 15 letih bi lahko sklepali, da je zaradi ve~je ozave{~enosti prebivalstva pri{lo do postavitve diagnoze `e v zgodnej{em stadiju in s tem do izbolj{anega pre`ivetja. To ka`ejo tudi podatki o manj{i povpre~ni debelini tumorja Rezultati porazdelitve bolnikov po stadijih v razli~nih obdobjih zadnjih 15 let so premalo natan~- ni, da bi lahko to zanesljivo potrdili. Velika ve~ina bolnikov (> 75 %) ima namre~ ob postavitvi Rak.qxd 22.7.2009 12:39 Page 146 The relative survival rate of patients with skin melanoma has been gradually increasing: in 15 years, the 5-year relative survival increased by 12% (Figure 2), in males slightly more than in females (Table 3). The relevance of stage at diagnosis is shown in Figure 3. In the last period, 5-year relative survival of patients with localized stage has exceeded 90%. The 5-year relative survival of patients with regional stage is near to 50%, whereas patients with disseminated disease are so scarce that the evaluation of their survival is unreliable. Age is a prognostic factor as well, since the relative survival is the lowest in patients aged 75 years or older, while the survival of those diagnosed between 50–74 years of age was lagging behind the relative survival of the patients diagnosed before the age of 50 throughout the observation period (Figure 4). The five-year relative survival of all patients diagnosed in the period 2001–2005 was 81% (Figure 2); patients surviving the first year may expect to survive five years in 85%. According to the results of EUROCARE-4 study for patients diagnosed in 2000–2002, the survival of patients with skin melanoma in Slovenia is statistically significantly below the European average (Figure 5). 147 SKIN, MELANOMA CLINICAL COMMENT ARY Marko Ho~evar 01 02 0 30 40 50 60 70 80 90 100 % Slovensko povpre~je / 2000–2002 (EUROCARE-4) Slovenian average Evropsko povpre~je / 2000–2002 (EUROCARE-4) European average Povpre~je ZDA / 2000–2002 (SEER-13) USA average Slika 5: Petletno relativno pre`ivetje bolnikov z malignim melanomom (povpre~je in 95-odstotni interval zaupanja), zbolelih v letih 2000–2002 v Sloveniji, Evropi in nekaterih obmo~jih v ZDA. Figure 5: 5-year relative survival of malignant melanoma patients (average and 95% confidence interval) diag- nosed in the period 2000–2002 in Slovenia, Europe and in some regions of the USA. The survival of melanoma patients still depends to the greatest extent on the stage of the dis- ease at diagnosis. In melanoma, more than in any other cancer, stage at diagnosis reflects the level of public awareness, since melanoma occurs in form of a skin change that every one of us can see with bare eye. Considering the improved 5-year survival in the last 15 years, we might presume that greater public awareness resulted in the diagnosis being established at an earli- er stage, thus facilitating better survival. This is consistent with the data on smaller average tumor thickness. However, the results of patient distribution by stage in different observation periods in the last 15 years are insufficiently accurate to confirm this hypothesis. Namely, throughout the 15-year observation period, a vast majority of patients (> 75%) presented with localized stage at diag- nosis. In the last 15 years the percentage of patients with regional disease at diagnosis has not changed either (approximately 15–20%). Patients with localized stage at diagnosis, which are Rak.qxd 22.7.2009 12:39 Page 147 diagnoze vse 15-letno obdobje omejeni stadij bolezni. Tudi odstotek bolnikov z raz{irjenim stadijem bolezni ob postavitvi diagnoze se v zadnjih 15 letih ni spremenil (pribli`no 15–20 %). Bolniki z omejenim stadijem bolezni ob postavitvi diagnoze, ki so naj{tevil~nej{i, so glede pre- `ivetja zelo heterogena skupina. Pre`ivetje je odvisno predvsem od debeline primarnega melanoma in morebitne ulceracije tumorja. Vseh podatkov sicer nimamo na voljo, ka`e pa, da se povpre~- na debelina melanomov v Sloveniji ne zni`uje tako, kot bi si `eleli. Povpre~na debelina ob postavitvi diagnoze je nad 2 mm in je {e vedno bistveno ve~ja kot v dr`avah z najbolj{im pre- `ivetjem, v Avstraliji, na [vedskem in [kotskem (bolniki s povpre~no debelino pod 1 mm imajo petletno pre`ivetje nad 90 %). Razlog bolj{ega pre`ivetja je zato potrebno iskati {e drugje. Drug razlog za izbolj{ano pre`ivetje bolnikov z melanomom bi lahko bila uvedba novih na~i- nov zdravljenja. V zadnjih 30 letih pri zdravljenju melanoma ni bistvenega napredka. Osnovno zdravljenje je {e naprej preprosta radikalna ekscizija primarnega melanoma. Adjuvantno zdrav- ljenje je {e naprej ve~inoma samo v sklopu klini~nih {tudij, ~eprav so nekatere dr`ave, med njimi tudi Slovenija, uvrstile zdravljenje z interferonom v svoja klini~na priporo~ila. Podobno je pri bolnikih z raz{irjenim stadijem ob postavitvi diagnoze. Tudi tu ostaja odstotek teh bolnikov v zadnjih 15 letih nespremenjen. Prav tako ostaja nespremenjen na~in zdravljenja – radikalna disekcija podro~nih bezgavk. Tudi v tej skupini bolnikov opa`amo skoraj 10-odstotno izbolj- {anje petletnega pre`ivetja. Razlog za bolj{e pre`ivetje bolnikov z melanomom v zadnjih 15 letih je zato verjetno v spre- menjeni biologiji (naravnem poteku) samega melanoma. Kot se je pokazalo v multivariatni analizi, ki smo jo opravili na OI Ljubljana, in v kateri smo upo{tevali obdobje diagnoze in debelino primarnega melanoma, je obdobje, v katerem so bolniki zboleli, najpomembnej{a neodvisna spremenljivka. Bolniki z melanomom, debelim 4 mm, imajo danes tak{no napoved izida, kot so jo imeli pred 20 leti bolniki z melanomom, debelim 1 mm. Ve~ina razlogov za tako spre- menjen naravni potek melanoma s ~asom {e ni znana. Vse ve~ podatkov pa ka`e, da gre pri melanomu za hetereogeno skupino bolezni z razli~no patogenezo – razli~no spremenjenim genskim zapi- som, ki je odvisen predvsem od tega, kje na telesu se melanom razvije. Razlog je verjetno razli~na izpostavljenost (intermitentna ali kroni~na) razli~nih delov telesa UV `arkom. Glede na to, da je povpre~na debelina melanoma v Sloveniji {e vedno precej ve~ja kot v naj- bolj razvitih dr`avah, pa imamo veliko prilo`nost, da z bolj{im ozave{~anjem prebivalstva dodatno izbolj{amo pre`ivetje bolnikov s ko`nim melanomom. Lasithiotakis KG, Leiter U, Eigentler T , Breuninger H, Metzler G, Meier F, et al. Improvement of overall sur- vival of patients with cutaneous melanoma in Germany, 1976–2001: which factors contributed? Cancer 2007; 109: 1174–82. Peri~ B, @gajnar J, Be{i} N, Ho~evar M. Changing biology of cutaneous melanoma. Melanoma Res 2008; 18: 225–9. 148 KO@A, MELANOM KLINI^NI KOMENT AR Janja Ocvirk Pre`ivetje bolnikov z rakom je odvisno od stadija bolezni ob postavitvi diagnoze in na~ina zdrav- ljenja. Pri melanomu nimamo presejalnega programa, tako da je veliko odvisno od ozave{~enosti prebivalstva, za katero je bilo v Sloveniji v letih, ki jih obravnava publikacija, storjenega malo. Veliko ve~ pa so za osve{~anje prinesla zadnja leta. Diagnoza je v ve~ini primerov mogo~a `e s pregledom ko`e, zaradi ~esar je velikega pomena samopregledovanje in poznavanje enostav- nega sistema diagnosticiranja (sistem ABCDE iz angle{kih besed, ki v sloven{~ini pomenijo: A – asimetrija, B – rob, C – barva, D – premer (diameter) in E – evolucija in elevacija). V dr`a- vah z bolj{o ozave{~enostjo in poznavanjem tega sistema si 80–90 % bolnikov samih postavi diagnozo oz. pridejo k zdravniku v za~etni fazi bolezni. VIRI Literature Rak.qxd 22.7.2009 12:39 Page 148 most numerous, represent in terms of their survival a very heterogeneous group. The survival primarily depends on the thickness of primary melanoma and possible tumor ulceration. Although not all the data are available, it seems that the average melanoma thickness in Slovenia is not decreasing as anticipated. The average thickness at diagnosis exceeds 2 mm and is still signifi- cantly greater than in countries with the best survival, i. e. in Australia, Sweden and Scotland (patients with average thickness less than 1mm have 90% 5-year survival). Therefore the cause of better survival should also be sought elsewhere. Another reason for better survival of melanoma patients might be attributable to the imple- mentation of new treatment modalities. In the last 30 years, no significant progress has been achieved in the area of melanoma treatment. The basic therapy still consists of a simple rad- ical excision of the primary melanoma. Adjuvant therapy is still carried out mainly in the framework of clinical studies, although certain countries, among them also Slovenia, have included inter- feron-based treatment into their clinical recommendations. The situation in patients with regional disease at diagnosis is similar. In the last 15 years, their proportion too has remained unchanged. The mode of treatment – radical regional lymph node dissection – has remained unchanged too. In this group of patients too we observe an almost 10% improvement in the 5-year sur- vival. The reason for better survival of melanoma patients in the last 15 years should probably be sought in a changed biology (natural course) of melanoma itself. As shown by the results of a multivariate analysis carried out at the IO Ljubljana, where the time at diagnosis and pri- mary melanoma thickness were considered, the period of patients' diagnosis turned out to be the most relevant independent variable. Today the prognosis in patients with melanoma thick- ness of 4 mm is comparable with the prognosis in patients with melanoma thickness of 1mm 20 years ago. Most reasons for the changed natural course of melanoma with time have not been explained yet. However, there is growing evidence in favor of the belief that melanoma represents a heterogeneous group of diseases with varying pathogenesis – differently changed genetic code, primarily depending on the site of melanoma origin. The reason probably lies in different exposure (intermittent or chronic) of various body parts to UV rays. In view of the fact that the average thickness of melanoma in Slovenia is still greater than in the most developed countries, we have an ample opportunity to further improve the survival of patients with skin melanoma by raising public awareness. 149 SKIN, MELANOMA CLINICAL COMMENT ARY Janja Ocvirk Survival of cancer patients depends on the stage of the disease at diagnosis and the mode of treatment. No screening program being available for melanoma, a lot depends on public aware- ness, though not much has been done in this respect in the years covered by this report. In recent years, however, the situation as regards awareness rising has improved considerably. In most cases the diagnosis is possible already on the basis of skin examination, which points out the importance of self-examination; it is also important to know the simple system of diag- nosis (ABCDE system meaning: A – asymmetry, B – border, C – color, D – diameter and E – elevation). In the countries with greater awareness and knowledge of this system, 80–90% of patients will make their own diagnosis or see the doctor at an early stage of the disease. The incidence of melanoma is increasing, which could be ascribed to the environmental influ- ences as well as to a changed lifestyle and longer lifespan, which also explains a higher number of the elderly among melanoma patients. In recent years we changed the approach to melanoma patients, introduced the sentinel node biopsy, which facilitates more accurate staging of the disease and thus treatment already at the presence of micrometastases in the lymph nodes, resulting in a longer survival of patients with Rak.qxd 22.7.2009 12:39 Page 149 Incidenca melanoma se ve~a, kar bi lahko pripisali vplivu okolja in spremenjenemu na~inu `iv- ljenja, pa tudi dalj{i `ivljenjski dobi, zaradi ~esar je med bolniki z melanomom tudi ve~ starej{ih. V zadnjih letih smo spremenili obravnavo bolnikov z melanomom, uvedli smo biopsijo varo- valne bezgavke, ki omogo~a natan~nej{o dolo~itev stadija bolezni in s tem zdravljenje `e ob prisotnosti mikrozasevkov v bezgavkah, kar vodi v podalj{anje pre`ivetja bolnikov s to bolez- nijo. Uveden je bil tudi nov sistem dolo~anja stadijev melanoma; poleg biopsije varovalne bezgavke omogo~a bolj natan~no odbiro bolnikov tudi za sistemsko adjuvantno zdravljenje, ki je bilo uvedeno v zadnjem petletju in je vplivalo na podalj{anje pre`ivetja bolnikov z lokalno raz{ir- jeno boleznijo. Relativno 1-, 3-, 5- in 10-letno pre`ivetje bolnikov se ve~a v vseh opazovanih obdobjih, {e pose- bej bolnikov z omejeno in raz{irjeno boleznijo zaradi uvedbe novih na~inov zdravljenja: biopsije varovalne bezgavke in sistemskega adjuvantnega zdravljenja, `al pa ostaja pre`ivetje bolnikov z razsejano boleznijo {e vedno slabo, pri teh bolnikih tako v Sloveniji kakor v svetu {e nima- mo na voljo u~inkovitega zdravljenja. Z vse ve~jo ozave{~enostjo prebivalstva, ob izbolj{anih na~inih zdravljenja in seveda njegovem izvajanju ter ob multidisciplinarni obravnavi bolnika lahko pri~akujemo, da se bo pre`ivetje tudi v nadaljnjih letih {e izbolj{evalo. Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 2001; 19: 3635–48. Ocvirk J. Dopolnilno sistemsko zdravljenje melanoma. In: Ocvirk J, Snoj M, Strojan P , eds. [ola o melanomu. Radiol Oncol 2007; 41: S43–S45. 150 KO@A, MELANOM VIRI Literature Rak.qxd 22.7.2009 12:39 Page 150 this disease. The newly introduced system of melanoma staging facilitates, apart from sentinel node biopsy, a more accurate selection of patients for systemic adjuvant therapy introduced in the last 5-year period and influencing a longer survival of patients with locally advanced di- sease. The relative 1-, 3-, 5- and 10-year survival of patients has been increasing in all the observed periods, particularly in patients with localized and regional disease as a result of new treatment methods: sentinel lymph node biopsy and adjuvant systemic therapy. Unfortunately, however, the survival of patients with disseminated disease is still poor; there is no effective treatment method available for these patients either in Slovenia or elsewhere in the world. Ever greater public awareness, improved treatment methods and their implementation as well as the multidisciplinary treatment approach to these patients are expected to contribute to a fur- ther increase in the survival in the future. 151 SKIN, MELANOMA Rak.qxd 22.7.2009 12:39 Page 151 V obdobju 1991–2005 je za rakom dojk zbolelo 13.756 ljudi, 13.635 `ensk in 121 mo{kih. Kot je razvidno s Slike 1, ki prikazuje podatke le za `enske, sta se v opazovanem obdobju pove~e- vali groba in starostno standardizirana inciden~na stopnja; bolj do leta 1998 (5,8 % oz. 4,6 % povpre~no letno) kot kasneje (2,2 % oz. 1,4 % povpre~no letno). Umrljivostna stopnja se zmanj- {uje od leta 1991, bolj starostno standardizirana (1,3% povpre~no letno) kot groba (0,4% povpre~no letno). DOJKA MKB 10: C50 152 0 20 40 60 80 100 120 1986 1990 1995 2000 2005 Leto / Year Incidenca – groba stopnja / Incidence – crude rate Incidenca – SSS* / Incidence – ASR** Umrljivost – groba stopnja / Mortality – crude rate Umrljivost – SSS* / Mortality – ASR** Stopnja na 100.000 / Rate per 100,000 * SSS – starostno standardizirana stopnja (standard – slovenska populacija leta 1986) ** ASR – age standardized rate (standard Slovenian population in 1986) Slika 1: Groba in starostno standardizirana inciden~na in umrljivostna stopnja raka dojk, Slovenija 1986–2005. Figure 1: Crude and age-standardized incidence and mortality rate of breast cancer, Slovenia 1986–2005. @enske / Females Obdobje / {tevilo / 20–49 let / 50–74 let / 75+ let / Period number years (%) years (%) years (%) 1991–1995 3552 25,9 59,1 15,0 1996–2000 4623 24,2 59,6 16,1 2001–2005 5236 22,3 59,0 18,7 Tabela 1: [tevilo bolnic z rakom dojk po obdobju postavitve diagnoze ter njihovi dele`i po starosti. Table 1: Number of breast cancer patients by period of diagnosis with their proportions by age. V analizo pre`ivetja je vklju~enih 13.411 bolnic; 224 (1,6 %) jih nismo upo{tevali, ker jim je bila diagnoza postavljena po smrti. Izklju~ili smo tudi 121 mo{kih, tako da se vsi rezultati nana- {ajo samo na `enske. V obdobju 2001–2005 je imelo 3241 bolnic (od 5236) natan~neje opredeljeno mesto vznika tumorja v dojki. V 35 % je bil to zgornji zunanji kvadrant, tumorjev ostalih treh kvadrantov je bilo manj kot po 8 %, v dva kvadranta ali ve~ je segalo 36 % tumorjev, manj kot po 1 % pa so zavzemali tumorji bradavice in pazdu{nega predela dojke. Odstotek mikroskopsko potrjenih primerov se je pove~al s 96% v letih 1991–1995 na 98% v letih 2001–2005. V vseh treh obdobjih so prevladovali karcinomi, druge histolo{ke vrste so EPIDEMIOLOGIJA Rak.qxd 22.7.2009 12:39 Page 152 In the period 1991–2005, a total of 13,756 persons were diagnosed with breast cancer, of these 13,635 females and 121 males. As evident from Figure 1, which is shown the female data only, in the study period the crude and age-standardized incidence rates have been increasing, more so till 1998 (by 5.8% and 4.6% annually on average) than later on (by 2.2% and 1.4% annu- ally on average). Since 1991, the mortality rates have been decreasing, the age-standardized more than the crude rates (1.3% vs. 0.4% annually on average). The survival analysis included 13,411 patients; 224 patients (1.6%) diagnosed only after death were not considered in the analysis. There were 121 males excluded as well, so that the results apply to women. In the period 2001–2005, 3241 patients (out of total 5236) had the site of tumor origin in the breast more precisely defined. Thus, in 35% of cases tumor was situated in the upper outer quadrant, sites in the remaining three quadrants were present in less than 8% each, 36% of tumors involved two or more quadrants, while tumors of the nipple and axil- lary area of the breast occurred in less than 1% each. The percentage of microscopically confirmed cases increased from 96% in the years 1991–1995 to 98% in the years 2001–2005. With respect to histological type, carcinomas were prevailing while other histological types were rare; in the last period there were 8 cases of sarcoma and 4 cases of fibroepithelial malignomas (malignant phyloid tumors). Compared to the first period, in the last one, the proportion of younger patients (20–49 years) was lower by 4%, the proportion of those at an age between 50–74 years has not changed sig- nificantly while the proportion of patients aged 75 years or older has increased by 4% (Table 1). The proportion of patients with localized disease has gradually increased, in the last period the proportion of newly diagnosed cases with localized stage being 50%, i. e. 7% more than in the first period (Table 2). In all three time-periods, most patients received specific treatment, 5050 (96%) in the peri- od 2001–2005. In the period 2001–2005, 10% were treated only locally, by surgery and/or radiotherapy, (12% less than in the period 1991–1995); 8% underwent surgery alone (vs. 14% in the past), while 2% had radiotherapy either with or without surgery (vs. 8% in the past). In comparison with the first period, in the last one the greatest increase (16%) was observed in the proportion of patients who received adjuvant hormonal therapy: In the period 2001–2005, there were 39% such patients (21% underwent surgery alone and 18% also received radiotherapy) vs. 23% in the period 1991–1995 (13% had surgery alone while 10% also received irradiation). In the period 2001–2005, 26% of patients received chemotherapy besides adjuvant hormon- al therapy, the rate being comparable with the one in the first period (26.0%); in this group, as compared to the first period, the proportion of those treated by surgery alone has increased by 2% only (on the account of adjuvant irradiation), from previous 5% to 7%. Seventeen per- BREAST ICD 10: C50 153 Tabela 2: [tevilo bolnic z rakom dojk po obdobju postavitve diagnoze ter njihovi dele`i po stadiju. Table 2: Number of breast cancer patients by period of diagnosis with their proportions by stage. @enske / Females Obdobje / {tevilo / omejen / raz{irjen / razsejan / neznan / Period number localized regional distant unknown (%) (%) (%) (%) 1991–1995 3552 42,6 45,9 10,2 1,4 1996–2000 4623 46,9 42,0 9,7 1,4 2001–2005 5236 50,0 41,1 8,0 0,9 EPIDEMIOLOGY Rak.qxd 22.7.2009 12:39 Page 153 izjemno redke; v zadnjem obdobju je bilo 8 primerov sarkomov in 4 primeri fibroepitelijskih malignomov (malignih filodnih tumorjev). V zadnjem obdobju je bilo 4 % manj mlaj{ih bolnic (20–49 let) kot v prvem, odstotek bolnic v starosti 50–74 let se ni bistveno spreminjal, za 4 % pa se je pove~al odstotek starih 75 let in ve~ (Tabela 1). Odstotek bolnic z omejeno boleznijo se je postopno ve~al, v zadnjem obdobju je bilo z ome- jeno boleznijo odkritih 50 % novih primerov, 7 % ve~ kot v prvem (Tabela 2). V obdobju 2001–2005 je bilo zdravljenih samo lokalno, z operacijo in/ali obsevanjem, 10 % bolnic (za 12 % manj kot v letih 1991–1995); samo operiranih je bilo 8 % bolnic (prej 14 %), obsevanih (poleg operacije ali brez nje) pa 2 % (prej 8 %). V primerjavi s prvim obdobjem se 154 DOJKA 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Slika 2: Deset-, pet-, tri- in enoletno relativno pre`ivetje bolnic z rakom dojk po obdobju postavitve diagnoze. Figure 2: 10-, 5-, 3- and 1-year relative survival of breast cancer patients by period of diagnosis. Tabela 3: Opazovano in relativno pre`ivetje bolnic z rakom dojk po obdobju postavitve diagnoze s 95-odstotnim intervalom zaupanja (IZ). Table 3: Observed and relative survival of breast cancer patients by period of diagnosis with 95% confidence interval (CI). Opazovano pre`ivetje / Observed survival (%) @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 89,1 (88,1–90,1) 73,0 (71,5–74,4) 61,1 (59,5–62,7) 1996–2000 92,3 (91,5–93,0) 79,3 (78,2–80,5) 68,7 (67,4–70,1) 2001–2005 93,1 (92,4–93,8) 83,1 (82,0–84,1) 74,2 (72,9–75,6) Relativno pre`ivetje / Relative survival (%) @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 91,2 (90,1–92,2) 78,4 (76,8–80,0) 69,0 (67,2–70,9) 1996–2000 94,3 (93,5–95,1) 84,7 (83,5–86,0) 77,0 (75,5–78,5) 2001–2005 95,1 (94,4–95,8) 88,7 (87,6–89,8) 83,3 (81,8–84,8) Rak.qxd 22.7.2009 12:39 Page 154 cents of patients received only adjuvant chemotherapy (4% less than in the first period); 7% underwent surgery alone while 10% also received radiotherapy (in the first period out of 21% of patients receiving chemotherapy 10% underwent surgery alone and 11% also received radio- therapy). In all three time-periods nearly 9% of patients were not treated locally but only systemically, with chemotherapy, hormones or a combination of both. In the last period 58% of patients started their treatment at the IO Ljubljana (the percentage being comparable with those in the previous periods), 18% in the UMC Maribor, 9% in the GH Nova Gorica, 8% in the GH Celje, and 3% in the GH Slovenj Gradec and GH Novo mesto respectively. Ten or less patients started their treatment in UMC Ljubljana and GH in Murska Sobota, Izola, Trbovlje, and Jesenice and in the hospitals for gynecology and obstetrics in Postojna and Kranj. The relative survival of patients has been gradually increasing, particularly in the last period; in 15 years, the 5-year relative survival increased by 14% (Figure 2; Table 3). The relevance of stage at diagnosis is shown in Figure 3. Compared to the period 1991–1995, in the last period 155 BREAST 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 Omejen / Localized Raz{irjen / Regional Razsejan / Distant Vsi / All Slika 3: Petletno relativno pre`ivetje bolnic z rakom dojk po stadiju in obdobju postavitve diagnoze. Figure 3: 5-year relative survival of breast cancer patients by stage and period of diagnosis. 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 20–49 let / years 50–74 let / years 75+ let / years Vsi / All Slika 4: Petletno relativno pre`ivetje bolnic z rakom dojk po starosti in obdobju postavitve diagnoze. Figure 4: 5-year relative survival of breast cancer patients by age and period of diagnosis. Rak.qxd 22.7.2009 12:39 Page 155 je v zadnjem najbolj, za 16 %, pove~al dele` bolnic, ki so prejele dopolnilno hormonsko zdrav- ljenje: v letih 2001–2005 je bilo takih 39 % (21 % samo operiranih in 18 % dodatno obsevanih), v letih 1991–1995 pa 23 % (13 % samo operiranih, 10 % {e obsevanih). V letih 2001–2005 je 26 % bolnic poleg hormonskega dopolnilnega zdravljenja prejelo {e kemoterapijo; ta dele` je skoraj enak kot v prvem obdobju (26 %); v tej skupini se je v primerjavi s prvim obdobjem le za 2 % pove~al dele` samo operiranih (na ra~un dodatnega obsevanja), s 5 % na 7 %. Samo dopol- nilno kemoterapijo je prejelo 17 % bolnic (4 % manj kot v prvem obdobju); 7 % je bilo samo operiranih, 10 % pa tudi obsevanih (v prvem obdobju pa je bilo od 21 %, ki so prejele kemotera- pijo, 10 % samo operiranih, 11 % pa tudi obsevanih). V vseh treh obdobjih blizu 9 % bolnic ni bilo zdravljenih lokalno, pa~ pa le sistemsko, s kemoterapijo, hormoni ali s kombinacijo obeh vrst. V vseh treh obdobjih je bila specifi~no zdravljena ve~ina bolnic, 5050 (96 %) v letih 2001–2005. V tem obdobju se je za~elo zdraviti na OI Ljubljana 58 % bolnic (podoben odstotek tudi v prej{- njih obdobjih), 18 % v UKC Maribor, 9 % v SB Nova Gorica, 8 % v SB Celje, po 3 % pa v SB Slovenj Gradec in SB Novo mesto. Po 10 ali manj bolnic se je za~elo zdraviti {e v drugih bolni{ni- cah, v UKC Ljubljana, v SB Murska Sobota, SB Izola, SB Trbovlje, SB Jesenice ter v bolni{nicah za porodni{tvo in `enske bolezni Postojna in Kranj. Relativno pre`ivetje se postopno ve~a, predvsem v zadnjem obdobju; v 15 letih se je petletno relativno pre`ivetje pove~alo za 14 % (Slika 2; Tabela 3). Kako pomemben je stadij ob diag- nozi, ka`e Slika 3: v zadnjem obdobju je petletno relativno pre`ivetje bolnic z omejenim stadijem `e ve~ kot 95-odstotno in se je v primerjavi z leti 1991–1995 pove~alo za 9 %, za 19 % se je pove~alo tudi petletno relativno pre`ivetje bolnic z raz{irjeno boleznijo, za 8 % pa bolnic z raz- sejano boleznijo. Napovedni dejavnik je tudi starost, saj so v zadnjem obdobju mlaj{e od 50 let imele za 10 % ve~je relativno pre`ivetje kot stare 75 let in ve~ (Slika 4). Petletno relativno pre`ivetje vseh zbolelih v obdobju 2001–2005 je bilo 83 % (Slika 2); bolni- ce, ki pre`ivijo prvo leto, pa lahko pri~akujejo 87-odstotno petletno relativno pre`ivetje. Rezultati {tudije EUROCARE-4 za zbolele v obdobju 2000–2002 ka`ejo, da je pre`ivetje sloven- skih bolnic z rakom dojk {e vedno statisti~no zna~ilno manj{e od evropskega povpre~ja (Slika 5). 156 DOJKA KLINI^NI KOMENT AR Janez @gajnar Podatki, ki jih obravnavamo v tej publikaciji, so ohrabrujo~i. Ka`ejo namre~, da se obravnava raka dojk v dr`avi izbolj{uje, kar se odslikava v vedno ve~jem pre`ivetju bolnic vseh starosti ne glede na stadij ob postavitvi diagnoze in tudi v dalj{em opazovanem obdobju. Omenjeni napre- dek je v ve~ji meri posledica bolj{ega sistemskega zdravljenja, le v manj{i meri pa premika k bolj omejenemu stadiju ob postavitvi diagnoze, oziroma h kakovosti podro~nega zdravljenja. Ob pregledu podatkov {e vedno vznemirja velika razpr{enost zdravljenja po {tevilnih zdrav- stvenih ustanovah, kar je v nasprotju z evropskimi priporo~ili in z na~eli, sprejetimi v Sloveniji. Dokazano je, da je zdravljenje uspe{nej{e v centrih z dovolj znanja, opreme ter obenem z za- dostnim {tevilom novih bolnic (najmanj 150 letno), zato pri~akujemo, da bodo odgovorni odlo~no ukrepali in bodo zdravljenje raka dojk omejili le na nekaj ustanov, ki izpolnjujejo evropske stan- darde. Pre`ivetje bolnic z omejenim stadijem je `e sedaj odli~no, kar posredno potrjuje izjemen pomen zgodnjega odkrivanja raka dojk. Z oportunisti~nim presejanjem, kot smo ga imeli (in ga {e imamo) v Sloveniji, o~itno ve~jega premika k ve~jemu dele`u omejenih rakov ne moremo napraviti. Upa- mo lahko, da se bo program DORA kmalu raz{iril na celotno Slovenijo in bo v prihodnjem obdobju zmanj{al dele` raz{irjene bolezni. V zadnjem obdobju se je dele` omejenega raka dojk pove~al le za 3 %, na 50 %. Pri tem moramo upo{tevati, da se je prav v tem obdobju v kirur{kem zdravljenju uveljavljala biopsija prve (sentinel) bezgavke in da pri 10–20% bolnic najdemo Rak.qxd 22.7.2009 12:39 Page 156 the 5-year relative survival of patients with localized stage was already 95%, thus having increased by 9%, while the 5-year relative survival of patients with regional disease has increased by 19% and of patients with disseminated disease by 8%. Age is a prognostic factor as well, since in the last period all the patients under 50 years of age had 10% higher relative survival than those aged 75 years or older (Figure 4). The 5-year relative survival of all patients diagnosed in the period 2001–2005 was 83% (Figure 2); patients surviving the first year may expect to survive five years in 87%. According to the results of EUROCARE-4 study for patients diagnosed in 2000–2002, the survival of breast cancer patients in Slovenia is still statistically significantly below the European average (Figure 5). 157 BREAST CLINICAL COMMENT ARY Janez @gajnar 01 02 0 30 40 50 60 70 80 90 100 % Slovensko povpre~je / 2000–2002 (EUROCARE-4) Slovenian average Evropsko povpre~je / 2000–2002 (EUROCARE-4) European average Povpre~je ZDA / 2000–2002 (SEER-13) USA average Slika 5: Petletno relativno pre`ivetje bolnic z rakom dojk (povpre~je in 95-odstotni interval zaupanja), zbolelih v letih 2000–2002 v Sloveniji, Evropi in nekaterih obmo~jih v ZDA. Figure 5: 5-year relative survival of breast cancer patients (average and 95% confidence interval) diagnosed in the period 2000–2002 in Slovenia, Europe and in some regions of the USA. The data presented in the current report of the CRS are encouraging. They indicate that breast cancer treatment in Slovenia is improving, which is reflected in increasingly better survival of patients in all age groups, regardless of the stage at diagnosis, and evident even through a longer observation period. This progress is mainly attributable to better systemic therapy and only to a lesser extent to the shift towards more localized stage at diagnosis or the quality of locore- gional treatment. The data review still raises concern due to wide dispersion of treatment throughout several healthcare institutions, which is in contradiction with the European recommendations as well as with the principles established in Slovenia. It has been proved that the treatment performed in centers with adequate knowledge and equipment, and at the same time a sufficient num- ber of newly diagnosed patients (at least 150 per year), has better results, therefore we expect that the competent authorities will take the necessary measures to restrict breast cancer treat- ment to few institutions that meet the European standards. The survival of patients with localized stage is already excellent, which indirectly proves the outstanding importance of early breast cancer detection. The opportunistic screening for breast cancer, which has been practiced in Slovenia, is apparently unable to contribute further to a greater Rak.qxd 22.7.2009 12:39 Page 157 v bezgavkah zaradi natan~nej{e histopatolo{ke preiskave zasevke, ki jih prej nismo na{li. Pove- ~an dele` bolnic z omejenim stadijem bolezni je zato manj{i, kot bi morda pri~akovali. V obravnavanem obdobju se je za 12 % (na skupaj 10 %) zmanj{al dele` bolnic, ki so bile zdrav- ljenje le lokalno – kirur{ko in/ali z obsevanjem. To je nedvomno posledica spremenjenih indikacij za sistemsko zdravljenje. Po drugi strani pa lahko pri~akujemo, da se bo z raz{iritvijo mamo- grafskega presejanja pove~al dele` neinvazivnega raka dojk in zelo majhnih invazivnih rakov, ki jih bomo zdravili le lokalno. Vsekakor bi za celostno podobo kakovosti obravnave raka dojk in razlago rezultatov potrebo- vali tudi podatke, ki jih RRS tokrat ne prikazuje. Predvsem bi bilo zanimivo primerjati pre`ivetja glede na ustanovo, kjer je zdravljenje potekalo. V Sloveniji je to {e posebej zapleteno, ker bol- niki (razen tistih z OI) prehajajo med {tevilnimi ustanovami na poti od diagnostike do razli~nih vrst zdravljenj. Manjka tudi podatek, ki pa ga v na{em registru ni, in sicer, koliko bolnic je bilo multidisciplinarno obravnavanih pred za~etkom zdravljenja; prav pravilno prvo zdravljenje pa je klju~no za izid zdravljenja. ^e se omejim na kirur{ko zdravljenje, naj na{tejem le nekaj pomembnih kazalcev kakovosti zdravljenja, ki tudi niso dostopni: dele` operacij z ohranitvijo dojke, {tevilo operacij za isto bole- zen, dele` predoperativnega sistemskega zdravljenja, rekonstrukcij po odstranitvi dojk in drugih. Doslej smo v Sloveniji ob~asno opravljali analize v posameznih ustanovah, kar pa ne odseva stanja v dr`avi. Leta 2005 smo tako na OI opravili pri pribli`no polovici bolnic konservirajo- ~o operacijo dojke, kar je {e vedno premajhen dele`. Majhen ostaja tudi dele` rekonstrukcij dojk po mastektomiji, ~eprav je v zadnjih letih zrasel na 30 %. [ele sistemati~en zajem vseh klju~nih podatkov za ocenjevanje kakovosti zdravljenja bo omogo~al tako potreben nadzor in primerjavo znotraj ustanov in med njimi. Zato je nujno, da za`ivi Dr`avni program obvlado- vanja raka, katerega del je tudi elektronski popis bolnika z rakom, ki bi bil povezan z RRS. Obravnava raka dojk mora biti zaupana le tistim, ki dosegajo zahtevana merila kakovosti. Zaklju~imo lahko, da v Sloveniji po~asi zmanj{ujemo zaostanek za najbolj{imi v svetu pri pre- `ivetju bolnic z rakom dojk, ~eprav {e zdale~ ni na `eleni ravni. Predvsem bo treba ~im prej omogo~iti vsem bolnicam z rakom dojk v Sloveniji enako kakovostno celostno obravnavo. To se bo odrazilo tudi v rezultatih pre`ivetja. Blamey L, Cataliotti R. The requirements of a specialist Breast Unit. Eur J Cancer 2000; 36: 2288–93. Revi- sion 2004, www.eusoma.org. Cserni G, Amendoeira I, Apostolikas N, Bellocq JP, Bianchi S, Bussolati G, et al. Pathological work-up of sentinel lymph nodes in breast cancer. Review of current data to be considered for the formulation of guide- lines. European Working Group for Breast Screening Pathology. Eur J Cancer. 2003; 39: 1654–67. Novak M, @gajnar J: Kontrola kakovosti pri lokoregionalnem zdravljenju karcinoma dojk; Onkologija 2008, 1: 39–42. Perry N, Broeders M, de Wolf C, Törnberg S, Holland R, von Karsa L, Puthaar E, eds. European Guidelines for Quality Assurance in Breast Cancer Screening and Diagnosis. Fourth Edition. European Commission. Luxembourg, Office for Official Publications of the European Communities, 2006. 158 DOJKA KLINI^NI KOMENT AR Elga Majdi~ ^eprav podatki o na~inu zdravljenja bolnic z rakom dojk, zbolelih v 15-letnem obdobju, ne ka`ejo, da se je dele` bolnic, obsevanih v okviru prvega zdravljenja, v zadnjem obdobju (48 %) pove~al v primerjavi z dele`em obsevanih v prvem obdobju (51 %), pa se je pove~alo absolut- no {tevilo bolnic, ki smo jih z obsevanjem zdravili na OI Ljubljana z okrog 1700 na skoraj 2500 v letih 2001–2005. To {tevilo se {e ve~a, saj smo v obdobju od junija 2006 do junija 2007 z obsevanjem zdravili ve~ kot 1000 bolnic. V teh letih se je pove~alo tako opazovano kot relativno VIRI Literature Rak.qxd 22.7.2009 12:39 Page 158 proportion of localized stages. Hopefully, the organized breast cancer screening program (DORA program) will soon spread throughout Slovenia and thus help to reduce the proportion of advanced disease in future. In the last period the proportion of localized breast cancer has increased by 3% only, thus amounting to 50%. Further to that, we have to take into account that in the very same period surgical treatment was upgraded by sentinel node biopsy and that more accu- rate histopathologic investigations help to detect metastases in 10–20% of patients, which would previously remain undetected. The proportion of patients with localized stage is therefore small- er than it might be expected. In the observed period the proportion of patients treated only locally, either by radiotherapy and/or surgery has decreased by 12% (to a total of 10%). This is obviously a result of changed indications for systemic therapy. On the other hand, it may be expected that wider use of mam- mographic screening will result in a greater proportion of non-invasive breast cancers and very small invasive cancers that will be treated only locally. Certainly, in order to present an overall image of quality in breast cancer treatment, and to explain the results, data beyond those presented by the CRS are needed. In particular, it will be inter- esting to compare survival with respect to the institution of treatment. In Slovenia, this issue is particularly complex since on their way from diagnosis to different treatment modalities, the patients (except those treated at the IO Ljubljana) are migrating between several institutions. We also miss information, neither available in our CRS, on how many patients had been sub- ject to multidisciplinary approach prior to the beginning of therapy; it is generally accepted that appropriate primary treatment is the most important for a good outcome of treatment. Speaking strictly about surgical therapy, let me point out just a few indicators of the quality of treatment that are not available: the proportion of breast preserving procedures, the num- ber of surgeries for the same disease, the proportion of preoperative systemic therapy, breast reconstructions after mastectomy and others. So far, sporadic analyses have been carried out by individual institutions in Slovenia, which however do not reflect the actual situation in the country. Thus in 2005, approximately half of the patients underwent a breast preserving sur- gical procedure at the IO Ljubljana, the proportion still being too low. The proportion of breast reconstructions after mastectomy remains low as well, though it has increased to 30% in the recent years. Only a systematic pooling of all key data for the evaluation of the quality of treat- ment will facilitate the necessary supervision and comparison within different institutions and between them. Therefore it is necessary that the National Cancer Control Program is imple- mented as soon as possible, part of which is also an electronic cancer patients' record that would be linked with the CRS. Breast cancer treatment should be limited only to those institutions that meet the required quality standards. We can conclude that in Slovenia we are gradually catching up with the state of the-art in the world as regards the survival of breast cancer patients, though the results obtained are still far from the desired. First of all, it will be necessary to ensure equal access to a quality compre- hensive treatment for all breast cancer patients in Slovenia. This will certainly reflect in better survival results. 159 BREAST CLINICAL COMMENT ARY Elga Majdi~ The data on the method of treatment in breast cancer patients diagnosed in the 15-year obser- vation period do not show that the proportion of patients irradiated in the course of their primary treatment in the last period (48%) has increased as compared to the first period (51%), but nevertheless, the absolute number of patients treated by radiotherapy at the IO Ljubljana increased from previous 1700 to almost 2500 in the period 2001–2005. This number is still growing, since more than 1000 patients were treated by radiotherapy in the period from June 2006 to Rak.qxd 22.7.2009 12:39 Page 159 pre`ivetje (Tabela 3) in to predvsem v omejenem in lokalno raz{irjenem stadiju (Slika 3), torej v stadijih, v katerih ima radioterapija v zadnjih letih vedno pomembnej{o vlogo. Pove~alo se je {tevilo delnih resekcij dojke s pooperativnim obsevanjem, pomembna sprememba pa je uved- ba pooperativnega obsevanja po mastektomiji pri bolnicah z velikim tveganjem za lokalno ponovitev bolezni. Metaanaliza randomiziranih klini~nih {tudij je pokazala, da lokalni nad- zor pomembno vpliva na pre`ivetje. Ocenjujejo, da dodatek obsevanja po operaciji zmanj{a verjetnost lokalne ponovitve pri vseh skupinah bolnic za dve tretjini, kar izbolj{a 15-letno absolutno pre`ivetje bolnic po ohranitveni kirurgiji za 5,3 % in bolnic z zasevki v pazduhi po modificirani radikalni mastektomiji za 4,4 %, kar je primerljivo z u~inkom sistemskega zdravlje- nja. Pri na{ih bolnicah tako dolge opazovalne dobe {e nimamo, trend pa je o~iten. Ob dosedanjih ugotovitvah o tem, kako u~inkovito je pooperativno obsevanje, je pri~akovati {e raz{iritev te indikacije. Ve~je pre`ivetje omogo~a predvsem dober lokalni nadzor skupaj s sistemskim zdrav- ljenjem, ki uni~uje mikrometastaze. V zadnjih letih smo s pomo~jo novih naprav in novih tehnik obsevanja (3 D) izbolj{ali natan~- nost obsevanja, s ~imer zmanj{amo mo`nost negativnih posledic na zdravem tkivu. Pri~akovati je, da bo to dolgoro~no pozitivno vplivalo tudi na pre`ivetje na{i bolnic. Clarke M, Colins R, Darby S, Davies C, Elphinstone P, Evans E, et al. Effects of radiotherapy and of diffe- rences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 366: 2087–106. Punglia R, Morrow M, Winer E, Harris J. Local therapy and survival in breast cancer. N Engl J Med 2007; 356: 2399–405. Truong P, Woodward W, Buchholz T. Optimizing locoregional control and survival for women with breast cancer: a review of current developments in postmastectomy radiotherapy. Expert Rev. Anticancer Ther 2006; 6: 205–16. 160 DOJKA KLINI^NI KOMENT AR Tanja ^ufer Rak dojke je v Sloveniji {e vedno najpogostej{i rak in najpogostej{i vzrok smrti za rakom pri `enskah. Zato je dobro obvladovanje te bolezni izrednega pomena za vso dru`bo. Znano je, da sta k dobremu obvladovanju, ki se je pokazalo z zmanj{anjem umrljivosti za rakom dojk, v ZDA in Evropi v zgodnjih devetdesetih letih prej{njega stoletja pripomogla zgodnje odkri- vanje bolezni s presejanjem in uvedba novih, u~inkovitih na~inov dopolnilnega sistemskega zdravljenja pri bolnicah z operabilnim rakom dojk. V Sloveniji se umrljivost zaradi raka dojk `al zmanj{uje prepo~asi, se pa od leta 1999 nakazuje bolj izrazito padajo~ trend; leta 1999 je bila starostno standardizirana umrljivost 45,9/100.000, v letih 2003–2005 pa okoli 39,0/100.000. Z uvedbo organiziranega presejanja za raka dojk pri~akujemo {e nadaljnje izbolj{anje. V obdobju 2001–2005 se je v Sloveniji pomembno pove~alo petletno relativno pre`ivetje bol- nic z rakom dojk v primerjavi s petletnim pre`ivetjem bolnic, ki so zbolele v letih 1996–2000 (83 % proti 77 %) in {e bolj glede na obdobje 1991–1995, ko je bilo petletno pre`ivetje samo 69 %. Medtem ko je petletno pre`ivetje bolnic z rakom dojk, zbolelih v letih 1991–1995, kar za okoli 10 % zaostajalo za povpre~nim evropskim pre`ivetjem (EUROCARE-3), pa izsled- ki raziskave EUROCARE-4 ka`ejo, da smo pri bolnicah, zbolelih v letih 2000–2002, kljub temu, da {e nismo imeli organiziranega presejanja za raka dojk, skoraj dosegli evropsko pov- pre~je in za njim zaostajamo le {e za nekaj odstotkov. Ti podatki so zelo ohrabrujo~i. Dobra novica je tudi, da se je po letu 1995 za~elo ve~ati predvsem dolgotrajno, 3-, 5- in celo 10-let- no pre`ivetje. Izbolj{ala se je napoved izida pri nas {e vedno zelo pogostega raz{irjenega raka dojk, ki je ob ustreznem zdravljenju tudi ozdravljiva bolezen. Napoved izida omejenega raka dojk, ki je bila `e v prej{njih obdobjih razmeroma dobra, pa se je {e bolj popravila. Dobri rezul- tati so posledica tako zgodnej{ega odkrivanja bolezni, saj se je pove~al dele` bolnic z omejeno VIRI Literature Rak.qxd 22.7.2009 12:39 Page 160 June 2007. In these years both observed as well as relative survival rates increased (Table 3), particularly as regards localized and regional disease (Figure 3), i. e. in the stages in which radio- therapy recently has been gaining in importance. The number of partial breast resections with postoperative irradiation has increased, and an important change has been introduced in form of postoperative irradiation following mastectomy in patients with high risk of local recurrence. Meta-analysis of randomized clinical studies has shown that local control significantly influ- ences patient survival. It is estimated that adjuvant radiotherapy after surgery reduces the risk of local recurrence by two thirds in all groups of patients, which contributes to a 5.3% increase in the 15-year absolute survival of patients after conservative surgery and to a 4.4% increase in patients with axillary lymph node metastases after modified radical mastectomy, these results being comparable with the effects of systemic therapy. In our patients such a long observation period has not been available yet, however, the relevant trend is nevertheless obvious. Present findings on the effectiveness of postoperative irradiation are indicative of further expansion of these indications. Better survival results are attainable particularly by good local control of the disease combined with systemic treatment for the elimination of micrometastases. In recent years, the accuracy of irradiation has been improved by means of new machines and novel 3D irradiation techniques, which reduces the risk of adverse effects on the healthy tis- sue. It is expected that such an approach will have a long-term positive impact on the survival of our patients. 161 BREAST CLINICAL COMMENT ARY Tanja ^ufer In Slovenia, breast cancer still represents the most frequent cancer and the most frequent cause of death in female population. Therefore, good control of the disease is of outstanding impor- tance for the whole society. It is well known that in early 90's of the previous century good control and the associated decrease in breast cancer mortality rates in the United States and Europe were largely influenced by early detection of the disease with screening and the imple- mentation of new effective methods of adjuvant systemic therapy in patients with operable breast cancer. In Slovenia, unfortunately, breast cancer mortality rates have been decreasing rather slowly, however, a more apparent decreasing trend has been noted since 1999: thus in 1999 the age-standardized mortality rate was 45.9/100,000 while in the years 2003–2005 it was approxi- mately 39.0/100,000. Further progress may be expected with the introduction of an organized screening for breast cancer. In the period 2001–2005, a significant increase in the 5-year relative survival of breast cancer patients was noted in Slovenia as compared to the 5-year survival of patients diagnosed in the period 1996–2000 (83% vs. 77%), the increase being even more apparent when compared with the period 1991–1995 when the 5-year survival reached only 69%. While the 5-year survival of breast cancer patients diagnosed in the years 1991–1995 lags behind the European average survival by some 10% (EUROCARE-3), the findings of EUROCARE-4 study show that in Slovenian patients diagnosed in the years 2000–2002 survival almost reached the European average, lagging behind only by few percents, despite the fact that no organized screening for breast cancer had been available in that period. These data are very encouraging. Another good news is that after the year 1995, particularly long-term survival, i. e. 3-. 5- and even 10-year survival of breast cancer patients increased. Improvement was noted in still rather common advanced forms of breast cancer, which is – subject to suitable treatment – a treatable disease and in the early disease, prognosis of which was already relatively favorable in the past peri- ods. Favorable results are attributable to earlier detection, which is reflected in an increase in the proportion of patients with localized disease (from 43% in the period 1991–1995 to 50% in the period 2001–2005), as well as to more effective treatment, particularly adjuvant systemic therapy for operable breast cancer. After the year 1995, adjuvant therapy in all patients with Rak.qxd 22.7.2009 12:39 Page 161 boleznijo (s 43 % v letih 1991–1995 na 50 % v letih 2001–2005), kot tudi bolj{ega zdravljenja, predvsem dopolnilnega sistemskega zdravljenja operabilnega raka dojk. V obdobju po letu 1995 se je v dopolnilno zdravljenje vseh bolnic s hormonsko odvisnim rakom dojk postopoma uvedlo za to vrsto raka naju~inkovitej{e hormonsko zdravljenje, uvedena je bila dopolnilna kemote- rapija z antraciklini in po letu 2000 v vse ve~ji meri tudi s taksani. Nadaljnje izbolj{anje po letu 2000 je delno `e posledica podalj{anega hormonskega zdravljenja hormonsko odvisne bolezni, ki bo skupaj z uvedbo aromataznih inhibitorjev v dopolnilno zdravljenje hormonsko odvisne bolez- ni in trastuzumaba v dopolnilno zdravljenje bolnic s HER2 pozitivnim rakom dojk leta 2005 nesporno {e pove~alo pre`ivetje bolnic, ki trenutno zbolevajo in se zdravijo za rakom dojk. Tudi pre`ivetje bolnic z razsejanim rakom dojk ob postavitvi diagnoze se postopno ve~a, ~eprav ne toliko, kot bi si `eleli. Primerjava z nekaterimi drugimi skupinami bolnic ka`e na to, da bi bilo mogo~e pre`ivetje bolnic z razsejano boleznijo {e izbolj{ati. Glede na to, da je ve~ina (oko- li 70 %) rakov dojk hormonsko odvisnih, bi morali za pove~anje pre`ivetja bolnic z razsejanim rakom dojk pri nas predvsem posvetiti ve~ pozornosti dobro vodenemu, dolgotrajnemu hor- monskemu zdravljenju te bolezni. Ob pojavu vse ve~ novih hormonskih zdravil za raka dojk, kot so aromatazni inhibitorji, fulvestrant in {e nekatera druga, to ne bi smelo biti problem. Ne nazadnje je dobra novica, da se je od leta 1995 le pri~elo izbolj{evati tudi pre`ivetje starej- {ih bolnic z rakom dojk, ki pa tako kot tudi drugje v svetu tudi pri nas {e vedno preve~ zaostaja za pre`ivetjem mlaj{ih bolnic. Na tem podro~ju bomo morali, ne samo v Sloveniji, ampak tudi v Evropi, {e veliko narediti. Andre F, Slimane K, Bachelot T , Dunant A, Namer M, Barrelier A, et al. Breast cancer with synchronous meta- stases: Trends in survival during a 14-year period. J Clin Oncol 2005; 22: 3302–8. Berry DA, Cronin KA, Plevritis SK, Fryback DG, Clarke L, Zelen M, et al. Cancer Intervention and Sur- veillance Modeling Network (CISNET) Collaborators. Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med. 2005; 353: 1784–92. ^ufer T. Reducing the risk of late recurrence in hormone-responsive breast cancer. Ann Oncol 2007; 18 Suppl 8: viii18–25. Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: an overview of the ran- domised trials. Lancet 1998; 351: 1451–67. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal the- rapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 356: 1687–717. Matos E, Pajk B, Bor{tnar S, ^ufer T . Dopolnilno zdravljenje bolnic z rakom dojke s trastuzumabom: trenutno priporo~eni izbor zdravljenja na Onkolo{kem in{titutu v Ljubljani. Onkologija 2006; 10: 109–12. Program DORA: http://dora.onko-i.si/. 162 DOJKA VIRI Literature Rak.qxd 22.7.2009 12:39 Page 162 hormone-dependent breast cancer was gradually upgraded with hormonal therapy, known to be the most effective therapy for this type of cancer. In addition, at that time, adjuvant chemotherapy with anthracyclins was introduced and after the year 2000 taxanes were added to anthracy- cline-based chemotherapy as well. Further improvement achieved after the year 2000 is partly a result of extended hormonal therapy, which will – together with the introduction of aromatase inhibitors into the adjuvant treatment of hormone-dependent disease, and of transtuzumab into the adjuvant therapy of patients with HER2 positive breast cancer in 2005 – undoubt- edly contribute to an even better survival of patients who are currently diagnosed and treated for breast cancer. The survival of patients with metastatic breast cancer at diagnosis has been gradually increa- sing, though not as much as desired. The comparison with some other groups of patients indicates that the survival of patients with disseminated disease could still be improved in our country. Considering that a majority (around 70%) of breast cancers are hormone-dependent, in order to improve the survival of patients with metastatic disease, we should pay more attention to well managed long-term hormonal therapy of this disease. With the development of ever new hormonal therapies for breast cancer, such as aromatase inhibitors, fulvestrant and some oth- ers, this should not be difficult. Last but not least, it is encouraging to note that since 1995, the survival of elderly breast can- cer patients has finally started to increase as well, though as elsewhere in the world in Slovenia too it is still lagging too much behind the survival of younger patients. In this area a lot more needs to be done not only in Slovenia but also in whole Europe. 163 BREAST Rak.qxd 22.7.2009 12:39 Page 163 V obdobju 1991–2005 je za rakom materni~nega vratu zbolelo 2957 `ensk. Kot je razvidno s Sli- ke 1, se je inciden~na stopnja do leta 1997 ve~ala, od takrat naprej pa se zmanj{uje za povpre~no 2,1 % letno. Umrljivostna stopnja se pri bolnicah z rakom materni~nega vratu ves ~as opazovanja zmanj{uje, groba povpre~no za 1,7 % letno, starostno standardizirana pa za povpre~no 3,3 % letno. MATERNI^NI VRAT MKB 10: C53 164 0 5 10 15 20 25 1986 1990 1995 2000 2005 Leto / Year Incidenca – groba stopnja / Incidence – crude rate Incidenca – SSS* / Incidence – ASR** Umrljivost – groba stopnja / Mortality – crude rate Umrljivost – SSS* / Mortality – ASR** Stopnja na 100.000 / Rate per 100,000 * SSS – starostno standardizirana stopnja (standard – slovenska populacija leta 1986) ** ASR – age standardized rate (standard Slovenian population in 1986) Slika 1: Groba in starostno standardizirana inciden~na in umrljivostna stopnja raka materni~nega vratu, Slovenija 1986–2005. Figure 1: Crude and age-standardized incidence and mortality rate of cervical cancer, Slovenia 1986–2005. @enske / Females Obdobje / {tevilo / 20–49 let / 50–74 let / 75+ let / Period number years (%) years (%) years (%) 1991–1995 901 55,8 36,5 7,7 1996–2000 1065 56,6 35,3 8,1 2001–2005 971 57,2 33,8 9,1 Tabela 1: [tevilo bolnic z rakom materni~nega vratu po obdobju postavitve diagnoze ter njihovi dele`i po starosti. Table 1: Number of cervical cancer patients by period of diagnosis with their proportions by age. V analizo pre`ivetja je vklju~enih 2937 primerov; 18 bolnic (0,6 %) nismo upo{tevali, ker jim je bila diagnoza postavljena po smrti, 2 bolnici, mlaj{i od 20 let, pa obravnavamo v poglavju o pre`ivetju pri otrocih in mladostnikih. Manj kot 1 % bolnic v vsakem obdobju ni imelo mikroskopsko potrjene bolezni. Najve~ je bilo plo{~atoceli~nih karcinomov (80 %), 11 % je bilo adenokarcinomov, 7 % je bilo drugih opre- deljenih karcinomov, pri preostalih 3 % pa histolo{ka vrsta ni bila natan~neje opredeljena. Ve~ kot polovica bolnic zboli pred 50. letom starosti, okrog tretjina jih je ob diagnozi stara med 50 in 74 let, starej{e bolnice so redke (Tabela 1). Dele`i v posameznih starostnih skupinah se s ~asom niso bistveno spreminjali. EPIDEMIOLOGIJA Rak.qxd 22.7.2009 12:39 Page 164 In the period 1991–2005, a total of 2957 women were diagnosed with cervical cancer. As evi- dent from Figure 1, the crude incidence rate was increasing till 1997, since then it is decreasing by 2.1% annually on average. The mortality rate has been decreasing throughout the obser- vation period, the crude rate by 1.7% annually on average, and the age-standardized by 3.3%. The survival analysis included 2937 cases; 18 patients (0.6%) diagnosed only after death were not considered in the analysis, 2 patients less than 20 years of age are presented in the chap- ter on the survival of children and adolescents. Less than 1% of patients in each time period did not have microscopically confirmed disease. The majority was planocellular carcinomas (80%), 11% were adenocarcinomas and 7% other types of carcinoma, while in the remaining 3% histological type was not precisely determined. More than half of patients are diagnosed before 50 years of age, approximately one third are diag- nosed at an age between 50–74 years, while those developing the disease aged 75 years or older are rare (Table 1). The proportions in individual age groups did not change significantly with time. The proportion of patients diagnosed with localized stage of the disease has been increasing throughout the observation period; it was 62% in the last period (Table 2). While the pro- portion of patients with regional stage has decreased on the account of a greater proportion of patients with localized stage, the proportion of patients with disseminated and undefined stages has remained all the time practically the same. In the years 2001–2005, 5% of patients did not receive specific treatment. The proportion of untreated patients has remained approximately the same throughout the observation period. Among the patients receiving specific treatment in the period 2001–2005, 52% were treated by surgery alone, 10% received teleradiotherapy in addition to surgery, while in 5% this com- bination also included chemotherapy. Teleradiotherapy alone was used in 8% of patients, a combination of tele- and brachyradiotherapy with or without chemotherapy in 18%, while other combinations were used in less than 2% of patients. The proportion of patients treated only by surgery has been increasing throughout the observation period, mainly on the account of the decreasing proportion of postoperatively irradiated patients. The proportion of patients treated with a combination of tele- and brachyradiotherapy combined with chemotherapy has been increasing too. In the period 2001–2005 the majority of patients started their treatment at the Department of Gynecology of the UMC Ljubljana (36%); 31% of patients started their treatment at the IO Ljubljana, 9% in the UMC Maribor, and the remaining 24% in a greater or lesser proportion in practically all general hospitals of Slovenia. CERVIX UTERI ICD 10: C53 165 Tabela 2: [tevilo bolnic z rakom materni~nega vratu po obdobju postavitve diagnoze ter njihovi dele`i po stadiju. Table 2: Number of cervical cancer patients by period of diagnosis with their proportions by stage. @enske / Females Obdobje / {tevilo / omejen / raz{irjen / razsejan / neznan / Period number localized regional distant unknown (%) (%) (%) (%) 1991–1995 901 50,1 44,3 4,9 0,8 1996–2000 1065 54,6 41,1 3,5 0,8 2001–2005 971 61,7 34,0 3,4 0,9 EPIDEMIOLOGY Rak.qxd 22.7.2009 12:39 Page 165 Ves ~as opazovanja pa se je pove~eval dele` bolnic, ki jim je bila bolezen odkrita v omejenem stadiju bolezni; v zadnjem obdobju je bilo teh 62 % (Tabela 2). Na ra~un ve~jega dele`a bol- nic z omejenim stadijem se je zmanj{al dele` bolnic z raz{irjenim stadijem, dele` tistih z razsejanim in neznanim stadijem pa ostaja ves ~as pribli`no enak. V letih 2001–2005 se ni specifi~no zdravilo 5 % bolnic. Dele` nezdravljenih ostaja v celotnem obdobju analize pribli`no enak. Med specifi~no zdravljenimi je bilo v letih 2001–2005 52 % bolnic samo operiranih, pri 10 % je bila operaciji dodana {e teleradioterapija, pri 5 % pa so tej kombinaciji dodali {e kemoterapijo. Samo s teleradioterapijo je bilo zdravljenih 8 % bolnic, s kom- binacijo tele- in brahiradioterapije s kemoterapijo ali brez pa 18 %; druge kombinacije so uporabili pri manj kot 2 % bolnic. Dele` samo operiranih se je ves ~as opazovanja ve~al, predvsem na 166 MATERNI^NI VRAT 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Slika 2: Deset-, pet-, tri- in enoletno relativno pre`ivetje bolnic z rakom materni~nega vratu po obdobju postavitve diagnoze. Figure 2: 10-, 5-, 3- and 1-year relative survival of cervical cancer patients by period of diagnosis. Tabela 3: Opazovano in relativno pre`ivetje bolnic z rakom materni~nega vratu po obdobju postavitve diagnoze s 95-odstotnim intervalom zaupanja (IZ). Table 3: Observed and relative survival of cervical cancer patients by period of diagnosis with 95% confidence interva (CI). Opazovano pre`ivetje / Observed survival (%) @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 85,5 (83,2–87,8) 67,6 (64,6–70,7) 60,9 (57,8–64,2) 1996–2000 86,8 (84,7–88,8) 74,8 (72,3–77,5) 68,5 (65,8–71,4) 2001–2005 88,7 (86,7–90,7) 77,6 (75,0–80,3) 74,2 (71,3–77,1) Relativno pre`ivetje / Relative survival (%) @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 86,6 (84,2–88,9) 70,3 (67,0–73,5) 65,0 (61,5–68,5) 1996–2000 87,7 (85,6–89,8) 77,4 (74,7–80,2) 72,6 (69,6–75,6) 2001–2005 89,7 (87,6–91,7) 80,3 (77,5–83,1) 78,6 (75,5–81,7) Rak.qxd 22.7.2009 12:39 Page 166 The relative survival rate of patients with cervical cancer has been gradually increasing: thus in 15 years, the 5-year relative survival increased by 14% (Figure 2, Table 3). The relevance of stage at diagnosis is shown in Figure 3: in the last two periods, 5-year relative survival of patients with localized stage has reached 95%. The survival of patients with regional and dissemina- ted disease has been increasing throughout the observation period as well; the 5-year relative survival of those diagnosed between the years 2001–2005 being 53% and 20% respectively. Age is a prognostic factor as well, since the 5-year relative survival in patients less than 50 years of age is 89%, while in those aged 75 years or older is 41% (Figure 4). The 5-year relative survival of all patients diagnosed in the period 2001–2005 was 79% (Figure 2); patients surviving the first year may expect to survive five years in 87%. According to the results of EUROCARE-4 study for patients diagnosed in 2000–2002, the survival of cervical cancer patients in Slovenia is equal to the European average (Figure 5). 167 CERVIX UTERI 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 Omejen / Localized Raz{irjen / Regional Razsejan / Distant Vsi / All Slika 3: Petletno relativno pre`ivetje bolnic z rakom materni~nega vratu po stadiju in obdobju postavitve diagnoze. Figure 3: 5-year relative survival of cervical cancer patients by stage and period of diagnosis. 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 20–49 let / years 50–74 let / years 75+ let / years Vsi / All Slika 4: Petletno relativno pre`ivetje bolnic z rakom materni~nega vratu po starosti in obdobju postavitve diagnoze. Figure 4: 5-year relative survival of cervical cancer patients by age and period of diagnosis. Rak.qxd 22.7.2009 12:39 Page 167 ra~un manj{anja dele`a bolnic, ki so bile poleg operacije {e obsevane, in tistih, ki so prejele tele- in brahiradioterapijo. Pove~uje se tudi dele` bolnic, ki so bile zdravljene s kombinacijo tele- in brahiradioterapije in kemoterapije. V obdobju 2001–2005 so najve~ bolnic za~eli zdraviti na Ginekolo{ki kliniki UKC Ljubljana (36 %). Na OI Ljubljana so za~eli zdraviti 31 % bolnic, 9 % v UKC Maribor, preostalih 24 % pa so v ve~jem ali manj{em dele`u za~ele zdravljenje v skoraj vseh slovenskih bolni{nicah. Relativno pre`ivetje bolnic z rakom materni~nega vratu se postopno pove~uje; v 15 letih se je petletno relativno pre`ivetje pove~alo za 14 % (Slika 2, Tabela 3). Kako pomemben je stadij ob diagnozi, ka`e Slika 3: petletno relativno pre`ivetje bolnic z omejenim stadijem je v zadnjih dveh obdobjih 95 %. Ves ~as se ve~a tudi pre`ivetje bolnic z raz{irjenim in razsejanim stadijem; zbo- lele v letih 2001–2005 z raz{irjenim stadijem so imele petletno relativno pre`ivetje 53 %, zbolele z razsejanim stadijem pa 20 %. Napovedni dejavnik je tudi starost, saj je petletno relativno pre- `ivetje mlaj{ih od 50 let 89 %, starih 75 let in ve~ pa 41 % (Slika 4). Petletno relativno pre`ivetje vseh zbolelih v obdobju 2001–2005 je bilo 79 % (Slika 2, Tabe- la 3); bolnice, ki pre`ivijo prvo leto, pa lahko pri~akujejo 87-odstotno petletno relativno pre`ivetje. Rezultati {tudije EUROCARE-4 za zbolele v obdobju 2000–2002 ka`ejo, da je pre`ivetje slo- venskih bolnic z rakom materni~nega vratu enako kot evropsko povpre~je (Slika 5). 168 MATERNI^NI VRAT KLINI^NI KOMENT AR Albert Peter Fras Praviloma so vse bolnice z rakom materni~nega vratu predstavljene multidisciplinarnemu tim- skemu konziliju, ki izbere za vsako bolnico posebej individualizirani na~in zdravljenja. Seveda ta bistveno ne odstopa od dogovorjenih smernic zdravljenja ginekolo{kih rakov; smernice se posodabljajo, tako da upo{tevajo vse znane novej{e pristope pri zdravljenju. [tevilo bolnic, pri katerih specifi~no onkolo{ko zdravljenje ni bilo odrejeno, je skoraj enako v vseh treh obdobjih. Pri~akovati pa je treba, da se bo s~asoma {tevilo teh bolnic manj{alo, saj je z uvajanjem paliativnega zdravljenja bolnic z napredovalim rakom materni~nega vratu v izra- zito slabem splo{nem stanju mo`no splo{no stanje toliko izbolj{ati, da je mo~ izpeljati vsaj kurativno radioterapijo. Primerjava treh petletnih obdobij 1991–1995, 1996–2000 in 2001–2005 ka`e pove~anje {te- vila kirur{kih posegov; v zadnjem obdobju je `e polovica bolnic zdravljena samo kirur{ko. To je mogo~e zato, ker ima vedno ve~ bolnic ob prvem zdravljenju ni`ji stadij bolezni in tako manj napovedno neugodnih kazalcev po kirur{kem posegu (infiltrati v parametrijih, zasevki v pelvi~nih bezgavkah in druge neugodne napovedne dejavnike). To potrjujejo tudi podatki o pooperativnem zdravljenju z obsevanjem samim ali v kombinaciji s kemoterapijo, saj po kurativnem kirur{- kem posegu manj bolnic nadaljuje s tem dopolnilnim zdravljenjem. Zagotovo lahko ve~ji dele` omejenega stadija pripi{emo tudi organiziranemu presejalnemu programu za raka materni~- nega vratu ZORA, ki na dr`avni ravni deluje od leta 2003. Pri~akujemo, da se bo v naslednjih letih poleg manj{anja incidence raka materni~nega vratu {e naprej ve~al dele` bolezni, odkri- te v omejenem stadiju. Napredovali stadiji raka materni~nega vratu so izklju~na domena radioterapije ali kombinacije radioterapije in kemoterapije. Kombinacija radioterapije in kemoterapije je v zadnjih letih najpogo- stej{i na~in zdravljenja bolnic z rakom materni~nega vratu, ki imajo kljub napredovali bolezni ohranjeno splo{no telesno kondicijo. Na to ka`e tudi podatek, da se je v obdobju 2001–2005 v primerjavi z obdobjem 1991–1995 dele` bolnic, zdravljenih kombinirano, pove~al z 0,3 % na 8,1 %, medtem ko se je dele` samo obsevanih (tele- in brahiterapija) zmanj{al s 16,3 % na 6,1 %. Pri~akovati je treba, da bo uvajanje tridimenzionalnih na~rtovanj v teleterapiji in bra- hiterapiji, ki omogo~a pove~anje kancericidnega odmerka ob manj{i prizadetosti okolnih tkiv, Rak.qxd 22.7.2009 12:39 Page 168 As a rule, all patients with cervical cancer are presented at multidisciplinary team consulta- tion meeting, where a treatment approach is selected for each patient individually. Of course, the selected approach does not deviate from the established guidelines for gynecological can- cer treatment; however, the guidelines themselves are being updated by newly adopted treatment approaches. The number of patients in whom specific oncological treatment was not indicated, remained almost the same in all three observation periods. However, it is expected that the number of these patients will gradually decrease, as the use of palliative therapy in patients with advanced cancer may improve their otherwise extremely poor general condition to such an extent, that at least curative radiotherapy is rendered feasible. The comparison of three 5-year periods, i. e. 1991–1995, 1996–2000 and 2001–2005, shows an increase in the number of surgical procedures; in the last period half of the patients were treated surgically only. This is a consequence of an increasing number of patients with lower stages at first treatment, and thus with less unfavorable prognostic factors after the surgery (para- metrial infiltrations, pelvic lymph node metastases and other unfavorable prognostic factors). This finding is confirmed by the data on less frequent postoperative treatment either with irra- diation since less patients require such adjuvant therapy after a curative surgical intervention. An increasing proportion of localized disease can be ascribed to the organised cervical cancer screening programme ZORA, that has been implemented on the national level in 2003. It is expected that along with lower incidence of cervical cancer it will further increase the proportion of localized disease in the following years. Advanced stages of cervical cancer are strictly the domain of radiotherapy or radiotherapy in combination with chemotherapy. In recent years, combination of radiotherapy and chemothe- rapy represents the most frequent method of treatment in patients with cervical cancer, when their general condition is adequate, despite an advanced stage of the disease. This is support- ed by the observation that in comparison with the period 1991–1995, in the period 2001–2005 the proportion of patients with combined treatment increased from 0.3% to 8.1%, while the proportion of those with irradiation alone (tele- and brachytherapy) decreased from 16.3% to 6.1%. 169 CERVIX UTERI CLINICAL COMMENT ARY Albert Peter Fras 01 02 0 30 40 50 60 70 80 90 100 % Slovensko povpre~je / 2000–2002 (EUROCARE-4) Slovenian average Evropsko povpre~je / 2000–2002 (EUROCARE-4) European average Povpre~je ZDA / 2000–2002 (SEER-13) USA average Slika 5: Petletno relativno pre`ivetje bolnic z rakom materni~nega vratu (povpre~je in 95-odstotni interval zaupanja), zbolelih v letih 2000–2002 v Sloveniji, Evropi in nekaterih obmo~jih v ZDA. Figure 5: 5-year relative survival of cervical cancer patients (average and 95% confidence interval) diagnosed in the period 2000–2002 in Slovenia, Europe and in some regions of the USA. Rak.qxd 22.7.2009 12:39 Page 169 {e dodatno izbolj{alo mo`nosti zazdravitve napredovalih rakov materni~nega vratu ob manj- {ih poobsevalnih zapletih. Ti pozni zapleti namre~ hudo prizadenejo kakovost `ivljenja teh bolnic. Z uvajanjem doktrine zdravljenja raka rodil je tudi vedno manj bolni{nic, v katerih pri~nejo prvo specifi~no zdravljenje raka materni~nega vratu. Vpra{anje je, ali so pri za~etnem zdrav- ljenju v nespecializiranih ustanovah naklju~no odkrili raka materni~nega vratu pri zdravljenju drugih ginekolo{kih bolezni. Da sodi zdravljenje raka materni~nega vratu v ustanove, ki imajo s tem najve~je izku{nje, ka`ejo tudi podatki o ve~jem relativnem pre`ivetju (65-odstotno relativ- no petletno pre`ivetje v obdobju 1991–1995 in 79-odstotno v obdobju 2001–2005). Sprejetje in posodabljanje doktrine zdravljenja raka rodil je gotovo prispevalo k dvigu strokovnosti predvsem v osnovni ginekolo{ki slu`bi, saj je tako bolnicam omogo~eno zdravljenje v visoko specializi- ranih ustanovah z najve~ izku{njami (Ginekolo{ka klinika UKC Ljubljana, OI Ljubljana, UKC Maribor). Fras AP , ed. Doktrina zdravljenja ginekolo{kih malignomov. Ljubljana: Onkolo{ki in{titut; 1992. Pompe-Kirn V, Zakotnik B, Zadnik V. Pre`ivetje bolnikov z rakom v Sloveniji 1983–1997. Ljubljana: Register raka za Slovenijo. Onkolo{ki in{titut Ljubljana; 2003. Program ZORA: www.onko-i.si/zora. Str`inar V, Ba{kovi~ M, Bebar S, Cerar O, Fras AP , Koritnik K, et al. Ginekolo{ki malignomi: doktrina zdravljenja ginekolo{kih malignomov na Onkolo{kem in{titutu in Univerzitetni ginekolo{ki kliniki. 2. rev. izd. Zveza slovenskih dru{tev za boj proti raku, 2001. 170 MATERNI^NI VRAT VIRI Literature Rak.qxd 22.7.2009 12:39 Page 170 It is expected that the implementation of three-dimensional radiation treatment planning in teleradiotherapy and brachytherapy, which facilitates increasing cancericidal dosages at lesser exposure of the surrounding tissue, will further improve the possibilities of achieving control of advanced cervical cancer and reducing the irradiation related complications. These late sequels severely affect the quality of patient's life. As a result of implementing the guidelines of gynecological cancer treatment, the number of hospitals starting a specific treatment for cervical cancer has been considerably reduced. The question is whether cervical cancer initially treated in non-specialized institutions has been detected incidentally, during treatment for other gynecological conditions. The fact that cer- vical cancer treatment should be performed in institutions with most experience in this area is further supported by the data on greater relative survival rates (65% relative 5-year survival in the period 1991–1995 vs. 79% in the period 2001–2005). The implementation of the guide- lines for gynecological cancer treatment and their upgrading has certainly contributed towards improvement of expertise, particularly in primary oncological services, thus enabling the patients access to treatment in highly specialized institutions with most experience in the treatment of these cancers (UMC Ljubljana – Department of Gynecology, IO Ljubljana, UMC Maribor – Department of Perinatology and Gynecology). 171 CERVIX UTERI Rak.qxd 22.7.2009 12:39 Page 171 V obdobju 1991–2005 je za rakom materni~nega telesa zbolelo 3942 `ensk. Kot je razvidno s Slike 1, se obe inciden~ni stopnji ves ~as opazovanja ve~ata, groba za povpre~no 3,0 %, sta- rostno standardizirana pa se ve~a po~asneje (za 1,7 %), saj je rak materni~nega telesa bolezen predvsem starej{ih `ensk (Tabela 1). Pove~uje se tudi groba umrljivostna stopnja, povpre~no za 2,6 % letno, medtem ko je starostno standardizirana umrljivostna stopnja prakti~no konstantna. MATERNI^NO TELO MKB 10: C54 172 0 5 10 15 20 25 30 35 1986 1990 1995 2000 2005 Leto / Year Incidenca – groba stopnja / Incidence – crude rate Incidenca – SSS* / Incidence – ASR** Umrljivost – groba stopnja / Mortality – crude rate Umrljivost – SSS* / Mortality – ASR** Stopnja na 100.000 / Rate per 100,000 * SSS – starostno standardizirana stopnja (standard – slovenska populacija leta 1986) ** ASR – age standardized rate (standard Slovenian population in 1986) Slika 1: Groba in starostno standardizirana inciden~na in umrljivostna stopnja raka materni~nega telesa, Slovenija 1986–2005. Figure 1: Crude and age-standardized incidence and mortality rate of corpus uteri cancer, Slovenia 1986–2005. @enske / Females Obdobje / {tevilo / 20–49 let / 50–74 let / 75+ let / Period number years (%) years (%) years (%) 1991–1995 1108 8,0 76,5 15,4 1996–2000 1322 10,6 74,1 15,3 2001–2005 1488 8,1 70,6 21,3 Tabela 1: [tevilo bolnic z rakom materni~nega telesa po obdobju postavitve diagnoze ter njihovi dele`i po starosti. Table 1: Number of corpus uteri cancer patients by period of diagnosis with their proportions by age. V analizo pre`ivetja je vklju~enih 3918 primerov; 24 bolnic (0,6 %) nismo upo{tevali, ker jim je bila diagnoza postavljena po smrti. Manj kot 1 % bolnic v vsakem obdobju ni imel mikroskopsko potrjene bolezni. Prakti~no vsi mikroskopsko potrjeni primeri so bili adenokarcinomi ali drugi opredeljeni karcinomi; leio- miosarkomov je bilo le 0,4 %. Ve~ kot 70 % bolnic je zbolelo med 50. in 74. letom starosti, pred 50. letom je zbolelo manj kot 10 % bolnic. Dele` starih 75 let in ve~ se s ~asom ve~a; v zadnjem obdobju je zna{al 21 % (Tabela 1). EPIDEMIOLOGIJA Rak.qxd 22.7.2009 12:39 Page 172 In the period 1991–2005, a total of 3942 women were diagnosed with endometrial cancer. As evident from Figure 1, both incidence rates have been increasing throughout the observation period, the crude incidence rate by 3.0% annually on average. Age-standardized rate has been increasing more slowly (by 1.7%), since endometrial cancer is prevailingly a disease of elder- ly women (Table 1). Crude mortality rate has been increasing as well, by 2.6% annually on average, while the age-standardized mortality rate remains stable. The survival analysis included 3918 cases; 24 patients (0.6%) diagnosed only after death were not considered in the analysis. Less than 1% of patients in each time period did not have microscopically confirmed disease. Practically all microscopically confirmed cases were either adenocarcinomas or other specified carcinomas; there were only 0.4% of leiomyosarcomas. More than 70% of patients were diagnosed at an age between 50 and 74 years, and less than 10% of patients were younger than 50 years. The proportion of those aged 75 years or older has been increasing with time, in the last period reaching 21% (Table 1). In all three time-periods, approximately three fourths of patients were diagnosed with locali- zed disease; the proportion of those with the disease diagnosed in regional stage has been increasing while patients with disseminated disease at diagnosis are rare (Table 2). In the years 2001–2005, 6% of patients did not receive specific treatment. The proportion of untreated patients is practically the same throughout the study period. Among the patients receiving specific treatment in the period 2001–2005, 43% were treated by surgery alone while 45% received tele- and/or brachyradiotherapy in addition to surgery. Other combinations were used in less than 3% of the patients. The proportion of patients treated only by surgery has been increasing throughout the observation period, mainly on the account of the smaller pro- portion of postoperatively irradiated patients. In the period 2001–2005, the majority of patients started their treatment at the Department of Gynecology of the UMC Ljubljana (43%), 15% of patients started their treatment at the IO Ljubljana, 12% in the UMC Maribor, and the remaining 23% in lesser proportions in prac- tically all general hospitals of Slovenia. The relative survival rate of patients with endometrial cancer has been gradually increasing: thus in 15 years, the 5-year relative survival increased by 4% (Figure 2, Table 3). The relevance of stage at diagnosis is shown in Figure 3. In the recent period, the 5-year relative survival of patients with localized disease was 95%, while patients with advanced disease had 54% rela- tive 5-year survival, and those with disseminated disease only 34%. The survival rates of patients with endometrial cancer by stage did not change significantly with time. Age is a prognostic CORPUS UTERI ICD 10: C54 173 Tabela 2: [tevilo bolnic z rakom materni~nega telesa po obdobju postavitve diagnoze ter njihovi dele`i po stadiju. Table 2: Number of corpus uteri cancer patients by period of diagnosis with their proportions by stage. @enske / Females Obdobje / {tevilo / omejen / raz{irjen / razsejan / neznan / Period number localized regional distant unknown (%) (%) (%) (%) 1991–1995 1108 76,5 13,4 8,1 2,0 1996–2000 1322 76,3 15,6 6,1 2,0 2001–2005 1488 73,5 17,7 7,3 1,4 EPIDEMIOLOGY Rak.qxd 22.7.2009 12:39 Page 173 V vseh treh obdobjih je bila pri pribli`no treh ~etrtinah bolnic ob diagnozi bolezen omejena; ve~a se dele` tistih, ki jim bolezen odkrijejo v raz{irjenem stadiju, redke pa so bolnice z raz- sejano boleznijo ob diagnozi (Tabela 2). V letih 2001–2005 ni bilo specifi~no zdravljenih 6 % bolnic. Dele` nezdravljenih je vse obdob- je analize pribli`no enak. Med specifi~no zdravljenimi je bilo v letih 2001–2005 43 % bolnic le operiranih, pri 45 % je bila operaciji dodana {e tele- in/ali brahiradioterapija. Druge kom- binacije so uporabili pri manj kot 3 % bolnic. Dele` samo operiranih se je ves ~as opazovanja ve~al, predvsem na ra~un manj{ega dele`a bolnic, ki so bile po operaciji dopolnilno zdravljene {e z obsevanjem. 174 MATERNI^NO TELO 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Slika 2: Deset-, pet-, tri- in enoletno relativno pre`ivetje bolnic z rakom materni~nega telesa po obdobju postavitve diagnoze. Figure 2: 10-, 5-, 3- and 1-year relative survival of corpus uteri cancer patients by period of diagnosis. Tabela 3: Opazovano in relativno pre`ivetje bolnic z rakom materni~nega telesa po obdobju postavitve diagnoze s 95-odstotnim intervalom zaupanja (IZ). Table 3: Observed and relative survival of corpus uteri cancer patients by period of diagnosis with 95% con- fidence interval (CI). Opazovano pre`ivetje / Observed survival (%) @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 89,3 (87,5–91,1) 74,6 (72,1–77,2) 68,5 (65,8–71,3) 1996–2000 88,7 (87,0–90,5) 78,1 (75,9–80,4) 72,2 (69,8–74,6) 2001–2005 89,9 (88,4–91,5) 78,3 (76,2–80,5) 72,4 (70,0–74,9) Relativno pre`ivetje / Relative survival (%) @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 91,5 (89,7–93,4) 80,9 (78,1–83,7) 78,4 (75,2–81,6) 1996–2000 90,6 (88,9–92,4) 83,4 (81,0–85,8) 80,9 (78,1–83,6) 2001–2005 92,0 (90,4–93,6) 84,4 (82,1–86,7) 82,6 (79,8–85,5) Rak.qxd 22.7.2009 12:39 Page 174 factor as well, since the 5-year relative survival in patients less than 50 years of age is 91%, while in those aged 75 years or older is 47% (Figure 4). The 5-year relative survival of all patients diagnosed in the period 2001–2005 was 83% (Figure 2); patients surviving the first year may expect to survive five years in 89%. According to the results of EUROCARE-4 study for patients diagnosed in 2000–2002, the sur- vival of endometrial cancer patients in Slovenia is nearly equal to the European average (Figure 5). 175 CORPUS UTERI CLINICAL COMMENT ARY Albert Peter Fras 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 Omejen / Localized Raz{irjen / Regional Razsejan / Distant Vsi / All Slika 3: Petletno relativno pre`ivetje bolnic z rakom materni~nega telesa po stadiju in obdobju postavitve diagnoze. Figure 3: 5-year relative survival of corpus uteri cancer patients by stage and period of diagnosis. 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 20–49 let / years 50–74 let / years 75+ let / years Vsi / All Slika 4: Petletno relativno pre`ivetje bolnic z rakom materni~nega telesa po starosti in obdobju postavitve diagnoze. Figure 4: 5-year relative survival of corpus uteri cancer patients by age and period of diagnosis. Endometrial cancer is the most frequent type of gynecological cancer. The early symptoms also being the warning signs, most cancers are diagnosed at an operable stage, as surgery is the most suitable method of treatment. The adopted guidelines for gynecological cancer treatment include recommendations for diagnostic procedures that facilitate undelayed confirmation of the disease and thus also the beginning of treatment when the disease is confined to the endometrium. Rak.qxd 22.7.2009 12:39 Page 175 V obdobju 2001–2005 se je najve~ bolnic za~elo zdraviti na Ginekolo{ki kliniki UKC Ljub- ljana (43 %). Na OI Ljubljana je zdravljenje za~elo 15 % bolnic, 12 % v UKC Maribor, preostalih 23 % pa v manj{ih dele`ih v prakti~no vseh slovenskih bolni{nicah. Relativno pre`ivetje bolnic z rakom materni~nega telesa se zmerno pove~uje; v 15 letih se je petletno relativno pre`ivetje pove~alo za 4 % (Slika 2, Tabela 3). Kako pomemben je stadij ob diagnozi, ka`e Slika 3: petletno relativno pre`ivetje bolnic z omejenim stadijem je v zadnjem obdobju 95 %, medtem ko je pri bolnicah z raz{irjenim stadijem petletno relativno pre`ivetje 54 %, z razsejanim pa 34 %. Pre`ivetje bolnic z rakom materni~nega telesa po stadijih se s ~a- som ni bistveno spreminjalo. Napovedni dejavnik je tudi starost, saj je petletno relativno pre`ivetje mlaj{ih od 50 let 91 %, starih 75 let in ve~ pa 47 % (Slika 4). Petletno relativno pre`ivetje vseh zbolelih v obdobju 2001–2005 je bilo 83 % (Slika 2); bolni- ce, ki pre`ivijo prvo leto, pa lahko pri~akujejo 89-odstotno petletno relativno pre`ivetje. Rezultati {tudije EUROCARE-4 za zbolele v obdobju 2000–2002 ka`ejo, da je pre`ivetje slo- venskih bolnic z rakom materni~nega telesa skoraj enako evropskemu povpre~ju (Slika 5). 176 MATERNI^NO TELO KLINI^NI KOMENT AR Albert Peter Fras Rak materni~nega telesa je najpogostej{i rak rodil. Ker so zgodnji znaki tudi opozorilni znaki, se ve~ina bolezni diagnosticira v operabilnih stadijih. V sprejeti doktrini zdravljenja rakov rodil se tudi priporo~ajo diagnosti~ni postopki, ki omogo~ajo ~im hitrej{o potrditev bolezni, s tem pa tudi zdravljenje, ko je bolezen {e omejena na materni~no telo. Kirur{ko zdravljenje je najbolj ustrezno zdravljenje in tudi pre`ivetje tako zdravljenih bolnic je najve~je. Dopolnilno zdravljenje z bra- hiterapijo ali teleterapijo je ute~eni na~in zdravljenja, vendar se prav v zadnjem obdobju opa`a, da se deloma opu{~a teleterapija kot dopolnilno zdravljenje, saj se s tem manj{a verjetnost poobsevalnih zapletov, kot so fibroza male medenice, stenoze se~evodov, kroni~ni radiocistitis in radioproktitis. Klini~ni stadij II (FIGO) s potrjenim prodorom v materni~ni vrat je indikacija za radikalnej- {i kirur{ki poseg z odstranitvijo medeni~nih bezgavk. Le pri medicinskih kontraindikacijah za operativni poseg se uporablja kombinacija teleterapije in brahiterapije, vendar je petletno pre- `ivetje bistveno manj{e kot po operativnem posegu; po nekaterih navedbah je okoli 50 %. Pri ostanku bolezni v materni~ni votlini pa priporo~ajo histerektomijo kot odre{ilni poseg. Napredovali stadiji so izklju~no domena radioterapije, predvsem teleterapije ali kombinacije tele- in brahiterapije. Sama brahiterapija s svojimi tehni~nimi mo`nostmi je mo`na le pri manj- {i skupini izbranih bolnic. Uvajanje intrakavitarne brahiterapije z obsevanji s hitrim pretokom odmerka (HDR) bo verjetno nekoliko raz{irilo indikacije za uporabo takega na~ina zdravlje- nja, vendar le pri bolnicah z boleznijo, omejeno na maternico. Petletno relativno pre`ivetje se je v 15-letnem obdobju pove~alo. To lahko delno pripisujemo tudi temu, da je vedno ve~ bolnic za~elo specifi~no onkolo{ko zdravljenje v bolni{nicah, ki ima- jo s tovrstnim zdravljenjem najve~ izku{enj (Ginekolo{ka klinika UKC Ljubljana, OI Ljubljana ter UKC Maribor) in ne nazadnje tudi vedno vi{ji strokovni ravni v osnovni ginekolo{ki slu`bi. Cohen CJ, Thomas GM. Endometrial Cancer. In: Holland JF, Frei E III, Bast R Jr, eds. Cancer Medicine, Fourth Edition. Baltimore: W&W; 1997. Fras AP , Bebar S, Vr{~aj Ur{i~ M. Radikalna intrakavitarna brahiterapija endometrijskega karcinoma. In: Luki~ F, Kocijan A, Dem{ar F, Bergant O, eds. Onkolo{ki vikend, [marje{ke Toplice, november 1992. Zbornik. Ljubljana: Kancerolo{ka sekcija slovenskega zdravni{kega dru{tva, Zveza slovenskih dru{tev za boj proti raku; 1992. Str`inar V, Ba{kovi~ M, Bebar S, Cerar O, Fras AP , Koritnik K, et al. Ginekolo{ki malignomi: doktrina zdravljenja ginekolo{ki malignomov na Onkolo{kem in{titutu in Univerzitetni ginekolo{ki kliniki. 2. rev. izd. Zveza slovenskih dru{tev za boj proti raku, 2001. VIRI Literature Rak.qxd 22.7.2009 12:39 Page 176 Surgical treatment is the most appropriate and the survival of patients with such treatment is the highest. Adjuvant treatment with brachy- or teleradiotherapy is an established treatment approach, however, it has been noted particularly in the last period that teleradiotherapy as adjuvant treatment modality has been partly abandoned in order to reduce the possibility of post-irradiation sequels, such as pelvic fibrosis, stenoses of the urethers, chronic radiocystitis and radioproctitis. Clinical stage II (FIGO) with confirmed invasion into the uterine cervix represents an indi- cation for a radical surgical intervention with pelvic lymphadenectomy. A combination of teleradiotherapy and brachytherapy is indicated only in cases with medical contraindications for surgery; however, 5-year survival of these patients is significantly lower than with surgery, according to some reports being 50%. In cases with residual disease in the uterine cavity, hys- terectomy is recommended as salvage therapy. Advanced stages are strictly the domain of radiotherapy and in particular teletherapy or a com- bination of tele- and brachytherapy. Due to its technical potentials, brachytherapy alone is feasible only in a limited group of selected patients. The introduction of high-dose-rate intracavitary brachytherapy (HDR-ICR) will probably slightly broaden the indications for the use of such treatment modality, however only in patients with the disease confined to the uterus. Comparing all three observation periods, the 5-year relative survival has slightly increased. This can be partly ascribed to the fact that a growing number of patients have started their speci- fic oncological treatment at hospitals with the greatest experience in this type of treatment (UMC Ljubljana – Department of Gynecology, IO Ljubljana, and UMC Maribor – Department of Perinatology and Gynecology), and last but not least to the ever improving expertise of the primary gynecological services. 177 CORPUS UTERI 01 02 0 30 40 50 60 70 80 90 100 % Slovensko povpre~je / 2000–2002 (EUROCARE-4) Slovenian average Evropsko povpre~je / 2000–2002 (EUROCARE-4) European average Povpre~je ZDA / 2000–2002 (SEER-13) USA average Slika 5: Petletno relativno pre`ivetje bolnic z rakom materni~nega telesa (povpre~je in 95-odstotni interval zaupanja), zbolelih v letih 2000–2002 v Sloveniji, Evropi in nekaterih obmo~jih v ZDA. Figure 5: 5-year relative survival of corpus uteri cancer patients (average and 95% confidence interval) diag- nosed in the period 2000–2002 in Slovenia, Europe and in some regions of the USA. Rak.qxd 22.7.2009 12:39 Page 177 V obdobju 1991–2005 je za rakom jaj~nika zbolelo 2661 `ensk. Kot je razvidno s Slike 1, se v opazovanem obdobju grobi inciden~ni in umrljivostni stopnji zmerno ve~ata; inciden~na pov- pre~no za 0,8 % in umrljivostna za povpre~no 1,2 % letno. Obe starostno standardizirani stopnji ka`eta padajo~i trend; manj{ata se za povpre~no 0,5 % letno. JAJ^NIK MKB 10: C56 178 0 5 10 15 20 25 1986 1990 1995 2000 2005 Leto / Year Incidenca – groba stopnja / Incidence – crude rate Incidenca – SSS* / Incidence – ASR** Umrljivost – groba stopnja / Mortality – crude rate Umrljivost – SSS* / Mortality – ASR** Stopnja na 100.000 / Rate per 100,000 * SSS – starostno standardizirana stopnja (standard – slovenska populacija leta 1986) ** ASR – age standardized rate (standard Slovenian population in 1986) Slika 1: Groba in starostno standardizirana inciden~na in umrljivostna stopnja raka jaj~nika, Slovenija 1986–2005. Figure 1: Crude and age-standardized incidence and mortality rate of ovarian cancer, Slovenia 1986–2005. @enske / Females Obdobje / {tevilo / 20–49 let / 50–74 let / 75+ let / Period number years (%) years (%) years (%) 1991–1995 703 20,3 67,0 12,7 1996–2000 765 20,4 62,1 17,5 2001–2005 863 19,7 63,4 16,9 Tabela 1: [tevilo bolnic z rakom jaj~nika po obdobju postavitve diagnoze ter njihovi dele`i po starosti. Table 1: Number of ovarian cancer patients by period of diagnosis with their proportions by age. V analizo pre`ivetja je vklju~enih 2331 primerov; 59 bolnic (0,2 %) nismo upo{tevali, ker jim je bila diagnoza postavljena po smrti, 32 mlaj{ih od 20 let obravnavamo v poglavju o pre`ivet- ju pri otrocih in mladostnikih, iz vseh analiz pa smo izvzeli tudi 239 primerov mejno malignih rakov jaj~nika. Pribli`no 4 % bolnic v vsakem obdobju ni imelo mikroskopsko potrjene bolezni. Med mikro- skopsko potrjenimi je bilo najve~ (86 %) adenokarcinomov, 5 % je bilo drugih opredeljenih ali neopredeljenih karcinomov, 2 % tumorjev je bilo kompleksnih me{anih in stromalnih tumor- jev, ostalih histolo{kih vrst je bilo manj kot 1 %. Skoraj dve tretjini bolnic zboli v starosti 50–74 let. Dele` mlaj{ih od 50 let je v vseh obdobjih opazovanja podoben, v zadnjem desetletju se je pove~al dele` starih 75 let in ve~ (Tabela 1). EPIDEMIOLOGIJA Rak.qxd 22.7.2009 12:39 Page 178 In the period 1991–2005, a total of 2661 women were diagnosed with ovarian cancer. As evi- dent from Figure 1, in the observed period crude incidence and mortality rates have been increasing slowly. The estimated annual percentage increase in crude incidence rate was 0.8% and in crude mortality rate 1.2%. However, both age-standardized rates indicate a decreasing trend by 0.5% per year on average. The survival analysis included 2331 cases; 59 patients (0.2%) with ovarian cancer diagnosed only after death were not considered in the analysis, 32 patients under 20 years of age are pre- sented in the chapter on the survival of children and adolescents. 239 cases of ovarian cancer of borderline malignancy were excluded from the analysis as well. Approximately 4% of patients in each age group did not have microscopically confirmed dis- ease. Among the microscopically confirmed cancers adenocarcinomas (86%) were prevailing, the rest were specified or non-specified carcinomas (5%), complex mixed and stromal tumors (2%) and other histological types (less than 1%). Almost two-thirds of the patients present with the disease at an age between 50–74 years. The proportion of those less than 50 years of age is similar in all observation periods, while in the last decade, the proportion of patients aged 75 years or older has increased (Table 1). Approximately three-quarters of patients were diagnosed with disseminated disease. The pro- portion of patients with disseminated disease is increasing with time, while the rate of those with localized or regional stage of the disease is decreasing. In approximately 3% of patients stage at diagnosis was not determined (Table 2). In the period 2001–2005, 9% of patients did not receive specific treatment. The proportion of untreated patients slightly decreased, their percentage in the period 1991–1995 being 12%. Among the patients receiving specific treatment in the period 2001–2005, 65% were treated by surgery and chemotherapy, 15% underwent surgery alone, and 12% received chemothera- py alone while 5% of the patients had a combination of chemotherapy, surgery and radiotherapy. Other combinations were used in less than 5% of the patients. Compared to the period 1991–1995, in recent years significantly less patients had radiotherapy as primary treatment. In the period 2001–2005, 30% of patients started their treatment at the Department of Gynecology of the UMC Ljubljana and the IO Ljubljana, 14% in the UMC Maribor, and the remaining 26% by smaller proportions in almost all general hospitals of Slovenia. The relative survival rate of patients with ovarian cancer has been increasing: in 15 years, the relative 5-year survival increased by 10% (Figure 2, Table 3). The relevance of stage at diagno- sis is shown in Figure 3. In the recent period, the relative 5-year survival of patients with localized disease was 94%, patients with regional disease had 55% relative 5-year survival, and those with disseminated disease only 34%. A significant improvement in the relative 5-year survival rates OVARY ICD 10: C56 179 Tabela 2: [tevilo bolnic z rakom jaj~nika po obdobju postavitve diagnoze ter njihovi dele`i po stadiju. Table 2: Number of ovarian cancer patients by period of diagnosis with their proportions by stage. @enske / Females Obdobje / {tevilo / omejen / raz{irjen / razsejan / neznan / Period number localized regional distant unknown (%) (%) (%) (%) 1991–1995 703 16,2 12,9 67,7 3,1 1996–2000 765 16,7 14,5 66,7 2,1 2001–2005 863 13,1 7,8 76,4 2,8 EPIDEMIOLOGY Rak.qxd 22.7.2009 12:39 Page 179 Pribli`no pri treh ~etrtinah bolnic je bila bolezen odkrita v razsejanem stadiju. Dele` bolnic z razsejano boleznijo se s ~asom ve~a, manj{a pa se dele` odkritih v omejenem ali raz{irjenem stadiju bolezni. Pribli`no pri 3 % bolnic stadij ob diagnozi ni bil dolo~en (Tabela 2). V obdobju 2001–2005 ni bilo specifi~no zdravljenih 9 % bolnic. Dele` nezdravljenih bolnic se je nekoliko zmanj{al; v letih 1991–1995 ni bilo specifi~no zdravljenih 12 % bolnic. Med spe- cifi~no zdravljenimi bolnicami jih je bilo v letih 2001–2005 65% operiranih in zdravljenih s kemoterapijo, 15 % jih je bilo samo operiranih, 12 % pa je prejelo samo kemoterapijo; 5 % bol- nic je bilo poleg kemoterapije in operacije {e obsevanih. Druge kombinacije so uporabili pri manj kot 5 % bolnic. V primerjavi z obdobjem 1991–1995 je bilo v sklopu prvega zdravljenja v zadnjih letih obsevanih bistveno manj bolnic. 180 JAJ^NIK 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Slika 2: Deset-, pet-, tri- in enoletno relativno pre`ivetje bolnic z rakom jaj~nika po obdobju postavitve diagnoze. Figure 2: 10-, 5-, 3- and 1-year relative survival of ovarian cancer patients by period of diagnosis. Tabela 3: Opazovano in relativno pre`ivetje bolnic z rakom jaj~nika po obdobju postavitve diagnoze s 95- odstotnim intervalom zaupanja (IZ). Table 3: Observed and relative survival of ovarian cancer patients by period of diagnosis with 95% confidence interval (CI). Opazovano pre`ivetje / Observed survival (%) @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 68,8 (65,5–72,4) 41,0 (37,5–44,8) 30,7 (27,5–34,3) 1996–2000 70,9 (67,7–74,1) 45,9 (42,5–49,6) 36,2 (33,0–39,8) 2001–2005 75,2 (72,4–78,1) 48,4 (45,2–51,9) 39,7 (36,2–43,4) Relativno pre`ivetje / Relative survival (%) @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 70,2 (66,7–73,8) 43,6 (39,5–47,6) 34,2 (30,2–38,2) 1996–2000 72,4 (69,0–75,7) 49,0 (45,1–53,0) 40,7 (36,7–44,7) 2001–2005 76,6 (73,6–79,6) 51,4 (47,7–55,1) 44,2 (40,0–48,4) Rak.qxd 22.7.2009 12:39 Page 180 was evident in all stages. Age is a prognostic factor as well, since the relative 5-year survival in patients less than 50 years of age is 62%, while in those aged 75 years or older it is only 20%. An increasing time trend in survival was most apparent in the age group 50–74 years (Figure 4). The 5-year relative survival rate of all patients diagnosed in the period 2001–2005 was 44% (Figure 2); patients surviving the first year may expect to survive five years in 57%. According to the results of EUROCARE-4 study for patients diagnosed in 2000–2002, the sur- vival of ovarian cancer patients in Slovenia is nearly equal to the European average (Figure 5). 181 OVARY CLINICAL COMMENT ARY Marjetka Ur{i~ Vr{~aj Olga Cerar 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 Omejen / Localized Raz{irjen / Regional Razsejan / Distant Vsi / All Slika 3: Petletno relativno pre`ivetje bolnic z rakom jaj~nika po stadiju in obdobju postavitve diagnoze. Figure 3: 5-year relative survival of ovarian cancer patients by stage and period of diagnosis. 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 20–49 let / years 50–74 let / years 75+ let / years Vsi / All Slika 4: Petletno relativno pre`ivetje bolnic z rakom jaj~nika po starosti in obdobju postavitve diagnoze. Figure 4: 5-year relative survival of ovarian cancer patients by age and period of diagnosis. The data on ovarian cancer in this presentation include only the data on invasive ovarian can- cer without those of borderline malignancy. Ovarian tumors of borderline malignancy differ from the invasive type since their growth is not invasive, they rarely become recurrent, and even Rak.qxd 22.7.2009 12:39 Page 181 V obdobju 2001–2005 je zdravljenje po 30 % bolnic pri~elo na Ginekolo{ki kliniki UKC Ljub- ljana in na OI Ljubljana, 14 % v UKC Maribor, preostalih 26 % pa v manj{ih dele`ih v skoraj vseh slovenskih splo{nih bolni{nicah. Relativno pre`ivetje bolnic z rakom jaj~nika se pove~uje; v 15 letih se je petletno relativno pre- `ivetje pove~alo za 10 % (Slika 2, Tabela 3). Kako pomemben je stadij ob diagnozi, ka`e Slika 3: petletno relativno pre`ivetje bolnic z omejenim stadijem je v zadnjem obdobju 94 %, medtem ko je pri bolnicah z raz{irjenim stadijem petletno relativno pre`ivetje 55 %, pri tistih z razse- janim pa le 34 %. Izbolj{anje petletnih relativnih pre`ivetij je zna~ilno pri vseh stadijih. Napovedni dejavnik je tudi starost, saj je petletno relativno pre`ivetje mlaj{ih od 50 let 62 %, pri starih 75 let in ve~ let pa je petletno relativno pre`ivetje 20 %. Rasto~i ~asovni trend pre`ivetja je najbolj izrazit v starostni skupini 50–74 let (Slika 4). Petletno relativno pre`ivetje vseh zbolelih v obdobju 2001–2005 je bilo 44 % (Slika 2); bolni- ce, ki pre`ivijo prvo leto, pa lahko pri~akujejo 57-odstotno petletno relativno pre`ivetje. Rezultati {tudije EUROCARE-4 za zbolele v obdobju 2000–2002 ka`ejo, da je pre`ivetje slo- venskih bolnic z rakom jaj~nika skoraj enako evropskemu povpre~ju (Slika 5). 182 JAJ^NIK KLINI^NI KOMENT AR Marjetka Ur{i~ Vr{~aj Olga Cerar Podatki o raku jaj~nikov v tej knjigi vklju~ujejo le podatke o invazivnem raku jaj~nikov brez podatkov o mejno malignih tumorjih. Mejno maligni tumorji jaj~nikov so klini~no druga~ni kot invazivni, ne rastejo invazivno, le redko in praviloma {ele po mnogih letih recidivirajo, zato je lo~evanje obeh skupin pomembno. Podatek o visokem dele`u razsejanega raka jaj~nikov v obdobju 2001–2005 po vsej verjetno- sti ka`e na bolj{e upo{tevanje smernic in izbolj{anje diagnosti~nih postopkov pri postavitvi pravilnega stadija bolezni, ki je klju~ni napovedni dejavnik in izhodi{~e za pravilno in u~inko- vito zdravljenje. Velik dele` razsejanega raka {e vedno odslikava pomanjkanje ustreznih metod za zgodnje odkrivanje tega raka, podobno kot drugod po Evropi. Na~in zdravljenja invazivnega raka jaj~nikov se je v tem 15-letnem obdobju spreminjal. V skla- du s priporo~ili o u~inkovitosti ~im bolj radikalne odstranitve tumorskega tkiva, ki mu sledi sistemsko zdravljenje s citostatiki, se pove~uje dele` bolnic, zdravljenih kirur{ko in s sistem- sko kemoterapijo. Skoraj 80 % bolnic, zdravljenih kirur{ko ali kirur{ko in s citostatiki (odvisno od raz{irjenosti bolezni) v obdobju 2001–2005 ka`e na sodoben pristop pri zdravljenju raka jaj~nikov. Iz podatkov o prvem specifi~nem zdravljenju bolnic z rakom jaj~nikov je razvidno, da se prvo (kirur{ko) zdravljenje pri tretjini bolnic {e vedno opravi po posameznih ({tevilnih) bolni{ni- cah v Sloveniji. Ostanek tumorskega tkiva po kirur{kem posegu je eden od najpomembnej{ih napovednih dejavnikov pri zdravljenju raka jaj~nikov. Izku{enost ginekolo{ko-kirur{ke ekipe, ki je predvsem odsev {tevila opravljenih tovrstnih posegov, je klju~nega pomena. Kljub stalne- mu izobra`evanju in poudarjanju tega dejstva pa je dele` bolnic, ki se zdravijo v manj{ih centrih v Sloveniji, v vseh treh obdobjih {e vedno nespremenjen in ne ka`e na izbolj{anje. Pomembno je, da se petletno relativno pre`ivetje vseh bolnic z rakom jaj~nikov postopno pove- ~uje, tako pri omejeni, raz{irjeni in razsejani bolezni. Izbolj{anje pre`ivetja je najverjetneje posledica bolj agresivnega zdravljenja, vklju~no z uporabo novih, u~inkovitej{ih citostatikov. Podatki so primerljivi s povpre~jem ostalih evropskih dr`av. Izbolj{anje relativnega pre`ivetja se ka`e tudi po desetih letih, kar je pri bolezni s slabo napovedjo izida, kot je rak jaj~nikov, {e toliko pomembneje. Petletno relativno pre`ivetje po starostnih obdobjih ka`e za obdobje 2001–2005 v primerjavi z obdobjem 1996–2000 na nekatere spremembe. ^eprav se je v obdobju 2001–2005 petletno Rak.qxd 22.7.2009 12:39 Page 182 then it generally takes years before their recurrence, therefore it is important to differentiate between the two groups. The data on a high rate of disseminated ovarian cancer in the period 2001–2005 probably indi- cates more consistent following of the guidelines and improved diagnostic procedures at establishing the correct stage of the disease, which are a key prognostic factor and the basis for an appropriate and effective treatment. High rate of disseminated cancer still reflects the lack of suitable methods for early diagnosis of this cancer, likewise elsewhere in Europe. In the last 15-year period, the mode of treatment for invasive ovarian cancer has been chan- ging. In compliance with the recommendations on the effectiveness of maximum radical removal of tumor tissue, followed by a systemic treatment with cytotoxic drugs, the proportion of patients treated with a combination of surgery and chemotherapy is increasing. Almost 80% of patients treated surgically or by means of surgery and chemotherapy (depending on the extent of the disease) in the period 2001–2005 are indicative of a modern approach to the treatment of ovar- ian cancer. The data on the primary specific treatment of patients with ovarian cancer show that in one-third of the patients the primary therapy (surgery) is still carried out in individual (several) hospi- tals in Slovenia. Tumor residue after surgery is one of the most important prognostic factors for ovarian cancer treatment. Experience and skills of surgical team, acquired mainly through numerous surgical interventions performed, are of key importance. Despite the permanent edu- cation and emphasizing that fact, the proportion of patients treated in minor centers throughout Slovenia has remained unchanged in all three observation periods, and there is no evidence of improvement in this respect. It is important to note that 5-year survival of all patients with ovarian cancer is gradually increas- ing in localized as well as in regional and disseminated disease. Improvement in the survival is most probably attributable to a more aggressive treatment, including the use of new, more 183 OVARY 01 02 0 30 40 50 60 70 80 90 100 % Slovensko povpre~je / 2000–2002 (EUROCARE-4) Slovenian average Evropsko povpre~je / 2000–2002 (EUROCARE-4) European average Povpre~je ZDA / 2000–2002 (SEER-13) USA average Slika 5: Petletno relativno pre`ivetje bolnic z rakom jaj~nika* (povpre~je in 95-odstotni interval zaupanja), zbolelih v letih 2000–2002 v Sloveniji, Evropi in nekaterih obmo~jih v ZDA. Figure 5: 5-year relative survival of ovarian cancer patients* (average and 95% confidence interval) diagnosed in the period 2000–2002 in Slovenia, Europe and in some regions of the USA. * Nabor MKB10 kod v {tudiji EUROCARE-4 je nekoliko druga~en kot smo ga uporabili pri ostalih analizah predstavljenih v tem poglavju: v {tudiji EURCARE-4 so v analizo vklju~ene tudi maligne neoplazme materni~nih priveskov in Wolfovih vodov (MKB10: C570–C577). * The ICD10 code selection in EUROCARE-4 study is slightly different in comparison to the selection applied in other analysis in this chapter: in EUROCARE-4 study the malignant neoplasm of uterine adnexa and Wolffian body (ICD10: C570–C577) are included. Rak.qxd 22.7.2009 12:39 Page 183 relativno pre`ivetje v {tevil~no najmo~nej{i skupini bolnic med 50 in 74 leti pove~alo, pa se pri bolnicah, starih 75 let in ve~, ni spremenilo, v starosti 20–49 let pa se je celo nekoliko zmanj- {alo. Pri starej{ih bolnicah je zdravljenje raka zaradi pridru`enih bolezni pogosto prilagojeno, kraj{e in zato manj kakovostno. Pomembno izbolj{anje pre`ivetja je zato te`je pri~akovati. Zmanj- {anje petletnega relativnega pre`ivetja pri mlaj{ih bolnicah, starih 20–49 let, pa potrebuje spremljanje v dalj{em obdobju in dodatne analize. Upo{tevati je treba, da dele` bolnic v tem starostnem obdobju predstavlja le petino vseh bolnic z rakom jaj~nikov, zato slab{e pre`ivetje posameznic lahko hitreje vpliva na rezultat cele skupine. @e zbrani podatki ka`ejo, da je odsto- tek adenokarcinomov, najpogostej{ih malignih tumorjev jaj~nikov, v tem starostnem obdobju pribli`no enak, tako v obdobju 1996–2000 (89,1 %) kot tudi v obdobju 2001–2005 (88,2 %), kar ne ka`e na spremenjeno patohistolo{ko strukturo tumorjev in morebitno posledi~no dru- ga~no napoved izida oz. pre`ivetje. Dele` omejenega, raz{irjenega in razsejanega raka jaj~nikov se je pri mlaj{ih spremenil podobno kot v drugih dveh starostnih skupinah. Kak{no je pre`i- vetje po enem in treh letih, kak{na je diferenciranost tumorjev, kako radikalni so kirur{ki posegi, in nenazadnje, v kolik{ni meri lahko na pre`ivetje vpliva t. i. konzervativno zdravljenje pri mlaj- {ih bolnicah itd. – vse to so vpra{anja, ki jih bo z dodatnimi analizami potrebno razjasniti. Epithelial ovarian carcinoma: ESMO Clinical Recommendations for diagnosis, treatment and follow up. 2007. http://annonc.oxfordjournals.org/cgi/reprint/18/suppl_2/ii12. NCCN Clinical Practice Guidelines in Oncology. Genetic/Familial High-Risk Assessment: Breast and Ovarian. V. I. 2007. www.nccn.org NCCN Updates Ovarian Cancer Guidelines. 2008. www.nccn.org. Register raka za Slovenijo. Poro~ilo za leto 2005, Onkolo{ki in{titut Ljubljana, 2008. Str`inar V, Ba{kovi~ M, Bebar S, Cerar O, Fras AP , Koritnik K, et al. Ginekolo{ki malignomi. Doktrina zdravljenja ginekolo{kih malignomov na Onkolo{kem in{titutu in Univerzitetni ginekolo{ki kliniki Ljubljana. 3. revi- dirana izd. Ljubljana: Zveza slovenskih dru{tev za boj proti raku, 2002. 184 JAJ^NIK VIRI Literature Rak.qxd 22.7.2009 12:39 Page 184 effective cytotoxic drugs. The data are comparable with the averages in other European coun- tries. The improvement in relative survival is also evident after a 10-year period, which is ever more important in the case of diseases with poor prognosis, such as ovarian cancer. Five-year survival by age group for the period 2001–2005 points out some differences as com- pared to the period 1996–2000. Although in the period 2001–2005 the relative 5-year survival in the most numerous group of patients aged 50–74 years has increased, in the patients aged 75 years or older it remained unchanged, while in the age group 20–49 years it was even slight- ly lower. In older patients cancer-specific therapy often needs to be adjusted and reduced due to concomitant diseases, which renders it less effective. Therefore, a significant improvement in the survival can hardly be expected. The decreased 5-year relative survival of younger patients aged 20–49 years calls for a longer follow-up period and additional analyses. It should be taken into consideration that the proportion of patients in this age group represents only a fifth of all patients with ovarian cancer, and therefore poor survival in individual cases may easily influ- ence the total score of the group. The data indicate that the percentage of adenocarcinomas, i. e. the most frequent malignant ovarian tumors, was in that age group practically the same in both periods: in 1996–2000 it was 89.1% and in 2001–2005 it was 88.2%. This is not indica- tive of a changed pathohistological tumor structure and thus of possibly different prognosis or survival. The proportion of localized, regional and disseminated ovarian cancers in younger patients was comparable with those in other age groups. What is the survival after one and three years, what is tumor differentiation, how radical are surgical interventions and, last but not least, to what extent may the so-called conservative treatment in younger patients influ- ence their survival, etc.? – All these are the questions that need to be clarified in further analyses. 185 OVARY Rak.qxd 22.7.2009 12:39 Page 185 V obdobju 1991–2005 je za rakom prostate zbolelo 7660 mo{kih. Kot je razvidno s Slike 1, se groba in starostno standardizirana inciden~na stopnja ves ~as opazovanja ve~ata, groba pov- pre~no za 10,0 % letno, starostno standardizirana pa povpre~no za 6,9 % letno. Ve~ata se tudi umrljivostni stopnji, groba povpre~no za 4,4 % letno, starostno standardizirana pa povpre~no za 2,1 % letno. PROSTATA MKB 10: C61 186 0 10 20 30 40 50 60 70 80 90 100 1986 1990 1995 2000 2005 Leto / Year Incidenca – groba stopnja / Incidence – crude rate Incidenca – SSS* / Incidence – ASR** Umrljivost – groba stopnja / Mortality – crude rate Umrljivost – SSS* / Mortality – ASR** Stopnja na 100.000 / Rate per 100,000 * SSS – starostno standardizirana stopnja (standard – slovenska populacija leta 1986) ** ASR – age standardized rate (standard Slovenian population in 1986) Slika 1: Groba in starostno standardizirana inciden~na in umrljivostna stopnja raka prostate, Slovenija 1986–2005. Figure 1: Crude and age-standardized incidence and mortality rate of prostatic cancer, Slovenia 1986–2005. Mo{ki / Males Obdobje / {tevilo / 20–49 let / 50–74 let / 75+ let / Period number years (%) years (%) years (%) 1991–1995 1361 1,0 58,2 40,9 1996–2000 2323 0,9 68,1 30,9 2001–2005 3615 0,7 71,4 27,9 Tabela 1: [tevilo bolnikov z rakom prostate po obdobju postavitve diagnoze ter njihovi dele`i po starosti. Table 1: Number of prostatic cancer patients by period of diagnosis with their proportions by age. V analizo pre`ivetja je vklju~enih 7299 primerov; 361 bolnikov (4,9 %) nismo upo{tevali, ker jim je bila diagnoza postavljena po smrti. V obdobju 2001–2005 je bilo 91 % primerov raka prostate mikroskopsko potrjenih. Dele` mikro- skopsko potrjenih primerov se je v primerjavi z obdobjem 1991–1995 pove~al za 2 %. V vseh treh obdobjih je imelo najve~ bolnikov adenokarcinom, v zadnjem obdobju je bil njegov dele` 80 %, za 14 % ve~ji kot v prvem. To pove~anje ni posledica spremenjenih histolo{kih vrst tumor- jev, pa~ pa ve~je natan~nosti patologov pri pisanju histolo{kega izvida. [e vedno pa v zadnjem obdobju ostaja 19 % karcinomov neopredeljenih. EPIDEMIOLOGIJA Rak.qxd 22.7.2009 12:39 Page 186 In the period 1991–2005, a total of 7660 men were diagnosed with prostate cancer. As evident from Figure 1, the crude and age standardized incidence rates have been increasing through- out the observation period, the crude rate by 10.0% and the age-standardized rate by 6.9% annually on average. The mortality rates have been increasing as well, the crude rate by 4.4% and the age standardized by 2.1% annually on average. The survival analysis included 7299 cases; 361 patients (4.9%) diagnosed only after death were not considered in the analysis. In the period 2001–2005, 91% of prostate cancers were microscopically verified. In compar- ison with the period 1991–1995 the proportion of microscopically confirmed cases has increased by 2%. In all three time-periods, the majority of patients had adenocarcinoma, in the last period their proportion was 80%, which is by 14% more than in the first period. This increase is not a result of changed histological types, but should be attributed to greater accu- racy of histological findings. However, in the last period 19% of carcinomas still remained undefined. More than half of the patients are diagnosed at an age between 50 to 70 years, their propor- tion in the last period being almost three fourths (Table 1); in comparison with the first period, in the last one the proportion of patients aged 75 years or older has decreased by 13%, howev- er, in absolute figures this still represents almost a half more new cases than in the period 1991–1995; the number of patients aged 50–74 years has increased threefold (from 792 to 2581 new can- cer cases in the period 2001–2005). Prostate cancer before 50 years of age is extremely rare. In all three time-periods, the majority of patients were diagnosed with localized disease; in the period 2001–2005 their proportion being 64% (Table 2). In the latter period, 17% of patients had regional and 10% disseminated disease; the proportion of patients with disseminated stage has been decreasing with time. In the first period there were 18% of patients with undefined stage, whereas in the last period their proportion was still 9%. In the years 2001–2005, 11% of patients did not receive specific treatment. In comparison with the first period, the proportion of untreated patients has increased by almost 2%. Among those receiv- ing specific treatment, 38% were treated with hormones and 30% with surgery only, 18% with a combination of surgery and hormones, 7% received radiotherapy besides hormonal treatment while 5% also had surgery, 1% of the patients received chemotherapy alone or in combination with other treatment modalities, while all other combinations represented less than 1%. In the course of the 15-year period, the most common therapeutic approaches have changed, the most frequent treatment modality in the period 1991–1995 being a combination of surgery and hor- mones (35%), followed by surgery alone (26%), while hormonal therapy alone was used in 14% of patients only. PROSTATE ICD 10: C61 187 Tabela 2: [tevilo bolnikov z rakom prostate po obdobju postavitve diagnoze ter njihovi dele`i po stadiju. Table 2: Number of prostatic cancer patients by period of diagnosis with their proportions by stage. Mo{ki / Males Obdobje / {tevilo / omejen / raz{irjen / razsejan / neznan / Period number localized regional distant unknown (%) (%) (%) (%) 1991–1995 1361 48,0 13,7 20,4 18,0 1996–2000 2323 52,6 14,6 15,9 16,8 2001–2005 3615 64,0 16,6 10,4 9,1 EPIDEMIOLOGY Rak.qxd 22.7.2009 12:39 Page 187 Ve~ kot polovica bolnikov zboli v starosti 50–74 let, v zadnjem obdobju skoraj tri ~etrtine (Ta- bela 1); dele` starih 75 let in ve~ se je sicer v zadnjem obdobju v primerjavi s prvim zmanj{al za 13 %, vendar v absolutnih {tevilkah to {e vedno pomeni v tej starosti skoraj polovico ve~ novih primerov kot v letih 1991–1995; {tevilo bolnikov v starosti 50–74 let se je pove~alo za trikrat (s 792 na 2581 novih primerov raka v letih 2001–2005). Rak prostate je pred 50. letom staro- sti izjemno redka bolezen. V vseh treh obdobjih je imelo najve~ bolnikov ob diagnozi omejeno bolezen; v letih 2001–2005 64 % (Tabela 2). V tem obdobju je imelo 17 % bolnikov raz{irjeni stadij, 10 % pa razsejanega; dele` bolnikov z razsejanim stadijem se z leti manj{a. V prvem obdobju stadija ni imelo dolo- ~enega 18 % bolnikov, v zadnjem pa {e vedno 9 %. 188 PROSTATA 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Slika 2: Deset-, pet-, tri- in enoletno relativno pre`ivetje bolnikov z rakom prostate po obdobju postavitve diagnoze. Figure 2: 10-, 5-, 3- and 1-year relative survival of prostatic cancer patients by period of diagnosis. Tabela 3: Opazovano in relativno pre`ivetje bolnikov z rakom prostate po obdobju postavitve diagnoze s 95- odstotnim intervalom zaupanja (IZ). Table 3: Observed and relative survival of prostatic cancer patients by period of diagnosis with 95% confidence interval (CI). Opazovano pre`ivetje / Observed survival (%) Mo{ki / Males Obdobje / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 77,7 (75,6–80,0) 50,6 (48,0–53,4) 35,2 (32,7–37,8) 1996–2000 81,9 (80,3–83,5) 59,1 (57,1–61,1) 46,9 (44,9–49,0) 2001–2005 86,4 (85,3–87,5) 68,5 (67,0–70,1) 57,5 (55,7–59,4) Relativno pre`ivetje / Relative survival (%) Mo{ki / Males Obdobje / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 83,9 (81,4–86,3) 63,9 (60,4–67,3) 52,4 (48,4–56,3) 1996–2000 87,2 (85,6–88,9) 71,9 (69,4–74,4) 65,6 (62,7–68,5) 2001–2005 91,2 (90,0–92,4) 81,5 (79,7–83,4) 78,2 (75,6–80,8) Rak.qxd 22.7.2009 12:39 Page 188 In the period 2001–2005, 30% of patients started their treatment in the UMC Ljubljana, 15% in GH Celje, 14% in the UMC Maribor, 12% in GH Slovenj Gradec, 6% in GH Murska Sobota, 4% each in GH Nova Gorica, GH Izola and GH Novo mesto, 3% at the IO Ljubljana and the remaining 8% in other hospitals and outpatient clinics for urology. The relative survival rate of patients with prostate cancer has been increasing: in 15 years, the 5-year relative survival increased by 26% (Figure 2, Table 3). The relevance of stage at diag- nosis is shown in Figure 3. In the last period, 5-year relative survival of patients with localized stage exceeded 90%, while in those with regional stage it increased by 33% in the 15-year peri- od, in the patients diagnosed in the period 2001–2005 being 80%. Treatment outcome in patients with disseminated stage was less encouraging, as their already poor survival in the first period (18%) has underwent a further decrease, thus being in patients diagnosed in the years 2001–2005 only 11%. Survival has been increasing in all age groups, most obviously in those aged 50–74 years, in whom it has increased by 30% in the 15-year period; lesser increase in the survival (8% only) was observed in the oldest age group (Figure 4). The evaluation of time trend in the 5-year relative survival of patients aged 20–49 years is not reliable due to a small number of patients. 189 PROSTATE 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 Omejen / Localized Raz{irjen / Regional Razsejan / Distant Vsi / All Slika 3: Petletno relativno pre`ivetje bolnikov z rakom prostate po stadiju in obdobju postavitve diagnoze. Figure 3: 5-year relative survival of prostatic cancer patients by stage and period of diagnosis. 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 20–49 let / years 50–74 let / years 75+ let / years Vsi / All Slika 4: Petletno relativno pre`ivetje bolnikov z rakom prostate po starosti in obdobju postavitve diagnoze. Figure 4: 5-year relative survival of prostatic cancer patients by age and period of diagnosis. Rak.qxd 22.7.2009 12:39 Page 189 V letih 2001–2005 ni bilo specifi~no zdravljenih 11 % bolnikov. Dele` nezdravljenih se je v pri- merjavi s prvim obdobjem pove~al za skoraj 2 %. Med specifi~no zdravljenimi je bilo 38 % bolnikov zdravljenih samo s hormoni, 30 % samo z operacijo, 18 % s kombinacijo operacije in hormo- nov, 7 % je poleg hormonske prejelo {e radioterapijo, 5 % pa so {e operirali, 1 % bolnikov je dobil kemoterapijo samo ali v kombinaciji z drugimi vrstami zdravljenja; vseh drugih kombinacij je bilo manj kot 1 %. Najpogostej{i terapevtski pristopi so se v petnajstletnem obdobju spremenili, saj je bilo v obdobju 1991–1995 najpogostej{e zdravljenje kombinacija operacije s hormoni (35 %), sledila mu je samo operacija (26 %), samo hormonsko pa je bilo zdravljenih le 14 % bolnikov. V obdobju 2001–2005 je 30 % bolnikov zdravljenje za~elo v UKC Ljubljana, 15 % v SB Celje, 14 % v UKC Maribor, 12 % v SB Slovenj Gradec, 6 % v SB Murska Sobota, po 4 % v SB Nova Gorica, SB Izola in SB Novo mesto, 3 % na OI Ljubljana, preostalih 8 % pa v drugih bolni- {nicah in v urolo{kih ambulantah. Relativno pre`ivetje bolnikov z rakom prostate se ve~a; v 15 letih se je petletno relativno pre- `ivetje pove~alo za 26 % (Slika 2, Tabela 3). Kako pomemben je stadij ob diagnozi, ka`e Slika 3: petletno relativno pre`ivetje bolnikov z omejenim stadijem je v zadnjem obdobju preseglo 90 %, pri bolnikih z raz{irjenim stadijem pa se je v 15 letih pove~alo za 33 % in je bilo pri tistih, diagno- sticiranih v letih 2001–2005, 80-odstotno. Manj spodbuden je izid zdravljenja bolnikov z razsejanim stadijem, saj se pri njih `e tako majhno pre`ivetje od prvega obdobja (18 %) manj{a in je bilo pri bolnikih, diagnosticiranih v letih 2001–2005, le 11-odstotno. Pre`ivetje se ve~a v vseh starostnih skupinah, najbolj pri starih 50–74 let, kjer se je v 15 letih pove~alo za 30 %, manj pa pri najstarej{ih, pri katerih se je pove~alo le za 8 % (Slika 4). Vred- notenje ~asovnega trenda petletnega relativnega pre`ivetja bolnikov, starih 20–49 let, pa ni zanesljivo, saj je bolnikov malo. Petletno relativno pre`ivetje vseh zbolelih v obdobju 2001–2005 je bilo 78 % (Slika 2); bolni- ki, ki pre`ivijo prvo leto, pa lahko pri~akujejo 85-odstotno petletno relativno pre`ivetje. Rezultati {tudije EUROCARE-4 za zbolele v obdobju 2000–2002 ka`ejo, da je pre`ivetje sloven- skih bolnikov z rakom prostate statisti~no zna~ilno manj{e od evropskega povpre~ja (Slika 5). 190 PROSTATA KLINI^NI KOMENT AR Andrej Kmetec Iz prikazanih podatkov je razvidno, da se incidenca raka prostate vztrajno ve~a; ve~a se pred- vsem groba stopnja, kar je razumljivo, saj se povpre~na starost mo{kih ve~a, manj izrazit je porast starostno standardizirane stopnje. Nara{~anja incidence raka prostate si ne moremo razlagati le z bolj{im prijavljanjem bolezni in z bolj{im odkrivanjem bolezni, ker pri vse ve~ mo{kih opra- vimo test PSA. Ob ve~anju incidence se ve~a tudi umrljivostna stopnja, ~eprav po~asneje, kar ka`e na to, da kljub zgodnjemu odkrivanju in ve~anju pre`ivetja {e vedno preve~ bolnikov umre zaradi te bolezni. Pregled umrljivosti v nekaterih evropskih dr`avah, ZDA in na Japonskem ka`e, da se ponekod umrljivost zmanj{uje, samo na Japonskem naj ne bi bila posledica prese- janja s PSA. Histolo{ko je rak potrjen v ve~ kot 90 %. Histolo{ka preiskava ni bila opravljena pri manj kot 10 % bolnikih, ki so prete`no mo{ki v visoki starosti s spremljajo~imi te`jimi boleznimi, kjer sumimo, da gre za raka prostate le na osnovi tipanja trde, gr~asto spremenjene prostate in viso- kih vrednosti PSA. Ve~ kot 85 % bolnikov je dobilo eno od ustreznih zdravljenj: hormonsko, kirur{ko, obsevalno ali kombinacijo teh vrst zdravljenja. [tevilo bolnikov, ki so bili radikalno kirur{ko zdravljeni, se je v zadnjem desetletju skoraj podvojilo. V zadnjih letih opa`amo, da se pove~uje {tevilo radi- kalnih prostatektomij pri lokaliziranem raku prostate za 10–12 % letno. Verjetno je to tudi eden od vzrokov, da se je v zadnjih letih pove~alo predvsem relativno pre`ivetje po petih letih in se Rak.qxd 22.7.2009 12:39 Page 190 The 5-year relative survival of all patients diagnosed in the period 2001–2005 was 78% (Figure 2); patients surviving the first year may expect to survive five years in 85%. According to the results of EUROCARE-4 study for patients diagnosed in 2000–2002, the survival of prostate cancer patients in Slovenia is statistically significantly below the European average (Figure 5). 191 PROSTATE CLINICAL COMMENT ARY Andrej Kmetec 01 02 0 30 40 50 60 70 80 90 100 % Slovensko povpre~je / 2000–2002 (EUROCARE-4) Slovenian average Evropsko povpre~je / 2000–2002 (EUROCARE-4) European average Povpre~je ZDA / 2000–2002 (SEER-13) USA average Slika 5: Petletno relativno pre`ivetje bolnikov z rakom prostate (povpre~je in 95-odstotni interval zaupanja), zbolelih v letih 2000–2002 v Sloveniji, Evropi in nekaterih obmo~jih v ZDA. Figure 5: 5-year relative survival of prostatic cancer patients (average and 95% confidence interval) diagnosed in the period 2000–2002 in Slovenia, Europe and in some regions of the USA. As evident from the presented data, the incidence of prostate cancer is steadily increasing, par- ticularly the crude rate, which is understandable since the life expectancy of men is increasing; the increase in age-standardized rates is less prominent. The increasing incidence of prostate cancer cannot be explained only by more systematic reporting of the disease and better can- cer detection due to more frequent use of the PSA test in males. Along with the increasing incidence the mortality rate is increasing too, though at a slower trend, which shows that despite early diagnosis and better survival still too many patients die from this disease. A survey of mortality rates in certain European countries, the United States and in Japan shows that in some areas the mortality is decreasing, however, except in Japan, this trend should not be asso- ciated with PSA screening. Cancer is histologically confirmed in over 90% of cases. Histological examination has not been performed in less than 10% of patients, mostly men at an advanced age with severe concomi- tant diseases, where the presence of prostate cancer was suspected only on the basis of palpation of a nodular prostate and high PSA levels. More than 85% of patients received one of the suitable treatments: hormones, surgery, irra- diation or a combination of these. The number of patients undergoing radical surgery has almost doubled in the past decade. In recent years we note that the number of radical prostatectomies in localized prostate cancer has been increasing by 10–12% per year. Probably this is one of the reasons for an increase in the 5-year relative survival in last years, which is already approach- ing 80%. Another reason may lie in a greater proportion of the localized prostate cancer, particularly in the middle age group, which means that the disease is detected at an early stage Rak.qxd 22.7.2009 12:39 Page 191 `e bli`a 80 %. Drugi vzrok je morda ve~ji dele` omejenega raka prostate, predvsem v srednji `ivljenjski dobi, kar pomeni, da gre za zgodaj odkrito obliko bolezni, pri kateri je {e mo`na ozdra- vitev. S tem v zvezi se je za polovico zni`al odstotek razsejane oblike raka, kar pomeni, da smo uspeli s pravo~asno diagnosti~no preiskavo odkriti zgodnje oblike raka in pove~ali mo`nost ozdra- vitve ter pre`ivetje bolnikov, vendar predvsem pri omejeni in raz{irjeni obliki bolezni. @al se relativno pre`ivetje manj{a pri razsejani obliki raka, morda zaradi bolj maligne, slabo diferencirane vrste raka, pozne prepoznave raz{irjenosti bolezni ali pa za~nemo prepozno inten- zivno zdraviti, zlasti s kombiniranimi na~ini zdravljenja. V zadnjem desetletju se vztrajno ve~a odstotek mo{kih, ki zbolijo v srednji `ivljenjski dobi, v sta- rosti 50–74 let, zmanj{uje pa se odstotek tistih, ki jim odkrijemo bolezen po 75. letu. To ka`e, da s testiranjem PSA uspemo odkriti bolezen v za~etni fazi razvoja, ko je {e omejena na `le- zo in je zdravljenje lahko bolj radikalno, zato je tudi pre`ivetje bolnikov bolj{e, saj je rak prostate bolezen, ki se razvija po~asi in se klini~no izrazi {ele po 10 do 14 letih. Pri bolnikih, ki jim odkrijemo bolezen v starosti 75 let ali ve~, gre pogosto za napredovalo bole- zen ali za bolj maligne vrste raka, ki jih je samo s testom PSA te`je odkriti, ~e ni hkrati tudi te`av z uriniranjem. Tako si lahko delno razlagamo slab{e relativno pre`ivetje v tej starostni skupini. Poleg tega se pri tej starosti te`je odlo~imo za bolj radikalne vrste zdravljenja (zlasti kirur{ko), prevladuje predvsem paliativni na~in zdravljenja, kar pa nikakor ne pomeni slab{e kakovosti zdravljenja ali celo opustitve zdravljenja. K slab{emu pre`ivetju pa prispevajo tudi dodatne bolezni starostnikov, ki v~asih ovirajo izbiro ustreznega na~ina zdravljenja. Rak prostate je bolezen, ki sama po sebi ne povzro~a nobenih te`av, ~e ni pridru`eno {e benig- no pove~anje prostate in s tem motnja uriniranja. Odkrivanje bolezni sloni predvsem na testiranju s PSA in zavedanju mo{kih o potrebnih preventivnih pregledih. Cookson MM. Prostate cancer: screening and early detection. Cancer Control 2001; 8: 133–40. Colombel M, Xavier M, Florence ML, Jean Marie M. Longterm survival after prostatectomy. Eur Urol Suppl 2006; 5: 127. European Associacion of Urology. Guidelines on prostate cancer, 2005. Marugame T , Mizuno S. Comparison of prostate cancer mortality in five countries: France, Italy, Japan, UK and USA from the WHO mortality database (1960–2000). Jpn J Clin Oncol 2005; 35: 690–1. Myers PR. Localised prostate cancer: important of conduct for radical prostatectomy. Eur Urol Suppl; 2001: 10–4. Schröder FH, Gosselaar C, Roemeling S, Postma R, Roobol JM, Bangma CH. PSA and the detection of prostate cancer after 2005. Part I. Eur Urol Suppl 4, 2006: 2–12. Schröder FH, Alexander FE, Bangma CH, Hugsson J, Smith DS. Screening and early detection of prostate cancer. Prostate 2000; 44: 255–63. Wallsh PC. Radical prostatectomy for localised prostate cancer provides durable cancer control with excellent quality of life: a structured debate. J Urol 2000; 163: 1802–7. 192 PROSTATA KLINI^NI KOMENT AR Borut Kragelj Ena od pomembnih zna~ilnosti raka prostate je pogosto po~asen naraven potek bolezni. Ra~unal- ni{ki modeli ka`ejo, da je potrebno pribli`no 15 let, da se iz PIN razvije invaziven karcinom, ki ostane v povpre~ju {e nadaljnjih 6 let omejen na prostato. Tudi pri bolnikih z `e klini~no jasnim sistemskim razsojem povpre~no pre`ivetje presega 5 let. Rak prostate zmanj{uje pre- `ivetje le pri bolnikih z oddaljenimi zasevki in morda pri manj{em delu bolnikov z zasevki v podro~nih bezgavkah oziroma z lokalno napredovalimi tumorji. In le pri teh je morda lah- ko petletno pre`ivetje odvisno od ustrezno vodenega in pravo~asno pri~etega sistemskega zdravljenja. Bolnike, pri katerih je rak omejen na prostato, sama bolezen `ivljenjsko ne ogro- `a. ^eprav se zasevki pri manj{em delu teh bolnikov sicer lahko pojavijo v petletnem obdobju VIRI Literature Rak.qxd 22.7.2009 12:39 Page 192 when cure is still possible. Further to that, the proportion of disseminated cancer has been reduced by half, indicating that timely diagnosis has enabled us to detect the disease at an early stage and thus improve the patients' chances of cure and survival, however prevailingly in the case of localized and regional forms of the disease. Unfortunately, the relative survival in disseminated disease has been decreasing, perhaps due to a more malignant poorly differentiated cancer type, late staging of the disease or delayed intensive therapy, and in particular combined treatment modality. In the last decade, the proportion of males diagnosed at an age between 50 to 74 years has been steadily increasing, while the proportion of those with the disease diagnosed aged 75 years or older is decreasing. This indicates that by means of the PSA test, the disease can be detec- ted at an early stage when it is still confined to the gland and thus the treatment can be more radical, and accordingly also the patients' survival is better; namely, prostate cancer is a slow- ly progressing disease which becomes clinically manifest only 10–14 years from the onset. In patients with the disease detected when aged 75 years or older, it often turns out that the patient either has regionally advanced disease or a more malignant caner type, which cannot be easily detected by PSA test alone, if the patient does not also present with urine voiding problems. This may partly explain worse survival of patients in this age group. Besides, at this age it is difficult to decide for more radical treatment (particularly surgical); palliative treat- ment is therefore prevailing, which by no means implies a lower quality of treatment or even abandonment of therapy. Worse survival is further aggravated by concomitant diseases of the elderly, which sometimes pose severe obstacles to the choice of suitable therapy. Prostate cancer is a disease, which in itself does not cause any difficulties if not associated with benign hyperplasia of the prostate and urine voiding problems. Its detection is primarily based on the PSA test and the awareness of male population about the need of preventive medical checks. 193 PROSTATE CLINICAL COMMENT ARY Borut Kragelj One of the important features of prostate cancer is frequently a slow natural course of the dis- ease. Computer models demonstrate that it takes approximately 15 years before a PIN progresses into an invasive carcinoma, the latter remaining confined to the prostate for another 6 years on average. Even in patients with clinically evident systemic dissemination the average sur- vival exceeds 5 years. Prostate cancer is associated with a lower survival only in patients with distant metastases and perhaps in a small proportion of patients with regional lymph node metas- tases or locally advanced tumors. In the latter only, the 5-year survival may depend on an adequately managed and timely introduced systemic therapy. In patients with cancer confined to the prostate this is not a life-threatening disease. Although in a smaller proportion of these patients metas- tases may appear within five years from diagnosis, patients with poorly differentiated tumors will die in 5 to 10 years from diagnosis, while those with well differentiated carcinomas may survive even more than 15 years. Therefore, the 5-year survival in prostate cancer is primarily a measure of effective early diag- nosis, indicating the ratio between patients with localized or regional disease or even distant metastases at the time of diagnosis. Early detection of prostate cancer is still based on the evalu- ation of PSA serum concentration. The rationale of organized early detection by means of this method is still under study. In Europe, the accessibility of PSA test and diagnosis by means of prostate biopsy and histological examination of the bioptic tissue sample varies a lot, although it is of key importance for the differences in 5-year survival. Rak.qxd 22.7.2009 12:39 Page 193 po diagnozi, pa je rak vzrok smrti bolnikov s slabo diferenciranimi tumorji ponavadi v obdob- ju 5–10 let po diagnozi, z dobro diferenciranimi karcinomi pa {ele po ve~ kot 15 letih. Petletno pre`ivetje je zato pri raku prostate v prvi vrsti merilo uspe{nosti zgodnjega odkriva- nja bolezni in ka`e na razmerja med bolniki, ki imajo ob diagnozi omejeno ali raz{irjeno bolezen, ali pa `e oddaljene zasevke. Zgodnje odkrivanje raka prostate {e vedno temelji na dolo~anju serumske koncentracije PSA. Smiselnost organiziranega zgodnjega odkrivanja s to metodo je {e vedno predmet raziskav. Dostopnost do individualne zgodnje diagnostike, dolo~anja PSA oziroma do diagnoze z biopsijo prostate in s histolo{kim pregledom biopti~nega tkiva je v Evro- pi zelo razli~na, vendar klju~na za razlike v petletnem pre`ivetju. Podatki RRS ka`ejo, da so se tudi pri nas v obdobju od 1991 do 2005 zgodile velike spremem- be. Zmanj{evanje dele`a bolnikov z razsejano boleznijo ob diagnozi na eni strani in na drugi strani ve~anje dele`a bolnikov z omejeno boleznijo ima za posledico vedno ve~je petletno pre- `ivetje. To ka`e tudi na vedno bolj dostopno in tudi uspe{no individualno zgodnje odkrivanje bolezni. Zgodnej{e odkrivanje karcinomov se ka`e tudi z relativnim in absolutnim pove~anjem {tevila novo odkritih rakov prostate pri mo{kih, starih 50–74 let. Prav odkrivanje raka pri ved- no mlaj{ih mo{kih v kon~ni fazi obeta, da se bo v prihodnosti zmanj{ala tudi specifi~na umrljivost. Ne glede na prikazano izbolj{anje pa prikazani rezultati ne dopu{~ajo, da bi bili z dose`enimi rezultati povsem zadovoljni. [e zlasti, ~e jih primerjamo s preliminarnimi poro~ili organizira- nega zgodnjega odkrivanja. V poro~ilu ERSPC (European Randomized Study of Screening for Prostate Cancer) tako navajajo, da je bilo ve~ kot 90 % primerov raka ob diagnozi omejenih na prostato (stadij T1 in T2), po drugi strani pa navajajo zgolj sporadi~ne primere `e ob diag- nozi prisotnega razsoja (v poro~ilih Rotterdama in Goeteborga je bil razsoj ugotovljen pri 6 od 1670 bolnikov). Podobna slika kot pri nas je na podro~jih, kjer je raz{irjeno individualno pre- sejanje. V regijah ZDA, ki jih pokrivajo registri raka, zdru`eni v projekt SEER (Surveillance, Epidemiology and End Results Project) ima le 4 % bolnikov ob diagnozi prisotne zasevke; 91 % bolnikov ima ob diagnozi omejeno ali podro~no raz{irjeno bolezen, za 4 % bolnikov podatki niso znani. Temu ustreza tudi 98,9 % petletno pre`ivetje bolnikov, zbolelih v letih 1996–2004. Zanimiv je tudi dokaj stalen dele` bolnikov z raz{irjeno boleznijo. Glede na metodologijo RRS so to bolniki z zasevki v podro~nih bezgavkah. Ugotavljanje stadija bolezni je pri raku prosta- te te`avno. Med standardne preiskave za zamejitev bolezni je v Sloveniji vklju~ena zgolj scintigrafija skeleta. Slikovne preiskave, s katerimi bi lahko ugotovili podro~ne zasevke, se izva- jajo le izjemoma. Nenazadnje verjetno tudi zaradi njihove nenatan~nosti. Klini~no dolo~en stadij je zato nezanesljiv in praviloma podcenjen. Podro~ni zasevki so zato ve~inoma ugotovljeni na osnovi pelvi~ne limfadenektomije. V tem primeru je glede na pribli`no 300 letno opravljenih prostatektomij po podatkih RRS pri pribli`no 120 bolnikih ugotovljen razsoj v podro~ne bezgav- ke. Dele` je presenetljivo visok glede na to, da imajo bolniki ve~inoma opravljeno standardno in ne raz{irjeno pelvi~no limfadenektomijo. Po podatkih RRS je dele` bolnikov, ki so v sklopu za~etnega zdravljenja prejeli obsevanje, nizek. Vsaj delno je bila temu vzrok zastarelost in pomanjkanje aparatov za perkutano obsevanje in za sodobno brahiradioterapijo neprimerna oprema na radiolo{kem oddelku. Razmere so se za~e- le izbolj{evati {ele po letu 2001, ko smo lahko z razpolo`ljivo opremo zadostili vsaj minimalnim standardom kakovosti perkutanega obsevanja z uvedbo 3D konformalnega obsevanja. Te`ave zaradi premajhnega {tevila obsevalnih naprav so se zmanj{ale {ele po letu 2006. [e po~asneje so se razmere izbolj{evale na oddelku za brahiradioterapijo. S prekinitvijo brahiradioterapije raka prostate v letu 2003 se je sodoben na~in obsevanja tudi pri brahiradioterapiji za~el odvi- jati {ele konec leta 2006. Z izbolj{evanjem mo`nosti obsevanja se je pove~evalo tudi {tevilo obsevanih bolnikov. V le- tih 2004 in 2005, za kateri so podatki o obsevanju dostopni tudi v elektronski obliki, je bilo obsevanih 233 bolnikov. Upo{tevani so zgolj tisti, pri katerih je bil cilj zdravljenja ozdravitev. 194 PROSTATA Rak.qxd 22.7.2009 12:39 Page 194 The data of the CRS show that in the period 1991–2005 major changes occurred in Slovenia as well. A decrease in the proportion of patients with disseminated disease at diagnosis on the one hand, and an increase in the proportion of patients with localized disease on the other, has resulted in a progressively better 5-year survival. This is indicative of a more accessible and also more successful early detection of the disease. Earlier detection of carcinomas is also reflec- ted in a relative and absolute increase in the number of newly detected prostate cancers in males aged 50–74 years. Finally, the detection of cancer in ever younger male population gives hope that in the future the specific mortality rates may decrease accordingly. Irrespective of the presented improvement, we should not be fully satisfied with the results obtained, particularly, if they are compared against the preliminary reports of organized early detection. Thus ERSPC (European Randomized Study of Screening for Prostate Cancer) reports that at the time of diagnosis more than 90% of cancers are confined to the prostate (stages T1 and T2), while cases of disseminated disease at diagnosis are reported only sporadically (in the report from Rotterdam and Goeteborg dissemination was found in 6 out of 1670 patients). A similar situation as in Slovenia is found in the regions with widely used individual screen- ing. In the USA regions covered by cancer registries joined in the SEER project (Surveillance, Epidemiology and End Results Project) only 4% of patients present with metastases at diag- nosis; 91% of patients have localized or regional disease at diagnosis while the relevant data for 4% of patients are not available. This is consistent with 98.9% 5-year survival of patients diagnosed in the period 1996–2004. The relatively stable proportion of patients with regional disease is interesting too. According to the methodology of the CRS, these are the patients with regional lymph node metastases. Staging of prostate cancer is difficult. In Slovenia, the standard procedures for staging of the disease include only bone scintigraphy. Imaging methods for the detection of regional metas- tases are applied only exceptionally, a possible reason for that being their inaccuracy. Clinically determined stage is therefore unreliable and generally underestimated. Thus, regional metas- tases are mostly determined on the basis of pelvic lymphadenectomy. In this case, according to the data of the CRS, in approximately 300 prostatectomies performed yearly, dissemina- tion into regional lymph nodes is found in some 120 patients. The proportion is surprisingly high in view of the fact that most patients underwent a standard rather than an extended pelvic lymphadenectomy. According to the CRS data, the proportion of patients receiving radiotherapy as part of their primary treatment is low. This is at least to a certain extent attributable to the obsolete and lacking devices for percutaneous irradiation and the existing equipment at brachytherapy depart- ment that is not in compliance with modern standards. The situation started to improve only after the year 2001, when the available equipment fulfilled at least minimum quality require- ments for percutaneous irradiation by means of 3D conformal irradiation. Problems due to an insufficient number of irradiation machines became less evident only after 2006. At the brachyra- diotherapy department the improvement was even slower. By the interruption of brachyradiotherapy of prostate cancer in 2003, up-to-date irradiation techniques in brachyradiotherapy started to be used only in the end of 2006. With the improvement of radiation facilities, the number of irradiated patients increased as well. In the years 2004 and 2005, for which the data on irradiation treatment are available in electron- ic form too, 233 patients received radiotherapy. Only those treated with curative intent were considered. Owing to the above mentioned reasons, all those patients were treated exclusively with per- cutaneous irradiation. In 210 of total 233 patients irradiation was the only form of local treatment while the rest of them were irradiated after previous prostatectomy. It is interesting to note, just in two years, an increase in the number of patients treated with the combination of prosta- tectomy and irradiation, where radiotherapy was applied either immediately after prostatectomy 195 PROSTATE Rak.qxd 22.7.2009 12:39 Page 195 Vsi so bili zaradi `e omenjenih razlogov zdravljeni izklju~no s perkutanim obsevanjem. Pri 210 (od 233) bolnikih je bilo obsevanje edina oblika lokalnega zdravljenja, ostali pa so bili obse- vani po predhodni prostatektomiji. Zanimivo je, da `e v teh dveh letih lahko ugotovimo porast {tevila bolnikov, ki so zdravljeni s kombinacijo prostatektomije in obsevanja, bodisi z obseva- njem neposredno po prostatektomiji bodisi ob biokemi~ni ponovitvi in/ali lokalnem recidivu. ^e upo{tevamo zgolj leti 2004 in 2005, lahko ugotovimo, da se bolniki v Sloveniji le nekoli- ko manj pogosto odlo~ajo za zdravljenje z obsevanjem kot drugod po Evropi oziroma v ZDA. V tem dveletnem obdobju bolnikom sicer nismo nudili mo`nosti obsevanja z brahiradiotera- pijo, vendar sedanje izku{nje po ponovni uvedbi brahiradioterapije konec leta 2006 ka`ejo, da se {tevilo obsevanih bolnikov tudi z uvedbo brahiradioterpije ni bistveno pove~alo. Razlog za to je najverjetneje, da mo`nosti zdravljenja predstavi bolniku urolog in le izjemoma multidis- ciplinarni konzilij. Albertsen PC, Hanley J, Fine J. Twenty year outcome following conservative management of clinically localized prostate cancer. JAMA 2005, 293: 2095–101. Bill-Axelson A, Holmberg L, Ruutu M. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2005; 352: 1977–84 Collin SM, Martin RM, Metcalfe C. prostate-cancer mortality in the USA and UK in 1975–2004: an ecologi- cal study. Lancet Oncol 2008; 9: 445–52. Loblaw DA, Virgo KS, Nam R. Initial hormonal management of androgen – sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an American society of Clinical Oncology practice guideline. J Clin Oncol 2007; 25: 1569–605. Messing EM, Manola J, Sarosdy M. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node positive prostate cancer. N Engl J Med 1999; 341: 1781–8. Murai M, Barry M. Epidemiology and natural history of bladder cancer. In: McConnell J, Denis L, Akaza H, Khoury S, Schalken J, eds. Prostate cancer. Editions 21, Paris 2006: 37–54. Roobol MJ, Grenabo A, Schroeder FH. Interval cancers in prostate cancer screening: comparing 2 and 4 year screening intervals in European Randomized Study of Screening for Prostate Cancer, Gothenburg and Rotterdam. 2007. Studer UE, Colette L, Whelan P . Using PSA to guide timing of androgen deprivation in patients with T0-4, N0-2 M0 prostate cancer not suitable for local curative treatment (EORTC 30981). Eur Urol 2008; 53: 941–9. 196 PROSTATA KLINI^NI KOMENT AR Tanja ^ufer Rak prostate postaja vedno pogosteje odkriti rak pri mo{kih. Incidenca bolezni se po svetu in pri nas strmo ve~a. Medtem ko je bila leta 1990 starostno standardizirana inciden~na stopnja v Sloveniji 32,5/100.000, je bila leta 2005 `e 84,8/100.000. Mnoge evropske dr`ave, {e zlasti pa ZDA, imajo {e veliko ve~jo inciden~no stopnjo tega raka. Tako velik porast incidence raka prostate je pripisati oportunisti~nemu presejanju z dolo~anjem PSA v krvi pri mo{kih, starih 50 let in ve~. Velik dele` tako odkritega raka prostate je biolo{ko malo agresiven, ne povzro~a te`av in ne ogro`a `ivljenja. Posledica tega je strm porast incidence, medtem ko se umrljivost za rakom prostate ob vedno bolj{em pre`ivetju tako v Evropi kot v ZDA zmanj{uje. In kako je pri nas? Ob pri~akovanem mo~nem porastu incidence se umrljivost za rakom pro- state pri nas `al {e vedno ve~a. Umrljivost za rakom prostate je v Sloveniji precej ve~ja kot v Evropi. Tudi petletno pre`ivetje bolnikov z rakom prostate je pri nas za okoli 15 % manj{e kot v Evropi. To velja tako za obdobje raziskave EUROCARE-3, ki zajema obdobje 1990–1994, kot tudi za kasnej{e obdobje, zajeto v raziskavo EUROCARE-4. Bolniki, zboleli pri nas v letih 2000–2002, so imeli 63-odstotno petletno relativno pre`ivetje, medtem ko je bilo evropsko povpre~je 80 %. Tako 3-, 5- kot {e bolj 10-letno pre`ivetje bolnikov se pri nas sicer pove~uje, `al pa ostaja razkorak med na{imi in evropskim povpre~jem enako velik. V zadnjem obdobju tudi pri nas odkrivamo VIRI Literature Rak.qxd 22.7.2009 12:39 Page 196 or at biochemical and/or local recurrence. Taking into account only the years 2004 and 2005, it turns out that the patients in Slovenia decide for radiotherapy slightly less often than else- where in Europe or in the USA. In this two-year period the patients were not offered the possibility of treatment with brachyradiotherapy, however the experience after reintroducing brachyradiotherapy in 2006 has shown that even then the number of irradiated patients has not increased significantly. In all probability the reason lies in the fact that the patient learns about treatment possibilities from an urologist and only exceptionally from a multidisciplinary team of experts. 197 PROSTATE CLINICAL COMMENT ARY Tanja ^ufer Prostate cancer is nowadays ever more frequently detected cancer in males. The incidence of this disease in the world as well as in Slovenia is rapidly increasing. While in 1990 the age-stan- dardized incidence rate in Slovenia was 32.5/100,000, in the year 2005 it was already 84.8/100,000. Many European countries, and in particular the USA, face an even higher incidence rates of this cancer. Such a high increase in the incidence of prostate cancer can be ascribed to the oppor- tunistic screening by PSA determination in the blood in males aged 50 years or older. A large proportion of prostate cancers detected in this way are of low-grade malignancy, do not cause any difficulties and are not a life-threatening disease. As a result, the incidence increases rap- idly but the mortality due to prostate cancer is on decline in some parts of Europe as well as in the USA, due to better survival rates. And what is the situation in Slovenia? Along with the expected high increase in the incidence, unfortunately the prostate cancer related mortality in Slovenia is still increasing. Thus prostate cancer mortality rates in Slovenia are much higher than elsewhere in Europe. The 5-year sur- vival of prostate cancer patients in our country is by approximately 15% lower than in other European countries. This applies to the time of EUROCARE-3 study, which covers the peri- od 1990–1994, as well as to the later period of EUROCARE-4 study. Patients diagnosed in Slovenia in the years 2000–2002 had 63% 5-year relative survival while the European avera- ge was 80%. Although in Slovenia the 3-, 5- and particularly the 10-year survival of patients is increasing, unfortunately its lagging behind the European average is not getting any lesser. In the last period also in our country more and more cancers are detected in a localized stage, however the absolute numbers of patients with regional or disseminated disease are increas- ing rather than decreasing. No improvement in the survival can be expected without advances in the treatment of regional and disseminated disease. In the last period, the 5-year survival of patients with localized and regional stages has increased; thus the 5-year survival of patients with regional disease has increased from 69% in the peri- od 1996–2000 to 80% in the period 2001–2005. However, the 5-year survival of patients with disseminated disease has even decreased. This is indicative of a relatively adequate treatment of lower stages of prostate cancer but not also of disseminated disease. In the former, a local surgical and/or irradiation therapy plays an important role, which is obviously adequate in our case. However, in locally advanced and particularly in disseminated disease hormone therapy is of crucial importance. In a majority of patients with regional or even disseminated disease a well managed hormone therapy may result in long lasting remissions and a relatively high 5-year survival rates. If we are to increase the survival of prostate cancer patients, more atten- tion should be attributed to well managed hormone therapy of this disease. Minor improvement in the survival may be expected by introducing cytostatic therapy for hormone-independent prostate cancer. It is fact however, that a great majority of prostate cancers are hormone-depen- dent in the beginning of treatment and that such treatment may result in several years of remission. Therefore all our efforts should be directed into improving this treatment approach. Rak.qxd 22.7.2009 12:39 Page 197 vse ve~ raka v omejenem stadiju, `al pa se {tevilo bolnikov z raz{irjeno ali razsejano boleznijo v absolutnem {tevilu ne zmanj{uje, ampak se celo ve~a. Brez napredka v zdravljenju raz{irje- ne in razsejane bolezni ni pri~akovati ve~jega pre`ivetja. V zadnjem obdobju se je sicer petletno pre`ivetje bolnikov z omejenim in raz{irjenim stadi- jem bolezni pove~alo; petletno pre`ivetje bolnikov z raz{irjenim stadijem se je pove~alo s 69 % v obdobju 1996–2000 na 80 % v obdobju 2001–2005. @al pa se je pri nas zmanj{alo petletno pre`ivetje bolnikov z razsejano boleznijo. To ka`e na dokaj ustrezno zdravljenje ni`jih stadi- jev raka prostate, ne pa razsejane bolezni. V prvem primeru je pomembno lokalno kirur{ko in/ali obsevalno zdravljenje, ki je o~itno pri nas ustrezno. Pri lokalno raz{irjeni in {e v ve~ji meri pri razsejani bolezni pa je izrednega pomena hormonsko zdravljenje raka prostate. Z dobro vode- nim hormonskim zdravljenjem je pri veliki ve~ini bolnikov z raz{irjeno ali celo razsejano boleznijo mogo~e dose~i ve~letne zazdravitve in razmeroma veliko petletno pre`ivetje. ^e `elimo pri nas pove~ati pre`ivetje bolnikov z rakom prostate, moramo ve~ pozornosti nameniti dobro vode- nemu hormonskemu zdravljenju te bolezni. Z uvajanjem citostatskega zdravljenja hormonsko neodzivnega raka prostate sicer lahko pri~akujemo manj{e izbolj{anje pre`ivetja. Dejstvo pa je, da je velika ve~ina raka prostate v za~etku zdravljenja hormonsko odvisnih in da je s tem zdravljenjem mogo~e dose~i ve~letno zazdravitev, zato je treba vse napore usmeriti v izbolj{a- nje tega zdravljenja. Tako v svetu kot pri nas je predvsem slabo pre`ivetje starej{ih bolnikov, starih 75 let in ve~. Medtem ko so se relativna petletna pre`ivetja mlaj{ih bolnikov pove~ala, se pre`ivetje bolnikov, starih 75 let in ve~, prakti~no ne pove~uje. Zdravljenju starej{ih bolnikov bo zato v prihodno- sti potrebno posvetiti ve~ pozornosti. Bor{tnar S, ^ufer T. Zdravljenje hormonsko neodvisnega raka prostate. Onkologija 2006; 10: 50–53. Ferlay J, Autier P , Boniol M, Heanue M, Colombet M, Boyle P . Estimates of the cancer incidence and morta- lity in Europe in 2006. Ann Oncol 2007; 18: 581–92. Seidenfeld J, Samson JD, Hasselblad V, Aronson N, Albertsen PC, Bennett CL, et al. Single-therapy andro- gen supression in men with advanced prostate cancer: A systematic review and meta-analysis. Ann Intern Med 2000; 132: 566–77. 198 PROSTATA VIRI Literature Rak.qxd 22.7.2009 12:39 Page 198 In the world as well as in Slovenia particularly poor survival is observed in patients aged 75 years or older. While the 5-year relative survivals of younger patients increased during the last years, there is practically no improvement in the survival of patients aged 75 years or older. Therefore, in the future more attention should be paid to the treatment of older patients. 199 PROSTATE Rak.qxd 22.7.2009 12:39 Page 199 V obdobju 1991–2005 je za rakom mod zbolelo 1129 mo{kih. Kot je razvidno s Slike 1, se groba in starostno standardizirana inciden~na stopnja ves ~as opazovanja pove~ujeta, groba stopnja povpre~no za 4,7 % letno. Ker ve~ina mo{kih zboli pred 50. letom starosti, je starostno stan- dardizirana stopnja ve~ja od grobe. Vsako leto umre le nekaj bolnikov z rakom mod; ~asovna trenda obeh umrljivostnih stopenj sta zato stabilna, njune vrednosti pa le okrog 1/100.000. MODO MKB 10: C62 200 0 2 4 6 8 10 12 1986 1990 1995 2000 2005 Leto / Year Incidenca – groba stopnja / Incidence – crude rate Incidenca – SSS* / Incidence – ASR** Umrljivost – groba stopnja / Mortality – crude rate Umrljivost – SSS* / Mortality – ASR** Stopnja na 100.000 / Rate per 100,000 * SSS – starostno standardizirana stopnja (standard – slovenska populacija leta 1986) ** ASR – age standardized rate (standard Slovenian population in 1986) Slika 1: Groba in starostno standardizirana inciden~na in umrljivostna stopnja raka mod, Slovenija 1986–2005. Figure 1: Crude and age-standardized incidence and mortality rate of testicular cancer, Slovenia 1986–2005. Mo{ki / Males Obdobje / {tevilo / 20–49 let / 50–74 let / 75+ let / Period number years (%) years (%) years (%) 1991–1995 262 93,1 6,1 0,8 1996–2000 365 92,9 7,1 0,0 2001–2005 448 94,9 5,1 0,0 Tabela 1: [tevilo bolnikov z rakom mod po obdobju postavitve diagnoze ter njihovi dele`i po starosti. Table 1: Number of testicular cancer patients by period of diagnosis with their proportions by age. V analizo pre`ivetja je vklju~enih 1075 primerov; 4 primeri (0,4 %) niso upo{tevani, ker jim je bila diagnoza postavljena po smrti, 50 mlaj{ih od 20 let pa obravnavamo v poglavju o pre`i- vetju pri otrocih in mladostnikih. V obdobju 1996–2005 so bili mikroskopsko potrjeni vsi primeri; le dva primera iz obdob- ja 1991–1995 nista imela mikroskopske potrditve. V celotnem obdobju je imelo 48 % bolnikov seminom, 21 % me{ani tumor kli~nih celic, 11 % embrionalni karcinom ter po 7 % teratokar- cinom in horiokarcinom. Ostale histolo{ke vrste so bile redke. V zadnjih letih se ve~a dele` me{anih tumorjev kli~nih celic in horiokarcinomov, manj{a pa se dele` embrionalnih karci- nomov in teratokarcinomov; dele` seminomov ostaja ves ~as opazovanja pribli`no enak. EPIDEMIOLOGIJA Rak.qxd 22.7.2009 12:39 Page 200 In the period 1991–2005, a total of 1129 males were diagnosed with testicular cancer. As evi- dent from Figure 1, the crude and age-standardized incidence rates have been increasing. The estimated annual percentage increase in crude incidence rate was 4.7%. As the majority of patients are diagnosed before 50 years of age, the age-standardized rate is higher than the crude rate. Every year there are only few deaths due to testicular cancer. Therefore, the time trends of both mortality rates are stable, their values ranging around 1/100,000. The survival analysis included 1075 cases; 4 cases (0.4%) diagnosed only after death were not considered in the analysis, 50 patients less than 20 years of age are presented in the chapter on the survival of children and adolescents. In the period 1996–2005, all the cases were microscopically verified, while in the period 1991–1995 only two cases lacked microscopic confirmation. In the total observation period, 48% of patients had seminoma, 21% mixed germ-cell tumors, 11% embryonal carcinoma, while teratocarci- noma and choriocarcinoma was found in 7% of patients each. Other histological types were rare. In recent years, the proportion of mixed germ-cell tumors and choriocarcinomas has been increasing while the proportion of embryonal carcinomas and teratocarcinomas exhibited a down- ward trend; the proportion of seminomas has remained practically the same throughout the observation period. The majority of patients were diagnosed before 50 years of age, approximately 6% were diag- nosed at an age between 50–74 years; in the whole observation period there were only two patients who developed the disease aged 75 years or older (Table 1). The majority of patients are diagnosed with localized disease, in the last period their propor- tion being 58% (Table 2). In the latter period 2001–2005, one third of patients had regional and 9% disseminated disease at diagnosis; the proportion of patients with disseminated stage has been decreasing with time. In the whole observation period only 6 patients did not receive specific treatment. Among the patients receiving specific treatment in the period 2001–2005, 78% were treated by surgery and chemotherapy, 19% underwent surgery only, while the rest were irradiated in addition to surgery and chemotherapy. In the period 2001–2005, 48% started their treatment in the UMC Ljubljana, 16% in the UMC Maribor and 12% in the GH Celje. Individual patients started their treatment in other Slo- venian general hospitals and at the IO Ljubljana. Practically all patients (99%), irrespective of the hospital of their initial treatment, were in the course of their primary treatment referred to the IO Ljubljana. TESTIS ICD 10: C62 201 Tabela 2: [tevilo bolnikov z rakom mod po obdobju postavitve diagnoze ter njihovi dele`i po stadiju. Table 2: Number of testicular cancer patients by period of diagnosis with their proportions by stage. Mo{ki / Males Obdobje / {tevilo / omejen / raz{irjen / razsejan / neznan / Period number localized regional distant unknown (%) (%) (%) (%) 1991–1995 262 46,6 40,1 12,6 0,8 1996–2000 365 57,3 27,4 15,3 0,0 2001–2005 448 57,6 33,3 8,5 0,7 EPIDEMIOLOGY Rak.qxd 22.7.2009 12:39 Page 201 Ve~ina bolnikov je zbolela pred 50. letom starosti, 6 % jih je bilo ob diagnozi starih med 50 in 74 let; v vsem opazovanem obdobju sta le dva bolnika zbolela v starosti 75 let in ve~ (Tabela 1). Najve~ bolnikov ima ob diagnozi omejen stadij bolezni; v zadnjem obdobju je bilo teh bolnikov 58 % (Tabela 2). V obdobju 2001–2005 je bila pri tretjini bolnikov ob diagnozi bolezen v raz- {irjenem stadiju, pri 9 % pa v razsejanem; dele` bolnikov z razsejanim stadijem se s ~asom manj{a. V vsem opazovanem obdobju le 6 bolnikov ni bilo specifi~no zdravljenih. Med specifi~no zdrav- ljenimi je bilo v letih 2001–2005 78 % bolnikov zdravljenih z operacijo in kemoterapijo, 19 % jih je bilo samo operiranih, ostali so bili poleg operacije in kemoterapije {e obsevani. V obdobju 2001–2005 se je 48 % bolnikov za~elo zdraviti v UKC Ljubljana, 16 % v UKC Mari- bor in 12 % v SB Celje. Posamezne bolnike so pri~eli zdraviti {e v ostalih slovenskih splo{nih 202 MODO 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Slika 2: Deset-, pet-, tri- in enoletno relativno pre`ivetje bolnikov z rakom mod po obdobju postavitve diagnoze. Figure 2: 10-, 5-, 3- and 1-year relative survival of testicular cancer patients by period of diagnosis. Tabela 3: Opazovano in relativno pre`ivetje bolnikov z rakom mod po obdobju postavitve diagnoze s 95- odstotnim intervalom zaupanja (IZ). Table 3: Observed and relative survival of testicular cancer patients by period of diagnosis with 95% confi- dence interval (CI). Opazovano pre`ivetje / Observed survival (%) Mo{ki / Males Obdobje / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 97,7 (95,9–99,5) 94,3 (91,5–97,1) 93,5 (90,6–96,5) 1996–2000 97,3 (95,6–98,9) 95,3 (93,2–97,5) 94,2 (91,9–96,7) 2001–2005 96,9 (95,3–98,5) 94,2 (92,0–96,4) 93,4 (91,1–95,9) Relativno pre`ivetje / Relative survival (%) Mo{ki / Males Obdobje / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 98,1 (96,3–100,0) 95,4 (92,5–98,3) 95,2 (92,1–98,2) 1996–2000 97,5 (95,8–99,2) 96,0 (93,8–98,2) 95,7 (93,2–98,1) 2001–2005 97,1 (95,5–98,8) 95,0 (92,8–97,2) 95,0 (92,5–97,5) Rak.qxd 22.7.2009 12:39 Page 202 In the last 15 years, the relative survival rate of patients with testicular cancer is not increa- sing any more: in all three observation periods the 5-year relative survival ranged around 95% (Figure 2, Table 3). In the period 2001–2005, all patients with localized stage at diagnosis sur- vived 5 years; among the patients with regional disease and those with disseminated disease there were 96% and 55% of 5-year survivors respectively (Figure 3). The estimation of nega- tive time trend in the 5-year relative survival of patients with disseminated stage is not reliable due to a small number of patients. Age is not a relevant prognostic factor of survival in patients with testicular cancer (Figure 4). The 5-year relative survival of all patients diagnosed in the period 2001–2005 was 95% (Figure 2); patients surviving the first year may expect to survive five years in 98%. According to the results of EUROCARE-4 study for patients diagnosed in 2000–2002, the crude 5-year relative survival of Slovenian patients with testicular cancer was nearly equal to the European average (Figure 5). 203 TESTIS 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 Omejen / Localized Raz{irjen / Regional Razsejan / Distant Vsi / All Slika 3: Petletno relativno pre`ivetje bolnikov z rakom mod po stadiju in obdobju postavitve diagnoze. Figure 3: 5-year relative survival of testicular cancer patients by stage and period of diagnosis. 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 20–49 let / years 50–74 let / years 75+ let / years Vsi / All Slika 4: Petletno relativno pre`ivetje bolnikov z rakom mod po starosti in obdobju postavitve diagnoze. Figure 4: 5-year relative survival of testicular cancer patients by age and period of diagnosis. Rak.qxd 22.7.2009 12:39 Page 203 bolni{nicah in na OI Ljubljana. Skoraj vsi bolniki (99 %), ne glede na bolni{nico za~etka zdrav- ljenja, pa so bili v okviru prvega zdravljenja obravnavani na OI Ljubljana. Relativno pre`ivetje bolnikov z rakom mod se v zadnjih 15 letih ne pove~uje ve~; petletno rela- tivno pre`ivetje je v vseh obdobjih okrog 95 % (Slika 2, Tabela 3). Med leti 2001–2005 so pet let pre`iveli vsi bolniki z omejenim stadijem bolezni ob diagnozi, 96 % tistih z raz{irjeno bolezni- jo in 55 % bolnikov z razsejanim stadijem (Slika 3). Vrednotenje negativnega ~asovnega trenda petletnega relativnega pre`ivetja bolnikov z razsejanim stadijem pa ni zanesljivo, saj je bolnikov malo. Starost ni pomemben napovedni dejavnik pre`ivetja bolnikov z rakom mod (Slika 4). Petletno relativno pre`ivetje vseh zbolelih v obdobju 2001–2005 je bilo 95 % (Slika 2); bolni- ki, ki pre`ivijo prvo leto, pa lahko pri~akujejo 98-odstotno petletno relativno pre`ivetje. Rezultati {tudije EUROCARE-4 za zbolele v obdobju 2000–2002 ka`ejo, da je grobo petlet- no relativno pre`ivetje slovenskih bolnikov z rakom mod skoraj enako evropskemu povpre~ju (Slika 5). 204 MODO KLINI^NI KOMENT AR Breda [krbinc Tumorji mod sodijo v skupino redkih vrst raka (1–2 % vseh vrst raka pri mo{kih), vendar se incidenca te bolezni v »razvitem« svetu strmo ve~a; to velja tudi za Slovenijo. Vzrok za to ni povsem pojasnjen, kot vzro~ni dejavnik veljajo {e neodkriti dejavniki v okolju, ki v ~asu intrau- terinega razvoja in verjetno tudi kasneje vplivajo na krhko hormonsko ravnovesje, potrebno za normalen razvoj gonad. Tumorji mod so v {tevilnih pogledih edinstvena vrsta raka. Pojavljajo se prete`no pri mladih mo{kih (najpogosteje med 18. in 30. letom starosti), njihova osnovna zna~ilnost je, da so prak- ti~no ozdravljivi. V fazi omejene bolezni je ozdravljivost skoraj 100 %, v raz{irjeni in zgodnji razsejani fazi preko 80 %, tudi {e v kasni razsejani fazi je bolezen potencialno ozdravljiva, ven- dar se mo`nost ozdravitve z napredovanjem bolezni pomembno manj{a. Bistvenega pomena za dober uspeh zdravljenja te vrste raka v vseh fazah bolezni je dobro sodelovanje bolnikov z brez- hibno usklajenim multidisciplinarnim timom izku{enih strokovnjakov, usmerjenih v zdravljenje raka mod. Skupno pre`ivetje bolnikov, zbolelih za rakom mod v obdobju 2001–2005, kakor tudi pre`ivetje podskupin bolnikov z omejeno in raz{irjeno obliko bolezni, je bilo v Sloveniji optimalno, v razsejani fazi bolezni pa analiza ka`e trend upadanja pre`ivetja glede na prete- klo desetletje. V tem petletnem obdobju smo zdravili bistveno manj bolnikov z razsejanim rakom mod (relativno in absolutno) kot v prej{njih dveh petletnih obdobjih (Tabela 3), kar govori v prid vedno bolj{e ozave{~enosti Slovencev o tej vrsti raka. Ravno zaradi majhnega {tevila bolnikov z razsejano boleznijo pa je trend upadanja te`ko ovrednotiti. Dejstvo je, da je skupina bolnikov z razsejano obliko bolezni zelo nehomogena. Bolniki z raz- sejanim rakom mod so v klasifikacijah, ki jih v klini~ni praksi uporabljamo za na~rtovanje intenzitete zdravljenja, razvr{~eni v dobro, srednje dobro in slabo napovedno skupino z bis- tveno razli~nimi mo`nostmi ozdravitve. Mo`nosti ozdravitve so bistveno ve~je, ~e imajo bolniki zasevke le v plju~ih in bezgavkah (okrog 80 % verjetnost ozdravitve), ne pa tudi v drugih vis- ceralnih organih, kosteh in centralnem `iv~evju; na mo`nosti ozdravitve pa deloma vpliva tudi histolo{ka vrsta tumorja mod. Podatka, kak{na je bila sestava bolnikov glede na napovedne skupine in histolo{ko vrsto, nimamo. Mo`no je, da smo v zadnjem petletnem obdobju zdravili soraz- merno ve~ji dele` bolnikov z napovedno slab{o obliko razsejanega raka mod. Druga, zopet {pekulativna mo`nost, ki bi po vseh merilih lahko tudi vplivala na pre`ivetje bolnikov z razse- janim rakom mod, je kadrovska in organizacijska turbulenca, ki je po upokojitvi ve~ dolgoletnih izku{enih ~lanov tima za zdravljenje bolnikov z rakom mod zaznamovala preteklo petletno obdobje. [e dodatna, zopet {pekulativna mo`nost razlage negativnega trenda pre`ivetja bol- nikov z razsejanim rakom mod pa bi lahko bila, da se analogno s skokovitim porastom incidence Rak.qxd 22.7.2009 12:39 Page 204 Testicular tumors belong to the group of rare cancers (1–2% of all cancers in males). However the incidence in the developed world as well as in Slovenia is on a steep increase. The reason for that has not been fully explained yet, but it is presumed that so far unidentified environ- mental factors in the course of intrauterine development, and possibly also later on, may influence the sensitive hormone balance which is a prerequisite for a normal development of the gonads. In many respects, testicular tumors are a unique type of cancer. It occurs prevailingly in young males (most frequently at an age between 18 and 30 years), their main feature being that they are virtually curable. In the stage of localized disease the cure rate is almost 100%, while in the stage of regional spread and early dissemination is over 80%; even in the stage of late dis- semination the disease remains potentially curable, however, with further progression of the disease the chances of cure are getting significantly smaller. A good cooperation of the patient with a well-coordinated multidisciplinary team of experts experienced in testicular cancer treat- ment is of essential importance for a favorable treatment outcome in all stages of this disease. Overall survival of patients diagnosed with testicular cancer in the period 2001–2005, as well as the survival of subgroups of patients with localized and regional stages of the disease in Slovenia was optimal, while in the disseminated stage, the analysis indicated a downward trend in the survival in comparison with the past decade. In the last 5-year period the number of patients treated for disseminated testicular cancer (relative and absolute) was significantly lower than in the previous two 5-year periods (Table 3), which is indicative of a greater awareness of this cancer among the Slovenian population. The very small number of patients with dissemina- ted disease renders the downward trends difficult to evaluate. As a matter of fact, the group of patients with disseminated disease is very heterogeneous. In the classification systems used in clinical practice for planning treatment intensity, patients with testicular cancer are distributed into groups with good, moderately good and poor prognosis, with significantly different chances of cure. The chances of cure are significantly higher if the patient presents with metastases in the lung and lymph nodes only (the chance of cure is around 80%) and not also in other visceral organs, bones and the central nervous system; besides, the pos- sibility of cure is partly also influenced by tumor histological type. Information on the composition 205 TESTIS CLINICAL COMMENT ARY Breda [krbinc 01 02 0 30 40 50 60 70 80 90 100 % Slovensko povpre~je / 2000–2002 (EUROCARE-4) Slovenian average Evropsko povpre~je / 2000–2002 (EUROCARE-4) European average Povpre~je ZDA / 2000–2002 (SEER-13) USA average Slika 5: Petletno relativno pre`ivetje bolnikov z rakom mod (povpre~e in 95-odstotni interval zaupanja), zbolelih v letih 2000–2002 v Sloveniji, Evropi in nekaterih obmo~jih v ZDA. Figure 5: 5-year relative survival of testicular cancer patients (average and 95% confidence interval) diagnosed in the period 2000–2002 in Slovenia, Europe and in some regions of the USA. Rak.qxd 22.7.2009 12:39 Page 205 raka mod spreminjajo tudi lastnosti te vrste raka, ki lahko postaja manj ob~utljiv na standard- ne oblike zdravljenja, v prvi vrsti na kemoterapijo. Gledano v celoti je v zadnjem petletnem obdobju uspeh zdravljenja bolnikov z rakom mod dober, {e posebej v skupini z dobro in srednje dobro napovedjo izida bolezni; ocena manj{anja pre- `ivetja bolnikov s slabo napovedjo izida pa je zaradi majhnega {tevila bolnikov v tej skupini nezanesljiva. Vseeno pa je treba v naslednjem obdobju posvetiti posebno pozornost tej skupi- ni bolnikov, da jim nudimo vse dostopne mo`nosti za ozdravitev. Huddart RA, O'Doherty MJ, Padhani A, Rustin GJS, Mead GM, Johnathan K. Joffe JK, et al. Fluorodeoxy- glucose positron emission tomography in the prediction of relapse in patients with high-risk, clinical stage I nonseminomatous germ cell tumors: preliminary report of MRC trial TE22 – the NCRI testis tumour clinical study group. JCO 2007; 25: 3090–5. Martin OV, Shialis T, Lester JN, Scrimshaw MD, Boobis AR, Voulvoulis N. Testicular dysgenesis syndrome and the estrogen hypothesis: a quantitative meta-analysis. Environmental Health Perspectives 2008; 116: 149–57. Pont J, Höltl W. Keimzelltumoren des Mannes. Bremen: UNI MED Verlag, 2004. Schmoll HJ, Souchon R, Krege S, Albers P , Beyer J, Kollmannsberger C, et al. European consensus on diagnostis and treatment of germ cell cancer: a report of the European German Cell Cancer Consensus Group (EGCCCG). European urology 2008; 53: 497–513. 206 MODO VIRI Literature Rak.qxd 22.7.2009 12:39 Page 206 of patients with respect to the prognostic groups and histological type is not available in cur- rent analysis. It is possible that in the last 5-year period we treated a greater proportion of patients with prognostically less favorable type of disseminated testicular cancer. The other, hypothe- tic possibility that might by all criteria also influence the survival of patients with disseminated testicular cancer is associated with staff and organizational turbulence which marked the past 5-year period, after a number of experienced and long-standing members of the team for tes- ticular tumor treatment had retired. Yet another, also a hypothetic explanation of the downward trend in the survival of patients with disseminated testicular cancer could be that along with the rapid increase in the incidence of testicular cancer the properties of this cancer have been changing too; thus it may become less sensitive to standard modalities of treatment, in par- ticular to chemotherapy. On the whole, in the last 5-year period the success of treatment in patients with testicular can- cer is good, particularly in the group with favorable or moderately favorable prognosis; the evaluation of a decrease in the survival of patients with poor prognosis is unreliable due to a small number of patients in this group. Nevertheless, in the future, particular attention should be devoted to this group of patients in order to offer them all the available options for cure. 207 TESTIS Rak.qxd 22.7.2009 12:39 Page 207 V obdobju 1991–2005 je za ledvi~nim rakom zbolelo 3093 ljudi, od tega 1869 mo{kih in 1224 `ensk. Kot je razvidno s Slike 1, se groba in starostno standardizirana inciden~na stopnja od leta 1991 ve~ata, groba stopnja povpre~no za 4,8 % letno, starostno standardizirana pa za 3,1 %. Prav tako se ve~ata obe umrljivostni stopnji, groba povpre~no za 4,0 % letno, starostno standardizirana pa povpre~no za 2,0 % letno. LEDVICA MKB 10: C64, C65 208 0 2 4 6 8 10 12 14 16 1986 1990 1995 2000 2005 Leto / Year Incidenca – groba stopnja / Incidence – crude rate Incidenca – SSS* / Incidence – ASR** Umrljivost – groba stopnja / Mortality – crude rate Umrljivost – SSS* / Mortality – ASR** Stopnja na 100.000 / Rate per 100,000 * SSS – starostno standardizirana stopnja (standard – slovenska populacija leta 1986) ** ASR – age standardized rate (standard Slovenian population in 1986) Slika 1: Groba in starostno standardizirana inciden~na in umrljivostna stopnja ledvi~nega raka, Slovenija 1986–2005. Figure 1: Crude and age-standardized incidence and mortality rate of kidney cancer, Slovenia 1986–2005. Mo{ki / Males @enske / Females Obdobje / {tevilo / 20–49 let / 50–74 let / 75+ let / {tevilo / 20–49 let / 50–74 let / 75+ let / Period number years (%) years (%) years (%) number years (%) years (%) years (%) 1991–1995 419 17,2 70,2 12,6 337 11,6 72,1 16,3 1996–2000 614 14,5 72,6 12,9 372 11,3 70,2 18,5 2001–2005 752 14,5 69,4 16,1 433 12,0 59,4 28,6 T abela 1: [tevilo bolnikov z ledvi~nim rakom po spolu in obdobju postavitve diagnoze ter njihovi dele`i po starosti. Table 1: Number of kidney cancer patients by sex and period of diagnosis with their proportions by age. V analizo pre`ivetja je vklju~enih 2927 primerov; 166 bolnikov (5,7 %) nismo upo{tevali, ker jim je bila diagnoza postavljena po smrti. Odstotek mikroskopsko potrjenih primerov se je zmanj{al z 90 % v letih 1991–1995 na 86 % v letih 2001–2005. V zadnjem obdobju je bilo 75 % adenokarcinomov, 9 % drugih opredeljenih histolo{kih vrst, 15 % malignomov pa ni imelo opredeljene histolo{ke vrste. V primerjavi s pr- vim obdobjem se je v zadnjem dele` histolo{ko neopredeljenih tumorjev pove~al za 4 %. Starost najve~jega dele`a zbolelih je bila ob diagnozi med 50–74 leti. Pred 50. letom zboli manj kot 15 % bolnikov (Tabela 1). Predvsem pri `enskah se s ~asom ve~a dele` starih 75 let in ve~, manj{a pa dele` starih 50–74 let. EPIDEMIOLOGIJA Rak.qxd 22.7.2009 12:39 Page 208 In the period 1991–2005, a total of 3093 persons were diagnosed with kidney cancer, of these 1869 males and 1224 females. As evident from Figure 1, the crude and age standardized inci- dence rates have been increasing since 1991, the crude rate by 4.8% and the age-standardized rate by 3.1% annually on average. The mortality rates have been increasing as well, the crude rate by 4.0% and the age standardized by 2.0% annually on average. The survival analysis included 2927 cases; 166 patients (5.7%) diagnosed only after death, were not considered in the analysis. The percentage of microscopically confirmed cases decreased from 90% in the period 1991–1995 to 86% in the period 2001–2005. In the last period, 75% were adenocarcinomas and 9% other defined histological types while in 15% of malignomas histological type was not determined. In comparison with the first period, in the last one the proportion of histologically undefined tumors increased by 4%. Age of the majority of patients at diagnosis ranged between 50 and 74 years. Less than 15% of patients will develop the disease before the age of 50 (Table 1). Particularly in females, the proportion of patients aged 75 years or older is increasing with time, while the proportion of those at an age between 50–74 years is decreasing (Table 1). In all three time-periods, slightly over a half of patients were diagnosed with localized disease; in the period 2001–2005 there were approximately 55% such patients. In 18% of males and 21% of females the disease was diagnosed in regional stage and in 23% of males and 18% of females in disseminated stage. The proportions of males with disseminated disease and females with regional disease were increasing with time (Table 2). In the period 2001–2005, 16% of patients did not receive specific treatment, i. e. 3% more than in the first period. In the period 2001–2005, 89% of patients with specific treatment under- went surgery. In 82% of patients primary treatment consisted of surgery alone, while 7% had surgery plus chemotherapy and/or irradiation; the remaining 11% of patients were treated with other combinations. In the period 2001–2005, 47% of patients started their treatment in the UMC Ljubljana, 15% in the UMC Maribor, 9% in GH Celje and Slovenj Gradec, 7% in GH Novo mesto, and 4% each at the IO Ljubljana and GH Izola, while 5% of patients started their treatment in other Slovenian hospitals. The relative survival rate of patients with kidney cancer has been gradually increasing: in 15 years, the 5-year relative survival increased by 8% (Figure 2), in males slightly more than in females (Table 3). The relevance of stage at diagnosis is shown in Figure 3; in the last period, relative 5-year survival of patients with localized stage has reached near to 90%. The 5-year relative KIDNEY ICD 10: C64, C65 209 Tabela 2: [tevilo bolnikov z ledvi~nim rakom po spolu in obdobju postavitve diagnoze ter njihovi dele`i po stadiju. Table 2: Number of kidney cancer patients by sex and period of diagnosis with their proportions by stage. Mo{ki / Males @enske / Females Obdobje / {tevilo / omejen / raz{irjen / razsejan / neznan / {tevilo / omejen / raz{irjen / razsejan / neznan / Period number localized regional distant unknown number localized regional distant unknown (%) (%) (%) (%) (%) (%) (%) (%) 1991–1995 419 55,6 18,1 18,6 7,6 337 58,2 16,3 16,6 8,9 1996–2000 614 59,9 15,6 19,4 5,0 372 57,0 16,7 18,5 7,8 2001–2005 752 54,1 18,2 22,6 5,1 433 55,0 20,6 18,2 6,2 EPIDEMIOLOGY Rak.qxd 22.7.2009 12:39 Page 209 V vseh treh obdobjih je imela dobra polovica bolnikov ob diagnozi omejeno bolezen; v ob- dobju 2001–2005 je bilo takih okrog 55 % bolnikov. Pri 18 % mo{kih in 21 % `ensk je bila bolezen odkrita v raz{irjenem stadiju, pri 23 % mo{kih in 18 % `ensk pa v razsejanem. Pri mo{kih se je s ~asom ve~al dele` bolnikov z razsejanim stadijem, pri `enskah pa z raz{irjenim (Tabela 2). V obdobju 2001–2005 ni bilo specifi~no zdravljenih 16% bolnikov, za 3% ve~ kot v prvem obdobju. Med specifi~no zdravljenimi je bilo v letih 2001–2005 89 % bolnikov operiranih. Pri 82 % bolnikov je bilo prvo zdravljenje zaklju~eno z operacijo, 7 % je poleg operacije prejelo {e kemoterapijo in/ali obsevanje; ostalih 11 % bolnikov je bilo zdravljenih z razli~nimi drugimi kombinacijami. 210 LEDVICA 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Slika 2: Deset-, pet-, tri- in enoletno relativno pre`ivetje bolnikov z ledvi~nim rakom po obdobju postavitve diagnoze. Figure 2: 10-, 5-, 3- and 1-year relative survival of kidney cancer patients by period of diagnosis. Tabela 3: Opazovano in relativno pre`ivetje bolnikov z ledvi~nim rakom po spolu in obdobju postavitve diagnoze s 95-odstotnim intervalom zaupanja (IZ). Table 3: Observed and relative survival of kidney cancer patients by sex and period of diagnosis with 95% con- fidence interval (CI). Opazovano pre`ivetje / Observed survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 66,6 (62,2–71,3) 50,8 (46,3–55,9) 41,3 (36,8–46,3) 70,6 (65,9–75,7) 56,1 (51,0–61,6) 48,1 (43,0–53,7) 1996–2000 69,1 (65,5–72,8) 54,4 (50,6–58,5) 47,1 (43,3–51,2) 73,1 (68,7–77,8) 60,5 (55,7–65,7) 54,3 (49,5–59,6) 2001–2005 69,0 (65,8–72,4) 56,7 (53,3–60,4) 48,6 (44,7–52,7) 70,2 (66,0–74,7) 58,4 (53,9–63,3) 53,4 (48,6–58,5) Relativno pre`ivetje / Relative survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 69,2 (64,3–74,1) 57,3 (51,6–63,0) 50,4 (44,3–56,5) 72,3 (67,2–77,5) 60,5 (54,5–66,5) 54,7 (48,3–61,1) 1996–2000 71,5 (67,6–75,3) 60,5 (55,9–65,0) 56,5 (51,6–61,5) 74,9 (70,1–79,6) 65,1 (59,5–70,7) 61,8 (55,8–67,8) 2001–2005 71,6 (68,1–75,1) 63,7 (59,6–67,8) 59,8 (54,7–65,0) 72,2 (67,6–76,8) 64,0 (58,6–69,3) 62,6 (56,6–68,7) Rak.qxd 22.7.2009 12:39 Page 210 survival of patients with regional stage of the disease is near to 50%, whereas patients with dis- seminated disease had only 5% 5-year relative survival. Age is a prognostic factor as well, since the relative survival is the lowest in patients aged 75 years or older, while survival at diagno- sis in the age group 50–74 years was lagging behind the relative survival of those diagnosed before the age of 50 throughout the observation period (Figure 4). The 5-year relative survival of all patients diagnosed in the period 2001–2005 was 61% (Figure 2); patients surviving the first year may expect to survive five years in 83%. According to the results of EUROCARE-4 study for patients diagnosed in 2000–2002 the sur- vival of patients with kidney cancer in Slovenia is below (statistically not significant) the European average (Figure 5). 211 KIDNEY 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 Omejen / Localized Raz{irjen / Regional Razsejan / Distant Vsi / All Slika 3: Petletno relativno pre`ivetje bolnikov z ledvi~nim rakom po stadiju in obdobju postavitve diagnoze. Figure 3: 5-year relative survival of kidney cancer patients by stage and period of diagnosis. 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 20–49 let / years 50–74 let / years 75+ let / years Vsi / All Slika 4: Petletno relativno pre`ivetje bolnikov z ledvi~nim rakom po starosti in obdobju postavitve diagnoze. Figure 4: 5-year relative survival of kidney cancer patients by age and period of diagnosis. Rak.qxd 22.7.2009 12:39 Page 211 V obdobju 2001–2005 se je 47 % bolnikov pri~elo zdraviti v UKC Ljubljana, 15 % v UKC Mari- bor, po 9 % SB Celje in SB Slovenj Gradec, 7 % v SB Novo mesto, po 4 % na OI Ljubljana in v SB Izola, 5 % bolnikov pa je za~elo zdravljenje v drugih slovenskih bolni{nicah. Relativno pre`ivetje bolnikov z ledvi~nim rakom se postopno ve~a; v 15 letih se je petletno rela- tivno pre`ivetje pove~alo za 8 % (Slika 2), pri mo{kih nekaj ve~ kot pri `enskah (Tabela 3). Kako pomemben je stadij ob diagnozi, ka`e Slika 3: petletno relativno pre`ivetje bolnikov z omeje- nim stadijem se je v zadnjem obdobju pribli`alo 90 %. Petletno relativno pre`ivetje bolnikov z raz{irjenim stadijem se pribli`uje 50 %, bolniki z razsejano boleznijo ob diagnozi pa imajo le 5-odstotno petletno relativno pre`ivetje. Napovedni dejavnik je tudi starost, saj je relativno pre`ivetje najmanj{e pri starih 75 let in ve~, pre`ivetje ob diagnozi pri starih 50–74 let pa ves ~as opazovanja zaostaja za relativnim pre`ivetjem pri zbolelih pred 50. letom starosti (Slika 4). Petletno relativno pre`ivetje vseh zbolelih v obdobju 2001–2005 je bilo 61 % (Slika 2); bolni- ki, ki pre`ivijo prvo leto, pa lahko pri~akujejo 83-odstotno petletno relativno pre`ivetje. Rezultati {tudije EUROCARE-4 za zbolele v obdobju 2000–2002 ka`ejo, da je pre`ivetje sloven- skih bolnikov z ledvi~nim rakom statisti~no nezna~ilno manj{e od evropskega povpre~ja (Slika 5). 212 LEDVICA KLINI^NI KOMENT AR Mirjana @umer Pregelj Za uspe{no zdravljenje ledvi~nega raka je najpomembnej{e, da je ~im prej odkrit. Dokler je rak omejen na ledvico, ve~inoma ne povzro~a te`av. V taki obliki je praviloma odkrit naklju~no, pri preiskavi z UZ, in je v velikem odstotku ozdravljiv. @al je odstotek omejenega ledvi~nega raka v zadnjih petnajstih letih skoraj nespremenjen in niha pri okrog 50 % vseh ledvi~nih rakov. Zdravljenje omejenega ledvi~nega raka je operativno. Pri tumorjih, ki so v premeru manj{i od 4 cm, napravimo, ~e je le mogo~e, delno nefrektomijo (nephron-sparing surgery), pri ve~jih pa praviloma odstranimo celo ledvico skupaj s pripadajo~o ma{~obno kapsulo; ~e je le mogo~e, odstranimo {e podro~ne bezgavke; od lege tumorja je odvisna {e morebitna odstranitev nad- ledvi~ne `leze. Pri majhnih tumorjih, najdenih pri starih in zelo {ibkih bolnikih, je mo`na radiofrekven~na ablacija tumorja. To je uspe{no le pri tumorjih, ki imajo premer, manj{i od 3 cm. Pri bolnikih, pri katerih poseg v anesteziji ni mogo~, pa preostane le opazovanje. Statisti~ni podatki ka`ejo, da se je v 15-letnem obdobju pove~alo pre`ivetje bolnikov z ome- jeno boleznijo s 76 % na 90 %. To je mogo~e pojasniti s tem, da se odkrije vedno ve~ manj{ih tumorjev, v premeru velikih 3–4 cm, pogosto pa najdejo, citolo{ko potrdijo in zdravijo tudi zelo majhne tumorje, manj{e od 2 cm. Sama operativna tehnika se namre~ v teh letih ni bistveno spremenila in ne prispeva k izbolj{anju pre`ivetja. Pri raz{irjenem raku je potreben obse`nej{i operativni poseg z odstranitvijo bezgavk in morebitnega tumorskega tromba iz ledvi~ne odvodnice. Petletno pre`ivetje bolnikov, starih 50–75 let, se zmerno ve~a; to bi lahko pojasnili s pogostej- {imi pregledi UZ zaradi drugih bolezni, pri mo{kih predvsem zaradi te`av s prostato. Ve~je pre`ivetje v starosti 75 let in ve~ je morda posledica bolj{e kondicije starostnikov in uspe{nej- {ega zdravljenja vzporednih bolezni, kar omogo~a operativni poseg tudi pri starej{ih bolnikih. Odstotek razsejanega ledvi~nega raka se vse opazovano obdobje giblje med 18 in 22 % vseh ledvi~nih rakov in je predvsem pri `enskah v rahlem porastu, verjetno zaradi dalj{e `ivljenjske dobe. Petletno pre`ivetje se pri tem stadiju tudi v obdobju med 1991 in 2005 ni izbolj{alo in je le okrog 4,5 %. V tem stadiju bolezni je obi~ajno mo`na le embolizacija tumorja, v~asih resek- cija solitarne metastaze, redko paliativna nefrektomija. ^e je bolnik {e v zadovoljivi kondiciji, je dodano {e sistemsko zdravljenje z imunoterapijo (pri nas interferon). V zadnjih letih pa se vedno bolj uveljavljajo pri zdravljenju ledvi~nega raka v tem stadiju tar~na zdravila, ki jih daje- jo onkologi, in bodo prav gotovo vplivala na pre`ivetje bolnikov z razsejanim ledvi~nim rakom v naslednjih letih. Rak.qxd 22.7.2009 12:39 Page 212 For successful treatment of kidney cancer it is of essential importance that it is detected as soon as possible. As long as cancer is limited to the kidney, it generally does not cause any prob- lems. At this stage, it is as a rule detected incidentally, on US examination, and is curable in a high percentage of cases. Unfortunately, in the last 15 years the proportion of localized kid- ney cancer has remained almost unchanged, representing around 50% of all kidney cancers. The treatment of choice for localized kidney cancer is surgery. In tumors smaller than 4 cm in diameter, partial nephrectomy (nephron-sparing surgery) is performed whenever possible; in bigger tumors a whole kidney is removed together with the adjoining renal capsule; if fea- sible, regional lymph nodes are removed as well and, depending on tumor site, possibly also the adrenal gland. In small tumors found in old and very weak patients, radiofrequency tumor ablation may be used. This however is successful only in tumors measuring less than 3 cm in diameter. Patients, in whom surgery under anesthesia is not feasible, are subjected to follow-up observation only. Statistical data show that in the 15-year period the survival of patients with localized disease has increased from 76% to 90%. This can be explained by the fact that more and more small tumors are detected, measuring 3–4 cm in diameter; frequently even very small tumors under 2 cm of size are found, cytologically confirmed and treated as well. The surgical technique itself has not changed significantly in these years and therefore does not contribute towards a bet- ter survival. Regionally advanced cancer requires a more extensive surgical procedure with lymphadenectomy and removal of a possible tumor thrombus from the renal vein. Five-year survival of patients aged 50–74 years is moderately increasing, which could be explained with more frequent US examinations for other diseases, in males particularly for prostate-related 213 KIDNEY CLINICAL COMMENT ARY Mirjana @umer Pregelj 01 02 0 30 40 50 60 70 80 90 100 % Slovensko povpre~je / 2000–2002 (EUROCARE-4) Slovenian average Evropsko povpre~je / 2000–2002 (EUROCARE-4) European average Povpre~je ZDA / 2000–2002 (SEER-13) USA average Slika 5: Petletno relativno pre`ivetje bolnikov z ledvi~nim rakom* (povpre~je in 95-odstotni interval zaupanja), zbolelih v letih 2000–2002 v Sloveniji, Evropi in nekaterih obmo~jih v ZDA. Figure 5: 5-year relative survival of kidney cancer patients* (average and 95% confidence interval) diagnosed in the period 2000–2002 in Slovenia, Europe and in some regions of the USA. * Nabor MKB10 kod v {tudiji EUROCARE-4 je nekoliko druga~en kot smo ga uporabili pri ostalih analizah predstavljenih v tem poglavju: v {tudiji EURCARE-4 so v analizo vklju~ene tudi maligne neoplazme se~ovoda (MKB10: C66) in maligne neoplazbe drugih urinarnih organov (MKB10: C68). * The ICD10 code selection in EUROCARE-4 study in slightly different in comparison to the selection applied in other analysis in this chapter: in EUROCARE-4 study the malignant neoplasm of ureter (ICD10: C66) malignant neoplasm of other and unspecified urinary organs (ICD10: C68) are also included. Rak.qxd 22.7.2009 12:39 Page 213 Za zaklju~ek naj poudarim, da bi preiskava z UZ, ki je popolnoma neinvazivna preiskava in je v vedno {ir{i rabi, v rokah ve{~ega pregledovalca ohranila marsikatero `ivljenje vsako leto. To je edini pregled, ki omogo~a odkritje ledvi~nega raka v zgodnji fazi. Preiskavo z UZ obi~ajno napravijo pri sumu na `ol~ne kamne, pri nezna~ilnih te`avah v trebuhu, pri nepojasnjenem huj- {anju, ob kontroli zaradi drugih bolezni (npr. ledvi~nih kamnov, te`av s prostato itd.), neredko pa prav na `eljo bolnika kot preventivni pregled. Albers P . Tretment Aprouches in renal cell carcinoma: past, present and future perspectives. Eur Urol Suppl 2008; 7: 36–45. Ljunberg B, Hanbury DC, Kuczyk MA, at al. Renal Cell Carcinoma guideline. Eur Urol 2007; 51: 1502–10. Kean T , Gilatt D, Evans CP , Tubaro A. Current and future trends in the Treatment of renal cancer. Eur Urol Suppl 2007; 6: 374–84. @umer Pregelj M, [urlan M, ^ernel~ B. Paliativno zdravljenje obse`nega ledvi~nega karcinoma z vra{~anjem tumorja v veno kavo in desni atrij. In: Drugi slovenski urolo{ki kongres z mednarodno udele`bo in Sim- pozij medicinskih sester in zdravstvenih tehnikov. Ljubljana: Lek; 2002. 214 LEDVICA KLINI^NI KOMENT AR Tanja ^ufer Ledvi~ni rak je razmeroma redek rak, vendar se incidenca te bolezni v svetu in pri nas ve~a. @al z rasto~im trendom incidence raste tudi trend umrljivosti. Razlog za ve~anje incidence pone- kod po svetu i{~ejo v ve~jem {tevilu preiskav z UZ, kar ima za posledico odkrivanje zgodnej{ih stadijev biolo{ko manj agresivne bolezni. Pri nas glede na to, da se porazdelitev stadijev v zad- njih 15 letih ni bistveno spremenila, vzroka ve~je incidence verjetno ni iskati v pogostej{ih radiolo{kih preiskavah. Glede na nespremenjene stadije bolezni in glede na to, da pri zdrav- ljenju raka ledvic `al do za~etka tega stoletja nismo imeli novih orodij, se skladno s porastom incidence pri~akovano pove~uje tudi umrljivost za to boleznijo. Dobra novica pa je, da umr- ljivost za tem rakom pri nas v zadnjem desetletju ni sledila rasti incidence. Pre`ivetje bolnikov z ledvi~nim rakom pri nas {e vedno zaostaja za evropskim povpre~jem, tudi pri bolnikih, zdravljenih v letih 2000–2002; v kolik{ni meri je ta zaostanek pripisati ve~jim tumor- jem ob diagnozi ali preve~ razpr{enemu kirur{kemu zdravljenju, pa mora biti predmet natan~nej{ih raziskav. V zadnjem obdobju so se v Sloveniji pove~ala predvsem dolgotrajno, petletno pre`ivetje in pre- `ivetje bolnikov z omejeno in tudi raz{irjeno boleznijo, medtem ko se pre`ivetje bolnikov z razsejano boleznijo ni spremenilo. To je pri~akovano in v skladu z opa`anji drugje po Evropi. Za omejeno in raz{irjeno bolezen imamo na voljo razmeroma u~inkovito kirur{ko zdravljenje, medtem ko za zdravljenje razsejane bolezni do leta 2005 ni bilo na voljo zdravil. Ve~je pre`i- vetje bolnikov z omejeno in po letu 2000 tudi z raz{irjeno boleznijo je posledica izpopolnjenih kirur{kih metod zdravljenja, bolj{e pooperativne oskrbe in tudi ve~jega dele`a bolnikov, ki so bili pri nas dele`ni tega zdravljenja. Pove~anje pre`ivetja bolnikov z razsejano boleznijo pa je pri~akovati po letu 2005, ko smo tako pri nas kot v svetu v zdravljenje te bolezni uvedli nova, u~inkovita tar~na zdravila. V skladu z dolgoletnimi opa`anji pri nas in po svetu je pre`ivetje `ensk z ledvi~nim rakom ve~- je od pre`ivetja mo{kih, ne glede na stadij bolezni. To se ka`e tudi pri na{ih bolnikih. Nedvoumne razlage za to ni, zanimivo pa bo opazovati vpliv tar~nih zdravil na ta pojav v naslednjih letih. Spodbudno je tudi opa`anje, da se je ob porastu pre`ivetij vseh starostnih skupin bolnikov pri nas v obdobju po letu 1995 strmo pove~evalo 5-letno pre`ivetje tudi bolnikov, starej{ih od 75 let, in se v obdobju 2001–2005 `e zelo pribli`alo pre`ivetju bolnikov v starosti 50–74 let (55 % in 61 %). Ledvi~ni rak je bolezen, pri kateri sicer zaostajamo v pre`ivetju za evropskim povpre~jem, vendar rezultate izbolj{ujemo. Dober uspeh pri omejenem stadiju je bil do sedaj posledica ustreznega, VIRI Literature Rak.qxd 22.7.2009 12:39 Page 214 problems. A higher survival in the age group 75 years or older is perhaps attributable to a bet- ter general condition of the elderly as well as to more successful treatment of their concomitant diseases, which renders surgery feasible in older patients as well. The percentage of disseminated disease has been ranging between 18% and 22% of all kidney cancers throughout the observation period, and has undergone a slight upward trend parti- cularly in females, probably due to their longer lifespan. Also in the period 1991–2005 5-year survival in this stage did not get any better, being only 4.5%. At this stage tumor emboliza- tion is generally the only option available, occasionally resection of a solitary metastasis and rarely palliative nephrectomy can be performed. If the patient is still in a relatively good gen- eral condition, systemic treatment with immunotherapy (in our case interferon) is used in addition. In recent years, targeted systemic therapy applied by oncologists is becoming increasingly impor- tant in the treatment of disseminated kidney cancer, and it will certainly influence the survival of these patients in the following years. In conclusion, let me point out that an US examination, which is a totally non-invasive and widely used method, when used by an experienced diagnostician may save lots of life every year. This is the only examination that has the potential of detecting kidney cancer in an early stage. US examination is generally performed in suspected bile stones, unspecific abdominal disorders, unexplained body weight loss, on a follow-up for other diseases (e. g. kidney stones, prostate-related problems, etc), and not infrequently at a request of the patient as a preven- tive check-up. 215 KIDNEY CLINICAL COMMENT ARY Tanja ^ufer Kidney cancer is a relatively rare disease, however its incidence worldwide as well as in Slovenia is on the increase. Unfortunately, the upward trend in incidence is associated with the same trend in mortality rates. In some countries the increasing incidence is attributed to a greater number of US examinations, which results in the detection of earlier stages of biologically less aggressive disease. In Slovenia, considering that stage distribution has not changed significantly in the last 15 years, the reason for higher incidence probably should not be sought in more frequent radiological examinations. Taking into account unchanged stage distribution and the fact that until the beginning of this century no new tools had been available in the treatment for kidney cancer, it is encouraging, that in the last decade the mortality for this cancer in Slovenia was lagging behind the increasing incidence rates. The survival of patients with kidney cancer in Slovenia is still below the European average, also in patients treated in the years 2000–2002; more in-depth studies are warranted in order to establish to what extent this backlog is due to larger tumors at diagnosis or to overdispersed surgical treatment. In the last period, mainly a long-term, 5-year survival and the survival of patients with locali- zed as well as with regional disease have increased, whereas the survival of patients with disseminated disease has remained unchanged. This is expected and consistent with the find- ings in other parts of Europe. While there is a relatively effective surgical treatment available for localized and regional disease, there was no effective systemic therapy available for dis- seminated disease until 2005. A higher survival of patients with localized, and after the year 2000 also with regional disease, is a result of upgraded surgical methods and better postoperative care. An increase in the survival of patients with disseminated disease may be expected after the year 2005, when in Slovenia, likewise elsewhere in the world, new and effective targeted systemic therapies have been introduced in the treatment for this disease. In accordance with long-term observations in Slovenia and worldwide, the survival of females with kidney cancer is higher than the survival of males, irrespective of the stage of disease. This Rak.qxd 22.7.2009 12:39 Page 215 edinega do sedaj dokazano u~inkovitega, kirur{kega zdravljenja. Pri~akovati je, da bo uvedba tar~nih zdravil v naslednjih letih {e izbolj{ala pre`ivetje bolnikov s tem rakom. ^ufer T . Rak ledvic. Onkologija 2005; 9: 76–79. Snoj N, ^ufer T. Biolo{ko in tar~no zdravljenje karcinomov. Onkologija 2007; 11: 72–76. 216 LEDVICA VIRI Literature Rak.qxd 22.7.2009 12:39 Page 216 is also evident in our patients. There is no clear explanation for that, but it will be interesting to follow the impact of targeted systemic therapies on this phenomenon in the following years. It is also encouraging to note that along with an increase in the survival of patients in all age groups after the year 1995, there was a steep increase in 5-year survival of patients aged 75 years or older in the period 2001–2005, closely approaching the survival of patients in the age group 50–74 years (55% and 61% respectively). Although the survival of kidney cancer patients in Slovenia lags behind the European avera- ge, the results are improving. So far, notable success achieved in the localized stage has been the result of the only proven effective treatment – surgery. It is expected that in the following years the implementation of targeted systemic therapies will further improve the survival of patients with this cancer. 217 KIDNEY Rak.qxd 22.7.2009 12:39 Page 217 V obdobju 1991–2005 je za rakom se~nega mehurja zbolelo 3213 ljudi, od tega 2390 mo{kih in 823 `ensk. Kot je razvidno s Slike 1, se groba in starostno standardizirana inciden~na in umr- ljivostna stopnja od leta 1991 pove~ujeta. Groba inciden~na stopnja se ve~a hitreje, povpre~no za 3,7 % letno, kot starostno standardizirana (1,8 %). Groba umrljivostna stopnja se ve~a povpre~- no za 2,2 %, starostno standardizirana umrljivostna stopnja pa je bila vse obdobje konstantna. SE^NI MEHUR MKB 10: C67 218 0 2 4 6 8 10 12 14 16 1986 1990 1995 2000 2005 Leto / Year Incidenca – groba stopnja / Incidence – crude rate Incidenca – SSS* / Incidence – ASR** Umrljivost – groba stopnja / Mortality – crude rate Umrljivost – SSS* / Mortality – ASR** Stopnja na 100.000 / Rate per 100,000 * SSS – starostno standardizirana stopnja (standard – slovenska populacija leta 1986) ** ASR – age standardized rate (standard Slovenian population in 1986) Slika 1: Groba in starostno standardizirana inciden~na in umrljivostna stopnja raka se~nega mehurja, Slovenija 1986–2005. Figure 1: Crude and age-standardized incidence and mortality rate of bladder cancer, Slovenia 1986–2005. Mo{ki / Males @enske / Females Obdobje / {tevilo / 20–49 let / 50–74 let / 75+ let / {tevilo / 20–49 let / 50–74 let / 75+ let / Period number years (%) years (%) years (%) number years (%) years (%) years (%) 1991–1995 657 4,4 66,2 29,4 211 2,4 59,2 38,4 1996–2000 760 4,9 69,1 26,1 244 5,3 59,4 35,2 2001–2005 917 4,6 65,3 30,1 325 4,6 49,5 45,8 Tabela 1: [tevilo bolnikov z rakom se~nega mehurja po spolu in obdobju postavitve diagnoze ter njihovi dele`i po starosti. Table 1: Number of bladdder cancer patients by sex and period of diagnosis with their proportions by age. V analizo pre`ivetja je vklju~enih 3114 primerov; 99 bolnikov (3,2 %) nismo upo{tevali, ker jim je bila diagnoza postavljena po smrti. V obdobju 2001–2005 je bilo 96 % primerov raka mikroskopsko potrjenih. Dele` mikroskop- sko potrjenih se je v primerjavi z obdobjem 1991–1995 pove~al za 2 %. V vseh treh obdobjih je imelo najve~ bolnikov karcinom prehodnega epitela, v zadnjem obdobju 88 %, po 2 % je bilo adeno- in plo{~atoceli~nih karcinomov, pri 8 % histolo{ka vrsta ni bila natan~neje opredeljena. EPIDEMIOLOGIJA Rak.qxd 22.7.2009 12:39 Page 218 In the period 1991–2005, a total of 3213 persons were diagnosed with cancer of the urinary bladder, of these 2390 males and 823 females. As evident from Figure 1, since 1991, crude as well as age-standardized incidence and mortality rates have been increasing. Thus crude inci- dence rate has been increasing more rapidly than age-standardized rate, by 3.7% vs. 1.8% per year respectively. The crude mortality rate has been increasing by 2.2% on average while the age-standardized mortality rate remained stable throughout the observation period. The survival analysis included 3114 cases; 99 patients (3.2%) diagnosed only after death were not considered in the analysis. In the period 2001–2005, 96% of cancers were microscopically verified. In comparison with the period 1991–1995 the proportion of microscopically confirmed cases has increased by 2%. In all three time-periods, the majority of patients presented with carcinoma of the transitional epithe- lium, in the last period there were 88% such patients, adeno- and planocellular carcinomas were diagnosed in 2% each, while histological type was not precisely determined in 8% of cases. The majority of patients were diagnosed at an age between 50 and 74 years; in these age-groups, there was approximately 65% of males and 50% of females (Table 1). In the period 2001–2005, the proportion of females aged between 50–74 years decreased while the proportion of those diagnosed at the age of 75 years or older increased. Less than 5% of patients will develop the disease before the age of 50. In all three time-periods, the majority of patients were diagnosed with localized disease; in the period 2001–2005 there were 70% such patients (Table 2). As compared to the peri- od 1991–1995, in the last period the proportion of localized stage in males increased by 6% and in females by 12%; in the latter the proportion of regional stage decreased by 9%. Approximately 20% of patients were diagnosed with regional disease. The proportions of patients with disseminated stage have increased with time, mainly on the account of smaller propor- tion of patients with an undefined stage. In the period 2001–2005, 7% of patients did not receive specific treatment. The proportion of untreated patients did not change significantly throughout the observation periods; among those diagnosed in the period 1991–1995, there were 8% of patients without specific treat- ment. Among the patients receiving specific treatment in the period 2001–2005, in 61% the primary treatment was completed by surgery (there are no data in CRS on how many there were radical cystectiomies and how many transurethral resections) 12% received radiothera- py and chemotherapy in addition to surgery, 10% received irradiation treatment after surgery, another 10% was treated with the combination of surgery, chemotherapy and irradiation; 7% of patients were treated with other combinations. URINARY BLADDER MKB 10: C67 219 Tabela 2: [tevilo bolnikov z rakom se~nega mehurja po spolu in obdobju postavitve diagnoze ter njihovi dele`i po stadiju. Table 2: Number of bladdder cancer patients by sex and period of diagnosis with their proportions by stage. Mo{ki / Males @enske / Females Obdobje / {tevilo / omejen / raz{irjen / razsejan / neznan / {tevilo / omejen / raz{irjen / razsejan / neznan / Period number localized regional distant unknown number localized regional distant unknown (%) (%) (%) (%) (%) (%) (%) (%) 1991–1995 657 65,8 20,7 4,4 9,1 211 58,3 26,5 3,3 11,8 1996–2000 760 71,3 19,6 3,4 5,7 244 70,5 19,3 8,6 1,6 2001–2005 917 71,5 19,4 6,1 2,9 325 70,5 17,5 5,5 6,5 EPIDEMIOLOGY Rak.qxd 22.7.2009 12:39 Page 219 Najve~ji dele` zbolelih je bil ob diagnozi star med 50 in 74 let, med mo{kimi jih je bilo v tej starostni skupini 65 %, med `enskami pa 50 % (Tabela 1). V obdobju 2001–2005 se je zmanj- {al dele` `ensk, starih 50–74 let, in pove~al dele` starih ob diagnozi 75 let in ve~. Pred 50. letom zboli manj kot 5 % bolnikov. V vseh treh obdobjih je imelo ob diagnozi najve~ bolnikov omejeno bolezen; v obdobju 2001–2005 jih je bilo okrog 70 % (Tabela 2). Pri mo{kih se je v zadnjem obdobju v primerjavi z obdob- jem 1991–1995 pove~al dele` omejenega stadija za 6 %, pri `enskah pa za 12 %; pri zadnjih se je zmanj{al dele` raz{irjenega stadija za 9 %. Z raz{irjenim stadijem je bilo diagnosticiranih bli- zu 20 % bolnikov. Dele` bolnikov z razsejanim stadijem se je s~asoma ve~al, predvsem na ra~un manj{ega dele`a bolnikov, pri katerih stadij ni bil opredeljen. 220 SE^NI MEHUR 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Slika 2: Deset-, pet-, tri- in enoletno relativno pre`ivetje bolnikov z rakom se~nega mehurja po obdobju postavitve diagnoze. Figure 2: 10-, 5-, 3- and 1-year relative survival of bladder cancer patients by period of diagnosis. Tabela 3: Opazovano in relativno pre`ivetje bolnikov z rakom se~nega mehurja po spolu in obdobju postavitve diagnoze s 95-odstotnim intervalom zaupanja (IZ). Table 3: Observed and relative survival of bladder cancer patients by sex and period of diagnosis with 95% confidence interval (CI). Opazovano pre`ivetje / Observed survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 65,6 (62,1–69,3) 46,0 (42,3–49,9) 34,4 (31,0–38,2) 60,2 (53,9–67,2) 43,6 (37,4–50,8) 37,4 (31,4–44,6) 1996–2000 70,9 (67,8–74,2) 50,5 (47,1–54,2) 38,7 (35,4–42,3) 71,7 (66,3–77,6) 50,0 (44,1–56,7) 42,6 (36,8–49,3) 2001–2005 71,2 (68,3–74,2) 50,1 (47,0–53,5) 37,9 (34,4–41,6) 67,4 (62,5–72,7) 45,0 (39,9–50,8) 37,2 (31,8–43,4) Relativno pre`ivetje / Relative survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 69,9 (65,9–73,9) 55,6 (50,8–60,4) 47,6 (42,3–52,9) 63,8 (56,4–71,2) 51,9 (43,3–60,5) 50,2 (40,6–59,8) 1996–2000 75,0 (71,5–78,5) 59,9 (55,6–64,3) 51,9 (47,0–56,7) 75,2 (69,1–81,4) 57,7 (50,0–65,4) 54,2 (45,7–62,7) 2001–2005 75,2 (72,0–78,4) 59,7 (55,6–63,7) 51,4 (46,3–56,5) 70,8 (65,3–76,4) 52,8 (46,0–59,6) 48,9 (40,7–57,1) Rak.qxd 22.7.2009 12:39 Page 220 In the period 2001–2005, 40% of patients started their treatment in the UMC Ljubljana, 15% each in the UMC Maribor and GH Celje, 6% each in GH Novo mesto, GH Slovenj Gradec, GH Izola and GH Nova Gorica, 3% in GH Murska Sobota and 2% at the IO Ljubljana. In the 15-year observation period, the relative survival of patient with bladder cancer has not changed significantly; in the last period it even decreased (to 51% vs. 53% in 1996–2000) (Figure 2), to a greater extent in females than in males (Table 3). Stage at diagnosis is a rele- vant prognostic factor of disease outcome as the best survival is observed in patients with localized stage, but nevertheless, even in these patients no significant improvement has been achieved in the last observation period (Figure 3). In the period 2001–2005, 5-year relative survival rate of patients with localized stage was 65%. Age is a prognostic factor as well, since the relative survival is the lowest in patients aged 75 years or older, where it underwent the strongest decrease in the last observation period; a minor improvement was observed only in patients diagnosed at an age between 50–74 years; the evaluation of survival in younger patients is not reliable because their number is too small (Figure 4). 221 URINARY BLADDER 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 Omejen / Localized Raz{irjen / Regional Razsejan / Distant Vsi / All Slika 3: Petletno relativno pre`ivetje bolnikov z rakom se~nega mehurja po stadiju in obdobju postavitve diagnoze. Figure 3: 5-year relative survival of bladder cancer patients by stage and period of diagnosis. 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 20–49 let / years 50–74 let / years 75+ let / years Vsi / All Slika 4: Petletno relativno pre`ivetje bolnikov z rakom se~nega mehurja po starosti in obdobju postavitve diagnoze. Figure 4: 5-year relative survival of bladder cancer patients by age and period of diagnosis. Rak.qxd 22.7.2009 12:39 Page 221 V obdobju 2001–2005 se ni specifi~no zdravilo 7 % bolnikov. Dele` nezdravljenih bolnikov se v vseh obdobjih ni bistveno spreminjal; med bolniki, zbolelimi v letih 1991–1995, se jih ni spe- cifi~no zdravilo 8 %. Med specifi~no zdravljenimi v letih 2001–2005 se je pri 61 % primerov prvo zdravljenje zaklju~ilo z operacijo (natan~nej{ih podatkov o tem, koliko je bilo radikalnih cistektomij, koliko pa transuretralnih resekcij, v RRS ni), 12 % jih je bilo poleg operacije dodat- no {e obsevanih in zdravljenih s kemoterapijo, 10 % pa je poleg kirur{kega prejelo {e obsevalno zdravljenje; {e dodatnih 10 % je bilo zdravljenih s kombinacijo operacije, citostatikov in obse- vanja; 7 % bolnikov je bilo zdravljenih z drugimi kombinacijami. V obdobju 2001–2005 se je 40 % bolnikov za~elo zdraviti v UKC Ljubljana, po 15 % v UKC Maribor in SB Celje, po 6 % v SB Novo mesto, SB Slovenj Gradec, SB Izola in SB Nova Gori- ca, 3 % v SB Murska Sobota in 2 % na OI Ljubljana. Relativno pre`ivetje bolnikov z rakom se~nega mehurja se v 15 letih ni bistveno pove~alo; v zad- njem obdobju se je celo zmanj{alo (na 51% v primerjavi z leti 1996–2000, ko je bilo 53%) (Slika 2), bolj pri `enskah kot pri mo{kih (Tabela 3). Stadij ob diagnozi je sicer napovedni dejav- nik izida bolezni, saj je pre`ivetje najve~je pri bolnikih z omejenim stadijem, vendar tudi pri teh bolnikih v zadnjem obdobju ni pomembnega izbolj{anja (Slika 3): petletno relativno pre- `ivetje bolnikov z omejenim stadijem v letih 2001–2005 je bilo 65-odstotno. Napovedni dejavnik je tudi starost, saj je relativno pre`ivetje najslab{e pri starih 75 let in ve~, pri katerih se je v zad- njem obdobju tudi najbolj zmanj{alo; manj{i napredek je le pri bolnikih, diagnosticiranih v starosti 50–74 let; vrednotenje pre`ivetja pri mlaj{ih pa ni zanesljivo, ker je primerov premalo (Slika 4). Petletno relativno pre`ivetje vseh zbolelih v obdobju 2001–2005 je bilo 51 % (Slika 2); bolni- ki, ki pre`ivijo prvo leto, pa lahko pri~akujejo 67-odstotno petletno relativno pre`ivetje. Rezultati {tudije EUROCARE-4 za zbolele v obdobju 2000–2002 ka`ejo, da je pre`ivetje slo- venskih bolnikov z rakom se~nega mehurja statisti~no zna~ilno manj{e od evropskega povpre~ja za 20 % (Slika 5). 222 SE^NI MEHUR KLINI^NI KOMENT AR Boris Sedmak V opazovanem 15-letnem obdobju se je incidenca invazivnega raka mehurja ve~ala. Kljub pora- stu dele`a bolnikov z omejeno boleznijo se je petletno pre`ivetje bolnikov v tem obdobju le malo pove~alo. Podatki o na~inih zdravljenja ka`ejo, da se je ve~al dele` bolnikov, ki so se zdra- vili samo s kirurgijo, zmanj{al pa se je dele` bolnikov, zdravljenih s kombiniranim zdravljenjem, kirurgijo, kemoterapijo in obsevanjem. Zavedati se moramo, da je radikalna cistektomija {e ved- no standardni na~in zdravljenja in da je pri invazivnem raku se~nega mehurja transuretralna resekcija kot edini na~in zdravljenja nezadostna. V po{tev pride le kot diagnosti~ni, ne pa kot terapevtski postopek. Le v izbranih primerih je mo`no zdraviti bolnika s transuretralno resek- cijo mehurja in zdravljenje nadaljevati s kemo- in radioterapijo. Bolnike, ki so se zdravili z metodo ohranitvenega zdravljenja mehurja, je treba natan~no slediti, za to pa so potrebni oprema in strokovno usposobljeno osebje. Za bolj{o napoved izida bolezni so zgodnja diagnostika ter pravilno in pravo~asno zdravljenje klju~nega pomena. Najpomembnej{a preiskava za diagnozo raka se~nega mehurja je cistosko- pija in nato endoskopska resekcija tumorja mehurja s patohistolo{ko preiskavo tkiva. Za zamejitev bolezni uporabljamo UZ preiskavo, intravenozno urografijo, CT , MRI in bimanualno palpa- cijo v anesteziji med transuretralno resekcijo. Velik pomen ima dostopnost slikovnih preiskav, posebej CT in MRI. ^akanje na omenjeni preiskavi podalj{uje ~as do za~etka zdravljenja in slab{a izid bolezni. Indikacija za radikalno cistektomijo je mi{i~no invazivni karcinom se~nega mehurja, oprede- ljen kot T2-T4a, N0–NX, M0, in obse`ni povr{inski papilarni rak mehurja, ki ga ni mogo~e zdraviti s konzervativnimi metodami. Ve~kratno ponavljanje transuretralnih resekcij mehurja Rak.qxd 22.7.2009 12:39 Page 222 The 5-year relative survival of all patients diagnosed in the period 2001–2005 was 51% (Figure 2); patients surviving the first year may expect to survive five years in 67%. According to the results of EUROCARE-4 study for patients diagnosed in 2000–2002, the survival of bladder cancer patients in Slovenia is statistically significantly below the European average (Figure 5). 223 URINARY BLADDER CLINICAL COMMENT ARY Boris Sedmak 01 02 0 30 40 50 60 70 80 90 100 % Slovensko povpre~je / 2000–2002 (EUROCARE-4) Slovenian average Evropsko povpre~je / 2000–2002 (EUROCARE-4) European average Povpre~je ZDA / 2000–2002 (SEER-13) USA average Slika 5: Petletno relativno pre`ivetje bolnikov z rakom se~nega mehurja (povpre~je in 95-odstotni interval zaupanja), zbolelih v letih 2000–2002 v Sloveniji, Evropi in nekaterih obmo~jih v ZDA. Figure 5: 5-year relative survival of bladder cancer patients (average and 95% confidence interval) diagnosed in the period 2000–2002 in Slovenia, Europe and in some regions of the USA. In the observed 15-year period the incidence of invasive bladder cancer has increased. Despite the greater proportion of patients with localized disease, an increase in the 5-year survival of patients observed in that period was negligible. The data on treatment approach show that the proportion of patients treated by surgery alone was increasing while the proportion of those treated with a combination of surgery, chemotherapy and irradiation was decreasing. It should be kept in mind that radical cystectomy still represents a standard treatment and that in inva- sive bladder cancer transurethral resection as single modality treatment is insufficient. It can be used as a diagnostic but not also as a therapeutic procedure. In certain cases only, the patient may be treated with transurethral bladder resection followed by chemo- and radiotherapy. The patients treated by bladder preserving approach require close monitoring, which calls for ade- quate equipment and competent staff. For better outcome of this disease, early diagnosis as well as correct and timely treatment is of essential importance. Cystoscopy is the most relevant procedure for the diagnosis of blad- der cancer; the next is endoscopic resection of the bladder tumor with pathohistological examination of the resected tissue. Staging of the disease is performed by means of US, intra- venous urography, CT scan, MRI and bimanual palpation under anesthesia during transurethral resection. The availability of imaging methods, particularly of CT and MRI, is of great impor- tance. Too long wwaiting for the investigations mentioned, delays the beginning of treatment and adversely affects the prognosis. Indications for radical cystectomy include muscle invasive carcinoma of the urinary bladder classified as T2-T4a, N0–NX, M0 and extensive superficial papillary bladder cancers, which Rak.qxd 22.7.2009 12:39 Page 223 pri ugotovljenem mi{i~no invazivnem raku se~nega mehurja in pri bolniku, kjer je cistektomi- ja mo`na, je nedopustno. Pogosteje bi morali bolnike zdraviti kombinirano z neoadjuvantno kemoterapijo in cistektomijo. Pri teh bolnikih bi morali pozorno spremljati u~inek kemote- rapije in v primeru, da ta ni u~inkovita, bolnika ~im prej operirati. Bolnike z rakom se~nega mehurja bi bilo treba zdraviti interdisciplinarno. Radikalna cistekotomija in ustrezna izpelja- va urina je obse`na operacija, za katero so potrebne velike izku{nje. Za bolj{e rezultate zdravljenja bi bilo treba bolnike obravnavati v ve~jih centrih. V opazovanem obdobju se je pre`ivetje bolnikov pri omejeni bolezni izbolj{alo, kar je verjetno posledica ve~jega {tevila radikalnih cistektomij. Slab{e pre`ivetje bolnikov pri raz{irjeni in {e posebej pri razsejani bolezni je verjetno posledi- ca tega, da ti bolniki niso v zadostnem {tevilu zdravljeni s kemoterapijo in z obsevanjem. Babjuk M, Oosterlinck W, Sylvester R. Guidelines on TaT1 (Non-Muscle invasive) Bladder Cancer. European Association of Urology 2008. Messing EM. Urotelial Tumors of the Bladder. In: Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA. Campbell-Walsh Urology. Philadelphia. Saunders, 2007: 2407–46. Jones JS, Campbell SC. No-Muscle-Invasive Bladder Cancer (Ta, T1, CIS). In: Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA. Campbell-Walsh Urology. Philadelphia. Saunders, 2007: 2447–68. Schoenberg MP, Gonzalgo M, Management of invasive and Metastatic Bladder Cancer. In: Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA. Campbell-Walsh Urology. Philadelphia. Saunders, 2007: 2468–79. Stenzl A, Cowan NC, Santis MD, Jakse G, Kuczyk M, Merseburger AS, et al. Guidelines on Bladder Cancer Muscle-invasive and Metastatic. European Association of Urology 2008. 224 SE^NI MEHUR KLINI^NI KOMENT AR Tanja ^ufer Rak se~nega mehurja je srednje pogost rak, za katerim nekoliko pogosteje zbolevajo mo{ki kot `enske. Incidenca bolezni tako pri nas kot v svetu po~asi raste. Incidenca, pa tudi pre`ivetje, sta odvisna tudi od tega, ali se prijavlja samo invazivni ali tudi neinvazivni, t. i. in situ rak mehur- ja. V ve~ini evropskih registrov raka in pri nas se prijavljajo samo invazivni primeri raka, zato je za razliko od ZDA incidenca bolezni v Evropi ni`ja, slab{e pa je tudi pre`ivetje bolnikov. Pri nas v zadnjem desetletju `al ne opa`amo padajo~ega trenda umrljivosti za tem rakom, kot ga opa`ajo ponekod v Evropi. Pre`ivetje bolnikov z rakom se~nega mehurja je pri nas slabo in se `al v zadnjih letih ni izbolj- {alo. Tudi to zadnje poro~ilo ne ka`e ve~jega, ampak celo manj{e petletno pre`ivetje vseh bolnikov, zbolelih v obdobju 2001–2005, glede na tiste, zbolele v letih 1996–2000 (Slika 2). Medtem ko se pre`ivetje bolnikov z rakom mehurja v Evropi izbolj{uje, pri nas temu `al ni tako. Kar 15-odstotni zaostanek v petletnem pre`ivetju, opazovan v raziskavi EUROCARE-3 pri bol- nikih, zbolelih v letih 1990–1994, se je v obdobju 2000–2002 glede na izsledke EUROCARE-4 raziskave {e pove~al. Petletno relativno pre`ivetje bolnikov z rakom se~nega mehurja je bilo pri diagnosticiranih v letih 2000–2002 v Evropi 68,9 %, v Sloveniji pa samo 48,0 %. Pri~ujo~e poro~ilo poka`e, da se je tako 1-, 3- kot 5-letno pre`ivetje bolnikov, diagnosticira- nih v letih 2001–2005, celo nekoliko zmanj{alo. Poslab{anje je opazno pri vseh stadijih bolezni, predvsem pri `enskah. Ker se dele` bolnikov z odkrito boleznijo po razli~nih stadijih v zad- njem obdobju ni spremenil, je vzrok manj{ega pre`ivetja iskati v neustreznem zdravljenju. Dele` bolnikov, zdravljenih z radikalno kirurgijo, je pri nas premajhen. Zgovorno je dejstvo, ki ga je v svojem magistrskem delu pokazala Ur{ka Bizjak Ogrinc, da je bilo v letih 1987, 1992 in 1997 samo 6,6 % bolnikov (5 % stadija T2 in 16 % stadija T3) dele`nih radikalne cistektomije. To je standardno zdravljenje mi{i~no invazivnega raka se~nega mehurja, s katerim je mogo~e ozdra- viti okoli polovico bolnikov. V teh letih je 57 % bolnikov v okviru kirur{kega zdravljenja imelo opravljeno samo TUR, ki za ve~ino bolnikov ni najustreznej{i na~in zdravljenja. Drugi na~in zdravljenja za izbrane bolnike z mi{i~noinvazivnim rakom mehurja je ohranitveno zdravlje- VIRI Literature Rak.qxd 22.7.2009 12:39 Page 224 cannot be treated by conservative methods. Repeated transurethral resections of the urinary bladder in a confirmed muscle-invasive bladder cancer and when cystectomy is feasible, is into- lerable. The patients should be treated more often with a combination of neoadjuvant chemotherapy and cystectomy. In these patients the effect of chemotherapy should be closely monitored and in the case that it turns out ineffective, the patient should be operated on as soon as possible. Bladder cancer patients should be treated by an interdisciplinary approach. Radical cystecto- my with a suitable urostomy (urinary diversion) is a major surgical procedure that requires a lot of experience. For better treatment outcomes, the patients should be treated in bigger specialized centers. In the period under observation, the survival of patients with localized disease has improved, which is probably attributable to the higher number of radical cystectomies. Worse survival of patients with regional and particularly with disseminated disease is probably due to the fact that an insufficient number of patients were treated by chemotherapy and irradia- tion. 225 URINARY BLADDER CLINICAL COMMENT ARY Tanja ^ufer The frequency of bladder cancer is moderate, with males being affected more often than females. The incidence in Slovenia as elsewhere in the world is slowly increasing. Both, the incidence as well as the survival rates depend on whether only invasive or also non-invasive, the so-called in situ bladder cancers are reported. In a majority of European cancer registries, and thus also in Slovenia, only invasive cancers are registered, and therefore – for the difference from the USA – the incidence in Europe is lower, but then the survival is lower too. In the last decade, unfortunately, no decreasing trend in the mortality for this cancer has been observed in Slovenia. The survival rates of bladder cancer in Slovenia are poor and have unfortunately not improved in last years. According to the current report, 5-year survival of all patients diagnosed in the period 2001–2005 is even lower compared to those diagnosed in the period 1996–2000 (Figure 2). While the survival of bladder cancer patients in Europe is improving, in Slovenia it is unfor- tunately not so. A fifteen-percent lagging behind in 5-year survival revealed by EUROCARE-3 in patients diagnosed in the period 1990–1994 underwent a further increase in the period 2002–2002, as evident from the results of EUROCARE-4 study. While in Europe the relative survival of bladder cancer patients diagnosed in the period 2000–2002 was 68.9%, in Slovenia it was only 48.0%. The current report shows that 1-, 2-, 3- as well as 5-year survival of patients diagnosed in the period 2001–2005 underwent a slight decrease compared to the previous period. The decrease is noted in all stages of the disease, particularly in women. Since in the last period the pro- portions of patients diagnosed with different stages of the disease have not changed, the cause for poor survival should be sought in inadequate treatment. In Slovenia, the proportion of patients treated by radical surgery is too low. A fact pointed out in the Master's thesis by Ur{ka Bizjak Ogrinc speaks for itself: in the years 1987, 1992 and 1997 only 6.6% of patients (5% with T2 and 16% with T3 stage) underwent radical cystectomy, a standard therapy for muscle-inva- sive bladder cancer, which can cure approximately 50% of the affected patients. In those years, in 57% of patients surgery consisted of TUR alone, though in a majority of cases this method is not the best choice. Another treatment approach to a selected group of patients with mus- cle-invasive bladder cancer is bladder-preserving treatment by means of TUR, chemotherapy and irradiation. However, this treatment is suitable only for selected patients with muscle-inva- sive bladder cancer, and therefore the proportion of patients treated in this way in Slovenia as well as elsewhere in the world is low. Thus, in the years 1992 and 1997 only about 6% of patients with muscle-invasive cancer received such therapy. The reason for poor survival of bladder cancer patients in Slovenia in last years is attributable to the sub-optimal surgery for muscle-invasive cancer, and therefore all the efforts should be direc- ted into improving this treatment approach. So far, adjuvant therapy of this type of cancer with Rak.qxd 22.7.2009 12:39 Page 225 nje s TUR, kemoterapijo in obsevanjem. To zdravljenje je primerno le za malo bolnikov z mi- {i~no invazivnim rakom, zato je dele` tako zdravljenih bolnikov povsod po svetu, pa tudi pri nas, majhen. Pri nas je bilo tako zdravljenih v letih 1992 in 1997 le okoli 6 % bolnikov z mi- {i~no invazivnim rakom mehurja. Razlog za slabo pre`ivetje bolnikov z rakom se~nega mehurja v Sloveniji v zadnjih letih je goto- vo iskati v suboptimalnem kirur{kem zdravljenju mi{i~noinvazinega raka, zato je treba vse mo~i usmeriti v izbolj{anje tega zdravljenja. Dopolnilno zdravljenje tega raka s citostatiki zaenkrat {e ni dalo prepri~ljivih rezultatov. To zdravljenje ima majhno dobrobit pri bolnikih s prizade- timi podro~nimi bezgavkami, a bistvenega izbolj{anja pre`ivetja z dopolnilno kemoterapijo, ki je danes na voljo, ni pri~akovati. Treba pa je z ustrezno vodenim citostatskim zdravljenjem izbolj{ati pre`ivetje bolnikov z razsejanim rakom se~nega mehurja, ki je s citostatskim zdrav- ljenjem zazdravljiva bolezen. Pri nas premajhen dele` bolnikov z razsejano boleznijo prejme ustrezno citostatsko zdravljenje. Zaskrbljujo~e je tudi, da je pre`ivetje slabo predvsem pri mlaj{ih od 50 let in pri starih 75 let in ve~. Tema dvema populacijama bo potrebno v prihodnosti posvetiti {e ve~jo pozornost. Bizjak-Ogrinc U. Pre`ivetje bolnikov z invazivnim rakom se~nega mehurja glede na stadij in na~in zdravljenja v Sloveniji v obdobju 1987–1997 v treh izbranih letih. [magistrska naloga]. Ljubljana: Univerza v Ljub- ljani; 2007. ^ufer T . Combined modality treatment with organ preservation in invasive bladder cancer = Kombinirano zdrav- ljenje raka se~nega mehurja z mo`nostjo ohranitve organa. Radiol Oncol 2000; 34: 21–25. Ferlay J, Autier P , Boniol M, Heanue M, Colombet M, Boyle P . Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 2007; 18: 581–92. Matos T, ^ufer T, ^ervek J, Bor{tnar S, Kragelj B, @umer-Pregelj M. Prognostic factors in invasive bladder carcinoma treated by combined modality protocol (organ-sparing approach). Int J Radiat Oncol Biol Phys. 2000; 46: 403–9. 226 SE^NI MEHUR VIRI Literature Rak.qxd 22.7.2009 12:39 Page 226 cytostatics has not yielded any convincing results. This treatment can be slightly beneficial for patients with local lymph node involvement; however, no major improvement in the survival can be expected from the use of currently available adjuvant chemotherapy without radical local therapy. Nevertheless, it is necessary to improve the survival of patients with disseminated blad- der cancer by means of systemic treatment, since this type of cancer can be effectively treated with cytostatics. In Slovenia, the proportion of patients with disseminated disease receiving chemotherapy is still too small. Furthermore, the fact that the survival is poor particularly in patients under 50 and over 75 years of age also raises concern. Therefore, more attention should be paid to these two population groups in the future. 227 URINARY BLADDER Rak.qxd 22.7.2009 12:39 Page 227 V obdobju 1991–2005 je za rakom mo`ganov zbolelo 1636 ljudi, od tega 878 mo{kih in 758 `ensk. Kot je razvidno s Slike 1, se inciden~ne in umrljivostne stopnje ve~ajo. Groba inciden~na stop- nja se je ve~ala za povpre~no 3,7% letno, starostno standardizirana pa za nekoliko manj, za 2,6 % letno. Groba in starostno standardizirana umrljivostna stopnja ka`eta bolj po~asen trend, ~eprav so ti podatki zaradi te`av pri {ifriranju vzrokov smrti manj zanesljivi; ve~krat je namre~ iz prijav vzroka smrti nemogo~e razlikovati med malignimi tumorji mo`ganov in tumorji nego- tovega in nejasnega zna~aja, ki morfolo{ko ne sodijo v skupino invazivnih rakov. MO@GANI MKB 10: C71 228 0 1 2 3 4 5 6 7 1986 1990 1995 2000 2005 Leto / Year Incidenca – groba stopnja / Incidence – crude rate Incidenca – SSS* / Incidence – ASR** Umrljivost – groba stopnja / Mortality – crude rate Umrljivost – SSS* / Mortality – ASR** Stopnja na 100.000 / Rate per 100,000 * SSS – starostno standardizirana stopnja (standard – slovenska populacija leta 1986) ** ASR – age standardized rate (standard Slovenian population in 1986) Slika 1: Groba in starostno standardizirana inciden~na in umrljivostna stopnja raka mo`ganov, Slovenija 1986–2005. Figure 1: Crude and age-standardized incidence and mortality rate of brain cancer, Slovenia 1986–2005. Mo{ki / Males @enske / Females Obdobje / {tevilo / 20–49 let / 50–74 let / 75+ let / {tevilo / 20–49 let / 50–74 let / 75+ let / Period number years (%) years (%) years (%) number years (%) years (%) years (%) 1991–1995 196 34,2 62,2 3,6 189 29,6 64,0 6,3 1996–2000 247 36,0 56,7 7,3 208 23,6 68,8 7,7 2001–2005 315 26,0 64,8 9,2 271 24,7 59,8 15,5 T abela 1: [tevilo bolnikov z rakom mo`ganov po spolu in obdobju postavitve diagnoze ter njihovi dele`i po starosti. Table 1: Number of brain cancer patients by sex and period of diagnosis with their proportions by age. V analizo pre`ivetja je vklju~enih 1426 primerov; 69 primerov (4,2 %) nismo upo{tevali, ker jim je bila diagnoza postavljena po smrti, 141 mlaj{ih od 20 let pa obravnavamo v poglavju o pre- `ivetju pri otrocih in mladostnikih. V obdobju 2001–2005 je bilo mikroskopsko potrjenih 83 % primerov. Dele` mikroskopsko potrjenih primerov se ves ~as opazovanja zmanj{uje; v obdobju 1991–1995 je bil 88 %. Med mikroskopsko potrjenimi primeri je bilo v obdobju 2001–2005 82 % gliomov, pri 11 % histolo{ka diagnoza ni bila opredeljena, redko pa so se pojavljali germinomi in sarkomi. Med gliomi je bilo pribli`no EPIDEMIOLOGIJA Rak.qxd 22.7.2009 12:39 Page 228 In the period 1991–2005, a total of 1636 persons were diagnosed with brain cancer, of these 878 males and 758 females. As evident from Figure 1, the incidence and mortality rates have been increasing. The crude mortality rate has been increasing by 3.7% and the age-standar- dized by 2.6% annually on average. The upward trend of crude and age-standardized mortality rates has been slower. However, these data are less reliable due to difficulties in coding the caus- es of death, as it is often not possible to distinguish between malignant brain tumors and tumors of uncertain origin, which morphologically do not belong into the group of invasive cancers, solely on the basis of death certificates. The survival analysis included 1426 cases; 69 cases (4.2%) diagnosed only after death, were not considered in the analysis, 141 patients under 20 years of age are presented in the chap- ter on the survival of children and adolescents. In the period 2001–2005, 83% of cancers were microscopically verified. The proportion of micro- scopically confirmed cases has been decreasing throughout the observation time; in the period 1991–1995 it was 88%. Among the microscopically confirmed cases in the period 2001–2005, 82% were gliomas while in 11% histological type was not precisely defined; germinomas and sarcomas were rare. Approximately two thirds of gliomas were classified as glioblastoma, 14% as astrocytoma and 10% as oligodendroglioma. Other types of glioma were rare. Approximately 60% of patients were diagnosed at an age between 50 to 74 years, and a fourth at an age between 20 to 49 years. The proportion of those aged 75 years or older is the low- est, however it is increasing with time in both genders (Table 1). Brain cancer is generally detected at a localized stage (Table 2). In the period 2001–2005, 21% of patients did not receive specific treatment. The proportion of untreated patients was increasing throughout the observation period; among those diag- nosed in the period 1991–1995 there were 18% of patients without specific treatment. Among the patients receiving specific treatment in the period 2001–2005, 36% were treated by sur- gery alone, 30% received radio- and chemotherapy in addition to surgery, while 28% were only irradiated. Other combinations of treatment were used in less than 5% of the patients. In com- parison with the previous periods, in the last one more patients received chemotherapy in addition to surgery and radiotherapy as part of their primary treatment. In the period 2001–2005, the majority of patients (80%) started their treatment in the UMC Ljubljana, 18% in the UMC Maribor and 3% at the IO Ljubljana. The relative survival rate of patients with brain cancer has not been changing significantly: in 15 years, the 5-year relative survival increased only by 1% (Figure 2); the survival in females is slightly better than in males (Table 3). The relevance of age at diagnosis is shown in Figure 3. The 5-year relative survival of patients diagnosed before 50 years of age is 45%, patients diagnosed BRAIN MKB 10: C71 229 Tabela 2: [tevilo bolnikov z rakom mo`ganov po spolu in obdobju postavitve diagnoze ter njihovi dele`i po stadiju. Table 2: Number of brain cancer patients by sex and period of diagnosis with their proportions by stage. Mo{ki / Males @enske / Females Obdobje / {tevilo / omejen / raz{irjen / razsejan / neznan / {tevilo / omejen / raz{irjen / razsejan / neznan / Period number localized regional distant unknown number localized regional distant unknown (%) (%) (%) (%) (%) (%) (%) (%) 1991–1995 196 99,5 0,5 0,0 0,0 189 97,4 2,6 0,0 0,0 1996–2000 247 95,5 2,4 0,4 1,6 208 99,0 1,0 0,0 0,0 2001–2005 315 99,4 0,3 0,3 0,0 271 97,0 2,6 0,4 0,0 EPIDEMIOLOGY Rak.qxd 22.7.2009 12:39 Page 229 dve tretjini tumorjev opredeljenih kot glioblastom, 14 % je bilo astrocitomov, 10 % pa oligo- dendrogliomov. Ostali gliomi so bili redki. Pribli`no 60 % zbolelih je bilo ob diagnozi starih 50–74 let, ~etrtina pa 20–49 let. Dele` sta- rih 75 let in ve~ je najmanj{i, vendar se pri obeh spolih s ~asom ve~a (Tabela 1). Rak mo`ganov je bolezen, ki je praviloma odkrita v omejenem stadiju (Tabela 2). V obdobju 2001–2005 ni bilo specifi~no zdravljenih 21 % bolnikov. Dele` nezdravljenih bolni- kov se je skozi opazovano obdobje nekoliko pove~al; med bolniki, zbolelimi v obdobju 1991–1995, jih 18 % ni bilo specifi~no zdravljenih. Med specifi~no zdravljenimi je bilo v letih 2001–2005 36 % bolnikov samo operiranih, pri 30 % je bila operaciji dodana {e radio- in kemoterapija, 28 % 230 MO@GANI 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Slika 2: Deset-, pet-, tri- in enoletno relativno pre`ivetje bolnikov z rakom mo`ganov po obdobju postavitve diagnoze. Figure 2: 10-, 5-, 3- and 1-year relative survival of brain cancer patients by period of diagnosis. Tabela 3: Opazovano in relativno pre`ivetje bolnikov z rakom mo`ganov po spolu in obdobju postavitve diagnoze s 95-odstotnim intervalom zaupanja (IZ). Table 3: Observed and relative survival of brain cancer patients by sex and period of diagnosis with 95% con- fidence interval (CI). Opazovano pre`ivetje / Observed survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 36,7 (30,6–44,1) 18,4 (13,7–24,7) 13,3 (9,3–19,0) 32,3 (26,3–39,7) 19,0 (14,2–25,6) 16,9 (12,3–23,2) 1996–2000 37,2 (31,7–43,8) 17,4 (13,3–22,8) 13,0 (9,4–17,9) 35,6 (29,6–42,7) 16,3 (12,0–22,2) 12,5 (8,7–17,9) 2001–2005 37,1 (32,2–42,9) 18,7 (14,8–23,5) 14,0 (10,4–18,8) 37,6 (32,3–43,9) 19,7 (15,4–25,1) 18,2 (14,0–23,5) Relativno pre`ivetje / Relative survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 37,5 (29,9–45,1) 19,6 (12,9–26,3) 14,8 (8,4–21,2) 32,7 (25,2–40,2) 19,8 (13,0–26,6) 18,1 (11,4–24,8) 1996–2000 38,1 (31,4–44,8) 18,7 (12,9–24,6) 14,7 (9,1–20,4) 36,0 (28,8–43,3) 17,0 (10,9–23,2) 13,5 (7,6–19,3) 2001–2005 38,1 (32,2–44,0) 20,2 (14,9–25,4) 16,0 (10,5–21,5) 38,3 (31,9–44,6) 20,7 (15,0–26,5) 20,0 (14,1–25,9) Rak.qxd 22.7.2009 12:39 Page 230 at an age between 50–74 years have 9% 5-year relative survival while those aged 75 years or older do not survive five years from diagnosis. The 5-year relative survival of all patients diagnosed in the period 2001–2005 was 18% (Figure 2); patients surviving the first year may expect to survive five years in 44%. According to the results of EUROCARE-4 study for patients diagnosed in 2000–2002, the survival of brain cancer patients in Slovenia is below (statistically not significant) the European average (Figure 4). 231 BRAIN CLINICAL COMMENT ARY Uro{ Smrdel 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 20–49 let / years 50–74 let / years 75+ let / years Vsi / All Slika 3: Petletno relativno pre`ivetje bolnikov z rakom mo`ganov po starosti in obdobju postavitve diagnoze. Figure 3: 5-year relative survival of brain cancer patients by age and period of diagnosis. When reviewing tables and curves pertaining to patients with brain tumors, at a first glance, one cannot note any particular difference between the beginning and the end of the observa- tion period. Most positive is an improved survival in the group of patients less than 50 years of age, observed after the year 2001. Improvement in survival in the last period, particularly after the inclusion of chemotherapy into treatment, has been reported by several authors. They also find the improvement to be the greatest in the group of younger patients. However, considering still poor survival of patients with brain tumors, a few facts need to be pointed out. Besides on age and method of treatment, the survival depends on the histologi- cal type and grade of tumor differentiation (grade, G). Thus, for example, the median survival of patients with G2 astrocytoma is 7 years while the survival of patients with glioblastoma is only 16 months; the survival of patients with oligodendrogliomas is higher than in those with astrocytoma. In the group of primary brain tumors, glioblastoma is the most frequent, thus most significantly influencing the survival. After the year 2004, however, major changes occurred in the treatment of glioblastoma. Considering the treatment of our patients, we need to call attention to the large proportion of surgical resection. While elsewhere biopsy is the most common method of tumor verifica- tion, in Slovenia the most frequent approach to diagnosis is still maximum surgical resection. Likewise, patients with progressive disease are relatively frequently subjected to reoperations, which are used less frequently in other countries. Throughout the observation period, radio- therapy remains indispensable in gliomas of high-grade malignancy. In recent period we note a moderate increase in the cumulative dose, mainly on the account of more radical treatment Rak.qxd 22.7.2009 12:39 Page 231 pa so samo obsevali. Ostale kombinacije zdravljenja so uporabili pri manj kot 5 % bolnikov. V zadnjih letih je v primerjavi s prej{njimi obdobji ve~ bolnikov v okviru prvega zdravljenja poleg operacije in radioterapije prejelo {e kemoterapijo. Ve~ina bolnikov (80 %) je v obdobju 2001–2005 zdravljenje pri~ela v UKC Ljubljana, 18 % v UKC Maribor in 3 % na OI Ljubljana. Relativno pre`ivetje bolnikov z rakom mo`ganov se bistveno ne spreminja; v 15 letih se je pet- letno relativno pre`ivetje pove~alo le za 1 % (Slika 2); nekoliko dlje pre`ivijo `enske (Tabela 3). Kako pomembna je starost ob diagnozi, ka`e Slika 3: petletno relativno pre`ivetje bolnikov, zbolelih pred 50. letom, je 45 %, bolniki, zboleli v starosti 50–74 let, imajo petletno relativno pre`ivetje 9 %, medtem ko stari 75 let in ve~ ne pre`ivijo petih let po diagnozi. Petletno relativno pre`ivetje vseh zbolelih v obdobju 2001–2005 je bilo 18 % (Slika 2); bolni- ki, ki pre`ivijo prvo leto, pa lahko pri~akujejo 44-odstotno petletno relativno pre`ivetje. Rezultati {tudije EUROCARE-4 za zbolele v obdobju 2000–2002 ka`ejo, da je pre`ivetje sloven- skih bolnikov z rakom mo`ganov statisti~no nezna~ilno manj{e od evropskega povpre~ja (Slika 4). 232 MO@GANI KLINI^NI KOMENT AR Uro{ Smrdel Ko pregledujem tabele in krivulje bolnikov z mo`ganskimi tumorji, na prvi pogled ne vidim pomembne razlike med za~etkom in koncem opazovanega obdobja. Najbolj pozitivno je izbolj- {anje pre`ivetja skupine bolnikov, mlaj{ih od 50 let, po letu 2001. Izbolj{anje pre`ivetja v zadnjem obdobju, predvsem po vklju~itvi kemoterapije v zdravljenje, opisujejo {tevilni avtorji. Tudi ti ugotavljajo, da je izbolj{anje najve~je v skupini mlaj{ih bolnikov. Glede na {e vedno slabo pre`ivetje bolnikov s tumorji mo`ganov, pa je potrebno poudariti {e nekaj dejstev. Pre`ivetje se pri bolnikih poleg starosti in na~ina zdravljenja razlikuje tudi gle- de na histolo{ko vrsto in stopnjo diferenciacije (gradus, G) tumorja. Tako je npr. srednje pre`ivetje bolnikov z astrocitomom G2 7 let, bolnikov z glioblastomom pa le 16 mesecev; pre`ivetje bolnikov z oligodendroglialnimi tumorji je ve~je kot tistih z astrocitomi. V skupini primarnih mo`gan- skih tumorjev je glioblastom najpogostej{i in tudi najpomembneje vpliva na pre`ivetje. Ravno pri glioblastomu pa je pri{lo po letu 2004 do najve~jih sprememb v na~inu zdravljenja. ^e pogledamo na~in zdravljenja na{ih bolnikov, moramo najprej opozoriti na velik dele` kirur{- kih resekcij. Medtem ko je drugod zelo pogost na~in verifikacije biopsija, pa je v Sloveniji maksimalna kirur{ka odstranitev {e vedno najpogostej{i na~in, ki privede do diagnoze. Rav- no tako so pri bolnikih, pri katerih pride do napredovanja bolezni, razmeroma pogoste ponovne operacije, ki so drugod redkej{e. Radioterapija ostaja v celotnem obdobju stalnica pri visoko malignih gliomih. V tem ~asu sicer opa`amo zmerno pove~anje skupnega odmerka, predvsem na ra~un bolj radikalnih zdravljenj, pomembnej{a pa je sprememba na~ina obsevanja z bolj natan~- no dolo~itvijo obsevalnih polj. Odprto pa ostaja vpra{anje zgodnje ali odlo`ene radioterapije pri nizko malignih gliomih. Kemoterapija se je v ve~ji meri pridru`ila zdravljenju po letu 2001 in to predvsem v obliki dodatnega zdravljenja; pred letom 2001 se je kemoterapija pri gliob- lastomih uporabljala predvsem paliativno ob napredovanju tumorja. S hkratno kemo- in radioterapijo smo pri~eli zdraviti bolnike leta 2004; do konca leta 2005 je bilo zdravljenih okrog 30 bolnikov, kar predstavlja v skupnem {tevilu le 2 % in v obdobju 2001 do 2005 5 % bolni- kov. @e prej smo za~eli uporabljati kemoterapijo pri anaplasti~nih oligodendrogliomih, vendar ti predstavljajo le manj{i del vseh primarnih mo`ganskih tumorjev. Tako kemoterapija pri tej skupini ni pomembno vplivala na pre`ivetje. Pri razmeroma majhnem dele`u bolnikov je bilo zdravljenje le podporno; ve~ina teh bolnikov se je zdravila tudi operativno. Za konec naj {e dodam, da se pri bolnikih z mo`ganskimi tumorji terapevtske mo`nosti {iri- jo, ~eprav je populacijsko pre`ivetje v Sloveniji {e vedno majhno. Terapevtski nihilizem, ki je Rak.qxd 22.7.2009 12:39 Page 232 schedules, however, the most important change has occurred in the irradiation technique using more accurate determination of irradiated fields. However, the issue of early or postponed radio- therapy in gliomas of low-grade malignancy remains unresolved. Chemotherapy started to be used in the treatment more regularly after the year 2001, particularly in the form of adjuvant therapy; before 2001, chemotherapy was used only with palliative intent in advanced glioblas- tomas. Simultaneous chemo- and radiotherapy was introduced into the treatment in 2004; by the end of 2005, there were approximately 30 patients treated in this way, which represents only 2% of the total and in the period 2001–2005, 5% of patients. Chemotherapy for the treat- ment of anaplastic oligodendrogliomas started to be used even earlier, however the latter type represents only a minor proportion of all primary brain tumors. Thus, chemotherapy in this group has not significantly influenced the survival. A relatively small proportion of patients received only supportive therapy; the majority of these patients also underwent surgery. Finally, let me add that in patients with brain tumors therapeutic options are expanding, although the population-based survival in Slovenia is still low. The therapeutic nihilism that used to pre- vail as regards the treatment of brain tumors has now been replaced by the search of prognostic factors predicting a better treatment outcome. Further development, particularly in the direc- tion of searching for molecular targets and treatment optimization, would probably contribute to further improvement of survival, at least in patients with a good performance status. 233 BRAIN 01 02 0 30 40 50 60 70 80 90 100 % Slovensko povpre~je / 2000–2002 (EUROCARE-4) Slovenian average Evropsko povpre~je / 2000–2002 (EUROCARE-4) European average Povpre~je ZDA / 2000–2002 (SEER-13) USA average Slika 4: Petletno relativno pre`ivetje bolnikov z rakom mo`ganov (povpre~je in 95-odstotni interval zaupanja), zbolelih v letih 2000–2002 v Sloveniji, Evropi in nekaterih obmo~jih v ZDA. Figure 4: 5-year relative survival of brain cancer patients (average and 95% confidence interval) diagnosed in the period 2000–2002 in Slovenia, Europe and in some regions of the USA. Rak.qxd 22.7.2009 12:39 Page 233 prej prevladoval pri zdravljenju mo`ganskih tumorjev, je sedaj zamenjalo iskanje napovednih dejavnikov, ki obetajo ve~jo uspe{nost zdravljenja. Z dodatnim razvojem, predvsem v smeri iska- nja molekularnih tar~ in optimiziranja zdravljenja, pa bi verjetno, vsaj pri bolnikih v dobrem stanju zmogljivosti, lahko uspeli {e dodatno izbolj{ati pre`ivetje. Barbagallo GM, Jenkinson MD, Brodbelt AR. šRecurrent’ glioblastoma multiforme, when should we reope- rate? Br J Neurosurg 2008; 22: 452–5. Brandes AA, Tosoni A, Franceschi E, Reni M, Gatta G, Vecht C. Glioblastoma in adults. Crit Rev Oncol Hematol 2008; 67: 139–52. Brandes AA, Tosoni A, Vastola F, Pasetto LM, Coria B, Danieli D, et al. Efficacy and feasibility of standard procarbazine, lomustine, and vincristine chemotherapy in anaplastic oligodendroglioma and oligoastrocy- toma recurrent after radiotherapy. A Phase II study. Cancer 2004; 101: 2079–85. Newton HB. Glioblastoma multiforme. Curr Treat Options Neurol 2008; 10: 285–94. Stummer W, Reulen HJ, Meinel T , Pichlmeier U, Schumacher W, Tonn JC, et al. Extent of resection and sur- vival in glioblastoma multiforme: identification of and adjustment for bias. Neurosurgery 2008; 62: 564–76. Stupp R, Mason WP , van den Bent MJ, Mason WP , Weller M, Mirimanoff RO, et al. Radiotherapy plus con- comitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352: 987–96. 234 MO@GANI VIRI Literature Rak.qxd 22.7.2009 12:39 Page 234 235 Rak.qxd 22.7.2009 12:39 Page 235 V obdobju 1991–2005 je za rakom {~itnice zbolelo 1316 ljudi, od tega 312 mo{kih in 1004 `en- ske. Kot je razvidno s Slike 1, se ~asovni trendi inciden~nih in umrljivostnih stopenj razlikujejo. Groba inciden~na stopnja je bila med letoma 1991 in 1995 stabilna, od 1996 naprej pa se pove- ~uje za 9,0 % letno. Umrljivostna stopnja se pri bolnikih z rakom {~itnice zmanj{uje za povpre~no 2,6 % letno. Ker so bolniki z rakom {~itnice ob diagnozi redko starej{i od 75 let (Tabela 1), sta obe starostno standardizirani meri prakti~no enaki grobim stopnjam. [^ITNICA MKB 10: C73 236 0 1 2 3 4 5 6 7 8 1986 1990 1995 2000 2005 Leto / Year Incidenca – groba stopnja / Incidence – crude rate Incidenca – SSS* / Incidence – ASR** Umrljivost – groba stopnja / Mortality – crude rate Umrljivost – SSS* / Mortality – ASR** Stopnja na 100.000 / Rate per 100,000 * SSS – starostno standardizirana stopnja (standard – slovenska populacija leta 1986) ** ASR – age standardized rate (standard Slovenian population in 1986) Slika 1: Groba in starostno standardizirana inciden~na in umrljivostna stopnja raka {~itnice, Slovenija 1986–2005. Figure 1: Crude and age-standardized incidence and mortality rate of thyroid cancer, Slovenia 1986–2005. Mo{ki / Males @enske / Females Obdobje / {tevilo / 20–49 let / 50–74 let / 75+ let / {tevilo / 20–49 let / 50–74 let / 75+ let / Period number years (%) years (%) years (%) number years (%) years (%) years (%) 1991–1995 70 45,7 51,4 2,9 235 44,7 41,7 13,6 1996–2000 95 35,8 54,7 9,5 284 44,7 43,7 11,6 2001–2005 122 38,5 54,9 6,6 435 45,3 45,3 9,4 T abela 1: [tevilo bolnikov z rakom {~itnice po spolu in obdobju postavitve diagnoze ter njihovi dele`i po starosti. Table 1: Number of thyroid cancer patients by sex and period of diagnosis with their proportions by age. V analizo pre`ivetja je vklju~enih 1241 primerov; 27 primerov (2,2 %) nismo upo{tevali, ker jim je bila diagnoza postavljena po smrti, 48 mlaj{ih od 20 let pa obravnavamo v poglavju o pre- `ivetju pri otrocih in mladostnikih. V obdobju 2001–2005 so bili mikroskopsko potrjeni vsi primeri, le trije niso imeli mikroskop- ske potrditve v desetletju 1991–2000. V celotnem obdobju je imelo 67 % bolnikov papilarni karcinom, 10 % folikularnega, po 7 % anaplasti~nega in karcinom Hürtlovih celic ter 5 % medu- larnega. Drugih opredeljenih histolo{kih vrst je bilo manj kot 1 %. Dele` papilarnega karcinoma EPIDEMIOLOGIJA Rak.qxd 22.7.2009 12:39 Page 236 In the period 1991–2005, a total of 1316 persons were diagnosed with cancer of the thyroid, of these 312 males and 1004 females. As evident from Figure 1, the trends in incidence and mortality rates differ from each other. Thus in the years 1991–1995 crude incidence rate was stable, while from 1996 on it has been increasing by 9.0% annually on average. Crude mor- tality rate was decreasing by 2.6% annually. Since thyroid cancer patients are hardly ever older than 75 years at diagnosis (Table 1), both age-standardized rates are practically the same as crude rates. The survival analysis included 1241 cases; 27 patients (2.2%) diagnosed only after death, were not considered in the analysis, 48 patients under 20 years of age are presented in the chapter on the survival of children and adolescents. In the period 2001–2005, all the cases were microscopically verified, while in the decade from 1991–2000 only three cases lacked microscopic confirmation. In the total observation peri- od, papillary carcinoma was found in 67% of patients, follicular in 10%, anaplastic and Hürthle-cell carcinoma in 7% each, and medullary carcinoma in 5% of patients. Other identified histological types represented less than 1% of cases. The proportion of papillary carcinoma has been increa- sing all the time; in the last period this histological type represented already 75% of all thyroid cancers. Although in different periods the number of patients diagnosed with follicular and anaplastic carcinomas has not changed significantly, in the last period their proportion among all thyroid cancers was smaller due to a higher total number of these cancers. More than half of male patients are at an age between 50 and 74 years, with few males devel- oping the disease aged 75 years or older. In females, the proportion of those aged between 50 and 74 years is roughly the same as the proportion of those aged between 20 and 50 years. Approximately 10% of patients are aged 75 years or older (Table 1). The proportions in indi- vidual age groups did not change significantly with time. The proportion of patients with localized stage has been increasing throughout the observa- tion period. In the last period 59% of male and 69% of female patients were diagnosed with localized thyroid cancer (Table 2). The proportions of patients with disseminated, regional and undefined stages have decreased on the account of a higher proportion of those with localized disease; in the last period there were less than 1% of patients with undefined stage. In the years 2001–2005, 2% of patients did not receive specific treatment. The proportion of untreated patients was decreasing throughout the duration of analysis; among those diagnosed in the period 1991–1995 there were 9% of patients without specific treatment. In the peri- od 2001–2005, 92% of patients with specific treatment underwent surgery. Two thirds of surgically treated patients also received radioiodine and hormonal treatment while 23% of them had only postoperative hormonal therapy. THYROID ICD 10: C73 237 Tabela 2: [tevilo bolnikov z rakom {~itnice po spolu in obdobju postavitve diagnoze ter njihovi dele`i po stadiju. Table 2: Number of thyroid cancer patients by sex and period of diagnosis with their proportions by stage. Mo{ki / Males @enske / Females Obdobje / {tevilo / omejen / raz{irjen / razsejan / neznan / {tevilo / omejen / raz{irjen / razsejan / neznan / Period number localized regional distant unknown number localized regional distant unknown (%) (%) (%) (%) (%) (%) (%) (%) 1991–1995 70 38,6 45,7 12,9 2,9 235 56,2 30,6 11,5 1,7 1996–2000 95 50,5 36,8 11,6 1,1 284 60,6 29,9 8,1 1,4 2001–2005 122 59,0 32,0 8,2 0,8 435 69,2 21,8 8,0 0,9 EPIDEMIOLOGY Rak.qxd 22.7.2009 12:39 Page 237 se ves ~as pove~uje. V zadnjem obdobju je ta histolo{ka vrsta predstavljala `e 75 % vseh rakov {~itnice. ^eprav se {tevilo zbolelih s folikularnim in anaplasti~nim karcinomom v razli~nih obdob- jih ni bistveno spreminjalo, pa je zaradi ve~jega skupnega {tevila njihov dele` med vsemi raki {~itnice v zadnjem obdobju manj{i. Ve~ kot polovica zbolelih mo{kih je stara med 50 in 74 let, redki mo{ki zbolijo po 75. letu. Pri `enskah je dele` starih od 50 do 74 let pribli`no enak dele`u starih 20–49 let. Pribli`no 10 % bolnic je starih 75 let in ve~ (Tabela 1). Dele`i v posameznih starostnih skupinah se s ~asom niso bistveno spreminjali. Ves ~as opazovanja pa se je ve~al dele` bolnikov z omejenim stadi- jem bolezni. V zadnjem obdobju je bilo z omejenim rakom {~itnice odkritih 59 % mo{kih in 69 % `ensk (Tabela 2). Na ra~un ve~jega dele`a raka v omejenem stadiju so se zmanj{ali dele`i 238 [^ITNICA 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Slika 2: Deset-, pet-, tri- in enoletno relativno pre`ivetje bolnikov z rakom {~itnice po obdobju postavitve diagnoze. Figure 2: 10-, 5-, 3- and 1-year relative survival of thyroid cancer patients by period of diagnosis. Tabela 3: Opazovano in relativno pre`ivetje bolnikov z rakom {~itnice po spolu in obdobju postavitve diagnoze s 95-odstotnim intervalom zaupanja (IZ). Table 3: Observed and relative survival of thyroid cancer patients by sex and period of diagnosis with 95% confidence interval (CI). Opazovano pre`ivetje / Observed survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 81,4 (72,8–91,1) 70,0 (60,0–81,6) 70,0 (60,0–81,6) 82,6 (77,8–87,6) 76,6 (71,4–82,2) 75,3 (70,0–81,0) 1996–2000 84,2 (77,2–91,9) 77,9 (70,0–86,7) 75,8 (67,6–84,9) 90,1 (86,7–93,7) 87,0 (83,1–91,0) 84,2 (80,0–88,5) 2001–2005 92,6 (88,1–97,4) 85,7 (79,7–92,3) 80,3 (72,9–88,6) 93,8 (91,6–96,1) 89,3 (86,4–92,3) 86,0 (82,4–89,7) Relativno pre`ivetje / Relative survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 83,0 (73,2–92,8) 74,3 (62,0–86,6) 77,0 (64,2–89,7) 84,2 (79,1–89,3) 81,4 (75,4–87,3) 82,7 (76,4–89,0) 1996–2000 86,6 (78,7–94,5) 85,0 (75,4–94,6) 86,3 (75,9–96,7) 91,4 (87,8–95,0) 91,0 (86,8–95,2) 90,2 (85,5–94,9) 2001–2005 94,3 (89,5–99,2) 91,4 (84,4–98,3) 90,2 (80,9–99,5) 94,7 (92,4–97,0) 92,4 (89,3–95,5) 91,5 (87,6–95,5) Rak.qxd 22.7.2009 12:39 Page 238 In the period 2001–2005, 73% started their treatment at the IO Ljubljana, 17% in the UMC Ljubljana and 7% in the UMC Maribor. Individual patients started their treatment in GH of Izola, Slovenj Gradec and Jesenice. Practically all patients (98%), irrespective of their initial treatment hospital, were in the course of their primary treatment referred to the IO Ljubljana. The relative survival rate of patients with thyroid cancer has been gradually increasing: in 15 years, the 5-year relative survival increased by 9% (Figure 2), in males slightly more than in females (Table 3). The relevance of stage at diagnosis is shown in Figure 3. In the last two periods, 5-year relative survival of patients with localized stage has reached 100%. The survival of patients with regional disease has been increasing throughout the observation period as well, the 5-year relative survival in those diagnosed between the years 2001–2005 being 88%. Age is a prog- nostic factor as well, since in the last period all the patients under 50 years of age survived five years, while 68% of those aged 75 years or older survived five years (Figure 4). The 5-year relative survival rate of all patients diagnosed in the period 2001–2005 was 91% (Figure 2). Patients surviving the first year may expect to survive five years in 96%. 239 THYROID 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 Omejen / Localized Raz{irjen / Regional Razsejan / Distant Vsi / All Slika 3: Petletno relativno pre`ivetje bolnikov z rakom {~itnice po stadiju in obdobju postavitve diagnoze. Figure 3: 5-year relative survival of thyroid cancer patients by stage and period of diagnosis. 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 20–49 let / years 50–74 let / years 75+ let / years Vsi / All Slika 4: Petletno relativno pre`ivetje bolnikov z rakom {~itnice po starosti in obdobju postavitve diagnoze. Figure 4: 5-year relative survival of thyroid cancer patients by age and period of diagnosis. Rak.qxd 22.7.2009 12:39 Page 239 bolnikov z razsejanim in raz{irjenim stadijem ter bolnikov brez dolo~enega stadija; zadnjih je bilo v obdobju 2001–2005 manj kot 1 %. V obdobju 2001–2005 ni bilo specifi~no zdravljenih 2 % bolnikov. Dele` nezdravljenih bol- nikov se je v celotnem obdobju analize zmanj{eval; med bolniki, zbolelimi v obdobju 1991–1995, jih je bilo brez specifi~nega zdravljenja 9 %. Med specifi~no zdravljenimi je bilo v letih 2001–2005 operiranih 92 % bolnikov. Med njimi sta bili dve tretjini bolnikov zdravljeni {e z radiojodom in s hormoni, 23 % jih je po operaciji prejelo le hormonska zdravila. V obdobju 2001–2005 je 73 % bolnikov pri~elo zdravljenje na OI Ljubljana, 17 % v UKC Ljub- ljana ter 7 % v UKC Maribor. Posamezne bolnike so pri~eli zdraviti {e v SB Izola, SB Slovenj Gradec in SB Jesenice. Skoraj vsi bolniki (98 %) so bili, ne glede na bolni{nico pri~etka zdrav- ljenja, v okviru prvega zdravljenja obravnavani tudi na OI Ljubljana. Relativno pre`ivetje bolnikov z rakom {~itnice se postopno pove~uje; v 15 letih se je petletno relativno pre`ivetje pove~alo za 9 % (Slika 2), pri mo{kih nekaj ve~ kot pri `enskah (Tabela 3). Kako pomemben je stadij ob diagnozi, ka`e Slika 3: petletno relativno pre`ivetje bolnikov z ome- jenim stadijem je v zadnjih dveh obdobjih 100 %. Ves ~as se pove~uje tudi pre`ivetje bolnikov z raz{irjenim stadijem; zboleli v letih 2001–2005 so imeli petletno relativno pre`ivetje 88 %. Napovedni dejavnik je tudi starost, saj so v zadnjem obdobju vsi mlaj{i od 50 let pre`iveli pet let, pri starih 75 let in ve~ pa je petletno relativno pre`ivetje 68 % (Slika 4). Petletno relativno pre`ivetje vseh zbolelih v obdobju 2001–2005 je bilo 91 % (Slika 2); bolni- ki, ki pre`ivijo prvo leto, pa lahko pri~akujejo 96-odstotno petletno relativno pre`ivetje. Rak {~itnice je ena redkih rakavih bolezni, pri kateri je petletno relativno pre`ivetje slovenskih bolnikov, zbolelih v obdobju 2000–2002, statisti~no zna~ilno ve~je od povpre~ja evropskih dr`av, zajetih v raziskavo EUROCARE-4 (Slika 5). 240 [^ITNICA KLINI^NI KOMENT AR Nikola Be{i} Tako kot povsod po svetu tudi v Sloveniji incidenca raka {~itnice raste. Najverjetneje je vzrok za to bolj{a in zgodnej{a diagnostika, saj se ve~a {tevilo ultrazvo~nih preiskav {~itnice in ultra- zvo~no vodenih tankoigelnih aspiracijskih biopsij. Ta omogo~a odkrivanje raka, {e preden je lahko klini~no prepoznan. Zato se je zelo pove~ala incidenca papilarnega mikrokarcinoma {~itnice. Tudi na{i bolniki s papilarnim mikrokarcinomom imajo zelo dobro napoved izida bolezni; petlet- no pre`ivetje teh bolnikov je bilo 99 %, desetletno pa 98 %. Sedaj bolnike z rakom {~itnice odkrijemo v zgodnej{ih stadijih (Tabela 2). Na to ka`e tudi manj{a povpre~na velikost tumorja. Med na{i- mi bolniki s citolo{ko postavljenim sumom za folikularnega raka je bil v obdobju od 1988–1993 povpre~ni premer tumorja 4,2 cm, v obdobju od 1994–1999 3,7 cm in v obdobju od 2000–2004 samo {e 3,3 cm. Razen zgodnej{ega diagnosticiranja raka {~itnice je izbolj{anje napovedi izida za bolnike, zdravljene v obdobju 1996–2005, v primerjavi s prej{njim obdobjem najverjetneje posledica dodatnega jodiranja kuhinjske soli v Sloveniji. V letih 1953–1998 je bilo soli dodano 10 mg kalijevega jodida na kilogram soli, od leta 1998 pa je kilogram soli jodiran s 25 mg kalijevega jodida. Dodatno jodiranje soli je spremenilo dele` podtipov raka {~itnice. Ve~ je tak{nih z ugodnej{o napovedjo izida. Na dobro pre`ivetje bolnikov zanesljivo vpliva tudi u~inkovito zdravljenje. Razveseljivo je, da skoraj vse bolnike z rakom {~itnice operirajo le na treh oddelkih samo kirurgi z izku{njami s ki- rurgijo {~itnice. Zato se pri ve~ini bolnikov opravi optimalni poseg – totalna ali skoraj totalna tiroidektomija. Vse nadaljnje zdravljenje in sledenje bolnikov izvajamo na OI Ljubljana, kjer zdravljenje poteka multidisciplinarno. Seveda sledimo vsem novostim pri diagnostiki in zdrav- ljenju. @e od leta 2001 uporabljamo rhTSH pri bolnikih, ki zaradi slabega splo{nega stanja ali spremljajo~ih bolezni ne bi mogli dobiti radiojoda ob hormonskem premoru. Zadnjih nekaj Rak.qxd 22.7.2009 12:39 Page 240 Thyroid cancer is one of the few cancer diseases in which 5-year relative survival of patients in Slovenia is statistically significantly above the average in other European countries includ- ed in EUROCARE-4 study for patients diagnosed in 2000–2002 study (Figure 5). 241 THYROID CLINICAL COMMENT ARY Nikola Be{i} 01 02 0 30 40 50 60 70 80 90 100 % Slovensko povpre~je / 2000–2002 (EUROCARE-4) Slovenian average Evropsko povpre~je / 2000–2002 (EUROCARE-4) European average Povpre~je ZDA / 2000–2002 (SEER-13) USA average Slika 5: Petletno relativno pre`ivetje bolnikov z rakom {~itnice (povpre~je in 95-odstotni interval zaupanja), zbolelih v letih 2000–2002 v Sloveniji, Evropi in nekaterih obmo~jih v ZDA. Figure 5: 5-year relative survival of thyroid cancer patients (average and 95% confidence interval) diagnosed in the period 2000–2002 in Slovenia, Europe and in some regions of the USA. As elsewhere in the world, in Slovenia too the incidence of thyroid cancer is increasing. Most probably, the reason for that is better and earlier diagnosis, as the number of ultrasonographies of the thyroid and US-guided fine-needle aspiration biopsies has been increasing, thus facil- itating cancer detection before the disease becomes clinically evident. Therefore, a marked increase has been observed in the incidence of papillary microcellular carcinoma of the thyroid. Our patients with papillary microcarcinoma also have a very favorable prognosis, their 5-year sur- vival being 99% and 10-year survival 98%. Nowadays, thyroid cancer patients are diagnosed at an earlier stage (Table 2), which is evident from their smaller average tumor size. In the peri- od 1988–1993, an average tumor diameter in patients with cytologically suspected follicular cancer was 4.2 cm, in the period 1994–1999 3.7 cm, whereas in the period 200–2004 it was only 3.3 cm. Apart from earlier diagnosis of thyroid cancer, better prognosis of patients treated in the peri- od 1996–2005 – as compared to the preceding period – is most probably attributable to the iodizing of table salt in Slovenia. In the years 1953–1998, 10 mg of potassium iodide were added per one kilogram of salt, whereas from 1998 on the iodization level has been 25 mg of potas- sium iodide per kg of salt. Additional iodization of table salt has brought about a change in the proportion of thyroid cancer subtypes, those with a favorable diagnosis being more fre- quent. Better survival of patients is certainly influenced by an effective treatment. It is encouraging that almost all thyroid cancer patients are operated on exclusively in three specialized depart- ments by surgeons-experts in thyroid surgery, and therefore most patients undergo an optimal procedure, i. e. total or near-total thyroidectomy. Any further treatment and patient follow up is performed at the IO Ljubljana, using multidisciplinary team approach. Of course, all advances Rak.qxd 22.7.2009 12:39 Page 241 let uporabljamo rhTSH tudi za ablacijo ostanka {~itnice z radiojodom in za testiranje kopi- ~enja radiojoda, kar bolnikom zelo zmanj{a te`ave, ki so jih imeli zaradi hipotiroze. Zaradi ve~jega dele`a bolnikov s prognosti~no ugodnim papilarnim mikrokarcinomom se je zve~al dele` bolni- kov, ki jih ni potrebno zdraviti z radiojodom. Ti bolniki morajo namesto zavornega zdravljenja s {~itni~nimi hormoni jemati hormone le v nadomestnih odmerkih. Be{i} N, @gajnar J, Ho~evar M, Frkovi}-Grazio S. Is patient's age a prognostic factor for follicular thyroid carci- noma in the TNM classification system? Thyroid 2005; 15: 439–48. Be{i} N, Se{ek M, Peri~ B, @gajnar J, Ho~evar M. Predictive factors of carcinoma in 327 patients with fol- licular neoplasm of the thyroid. Med Sci Monitor 2008; 14: CR 459–67. Be{i} N. Zavorno in nadomestno zdravljenje s {~itni~nimi hormoni. Onkologija 2008; 12: 33–4. 242 [^ITNICA VIRI Literature Rak.qxd 22.7.2009 12:39 Page 242 in diagnosis and treatment are considered, and thus ever since 2001 recombinant human TSH has been used in patients in whom the use of radio-iodine during hormonal pause is not pos- sible due to their poor general condition or concomitant diseases. In the last few years rhTSH has also been used for radioiodine ablation of residual thyroid tissue as well as for testing radioio- dine uptake, which significantly alleviates hypothyroidosis-related difficulties. Due to a greater proportion of patients with prognostically favorable papillary microcarcinoma, the proportion of patients not requiring radioiodine treatment has been increased accordingly. Instead of sup- pressive therapy with thyroid hormones, these patients need to receive only supplementary doses of hormones. 243 THYROID Rak.qxd 22.7.2009 12:39 Page 243 V obdobju 1991–2005 je za Hodgkinovim limfomom (HL) zbolelo 633 ljudi, od tega 333 mo{- kih in 300 `ensk. Kot je razvidno s Slike 1, se je groba inciden~na stopnja pove~evala od leta 1991 v povpre~ju za 1,8 % letno. Podatkov o umrljivosti do leta 1997 ni mogo~e interpretirati, saj do tedaj HL kot vzroka smrti niso ustrezno {ifrirali. Med letoma 1999 in 2005 se je groba umr- ljivostna stopnja zmanj{evala povpre~no za 2,9 % letno, starostno standardizirana pa za 4,3 %. HODGKINOV LIMFOM MKB 10: C81 244 0 1 2 3 1986 1990 1995 2000 2005 Leto / Year Incidenca – groba stopnja / Incidence – crude rate Incidenca – SSS* / Incidence – ASR** Umrljivost – groba stopnja / Mortality – crude rate Umrljivost – SSS* / Mortality – ASR** Stopnja na 100.000 / Rate per 100,000 * SSS – starostno standardizirana stopnja (standard – slovenska populacija leta 1986) ** ASR – age standardized rate (standard Slovenian population in 1986) Slika 1: Groba in starostno standardizirana inciden~na in umrljivostna stopnja Hodgkinovega limfoma, Slovenija 1986–2005. Figure 1: Crude and age-standardized incidence and mortality rate of Hodgkin's lymphoma, Slovenia 1986–2005. Mo{ki / Males @enske / Females Obdobje / {tevilo / 20–49 let / 50–74 let / 75+ let / {tevilo / 20–49 let / 50–74 let / 75+ let / Period number years (%) years (%) years (%) number years (%) years (%) years (%) 1991–1995 80 62,5 30,0 7,5 67 68,7 25,4 6,0 1996–2000 86 68,6 27,9 3,5 72 65,3 22,2 12,5 2001–2005 108 63,9 30,6 5,6 96 66,7 20,8 12,5 Tabela 1: [tevilo bolnikov s Hodgkinovim limfomom po spolu in obdobju postavitve diagnoze ter njihovi dele`i po starosti. T able 1: Number of Hodgkin's lymphoma patients by sex and period of diagnosis with their proportions by age. V analizo pre`ivetja je vklju~enih 509 primerov; 10 bolnikov (1,6 %) nismo upo{tevali, ker jim je bila diagnoza postavljena po smrti, 114 otrok in mladostnikov pa obravnavamo v poglavju o pre`ivetju pri otrocih in mladostnikih. Vsi tumorji bolnikov, vklju~enih v analizo, so bili mikro- skopsko potrjeni. Pribli`no dve tretjini bolnikov zbolita pred 50. letom, ve~ina ostalih do 74. leta, manj kot 10 % bolnikov pa je ob postavitvi diagnoze starih 75 let ali ve~ (Tabela 1). Razen pove~anega dele- `a najstarej{ih `ensk se dele`i v posameznih starostnih skupinah s ~asom niso bistveno spreminjali. V vseh treh obdobjih je bila najmanj{emu dele`u bolnikov diagnoza postavljena v za~etnem EPIDEMIOLOGIJA Rak.qxd 22.7.2009 12:39 Page 244 In the period 1991–2005, a total of 633 persons were diagnosed with Hodgkin's lymphoma (HL), of these 333 males and 300 females. As evident from Figure 1, the incidence rate has been increasing since 1991, by 1.8% annually on average. Mortality data till 1997 cannot be analyzed because until then HL as cause of death had not been coded appropriately. In the period between 1999 and 2005 the crude mortality rate in patients with HL was decreasing by 2.9% and age-standardized by 4.3% annually on average. The survival analysis included 509 cases; 10 patients (1.6%) diagnosed only after death, were not considered in the analysis; 114 children and adolescents are presented in the chapter on the survival of children and adolescents.All tumors of the patients under analysis were micro- scopically confirmed. Approximately two thirds of the patients were diagnosed before 50 years of age, most of the remaining ones up to the age of 74 years, while less than 10% of patients aged 75 years or older at diagnosis (Table 1). Except for the increased proportion of females in the oldest age group, the proportions in individual age groups did not change significantly with time. In all three periods the smallest proportion of patients were diagnosed in the initial stage. In last years, the proportion of patients diagnosed in the second stage has increased significant- ly. The increase is more apparent in females and is a consequence of the decreasing proportion of patients with the disease diagnosed in the third and fourth stages (Table 2). In the period 2001–2005, 7% of patients did not receive specific treatment. Nearly half of them were older than 80 years. The proportion of untreated patients has remained approximately the same throughout the period under analysis. Among the patients receiving specific treat- ment in the period 2001–2005, 55% were treated by chemotherapy and irradiation, 33% received only chemotherapy, while the rest were treated with other combinations of therapeutic modali- ties. Nearly all patients with HD received their specific treatment at the IO Ljubljana; in the peri- od 2001–2005 there were only 7 patients treated in the UMC Ljubljana, UMC Maribor and GH Izola. The relative survival has been gradually increasing; in 15 years, the 5-year relative survival increased by 9% (Figure 2), the increase being approximately the same in both genders (Table 3). The sur- vival of patients diagnosed in the first and second stage is very good; in the period 2001–2005 it was 96% in both cases. In the last 15 years the 5-year relative survival of patients with the third and fourth stage has not changed significantly, being approximately 80% (Figure 3). In patients with HL, age at diagnosis is also an important prognostic factor of survival. In the period 2001–2005, the 5-year relative survival of patients less than 50 years of age was 96%, HODGKIN's LYMPHOMA ICD 10: C81 245 Tabela 2: [tevilo bolnikov s Hodgkinovim limfomom po spolu in obdobju postavitve diagnoze ter njihovi dele`i po stadiju. T able 2: Number of Hodgkin's lymphoma patients by sex and period of diagnosis with their proportions by stage. Mo{ki / Males @enske / Females Obdobje / N I II III + IV Neznan N I II III + IV Neznan Period (%) (%) (%) (%) (%) (%) (%) (%) 1991–1995 80 16,3 30,0 53,8 0,0 67 13,4 35,8 47,8 3,0 1996–2000 86 16,3 30,2 48,8 4,7 72 13,9 40,3 41,7 4,2 2001–2005 108 14,8 37,0 46,3 1,9 96 10,4 51,0 33,3 5,2 EPIDEMIOLOGY Rak.qxd 22.7.2009 12:39 Page 245 stadiju. Zna~ilno se je v zadnjih letih ve~al dele` bolnikov z boleznijo, ugotovljeno v drugem stadiju. Pove~anje je bolj o~itno pri `enskah in je posledica tega, da se zmanj{uje dele` bolni- kov, pri katerih je bolezen ugotovljena v tretjem in ~etrtem stadiju (Tabela 2). V obdobju 2001–2005 ni bilo specifi~no zdravljenih 7 % bolnikov. Skoraj polovica med njimi je bila starej{a od 80 let. Dele` nezdravljenih bolnikov ostaja skozi vse obdobje analize prib- li`no enak. V letih 2001–2005 je bilo s kombinacijo kemoterapije in obsevanja zdravljenih 55 % od vseh specifi~no zdravljenih, 33 % jih je prejelo le kemoterapijo, ostali pa so bili zdravljeni z drugimi kombinacijami zdravljenj. Skoraj vsi bolniki so bili specifi~no zdravljeni na OI Ljubljana, v obdobju 2001–2005 je bilo le 7 bolnikov zdravljenih v UKC Ljubljana in UKC Maribor ter v SB Izola. 246 HODGKINOV LIMFOM 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Slika 2: Deset-, pet-, tri- in enoletno relativno pre`ivetje bolnikov s Hodgkinovim limfomom po obdobju postavitve diagnoze. Figure 2: 10-, 5-, 3- and 1-year relative survival of Hodgkin's lymphoma patients by period of diagnosis. Tabela 3: Opazovano in relativno pre`ivetje bolnikov s Hodgkinovim limfomom po spolu in obdobju postavitve diagnoze s 95-odstotnim intervalom zaupanja (IZ). Table 3: Observed and relative survival of Hodgkin's lymphoma patients by sex and period of diagnosis with 95% confidence interval (CI). Opazovano pre`ivetje / Observed survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 88,8 (82,1–96,0) 77,5 (68,9–87,2) 73,8 (64,7–84,1) 88,1 (80,6–96,2) 82,1 (73,4–91,8) 77,6 (68,2–88,3) 1996–2000 93,0 (87,8–98,6) 83,7 (76,3–91,9) 75,6 (67,0–85,2) 87,5 (80,2–95,5) 84,7 (76,8–93,5) 79,2 (70,3–89,1) 2001–2005 92,6 (87,8–97,7) 84,1 (77,4–91,3) 82,9 (76,0–90,5) 90,6 (85,0–96,6) 86,5 (79,9–93,6) 83,9 (76,7–91,8) Relativno pre`ivetje / Relative survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 90,3 (82,9–97,6) 81,3 (71,1–91,5) 80,5 (69,2–91,7) 88,7 (80,6–96,9) 84,0 (74,1–93,9) 81,1 (70,0–92,2) 1996–2000 94,0 (88,4–99,6) 86,7 (78,2–95,2) 80,0 (69,8–90,2) 88,5 (80,5–96,6) 88,1 (79,0–97,2) 84,4 (73,8–95,1) 2001–2005 93,8 (88,6–98,9) 87,5 (80,0–95,0) 88,8 (80,7–96,9) 92,0 (85,9–98,1) 90,6 (83,1–98,1) 90,3 (81,9–98,8) Rak.qxd 22.7.2009 12:39 Page 246 of patients aged 50–74 years it was 80% while the survival of those aged 75 years and older was near to 60% (Figure 4). The 5-year relative survival of all patients diagnosed in the period 2001–2005 was 90% (Figure 2); patients surviving the first year may expect to survive five years in 95%. According to the results of EUROCARE-4 study for patients diagnosed in 2000–2002, the survival of Hodgkin's lymphoma patients in Slovenia is above (statistically not significant) the European average (Figure 5). 247 HODGKIN's LYMPHOMA CLINICAL COMMENT ARY Barbara Jezer{ek Novakovi} 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 I II III + IV Vsi / All 2001–2005 Slika 3: Petletno relativno pre`ivetje bolnikov s Hodgkinovim limfomom po stadiju in obdobju postavitve diagnoze. Figure 3: 5-year relative survival of Hodgkin's lymphoma patients by stage and period of diagnosis. 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 20–49 let / years 50–74 let / years 75+ let / years Vsi / All Slika 4: Petletno relativno pre`ivetje bolnikov s Hodgkinovim limfomom po starosti in obdobju postavitve diagnoze. Figure 4: 5-year relative survival of Hodgkin's lymphoma patients by age and period of diagnosis. In the period 1991–2005, the 5-year relative survival of patients with HL increased from 81% to 90%, which is attributed to better diagnostics as well as to better treatment and an indi- vidualized approach to every patient. Patients with HL are treated prevailingly at the IO Ljubljana Rak.qxd 22.7.2009 12:39 Page 247 Relativno pre`ivetje se postopno pove~uje; v 15 letih se je petletno relativno pre`ivetje pove~a- lo za 9 % (Slika 2), pove~anje je pribli`no enako pri obeh spolih (Tabela 3). Zelo dobro je pre`ivetje bolnikov, odkritih v prvem in drugem stadiju; v obdobju 2001–2005 je v obeh primerih 96 %. Petletno relativno pre`ivetje bolnikov s tretjim in ~etrtim stadijem se v zadnjih 15 letih ni bis- tveno spremenilo in je pribli`no 80 % (Slika 3). Pomemben napovedni dejavnik pre`ivetja bolnikov s HL je tudi starost ob diagnozi. Petletno relativno pre`ivetje mlaj{ih od 50 let je bilo v ob- dobju 2001–2005 96 %, bolnikov, starih 50–74 let 80 %, starih 75 let in ve~ pa skoraj 60 % (Slika 4). Petletno relativno pre`ivetje vseh zbolelih v obdobju 2001–2005 je bilo 90 % (Slika 2); bolni- ki, ki pre`ivijo prvo leto, pa lahko pri~akujejo 95-odstotno petletno relativno pre`ivetje. Rezultati {tudije EUROCARE-4 za zbolele v obdobju 2000–2002 ka`ejo, da je pre`ivetje sloven- skih bolnikov s Hodgkinovim limfomom statisti~no nezna~ilno ve~je od evropskega povpre~ja (Slika 5). 248 HODGKINOV LIMFOM KLINI^NI KOMENT AR Barbara Jezer{ek Novakovi} Petletno relativno pre`ivetje bolnikov s HL se je v obdobju od 1991–2005 pove~alo z 81 % na 90 %, kar pripisujemo tako bolj{i diagnostiki kot bolj{emu zdravljenju in individualiziranemu pristopu k vsakemu bolniku. Bolniki s HL se zdravijo prete`no na OI Ljubljana (96 % vseh, ki so bili zdravljeni), kar se odra`a z zelo dobrim pre`ivetjem bolnikov v primerjavi z bolniki v ostalih evropskih dr`avah. Bolniki, ki so obravnavani na OI Ljubljana, se namre~ zdravijo po enotnih sodobnih doktrinarnih na~elih, tako glede diagnosti~nega kot terapevtskega pri- stopa, hkrati pa pri izbiri najprimernej{ega zdravljenja upo{tevamo individualne zna~ilnosti posameznega bolnika. Presene~a dokaj visok odstotek bolnikov (7 %), ki naj bi ne bili dele`ni zdravljenja; podatki ka`ejo, da gre ve~inoma za starej{e bolnike, verjetno s {tevilnimi pridru- `enimi boleznimi. Novost v zdravljenju bolnikov s HL v obravnavanem obdobju je zdravljenje s citostatsko she- mo BEACOPP (poleg standardne sheme ABVD) od leta 1997, ki daje bolj{e rezultate zdravljenja pri razsejani bolezni. Citostatskemu zdravljenju sledi obsevanje prizadetih podro~ij v prime- ru omejene in raz{irjene bolezni in obsevanje samo ostanka bolezni v primeru razsejane bolezni. Natan~nej{o zamejitev bolezni pred pri~etkom zdravljenja in natan~nej{o dolo~itev ostanka bolezni pri razsejani obliki je omogo~ila tudi uvedba preiskave PET CT v rutinsko obravna- vo bolnikov s HL. Skupno petletno relativno pre`ivetje se je v obdobju 1991–2005 ve~alo predvsem pri bolnikih z omejeno, pa tudi z raz{irjeno boleznijo. Pri bolnikih z razsejano boleznijo pa je bilo pre`i- vetje v obdobju 2001–2005 prakti~no enako kot v obdobju 1991–1995. Ob tem je potrebno omeniti, da se je v celotnem opazovanem obdobju zmanj{eval dele` bolnikov z omejeno in raz- sejano boleznijo predvsem na ra~un bolnikov z raz{irjeno boleznijo, kjer pa je podalj{anje pre`ivetja najbolj izrazito. Petletno relativno pre`ivetje bolnikov, starih 75 let in ve~, se je v obdobju po letu 1991 le malo spreminjalo; pre`ivetje se je ve~alo predvsem pri mlaj{ih, starih 20–49 let in 50–74 let, kar je posledica odlo~nej{ega in u~inkovitej{ega zdravljenja ter bolj{e diagnostike. Canellos GP , Lister T A, Sklar JL, eds. The lymphomas. 2nd edition. Philadelphia: W. B. Saunders Company; 2006. Dalla-Favera R, Gaidano G. Lymphomas. In: DeVita VTJr, Hellman S, Rosenberg SA, eds. Cancer Principles and Practice of Oncology. 7th edition. Philadelphia: Lippincott Williams and Wilkins; 2005. Jezer{ek-Novakovi} B, ed. Smernice za obravnavo bolnikov z malignimi limfomi. Ljubljana: Onkolo{ki in{titut Ljubljana; 2008. VIRI Literature Rak.qxd 22.7.2009 12:39 Page 248 (96% of all treated patients), which is reflected in their very good survival as compared to the patients in other European countries. Namely, the patients referred to the IO Ljubljana are treated according to the uniform up-to-date doctrinary principles in terms of diagnostic as well as therapeutic approach, while in selecting the treatment of choice, individual characteristics of every individual patient are taken into account. Surprising is a relatively high percentage of patients (7%) who are presumably left untreated; the data show that these are generally older patients, possibly with numerous concomitant diseases. A novelty in the treatment of patients with HL in the period under analysis is treatment with cytostatics according to BEACOPP schedule (besides the standard ABVD schedule) used since 1997, which is found to be more effective in the cases with disseminated disease. Cytostatic treatment is followed by irradiation of the affected areas in the case of localized and regional disease, whereas in a disseminated stage irradiation is limited to the residual disease. The intro- duction of PET CT examination into the routine management of patients with HL facilitated more accurate staging of the disease before the beginning of treatment as well as more accu- rate assessment of the residual disease in a disseminated stage. In the period 1991–2005, overall 5-year relative survival was increasing particularly in patients with localized and also in those with regional disease. In the period 2001–2005, the survival of patients with disseminated disease was practically the same as in the period 1991–1995. However, it should be pointed out that throughout the observation period the proportion of patients with localized and disseminated disease has been decreasing mainly on the account of patients with regional disease in whom an increase in survival is most apparent. In the period since 1991, the 5-year relative survival of patients aged 75 years or older has not undergone any particular change; the survival showed an upward trend only in younger age groups, i. e. 20–49 years and 50–74 years, as a result of more radical and effective treatment and better diagnostics. 249 HODGKIN's LYMPHOMA 01 02 0 30 40 50 60 70 80 90 100 % Slovensko povpre~je / 2000–2002 (EUROCARE-4) Slovenian average Evropsko povpre~je / 2000–2002 (EUROCARE-4) European average Povpre~je ZDA / 2000–2002 (SEER-13) USA average Slika 5: Petletno relativno pre`ivetje bolnikov s Hodgkinovim limfomom (povpre~je in 95-odstotni interval zaupanja), zbolelih v letih 2000–2002 v Sloveniji, Evropi in nekaterih obmo~jih v ZDA. Figure 5: 5-year relative survival of Hodgkin's lymphoma patients (average and 95% confidence interval) diag- nosed in the period 2000–2002 in Slovenia, Europe and in some regions of the USA. Rak.qxd 22.7.2009 12:39 Page 249 V obdobju 1991–2005 je za ne-Hodgkinovim limfomom (NHL) zbolelo 3068 ljudi, 1472 mo{- kih in 1596 `ensk. Kot je razvidno s Slike 1, sta se obe inciden~ni in umrljivostni stopnji v opazovanem obdobju pove~evali. Ker so NHL pogostej{i pri starej{ih (Tabela 1), je ve~anje bolj o~itno pri obeh grobih stopnjah. Incidenca se je ve~ala bolj kot umrljivost, v povpre~ju za 3,7 % letno; umrljivost se je ve~ala v povpre~ju za 3,2 % letno. NE-HODGKINOV LIMFOM MKB 10: C82–C85 250 HODGKINOV LIMFOM 0 2 4 6 8 10 12 14 1986 1990 1995 2000 2005 Leto / Year Incidenca – groba stopnja / Incidence – crude rate Incidenca – SSS* / Incidence – ASR** Umrljivost – groba stopnja / Mortality – crude rate Umrljivost – SSS* / Mortality – ASR** Stopnja na 100.000 / Rate per 100,000 * SSS – starostno standardizirana stopnja (standard – slovenska populacija leta 1986) ** ASR – age standardized rate (standard Slovenian population in 1986) Slika 1: Groba in starostno standardizirana inciden~na in umrljivostna stopnja ne-Hodgkinovega limfoma, Slovenija 1986–2005. Figure 1: Crude and age-standardized incidence and mortality rate of non-Hodgkin's lymphoma, Slovenia 1986–2005. Mo{ki / Males @enske / Females Obdobje / {tevilo / 20–49 let / 50–74 let / 75+ let / {tevilo / 20–49 let / 50–74 let / 75+ let / Period number years (%) years (%) years (%) number years (%) years (%) years (%) 1991–1995 390 23,3 56,2 20,5 409 17,6 55,3 27,1 1996–2000 455 20,9 62,2 16,9 505 19,0 53,5 27,5 2001–2005 537 22,9 54,0 23,1 628 14,8 53,0 32,2 Tabela 1: [tevilo bolnikov z ne-Hodgkinovim limfomom po spolu in obdobju postavitve diagnoze ter njihovi dele`i po starosti. Table 1: Number of non-Hodgkin's lymphoma patients by sex and period of diagnosis with their proportions by age. V analizo pre`ivetja je vklju~enih 2924 primerov; 49 bolnikov (1,6 %) nismo upo{tevali, ker jim je bila diagnoza postavljena po smrti, 95 otrok in mladostnikov pa obravnavamo v poseb- nem poglavju. Od vseh bolnikov le eden ni imel mikroskopsko potrjene bolezni; 1773 tumorjev je bilo nodalnega, 1151 pa ekstranodalnega izvora. Celotno skupino bolnikov z NHL smo glede na histolo{ko vrsto limfoma razdelili v {tiri pod- vrste: indolentne (MKB-O-3: 9670–9673, 9689, 9691–9699), agresivne (MKB-O-3: 9678, 9680–9687, 9727–9729), T-celi~ne (MKB-O-3: 9702–9705, 9709–9714, 9717–9719) in EPIDEMIOLOGIJA Rak.qxd 22.7.2009 12:39 Page 250 In the period 1991–2005, a total of 3068 persons were diagnosed with non-Hodgkin lymphoma (NHL), of these 1472 males and 1596 females. As evident from Figure 1, in the observed time period both incidence and mortality rates have been increasing. NHL being more frequent in the elderly (Table 1), the increase is more apparent in both crude rates. The incidence has been increasing more rapidly than the mortality, by 3.7% vs. 3.2% annually on average, respectively. The survival analysis included 2924 cases; 49 patients (1.6%) diagnosed only after death, were not considered in the analysis; 95 children and adolescents are presented in a separate chap- ter. Of all the patients, only one did not have microscopically verified disease; 1773 tumors were of nodal and 1151 of extranodal origin. According to histological type of lymphoma, the whole group of NHL patients was divided into four subgroups: indolent (ICD-O-3: 9670–9673, 9689, 9691–9699), aggressive (ICD-O-3: 9678, 9680–9687, 9727–9729), T-cell (ICD-O-3: 9702–9705, 9709–9714, 9717–9719) and undetermined (ICD-O-3: 9590, 9591). T-cell NHL with 240 patients (8%) represented the small- est group while undetermined and indolent NHL were present in a similar percentage: 839 cases of the former (29%) and 804 cases of the latter (28%). More than one third of all NHL are aggressive – 1041 cases (36%). In the earlier periods, the number of undetermined NHL was the highest, however, later on, by a more accurate histological classification, their number decreased significantly. In recent years, the majority of NHL patients present with aggressive and indo- lent NHL subtype (Figure 2). Approximately half of the patients are diagnosed at an age between 50–74 years (Table 1). The proportions in individual age groups did not change significantly with time. Likewise, there was no great difference in age at diagnosis when individual subgroups of NHL were compared with each other, except in the undetermined NHL, which are in the last period considerably less frequent in young patients and more frequent in patients aged 75 years and older. Almost half of the patients had the disease diagnosed in the first and the second stage, their proportion decreasing slightly in the last period while the proportion of patients with the third and the fourth stage, and surprisingly also the proportion of those with undefined stage at diag- nosis, have increased (Table 2). Most frequently the stage was not determined in undefined NHL (in nearly one third of cases); in T-cell and aggressive NHL the stage was not deter- mined in less than 10% of patients. In the years 2001–2005, 19% of patients did not receive specific treatment. Almost a half of the untreated patients were those with undefined NHL, one third had indolent NHL and very few (less than 5%) untreated patients had T-cell NHL. Also, patients under 50 years of age and those with stage I and stage II at diagnosis very rarely remain without specific treatment. The proportion of untreated patients has remained approximately the same throughout the NON-HODGKIN LYMPHOMA ICD 10: C82-C85 251 Tabela 2: [tevilo bolnikov z ne-Hodgkinovim limfomom po spolu in obdobju postavitve diagnoze ter njihovi dele`i po stadiju. Table 2: Number of non-Hodgkin's lymphoma patients by sex and period of diagnosis with their proportions by stage. Mo{ki / Males @enske / Females Obdobje / N I II III + IV Neznan N I II III + IV Neznan Period (%) (%) (%) (%) (%) (%) (%) (%) 1991–1995 390 27,4 23,6 38,5 10,5 409 29,8 22,0 36,2 12,0 1996–2000 455 24,4 26,4 37,1 12,1 505 27,1 21,0 38,4 13,5 2001–2005 537 22,9 20,9 41,2 15,1 628 24,7 19,4 41,1 14,8 EPIDEMIOLOGY Rak.qxd 22.7.2009 12:39 Page 251 neopredeljene (MKB-O-3: 9590, 9591). Z 240 bolniki (8 %) je bila najmanj{a skupina s T-ce- li~nimi NHL, neznanih in indolentnih NHL je bilo pribli`no enako: 839 primerov prvih (29 %) in 804 primerov drugih (28 %). Ve~ kot tretjina med vsemi NHL je agresivnih – 1041 prime- rov (36%). V za~etnih obdobjih je bilo najve~ neopredeljenih NHL, a se je njihovo {tevilo s kasnej{o bolj natan~no histolo{ko opredelitvijo bistveno zmanj{alo. Zadnja leta je med bol- niki z NHL najve~ tistih z agresivnimi in indolentnimi NHL (Slika 2). Pribli`no polovica bolnikov zboli v starosti 50–74 let (Tabela 1). Dele`i v posameznih starost- nih skupinah se z leti niso bistveno spreminjali. Prav tako ni velike razlike v starosti ob diagnozi, 252 NE-HODGKINOV LIMFOM 0 1 2 3 4 5 6 7 8 1986 1990 1995 2000 2005 Leto / Year Indolenetni tip / Indolent type Agresivni tip / Aggressive type T-celi~ni tip / T-cell type Neopredeljeni / Undetermined Stopnja na 100.000 / Rate per 100,000 Slika 2: Groba inciden~na stopnja {tirih histolo{kih podvrst ne-Hodgkinovega limfoma, Slovenija 1986–2005. Figure 2: Crude incidence rate of four hystological subgroups of non-Hodgkin's lymphoma, Slovenia 1986–2005. Tabela 3: Opazovano in relativno pre`ivetje bolnikov z ne-Hodgkinovim limfomom po spolu in obdobju postavitve diagnoze s 95-odstotnim intervalom zaupanja (IZ). Table 3: Observed and relative survival of non-Hodgkin's lymphoma patients by sex and period of diagnosis with 95% confidence interval (CI). Opazovano pre`ivetje / Observed survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 67,2 (62,7–72,0) 48,5 (43,7–53,7) 41,3 (36,7–46,5) 65,5 (61,1–70,3) 47,4 (42,8–52,5) 40,3 (35,9–45,4) 1996–2000 70,3 (66,3–74,7) 55,8 (51,4–60,6) 45,5 (41,1–50,3) 72,7 (68,9–76,7) 55,8 (51,7–60,3) 49,3 (45,1–53,9) 2001–2005 74,1 (70,5–77,9) 58,2 (54,1–62,5) 46,8 (42,3–51,8) 73,9 (70,5–77,4) 61,0 (57,3–65,0) 51,8 (47,6–56,3) Relativno pre`ivetje / Relative survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 70,2 (65,2–75,3) 55,3 (49,4–61,3) 51,5 (45,1–58,0) 68,0 (63,0–72,9) 53,1 (47,4–58,8) 48,8 (42,7–55,0) 1996–2000 73,2 (68,7–77,7) 63,1 (57,7–68,5) 56,2 (50,2–62,1) 75,0 (70,9–79,1) 61,5 (56,6–66,5) 58,4 (53,0–63,8) 2001–2005 77,2 (73,3–81,2) 66,2 (61,2–71,2) 58,8 (52,5–65,0) 76,4 (72,8–80,1) 67,9 (63,5–72,3) 62,5 (57,0–67,9) Rak.qxd 29.7.2009 7:24 Page 252 study period. Among the patients receiving specific treatment in the period 2001–2005, 80% were treated by chemotherapy, slightly over a half of them also had radiotherapy and/or sur- gery in addition. Radiotherapy alone was used in 9% and surgery alone in 6% of patients. Additional 14% of patients underwent surgery in combination with other treatment modali- ties. In the period 2001–2005, 14% of the treated patients received rituximab as part of their primary treatment; in the previous two periods there were only 4% such patients. Among all the rituximab-treated patients two thirds had aggressive NHL while 26% of the patients had indolent NHL. In the period 2001–2005, a half of specifically treated patients started their treatment at the IO Ljubljana, 13% in the UMC Ljubljana, 6% in the UMC Maribor, and the remaining ones in lesser proportions in practically all general hospitals of Slovenia. Of those that started their 253 NON-HODGKIN LYMPHOMA 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Slika 3: Deset-, pet-, tri- in enoletno relativno pre`ivetje vseh bolnikov z ne-Hodgkinovim limfomom po obdobju postavitve diagnoze. Figure 3: 10-, 5-, 3- and 1-year relative survival of all non-Hodgkin's lymphoma patients by period of diag- nosis. 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Slika 4: Deset-, pet-, tri- in enoletno relativno pre`ivetje bolnikov z indolentnim ne-Hodgkinovim limfomom po obdobju postavitve diagnoze. Figure 4: 10-, 5-, 3- and 1-year relative survival of indolent non-Hodgkin's lymphoma patients by period of diagnosis. Rak.qxd 22.7.2009 12:39 Page 253 ~e med seboj primerjamo posamezne podvrste NHL, razen pri neopredeljenih NHL, ki jih je v zadnjem obdobju bistveno manj pri mladih, ve~ pa pri starih 75 let in ve~. Pri pribli`no polovici bolnikov je bila bolezen odkrita v prvem in drugem stadiju bolezni; nji- hov dele` se je v zadnjem obdobju nekoliko zmanj{al, pove~al pa se je dele` bolnikov s tretjim in ~etrtim stadijem ter, presenetljivo, dele` tistih, ki jim stadij ob diagnozi ni bil dolo~en (Ta- bela 2). Najpogosteje stadij ni dolo~en pri neopredeljenih NHL (pri skoraj tretjini primerov), pri T-celi~nih in agresivnih NHL pa je bilo brez dolo~enega stadija manj kot 10 % bolnikov. V letih 2001–2005 ni bilo specifi~no zdravljenih 19 % bolnikov. Skoraj polovica med nezdrav- ljenimi so bolniki z neopredeljenimi NHL, ena tretjina jih je imela indolentni NHL, zelo malo (manj kot 5 % zbolelih) pa ni bilo zdravljenih bolnikov s T-celi~nimi NHL. Zelo redko osta- nejo brez specifi~nega zdravljenja tudi mlaj{i od 50 let in bolniki s prvim in drugim stadijem ob diagnozi. Dele` nezdravljenih bolnikov ostaja v celotnem obdobju analize pribli`no enak. Med specifi~no zdravljenimi je bilo v letih 2001–2005 80 % bolnikov zdravljenih s kemotera- pijo, dobra polovica med njimi je bila {e dodatno zdravljena z obsevanjem in/ali operativno. Samo obsevanih je bilo 9 % bolnikov, samo operiranih pa 6 %. V kombinaciji z drugimi na~i- ni zdravljenja je bilo operiranih {e dodatnih 14 % bolnikov. Med leti 2001–2005 je v okviru prvega zdravljenja rituksimab prejelo 14% zdravljenih, v prej{njih dveh obdobjih pa le 4%. Med vsemi, ki so bili zdravljeni z rituksimabom, je kar dve tretjini bolnikov z agresivnim NHL, 26 % bolnikov pa je imelo indolentni NHL. Polovica specifi~no zdravljenih je v obdobju 2001–2005 z zdravljenjem pri~ela na OI Ljub- ljana, 13 % v UKC Ljubljana, 6 % v UKC Maribor, ostali pa v manj{ih dele`ih prakti~no v vseh slovenskih splo{nih bolni{nicah. Od tistih, ki zdravljenja niso pri~eli na OI Ljubljana, jih je bilo tja po za~etku zdravljenja preusmerjenih ve~ kot polovica; v sklopu prvega zdravljenja je kar 80 % bolnikov z NHL prejelo vsaj del terapije na OI Ljubljana. Relativno pre`ivetje bolnikov z NHL se postopno pove~uje; v 15 letih se je petletno relativno pre`ivetje pove~alo za 11 % (Slika 3), za 14 % pri `enskah in za 7 % pri mo{kih (Tabela 3). Naj- bolj{e pre`ivetje imajo bolniki z indolentnim NHL (Slika 4); petletno relativno pre`ivetje pri bolnikih z indolentnim NHL je 78 %. Izbolj{anje relativnih pre`ivetij v zadnjih letih pri bol- nikih z agresivnim NHL prikazuje Slika 5. Petletna relativna pre`ivetja so pri obeh spolih podobna, v zadnjem obdobju 59 %. Preu~evanje relativnega pre`ivetja pri bolnikih s T-celi~nimi 254 NE-HODGKINOV LIMFOM 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Slika 5: Deset-, pet-, tri- in enoletno relativno pre`ivetje bolnikov z agresivnim ne-Hodgkinovim limfomom po obdobju postavitve diagnoze. Figure 5: 5-year relative survival of aggressive non-Hodgkin's lymphoma patients by period of diagnosis. Rak.qxd 22.7.2009 12:39 Page 254 treatment elsewhere, more than half were later referred to the IO Ljubljana, so that as many as 80% of all patients with NHL received at least a part of their primary treatment at the IO Ljubljana. The relative survival of patients with NHL has been gradually increasing; in 15 years, the 5-year relative survival increased by 11% (Figure 3), 14% in females and 7% in males (Table 3). The best survival is observed in patients with indolent NHL (Figure 4); 5-year relative survival in patients with indolent NHL is 78%. An improvement in the relative survival observed in patients with aggressive NHL in recent years is presented in Figure 5. 5-year relative survival rates are comparable in both genders, in the last period being 59%. The analysis of relative survival in patients with T-cell and undefined NHL is unreliable due to a very small number of patients with these two subtypes in individual periods. The relevance of stage at diagnosis is shown in Figure 6. In the last period, patients diagnosed in stage I had 80% 5-year relative survival while the rate in those with stages III and IV was only 50%. In comparison with the period 1991–1995, the survival of patients with all stages has increased. When analyzing the influence of stage on the survival of patients with indolent and aggressive NHL, the results are similar, howev- er, the average survivals in all stages are slightly lower in aggressive and slightly higher in indolent NHL. In patients with NHL, age at diagnosis is also an important prognostic factor of sur- vival. In the period 2001–2005, the 5-year relative survival of patients less than 50 years of age was 80%, of patients aged 50–74 years it was 60% and of those aged 75 years and older it was 43% (Figure 7). A similar association with age is also established in the survival of patients with indolent and aggressive NHL. The 5-year relative survival of all patients diagnosed in the period 2001–2005 was 60% (Figure 3); patients surviving the first year may expect to survive five years in 77%. The expectancy of sur- vival after one year is even higher in patients with aggressive NHL: after having survived the first year, these patients have 81% 5-year relative survival. In patients with indolent NHL an increase in the survival after the first year is less obvious (their 5-year relative survival increas- es from 71% to 77%). According to the EUROCARE-4 study results for those diagnosed in the period 2000–2002, the survival of patients with NHL in Slovenia is above (statistically not significant) the European average (Figure 8). 255 NON-HODGKIN LYMPHOMA 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 I II III + IV Vsi / All Slika 6: Petletno relativno pre`ivetje vseh bolnikov z ne-Hodgkinovim limfomom po stadiju in obdobju postavitve diagnoze. Figure 6: 5-year relative survival of all non-Hodgkin's lymphoma patients by stage and period of diagnosis. Rak.qxd 22.7.2009 12:39 Page 255 in neopredeljenimi NHL je nezanesljivo, saj je bilo {tevilo bolnikov pri teh dveh podvrstah v po- sameznih obdobjih zelo majhno. Kako pomemben je stadij ob diagnozi, ka`e Slika 6. Bolniki, ki jim je bila diagnoza postavljena v prvem stadiju, so v zadnjem obdobju imeli petletno relativno pre`ivetje 80 %, tisti s tretjim ali ~etrtim stadijem pa le 50 %. V primerjavi z obdobjem 1991–1995 se je ve~alo pre`ivetje bolnikov vseh stadijev. Pri analizi vpliva stadija na pre`ivetje pri bolni- kih z indolentnimi in agresivnimi NHL so rezultati podobni, seveda pa so pre`ivetja v povpre~ju pri vseh stadijih nekoliko manj{a pri agresivnih in nekoliko ve~ja pri indolentnih NHL. Pomem- ben napovedni dejavnik pre`ivetja bolnikov z NHL je tudi starost ob diagnozi. Petletno relativno pre`ivetje mlaj{ih od 50 let je bilo v obdobju 2001–2005 80 %, starih med 50 in 74 let 60 %, pri starih 75 let in ve~ pa je bilo 43 % (Slika 7). Podobno je s starostjo povezano tudi pre`ivet- je bolnikov z indolentnimi in agresivnimi NHL. Petletno relativno pre`ivetje vseh zbolelih z NHL v obdobju 2001–2005 je bilo 60 % (Slika 3); bolniki, ki pre`ivijo prvo leto, pa lahko pri~akujejo 77-odstotno petletno relativno pre`ivetje. [e bolj se po enem letu pove~a verjetnost pre`ivetja bolnikov z agresivnimi NHL: po pre`ive- tem prvem letu imajo ti bolniki 81-odstotno petletno relativno pre`ivetje. Pri bolnikih z indolentnimi NHL je izbolj{anje pre`ivetja po pre`ivetem prvem letu manj o~itno (petlet- no relativno pre`ivetje se pove~a z 71 na 77 %). Rezultati {tudije EUROCARE-4 za zbolele v obdobju 2000–2002 ka`ejo, da je pre`ivetje slo- venskih bolnikov z NHL statisti~no nezna~ilno ve~je od evropskega povpre~ja (Slika 8). 256 NE-HODGKINOV LIMFOM KLINI^NI KOMENT AR Barbara Jezer{ek Novakovi} 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 20–49 let / years 50–74 let / years 75+ let / years Vsi / All Slika 7: Petletno relativno pre`ivetje vseh bolnikov z ne-Hodgkinovim limfomom po starosti in obdobju postavitve diagnoze. Figure 7: 5-year relative survival of all non-Hodgkin's lymphoma patients by age and period of diagnosis. Izbolj{anje pre`ivetja bolnikov z NHL v prvi vrsti pripisujemo bolj{emu zdravljenju; precej ve~- ji dele` bolnikov v tem obdobju je bil namre~ zdravljen z monoklonskim protitelesom proti CD20 determinanti, rituksimabom. Ta je registriran za indukcijsko zdravljenje B-celi~nih CD20 pozitivnih limfomov (difuznih velikoceli~nih B, folikularnih in drugih indolentnih B-celi~nih limfomov) ter za vzdr`evalno zdravljenje po ponovitvi folikularnih in drugih indolentnih B-ce- li~nih limfomov po uspe{nem indukcijskem zdravljenju. V ZDA je v uporabi od leta 1997, v Sloveniji od leta 1998, v {ir{i uporabi pa od leta 2000. Zdravljenje z rituksimabom je po letu 2000 prispevalo k izbolj{anju pre`ivetja bolnikov tako z indolentnimi kot agresivnimi B-celi~nimi NHL, kar je v skladu z opa`anji Sehna s sodelavci, ki poro~a o 55-odstotnem 4-letnem pre- Rak.qxd 22.7.2009 12:39 Page 256 The improved survival of patients with NHL is mainly attributed to better treatment; name- ly, a considerably greater proportion of patients in this period were treated with rituximab, a monoclonal antibody against CD20 determinant. This medication is registered for the induc- tion therapy of B-cell CD20-positive lymphomas (diffuse large B-cell, follicular and other indolent B-cell lymphomas) as well as for maintenance therapy after the recurrence of follic- ular and other indolent B-cell lymphomas following a successful induction therapy. In the U. S. A. it has been in use since 1997, in Slovenia since 1998, but used more widely since 2000. After the year 2000, the treatment with rituximab has contributed to the improved survival of patients with indolent as well as aggressive B-cell NHL, which is consistent with the findings of Sehn and co-workers who reported on 55% 4-year survival of patients with diffuse large B-cell lym- phoma in a prognostically unfavorable group after treatment with rituximab and chemotherapy (after treatment with chemotherapy alone the 5-year survival of such patients is only 32%). Patients with NHL are most frequently treated at the IO Ljubljana, however, the proportion of patients with NHL treated at that institute (80%) is considerably lower than that of patients with HL (96%), which is reflected in a worse survival of NHL patients as compared to those with HL. Namely, the patients referred to the IO Ljubljana are treated according to the uni- form up-to-date doctrinary principles in terms of diagnostic as well as therapeutic approach, which is not the case in patients treated at other hospitals. In an additional analysis we compared certain characteristics of a group of 938 patients diag- nosed in the period 2001–2005, who had their primary treatment at the IO Ljubljana, with the survival in a group of 227 patients diagnosed in the same period, who were treated else- where. The median survival of patients treated at the IO Ljubljana was 5 years, while the survival of those treated at other hospitals was only 10 months. The median age at diagnosis of patients treated at the IO Ljubljana was 61 years, while the age of those treated elsewhere was 71 years. 257 NON-HODGKIN LYMPHOMA CLINICAL COMMENT ARY Barbara Jezer{ek Novakovi} 01 02 0 30 40 50 60 70 80 90 100 % Slovensko povpre~je / 2000–2002 (EUROCARE-4) Slovenian average Evropsko povpre~je / 2000–2002 (EUROCARE-4) European average Povpre~je ZDA / 2000–2002 (SEER-13) USA average Slika 8: Petletno relativno pre`ivetje bolnikov z ne-Hodgkinovim limfomom* (povpre~je in 95-odstotni interval zaupanja), zbolelih v letih 2000–2002 v Sloveniji, Evropi in nekaterih obmo~jih v ZDA. Figure 8: 5-year relative survival of of non-Hodgkin's lymphoma patients* (average and 95% confidence inter- val) diagnosed in the period 2000–2002 in Slovenia, Europe and in some regions of the USA. * Nabor MKB10 kod v {tudiji EUROCARE-4 je nekoliko druga~en kot smo ga uporabili pri ostalih analizah predstavljenih v tem poglavju: v {tudiji EURCARE-4 so v analizo vklju~ene tudi tudi levkemije celic T pri odraslih (MKB10: C915). * The ICD10 code selection in EUROCARE-4 study is slightly different in comparison to the selection applied in other analysis in this chapter: in EUROCARE-4 study the adult T-cell leukemia (ICD10: C915) is included. Rak.qxd 22.7.2009 12:39 Page 257 `ivetju bolnikov z difuznim velikoceli~nim B-limfomom v slabi prognosti~ni skupini po zdrav- ljenju z rituksimabom in kemoterapijo (po zdravljenju samo s kemoterapijo je petletno pre`ivetje takih bolnikov samo 32 %). Bolniki z NHL se najpogosteje zdravijo na OI Ljubljana, odstotek bolnikov z NHL, ki je v obrav- navi na tem in{titutu (80 %), pa je precej ni`ji kot pri bolnikih s Hodgkinovim limfomom (96 %), kar se zrcali tudi s slab{im pre`ivetjem bolnikov z NHL v primerjavi s Hodgkinovim limfomom. Bolniki, ki so obravnavani na OI Ljubljana, se namre~ zdravijo po enotnih sodobnih doktri- narnih na~elih tako glede diagnosti~nega kot terapevtskega pristopa, ~esar ne moremo trditi za obravnavo bolnikov v drugih zdravstvenih ustanovah. V dodatni analizi smo primerjali nekatere zna~ilnosti skupine 938 bolnikov, zbolelih v le- tih 2001–2005, ki so se zdravili na OI Ljubljana v okviru prvega zdravljenja, s pre`ivetjem skupine 227 zbolelih v istem obdobju, ki se v okviru prvega zdravljenja niso zdravili v tej ustanovi. Srednje pre`ivetje bolnikov, zdravljenih na OI Ljubljana, je bilo 5 let, zdravljenih v drugih bolni{ni- cah pa le 10 mesecev. Povpre~na starost zdravljenih na OI Ljubljana je bila 61 let, zdravljenih drugod pa 71 let. Pri drugod zdravljenih bolnikih stadij ni bil dolo~en pri 48 %, pri 34 % je bil razsejan (stadij III in IV), pri 10 % raz{irjen (stadij II) in pri 8 % omejen (stadij I); v skupini zdravljenih na OI Ljubljana pa stadij ni bil dolo~en pri 7 %, pri 43 % je bil razsejan (stadij III in IV), pri 23 % raz{irjen (stadij II) in pri 27 % omejen (stadij I). Ker na pre`ivetje pomemb- no vplivajo stadij, starost in zdravljenje, smo te napovedne dejavnike vklju~ili v multivariatni Coxov pre`ivetveni model (Tabela 4). S tem smo `eleli stvarno oceniti vpliv izbora bolni{ni- ce prvega zdravljenja na izid bolezni. Rezultat je zaskrbljujo~, saj prvo zdravljenje bolnika zunaj OI Ljubljana tudi v multivariatni analizi ostaja dejavnik tveganja smrti bolnika; bolniki, ki v ok- viru prvega zdravljenja niso zdravljeni na OI Ljubljana, imajo 2,5-krat ve~je relativno tveganje smrti v primerjavi s tistimi, ki so zdravljeni v tej ustanovi. Presenetljivo je, da se je v obdobju 2001–2005 glede na prej{nja obdobja pove~al dele` bolni- kov z razsejano boleznijo (stadij III in IV) in zmanj{al dele` tistih z omejeno (stadij I); to je posledica bolj{e diagnostike in s tem natan~nej{e zamejitve bolezni. Petletno relativno pre`ivetje bolnikov, starih 75 let in ve~, se je v obdobju po letu 1991 ve~a- lo. V istem obdobju se je tudi pove~al dele` bolnikov z NHL, ki so zboleli starej{i, tj. v skupini s sicer najmanj{im petletnim pre`ivetjem. Pre`ivetje bolnikov v tej starosti je slab{e `e zaradi {tevilnih spremljajo~ih bolezni, zna~ilnih za to `ivljenjsko obdobje; prav zaradi teh pa je tre- ba prilagoditi zdravljenje in zmanj{ati odmerke citostatikov, kar pomeni slab{o kakovost zdravljenja. V starostnih skupinah bolnikov, starih 20–49 let in 50–74 let, pa se je od leta 1991 do 2005 pre`ivetje stalno izbolj{evalo v skladu z odlo~nej{im in u~inkovitej{im zdravljenjem. Canellos GP , Lister T A, Sklar JL, eds. The lymphomas. 2nd edition. Philadelphia: W. B. Saunders Company; 2006. Dalla-Favera R, Gaidano G. Lymphomas. In: DeVita VTJr, Hellman S, Rosenberg SA, eds. Cancer Principles and Practice of Oncology. 7th edition. Philadelphia: Lippincott Williams and Wilkins; 2005. Jezer{ek-Novakovi} B, ed. Smernice za obravnavo bolnikov z malignimi limfomi. Ljubljana: Onkolo{ki in{titut Ljubljana; 2008. Molina A. A decade of rituximab: Improving survival outcomes in Non-Hodgkin's lymphoma. Annu Rev Med 2008; 59: 237–50. Shipp M, Harrington D, Anderson J. A predictive model for aggressive non-Hodgkin's lymphomas. N Engl J Med 1993; 329: 987–94. Sehn LH, Berry B, Chhanabhai M, Fitzgerald C, Gill K, Hoskins P , et al. The revised International Prognostic Index is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP . Blood 2007; 109: 1857–61. 258 NE-HODGKINOV LIMFOM VIRI Literature Rak.qxd 22.7.2009 12:39 Page 258 In patients treated elsewhere, the stage was not determined in 48%, disseminated (stage III and IV) in 34%, regional (stage II) in 10% and localized (stage I) in 8%; in the group treated at the IO Ljubljana, the stage was not determined in 7%, was found to be disseminated (stage III and IV) in 43%, regional (stage II) in 23% and localized (stage I) in 27%. Because survival is significantly influenced by stage, age and treatment, these prognostic factors were included into a multivariate Cox's survival model (Table 4). Thus we wanted to assess the influence of primary treatment hospital choice on the outcome of the disease controlling for different prognostic factors. The results raise concern since also in the multivariate analysis the primary treatment outside the IO Ljubljana remains associated with the risk of death; the patients who do not receive their primary treatment at the IO Ljubljana have 2.5 fold higher relative risk of death in comparison with those treated at the IO Ljubljana. It is surprising that – with respect to the pervious periods – in the period 2001–2005 the pro- portion of patients with disseminated disease increased (stage III and IV) while the proportion of those with localized disease (stage I) decreased as a result of better diagnostics and thus more accurate staging of the disease. In the period after 1991, the 5-year relative survival of patients aged 75 years and older has been increasing. In the same period, the proportion of NHL patients diagnosed at an advanced age, i. e. in the group with the lowest 5-year survival, has increased too. If for no other reasons, the survival of patients in that age group is worse because of numerous concomitant diseases characteristic for old age; these require adjustment of therapy and a reduced dosage of cytostatics, which entails a lower quality of treatment. In the age groups 20–49 and 50–74 years, in the period from 1991 to 2005, the survival has been steadily increasing along with the use of more radical and effective treatment. 259 NON-HODGKIN LYMPHOMA Napovedni dejavnik / Relativno tveganje / 95-odstotni interval zaupanja / Prognostic factor Relative risk 95% confidence interval V okviru prvega zdravljenja se JE bolnik zdravil na OIL / 1,0 Patient DID receive primary treatment at IOL V okviru prvega zdravljenja se bolnik NI zdravil na OIL / 2,5 2,00–3,10 Patient DID NOT receive primary treatment at IOL Starost / Age 20–49 1,0 Starost / Age 50–74 2,2 1,60–3,00 Starost / Age 75+ 4,7 3,40–6,52 Stadij / Stage I + II 1,0 Stadij / Stage III + IV 1,7 1,40–2,00 Stadij neznan / Stage unknown 0,8 0,60–1,10 Tabela 4: Multivariatna analiza tveganja smrti bolnikov z NHL v Sloveniji, zbolelih v obdobju 2001–2005. Table 4: Multivariate analysis of the risk of death in NHL patients in Slovenia, diagnosed in the period 2001–2005. Rak.qxd 22.7.2009 12:39 Page 259 V obdobju 1991–2005 je za plazmocitomom zbolelo 1178 ljudi, 527 mo{kih in 651 `ensk. Kot je razvidno s Slike 1, se ~asovni trendi inciden~nih in umrljivostnih stopenj razlikujejo. Inci- denca se ve~a za povpre~no 2,9 % letno, umrljivost pa se po velikem skoku med letoma 1991 in 1994 ve~a povpre~no za 2,4 % letno. Incidenca in umrljivost se ve~ata predvsem zaradi sta- ranja prebivalstva, saj se starostno standardizirani stopnji v opazovanem obdobju skoraj nista pove~ali. PLAZMOCITOM MKB 10: C90 260 0 1 2 3 4 5 6 1986 1990 1995 2000 2005 Leto / Year Incidenca – groba stopnja / Incidence – crude rate Incidenca – SSS* / Incidence – ASR** Umrljivost – groba stopnja / Mortality – crude rate Umrljivost – SSS* / Mortality – ASR** Stopnja na 100.000 / Rate per 100,000 * SSS – starostno standardizirana stopnja (standard – slovenska populacija leta 1986) ** ASR – age standardized rate (standard Slovenian population in 1986) Slika 1: Groba in starostno standardizirana inciden~na in umrljivostna stopnja plazmocitoma, Slovenija 1986–2005. Figure 1: Crude and age-standardized incidence and mortality rate of plasmacytoma, Slovenia 1986–2005. Mo{ki / Males @enske / Females Obdobje / {tevilo / 20–49 let / 50–74 let / 75+ let / {tevilo / 20–49 let / 50–74 let / 75+ let / Period number years (%) years (%) years (%) number years (%) years (%) years (%) 1991–1995 146 6,8 69,2 24,0 181 6,6 68,0 25,4 1996–2000 175 6,9 68,0 25,1 214 4,7 66,8 28,5 2001–2005 195 10,3 67,7 22,1 234 4,7 59,8 35,5 T abela 1: [tevilo bolnikov s plazmocitomom po spolu in obdobju postavitve diagnoze ter njihovi dele`i po starosti. Table 1: Number of plasmacytoma patients by sex and period of diagnosis with their proportions by age. V analizo pre`ivetja je vklju~enih 1145 primerov; 33 primerov (2,8 %) nismo upo{tevali, ker jim je bila diagnoza postavljena po smrti. Mikroskopsko potrjenih je bilo v vseh letih opazovanja 99 % primerov. V letih 2001–2005 je bilo pribli`no dve tretjini mo{kih in dobra polovica `ensk ob diagnozi starih 50–74 let. Bolezen je redka pri mlaj{ih od 50 let, v zadnjem obdobju se je pove~al dele` `ensk, starih 75 let in ve~ (Tabela 1). EPIDEMIOLOGIJA Rak.qxd 22.7.2009 12:39 Page 260 In the period 1991–2005, a total of 1178 persons were diagnosed with plasmacytoma, of these 527 males and 651 females. As evident from Figure 1, the time trends in incidence and mor- tality rates differ from each other. While the incidence rate has been increasing by 2.9% annually on average, the mortality – after a rapid increase in the period 1991–1994 – has been increas- ing by 2.4% annually on average. Both, incidence and mortality rates are increasing particularly owing to population aging, since the age-standardized rates have remained almost unchanged in the observation period. The survival analysis included 1145 cases; 33 patients (2.8%) diagnosed only after death, were not considered in the analysis. In all the years under observation 99% of cases were microscopically confirmed. In the period 2001–2005, approximately two thirds of males and a good half of females were aged 50–74 years at diagnosis. The disease rarely occurs in persons under 50 years of age; in the last period the proportion of female patients aged 75 years and older has increased (Table 1). Plasmacytoma typically appears in a diffuse disseminated form (Table 2). Out of 1445 patients at diagnosis 1118 (89%) had diffuse plasmacytoma, 43 (4%) solitary plasmacytoma of the bone, 36 (3%) solitary plasmacytoma of other organs and 6 (0.5%) plasma-cell leukemia. In 41 patients the type of plasmacytoma was not determined. In the years 2001–2005, 27% of patients did not receive specific treatment. The proportion of untreated patients was decreasing throughout the study period; among those diagnosed in the period 1991–1995 there were 40% of patients without specific treatment. Among the patients receiving specific treatment in the period 2001–2005, 39% were treated with a combination of cytostatics and corticosteroids, 16% with cytostatics alone, while 12% received radiothera- py in addition to cytostatics or a combination of cytostatics and corticosteroids; 6% patients were only irradiated. Other combinations of treatment were used in less than 5% of the patients. Hematopoietic stem-cell transplantation was performed in 5% of patients. Compared to the period 1991–1995, in last years significantly more patients have been treated with cytostatics and corticosteroids and much less with cytostatics or irradiation as single modality treatment. In the period 2001–2005, less than half of patients (45%) started their treatment in the UMC Ljubljana, 17% in the UMC Maribor, 13% at the IO Ljubljana and 10% in the GH Celje. Individual patients also started their treatment in the general hospitals of Nova Gorica, Murska Sobota, Slovenj Gradec, Novo mesto, Izola and Jesenice. The relative survival rate of patients with plasmacytoma has been gradually increasing: in 15 years, the 5-year relative survival increased by 4% (Figure 2), in males slightly more than in females (Table 3). The relevance of age at diagnosis is shown in Figure 3: the 5-year relative survival PLASMACYTOMA ICD 10: C90 261 Tabela 2: [tevilo bolnikov s plazmocitomom po spolu in obdobju postavitve diagnoze ter njihovi dele`i po stadiju. Table 2: Number of plasmacytoma patients by sex and period of diagnosis with their proportions by stage. Mo{ki / Males @enske / Females Obdobje / {tevilo / omejen / raz{irjen / razsejan / neznan / {tevilo / omejen / raz{irjen / razsejan / neznan / Period number localized regional distant unknown number localized regional distant unknown (%) (%) (%) (%) (%) (%) (%) (%) 1991–1995 146 1,4 0,7 97,9 0,0 181 0,0 0,0 100,0 0,0 1996–2000 175 4,0 0,6 94,9 0,6 214 0,9 0,5 98,6 0,0 2001–2005 195 3,6 0,5 93,8 2,1 234 0,9 0,0 98,7 0,4 EPIDEMIOLOGY Rak.qxd 22.7.2009 12:39 Page 261 Plazmocitom se tipi~no pojavlja v razsejani, difuzni obliki (Tabela 2). Med 1445 bolniki jih je imelo ob diagnozi 1118 (89 %) difuzni plazmocitom, 43 (4 %) solitarni plazmocitom kosti, 36 (3 %) solitarni plazmocitom drugih organov in 6 (0,5 %) plazmocitno levkemijo. Pri 41 bolnikih vrsta plazmocitoma ni bila dolo~ena. V letih 2001–2005 ni bilo specifi~no zdravljenih 27 % bolnikov. Dele` nezdravljenih bolnikov se je v celotnem obdobju analize zmanj{eval; med bolniki, zbolelimi v obdobju 1991–1995, jih je bilo brez specifi~nega zdravljenja 40 %. Med specifi~no zdravljenimi je bilo v letih 2001–2005 39 % bolnikov zdravljenih s kombinacijo citostatikov in kortikosteroidov, 16 % jih je prejelo le citostatike, po 12 % pa jih je poleg citostatikov ali kombinacije citostatikov in kortikosteroi- dov bilo {e obsevanih; samo obsevanih je bilo 6 % bolnikov. Druge kombinacije zdravljenja so 262 PLAZMOCITOM 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Slika 2: Deset-, pet-, tri- in enoletno relativno pre`ivetje bolnikov s plazmocitomom po obdobju postavitve diagnoze. Figure 2: 10-, 5-, 3- and 1-year relative survival of plasmacytoma patients by period of diagnosis. Tabela 3: Opazovano in relativno pre`ivetje bolnikov s plazmocitomom po spolu in obdobju postavitve diagnoze s 95-odstotnim intervalom zaupanja (IZ). Table 3: Observed and relative survival of plasmacytoma patients by sex and period of diagnosis with 95% confidence interval (CI). Opazovano pre`ivetje / Observed survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 64,4 (57,1–72,6) 43,2 (35,8–52,0) 22,6 (16,7–30,5) 68,5 (62,1–75,6) 33,1 (27,0–40,8) 21,0 (15,8–27,9) 1996–2000 59,4 (52,6–67,2) 38,3 (31,7–46,2) 24,6 (19,0–31,9) 65,4 (59,3–72,1) 38,8 (32,8–45,9) 25,2 (20,0–31,8) 2001–2005 62,6 (56,1–69,7) 40,1 (33,7–47,7) 28,0 (21,8–35,9) 59,0 (53,0–65,6) 34,9 (29,2–41,7) 23,0 (17,7–29,8) Relativno pre`ivetje / Relative survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 67,7 (59,1–76,4) 50,5 (40,2–60,9) 29,7 (19,3–40,1) 70,8 (63,4–78,1) 36,8 (28,3–45,3) 25,2 (17,0–33,4) 1996–2000 62,5 (54,4–70,7) 44,8 (35,5–54,0) 32,2 (22,7–41,7) 67,7 (60,8–74,7) 43,2 (35,3–51,1) 30,4 (22,5–38,3) 2001–2005 65,3 (57,8–72,8) 46,1 (37,4–54,9) 35,7 (25,5–45,8) 61,1 (54,2–68,0) 39,2 (31,6–46,9) 27,9 (19,7–36,2) Rak.qxd 22.7.2009 12:39 Page 262 of patients diagnosed before 50 years of age is 52%, patients diagnosed at an age between 50–74 years had 37% 5-year relative survival while the survival of those aged 75 years and older has decreased to 9% in the last period. The 5-year relative survival of all patients diagnosed in the period 2001–2005 was 31% (Figure 2); patients surviving the first year may expect to survive five years in 48%. According to the EUROCARE-4 study results for those diagnosed in the period 2000–2002, the survival of patients with plasmacytoma in Slovenia is statistically significantly below the European average (Figure 4). 263 PLASMACYTOMA CLINICAL COMMENT ARY Samo Zver 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 20–49 let / years 50–74 let / years 75+ let / years Vsi / All Slika 3: Petletno relativno pre`ivetje bolnikov s plazmocitomom po starosti in obdobju postavitve diagnoze. Figure 3: 5-year relative survival of plasmacytoma patients by age and period of diagnosis. There is no reasonable explanation for the fact that in the period 2001–2005 27% of patients with diffuse plasmacytoma were left without specific treatment. Perhaps the doctors have over- looked that specific therapy also includes monotherapy with corticosteroids (this applies to the era before the use of biological agents), which are often the treatment of choice in elderly patients in poor clinical condition (e. g., concomitant extensive pneumonia, acute renal failure or amy- loidosis at the time of diagnosis). Equal survival in all the periods under analysis is explainable by an equal treatment approach to diffuse plasmacytoma being used in all time periods. All this time, advances were made only in symptomatic treatment, e. g. by means of new antibi- otics, bisphosphonates, erythropoietin and analgesics. In Slovenia, a substantial increase in the number of patients treated by autologous hematopoietic stem-cell transplantation (HSCT) was observed only after the year 2000, while tandem autologous HSCT has been used since 2003. Only in the middle of the last observation period the age limit for autologous HSCT increased from previous 55 years to current 70 years. Moreover, all biological agents (with the exception of few cases of treatment with thalidomide) finally expected to contribute towards a signifi- cant increase in the survival of patients with diffuse plasmacytoma, in Slovenia likewise elsewhere in the world have become widely available (outside clinical studies) only after the year 2005. Thus, the best treatment results achieved in all time periods in patients less than 50 years of age are understandable, since this was the very age group that was the first to be treated by autologous HSCT. It is difficult to explain, why the oldest group of patients has had worse results in the last observation period. Rak.qxd 22.7.2009 12:39 Page 263 uporabili pri manj kot 5 % zbolelih. Petim odstotkom bolnikov so presadili krvotvorne mati~ne celice. V primerjavi z obdobjem 1991–1995 je bilo v zadnjih letih bistveno ve~ bolnikov zdrav- ljenih s citostatiki in kortikosteroidi, bistveno manj pa jih je prejelo le citostatike ali pa samo obsevanje. Manj kot polovica bolnikov (45 %) je v obdobju 2001–2005 zdravljenje za~ela v UKC Ljub- ljana, 17 % v UKC Maribor, 13 % na OI Ljubljana in 10 % v SB Celje. Posamezne bolnike so pri~eli zdraviti {e v splo{nih bolni{nicah v Novi Gorici, Murski Soboti, Slovenj Gradcu, Novem mestu, v Izoli in na Jesenicah. Relativno pre`ivetje bolnikov s plazmocitomom se le postopno pove~uje; v 15 letih se je pet- letno relativno pre`ivetje pove~alo za 4 % (Slika 2), pri mo{kih nekoliko ve~ kot pri `enskah (Tabela 3). Kako pomembna je starost ob diagnozi, ka`e Slika 3: petletno relativno pre`ivet- je bolnikov, zbolelih pred 50. letom, je 52 %, bolniki, zboleli v starosti 50–74 let imajo petletno relativno pre`ivetje 37 %, medtem ko se je pre`ivetje starih 75 let in ve~ v zadnjem obdobju zmanj{alo na 9 %. Petletno relativno pre`ivetje vseh zbolelih v obdobju 2001–2005 je bilo 31 % (Slika 2); bolni- ki, ki pre`ivijo prvo leto, pa lahko pri~akujejo 48-odstotno petletno relativno pre`ivetje. Rezultati {tudije EUROCARE-4 za zbolele v obdobju 2000–2002 ka`ejo, da je pre`ivetje slo- venskih bolnikov s plazmocitomom statisti~no zna~ilno manj{e od evropskega povpre~ja (Slika 4). 264 PLAZMOCITOM KLINI^NI KOMENT AR Samo Zver Za podatek, da specifi~nega zdravljenja v obdobju 2001–2005 ni bilo dele`nih 27 % bolnikov z difuznim plazmocitomom, ni mo~ najti prave razlage. Morda so zdravniki spregledali, da k spe- cifi~nemu zdravljenju sodi tudi monoterapija s kortikosteroidi (gre za obdobje pred biolo{kimi zdravili), ki so pogosto zdravilo izbire pri starej{ih bolnikih v slabem klini~nem stanju (npr. ob postavitvi diagnoze bolezni in so~asni obse`ni plju~nici, akutni ledvi~ni odpovedi ali pri- dru`eni amiloidozi). Enako pre`ivetje v vseh analiziranih obdobjih je razlo`ljivo z enakim na~inom zdravljenja difuznega plazmocitoma v vseh obdobjih. Ves ta ~as se je izbolj{evalo le simpto- matsko ukrepanje, npr. z novimi antibiotiki, bisfosfonati, eritropoetini in s protibole~inskimi zdravili. [ele po letu 2000 je v Sloveniji za~elo ob~utneje nara{~ati {tevilo bolnikov, zdravljenih z avtologno presaditvijo krvotvornih mati~nih celic (PKMC), tandemsko avtologno PKMC pa izvajamo od leta 2003. [ele nekje v sredini zadnjega opazovanega obdobja se je dvignila tudi starostna meja za zdravljenje z avtologno PKMC s 55 let na zdaj okoli 70 let. Tudi vsa biolo{ka zdravila (z izjemo nekaj primerov zdravljenja s talidomidom), od katerih si po dolgih letih obeta- mo zna~ilno pove~anje pre`ivetja bolnikov z difuznim plazmocitomom, so v Sloveniji, kot tudi drugod po svetu, postala {ir{e dostopna (zunaj klini~nih raziskav) {ele po letu 2005. Najbolj- {i rezultati zdravljenja pri bolnikih, mlaj{ih od 50 let, v vseh obdobjih so razumljivi, saj smo prav to starostno skupino pri~eli najprej zdraviti z avtologno PKMC. Zakaj ima v zadnjem obdob- ju najstarej{a skupina bolnikov slab{e rezultate, je te`ko pojasniti. Difuzni plazmocitom je neozdravljiva bolezen, lahko pa jo za dalj{e obdobje zazdravimo. Naj- bolj u~inkovit na~in zdravljenja je tandemska (dvojna) avtologna PKMC, ki jo v Sloveniji opravljamo od leta 2003. Zdravljenje poteka na Klini~nem oddelku za hematologijo UKC Ljub- ljana, zdravimo pa vse bolnike v Sloveniji, ki so za zdravljenje primerni. Lastna analiza zdravljenih bolnikov v {tiriletnem obdobju (2003–2006) je pokazala povpre~no pre`ivetje 50,2 meseca, srednje pre`ivetje pa v opazovanem obdobju {e ni bilo dose`eno. Na{i rezultati zdravljenja z avtolog- no PKMC so povsem primerljivi z rezultati zdravljenja v ostalih velikih evropskih in ameri{kih centrih. Pre`ivetje po PKMC verjetno lahko {e dodatno pove~amo z vzdr`evalnim zdravlje- njem ali zdravljenjem ponovitve bolezni po PKMC z novimi biolo{kimi zdravili (talidomid, bortezomib, lenalidomid). Rak.qxd 22.7.2009 12:39 Page 264 Diffuse plasmacytoma is an incurable disease, though treatment may result in a long-term remission. The most effective treatment is tandem autologous HSCT, which has been per- formed in Slovenia since 2003. The treatment is carried out at the Department of Hematology of the UMC Ljubljana in all patients assessed as suitable candidates for this type of treat- ment. Our own analysis of patients treated in the four-year period from 2003 to 2006 has revealed an average survival of 50.2 months, while the median survival in the period under observation has not been reached yet. Our treatment results obtained by autologous HSCT are fully comparable with the results of treatment in other large European and American cen- ters. Post-HSCT survival could possibly be further improved by maintenance therapy or by treatment of recurrences following HSCT using new biological agents (thalidomide, borte- zomib and lenalidomide). The fact is that diffuse plasmacytoma is prevailingly a disease of the elderly (Table 1). The pro- visional age limit for autologous HSCT is 70 years. For many years, AP (melphalan, prednisolone) and VAD (vincristine, pharmarubicin, dexamethason) schedules were the standards of treat- ment in elderly patients. In patients treated with AP and V AD, the median survival probability is 33.4 months (own data). In recent years, patients over 70 years of age and those who are not candidates for autologous HSCT due to concomitant diseases are treated with new bio- logical agents, such as thalidomide, bortezomib and lenalidomide. As a rule, the treatment is started in the case of AP or VAD failure (2 nd or 3 rd line therapy) and is combined with corti- costeroids. More detailed analyses of the survival of patients treated subsequently also with thalidomide and/or bortezomib and lenalidomide are still underway. The reason for that is main- ly in the short observation period and a small number of patients included in the analysis. It seems, however, that every new therapeutic approach may extend the survival for another 4–6 months. Elderly patients with disseminated plasmacytoma are treated in a majority of Slovenian gene- ral hospitals. The latter information is important in view of the fact that in a majority of peripheral Slovenian hospitals access to new biological drugs (thalidomide, lenalidomide, borte- zomib and finally also arsenic trioxide) is difficult if not straightforward impossible. The main obstacle is the extremely high price of new biological drugs and well-known financial prob- lems of hospitals. Only by providing an equal access to up-to-date therapeutic modalities for 265 PLASMACYTOMA 01 02 0 30 40 50 60 70 80 90 100 % Slovensko povpre~je / 2000–2002 (EUROCARE-4) Slovenian average Evropsko povpre~je / 2000–2002 (EUROCARE-4) European average Povpre~je ZDA / 2000–2002 (SEER-13) USA average Slika 4: Petletno relativno pre`ivetje bolnikov s plazmocitomom (povpre~je in 95-odstotni interval zaupanja), zbolelih v letih 2000–2002 v Sloveniji, Evropi in nekaterih obmo~jih v ZDA. Figure 4: 5-year relative survival of plasmacytoma patients (average and 95% confidence interval) diagnosed in the period 2000–2002 in Slovenia, Europe and in some regions of the USA. Rak.qxd 22.7.2009 12:39 Page 265 Dejstvo je, da je difuzni plazmocitom predvsem bolezen starej{ih ljudi (Tabela 1). Okvirna sta- rostna meja za zdravljenje z avtologno PKMC je 70 let. Standard zdravljenja pri starej{ih bolnikih sta vrsto let predstavljali shemi AP (melfalan, prednizolon) in V AD (vinkristin, farmarubicin, deksametazon). Pri bolnikih, zdravljenih z AP in V AD, je verjetnost srednjega pre`ivetja 33,4 me- seca (lastni podatki). Bolnike, ki so starej{i od 70 let, in tiste, ki zaradi spremljajo~ih bolezenskih stanj niso kandidati za avtologno PKMC, zdravimo v zadnjih letih z novej{imi biolo{kimi zdravi- li, kot so talidomid, bortezomib in lenalidomid. Z zdravljenjem praviloma za~enjamo v primeru neu~inkovitosti AP ali VAD (zdravljenje drugega ali tretjega reda) in ga kombiniramo s kor- tikosteroidi. Natan~nej{e analize pre`ivetja bolnikov, zdravljenih naknadno {e z talidomidom in/ali bortezomibom in/ali lenalidomidom, so {e v teku. Razlog je predvsem kratko obdobje opazovanja in tudi manj{e {tevilo vklju~enih bolnikov. Zdi pa se, da z vsakim novim na~inom zdravljenja lahko {e dodatno podalj{amo `ivljenje za 4–6 mesecev. Starej{i bolniki z diseminiranim plazmocitom se zdravijo v ve~ini slovenskih bolni{nic. Sled- nje je pomemben podatek, saj je dostop do novih biolo{kih zdravil (talidomid, lenalidomid, bortezomib in nenazadnje tudi arzenov trioksid) v ve~ini obmo~nih slovenskih bolni{nic ote- `en, ~e ne celo nemogo~. Ovira je seveda izjemno visoka cena novih biolo{kih zdravil in znane spremljajo~e finan~ne te`ave bolni{nic. Samo pri enaki dostopnosti sodobnih terapevtskih sred- stev za vse starej{e bolnike v Sloveniji (pa tudi tiste z relapsom bolezni po avtologni PKMC) si lahko obetamo tudi izbolj{anje pre`ivetja na populacijski ravni. Obstaja pa {e en problem. Kar nekaj slovenskih bolni{nic nima zaposlenega hematologa, kar nedvomno vpliva na zgod- nje odkrivanje difuznega plazmocitoma in kasneje tudi na zdravljenje bolnikov s to boleznijo. Kabakli} A, ^ernel~ P . Ocena uspe{nosti enajstletnega zdravljenja starej{ih bolnikov z diseminiranim plazmo- citomom. Zdrav Vestn 2008; 77: I-81–85. Zver A, Zver S, Mlakar U, Zupan IP , Pretnar J. Zdravljenje bolnikov z diseminiranim plazmocitomom s tandemsko avtologno presaditvijo krvotvornih mati~nih celic v Sloveniji. Zdrav Vestn 2008; 77: I-75–80. 266 PLAZMOCITOM VIRI Literature Rak.qxd 22.7.2009 12:39 Page 266 all elderly patients in Slovenia (as well as for those with recurrence after autologous HSCT) we may hope to improve the survival at the population level. However, there is yet another problem: quite a few Slovenian hospitals lack a qualified haematologist, which undoubtedly affects early detection of diffuse plasmacytoma and subsequently also the treatment of patients with this disease. 267 PLASMACYTOMA Rak.qxd 22.7.2009 12:39 Page 267 V obdobju 1991–2005 je za akutno limfoblastno levkemijo (ALL) zbolelo 417 ljudi, 235 mo{- kih in 182 `ensk. Kot je razvidno s Slike 1, se incidenca ve~a; groba stopnja za povpre~no za 0,8 % letno, starostno standardizirana pa za povpre~no 1,4 % letno. Umrljivost se manj{a, gro- ba stopnja za povpre~no 2,1 %, starostno standardizirana pa za povpre~no 2,8 % letno. AKUTNA LIMFOBLASTNA LEVKEMIJA MKB 10: C91.0 268 0 1 2 1986 1990 1995 2000 2005 Leto / Year Incidenca – groba stopnja / Incidence – crude rate Incidenca – SSS* / Incidence – ASR** Umrljivost – groba stopnja / Mortality – crude rate Umrljivost – SSS* / Mortality – ASR** Stopnja na 100.000 / Rate per 100,000 * SSS – starostno standardizirana stopnja (standard – slovenska populacija leta 1986) ** ASR – age standardized rate (standard Slovenian population in 1986) Slika 1: Groba in starostno standardizirana inciden~na in umrljivostna stopnja akutne limfoblastne levkemije, Slovenija 1986–2005. Figure 1: Crude and age-standardized incidence and mortality rate of acute lymphoblastic leukaemia, Slovenia 1986–2005. Mo{ki / Males @enske / Females Obdobje / {tevilo / 20–49 let / 50–74 let / 75+ let / {tevilo / 20–49 let / 50–74 let / 75+ let / Period number years (%) years (%) years (%) number years (%) years (%) years (%) 1991–1995 24 50,0 41,7 8,3 30 33,3 53,3 13,3 1996–2000 21 47,6 42,9 9,5 22 45,5 40,9 13,6 2001–2005 34 50,0 41,2 8,8 25 20,0 64,0 16,0 Tabela 1: [tevilo bolnikov z akutno limfoblastno levkemijo po spolu in obdobju postavitve diagnoze ter njihovi dele`i po starosti. Table 1: Number of acute lymphoblastic leukaemia patients by sex and period of diagnosis with their propor- tions by age. V analizo pre`ivetja je vklju~enih 156 primerov; 5 primerov (1,2 %) nismo upo{tevali, ker jim je bila diagnoza postavljena po smrti, 256, mlaj{ih od 20 let ob diagnozi, pa obravnavamo v po- glavju o otro{kih levkemijah. Vsi v analizo vklju~eni primeri so bili mikroskopsko potrjeni. EPIDEMIOLOGIJA Rak.qxd 22.7.2009 12:39 Page 268 In the period 1991–2005, a total of 417 persons were diagnosed with acute lymphoblastic leukemia (ALL), of these 235 males and 182 females. As evident from Figure 1, the incidence rate is increasing. The estimated annual percentage increase in crude incidence rate was 0.8% and in age standardized rate 1.4%. The mortality rate is decreasing, the estimated annual per- centage decrease in crude mortality rate was 2.1% and 2.8% in age-standardized rate. The survival analysis included 156 cases; 5 cases (1.2%) diagnosed only after death, were not considered in the analysis; 256 patients under 20 years of age at diagnosis are presented in the chapter on childhood leukemias. All cases under analysis were microscopically confirmed. Half of the male patients are younger than 50 years at diagnosis; patients aged 75 years and older are rare. Approximately two thirds of female patients are aged 50–74 years at diagnosis, while the proportions of younger and older patients are approximately equal (Table 1). In the years 2001–2005, 20% of patients did not receive specific treatment. The proportion of untreated patients was decreasing throughout the duration of analysis; among those diagnosed in the period 1991–1995 there were 61% of patients without specific treatment. Among the patients receiving specific treatment in the period 2001–2005, 81% were treated by cytostat- ics with or without corticosteroids, 10% were irradiated in addition to chemotherapy. Irradiation alone was used in 6% of patients; a combination of cytostatics, corticosteroids and irradiation or treatment with corticosteroids alone was applied in less than 5% of patients. In the period 2001–2005, 83% started their treatment in the UMC Ljubljana, 10% at the IO Ljubljana, while 3 patients were treated respectively in general hospitals of Bre`ice, Celje and Izola (one in each). The relative survival of patients with ALL has been gradually increasing: in 15 years, the 5-year relative survival increased by 10% (Figure 2), in females slightly more than in males (Table 2). The relevance of age at diagnosis is shown in Figure 3: the 5-year relative survival of patients diagnosed before 50 years of age is 41%, patients diagnosed at an age between 50–74 years had 7% 5-year relative survival in the last period, while those aged 75 years and more do not survive five years from diagnosis. The 5-year relative survival of all patients diagnosed in the period 2001–2005 was 23% (Figure 2); patients surviving the first year may expect to survive five years in 50%. According to the results of EUROCARE-4 study of patients diagnosed in 2000–2002, the survival of Slovenian patients with ALL is above (statistically not significant) the European average (Figure 4). ACUTE LYMPHOBLASTIC LEUKEMIA ICD 10: C91.0 269 CLINICAL COMMENT ARY Mojca Modic Acute lymphoblastic leukemia is a childhood disease. In childhood it has a very favorable prog- nosis and its biological course is totally different than in adults. In adult patients unfavorable cytogenetic changes in the bone marrow are prevailing (30% of patients present with Philadelphia chromosome); besides patient age, number of leukocytes at diagnosis and immunological type, these changes are one of the most relevant prognostic factors. The majority of adult patients EPIDEMIOLOGY Rak.qxd 22.7.2009 12:39 Page 269 Med mo{kimi je polovica zbolelih ob diagnozi mlaj{a od 50 let, bolniki, stari 75 let in ve~, pa so redki. Pribli`no dve tretjini `ensk je ob diagnozi starih od 50 do 74 let, medtem ko je dele` mlaj{ih in starej{ih pribli`no enak (Tabela 1). V letih 2001–2005 ni bilo specifi~no zdravljenih 20 % bolnikov. Dele` nezdravljenih se je vse obdobje analize zmanj{eval; med bolniki, zbolelimi v obdobju 1991–1995, jih je bilo brez spe- cifi~nega zdravljenja 61 %. Med specifi~no zdravljenimi je bilo v letih 2001–2005 81 % bolnikov zdravljenih s citostatiki s kortikosteroidi ali brez, 10 % pa je bilo poleg citostatikov {e obsevanih. Samo obsevanih je bilo 6 % bolnikov, kombinacijo citostatikov, kortikosteroidov in obsevanja ali pa samo zdravljenje s kortikosteroidi je prejelo manj kot 5 % bolnikov. V obdobju 2001–2005 se je 83 % bolnikov pri~elo zdraviti v UKC Ljubljana, 10 % na OI Ljub- ljana, po 1 bolnik pa v splo{nih bolni{nicah v Bre`icah, Celju in Izoli. Relativno pre`ivetje bolnikov z ALL se postopno pove~uje; v 15 letih se je petletno relativno pre`ivetje pove~alo za 10 % (Slika 2), pri `enskah nekoliko ve~ kot pri mo{kih (Tabela 2). Kako pomembna je starost ob diagnozi, ka`e Slika 3: petletno relativno pre`ivetje bolnikov, zbole- lih pred 50. letom, je 41 %, bolniki, stari 50–74 let, so imeli v zadnjem obdobju petletno relativno pre`ivetje 7 %, medtem ko bolniki, stari 75 let in ve~, ne `ivijo pet let po diagnozi. Petletno relativno pre`ivetje vseh zbolelih v obdobju 2001–2005 je bilo 23 % (Slika 2); bolni- ki, ki pre`ivijo prvo leto, pa lahko pri~akujejo 50-odstotno petletno relativno pre`ivetje. Rezultati {tudije EUROCARE-4 za zbolele v obdobju 2000–2002 ka`ejo, da je pre`ivetje slo- venskih bolnikov z ALL statisti~no nezna~ilno ve~je od evropskega povpre~ja (Slika 4). 270 AKUTNA LIMFOBLASTNA LEVKEMIJA KLINI^NI KOMENT AR Mojca Modic Tabela 2: Opazovano in relativno pre`ivetje bolnikov z akutno limfoblastno levkemijo po spolu in obdobju postavitve diagnoze s 95-odstotnim intervalom zaupanja (IZ). Table 2: Observed and relative survival of acute lymphoblastic leukaemia patients by sex and period of diag- nosis with 95% confidence interval (CI). Opazovano pre`ivetje / Observed survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 37,5 (22,4–62,9) 20,8 (9,6–45,4) 12,5 (4,3–36,0) 30,0 (17,4–51,8) 13,3 (5,4–33,2) 10,0 (3,4–29,3) 1996–2000 42,9 (26,2–70,2) 28,6 (14,5–56,2) 23,8 (11,1–51,2) 22,7 (10,5–49,1) 0,0 0,0 2001–2005 41,2 (27,6–61,5) 26,5 (15,1–46,4) 20,6 (10,6–39,8) 40,0 (24,7–64,6) 20,0 (9,1–43,8) 20,0 (9,1–43,8) Relativno pre`ivetje / Relative survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 38,3 (12,4–64,3) 22,4 (0,0–48,8) 14,0 (0,0–40,3) 30,6 (8,3–52,8) 14,2 (0,0–35,3) 11,0 (0,0–32,2) 1996–2000 44,1 (16,0–72,3) 31,3 (1,1–61,6) 27,8 (0,0–59,7) 23,3 (0,0–50,3) 0,0 0,0 2001–2005 42,1 (21,3–63,0) 28,0 (7,0–49,1) 23,1 (1,5–44,6) 40,8 (15,6–65,9) 21,0 (0,0–46,0) 22,0 (0,0–48,1) Akutna limfoblastna levkemija je bolezen otrok. V otro{ki dobi ima zelo ugoden izid in je bio- lo{ko povsem druga~na bolezen kot pri odraslih. Pri odraslih bolnikih prevladujejo neugodne citogenetske spremembe v kostnem mozgu (30% bolnikov ima kromosom Philadelphia), ki so poleg starosti bolnika, {tevila levkocitov ob odkritju bolezni in imunolo{kega tipa eden Rak.qxd 22.7.2009 12:39 Page 270 with ALL, intended to undergo an intensive cytostatics treatment and afterwards either related or unrelated allogeneic or autologous stem cell transplantation, are referred to the Department of Hematology of the UMC Ljubljana. This is the only center for stem cell transplantation in Slovenia. In order to achieve remission in these patients a combination of cytostatics, such as daunorubicin, cytosinarabinosid, vincristine, L-asparaginase and dexamethason, is used. In patients – candidates for stem-cell transplantation, a prophylaxis of the central nervous sys- tem with cranial irradiation and intrathecal injections of cytosar and methotrexate is considered. Patients older than 65 years, in whom intensive cytostatics therapy is not feasible, are treated at hematology department of other Slovenian general hospitals. In these patients, a sympto- matic treatment with transfusions, low doses of corticosteroids, purinethol, methotrexate or alkeran is chosen instead. New antibiotics, antimycotics, cytokines and immunosuppressive medi- cations contributed to an increase in the survival of these patients in last years. But nevertheless, the mortality of patients older than 65 years, particularly due to other septic infections and 271 ACUTE LYMPHOBLASTIC LEUKEMIA 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Slika 2: Deset-, pet-, tri- in enoletno relativno pre`ivetje bolnikov z akutno limfoblastno levkemijo po obdobju postavitve diagnoze. Figure 2: 10-, 5-, 3- and 1-year relative survival of acute lymphoblastic leukaemia patients by period of diag- nosis. 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 20–49 let / years 50–74 let / years 75+ let / years Vsi / All Slika 3: Petletno relativno pre`ivetje bolnikov z akutno limfoblastno levkemijo po starosti in obdobju postavitve diagnoze. Figure 3: 5-year relative survival of acute lymphoblastic leukaemia patients by age and period of diagnosis. Rak.qxd 22.7.2009 12:39 Page 271 najpomembnej{ih napovednih dejavnikov. Ve~ina odraslih bolnikov z ALL, pri katerih se odlo- ~imo za intenzivno citostatsko zdravljenje in kasnej{o sorodno ali nesorodno alogeni~no ali avtologno presaditev krvotvornih mati~nih celic, pride na hematolo{ki oddelek UKC Ljublja- na. To je tudi edini center za presaditev krvotvornih mati~nih celic v Sloveniji. Pri teh bolnikih uporabljamo za doseganje remisije kombinacije citostatikov, kot so daunorubicin, citozinara- binozid, vinkristin, L-asparaginaza in deksametazon. Pri bolnikih, pri katerih se ne odlo~amo za presaditev, pride v po{tev profilaksa centralnega `iv~nega sistema z obsevanjem glave in intra- tekalnimi injekcijami citozarja ter metotreksata. Bolniki, starej{i od 65 let, pri katerih intenzivno citostatsko zdravljenje ne prihaja v po{tev, se zdravijo na hematolo{kih oddelkih v drugih bol- ni{nicah po Sloveniji. Pri njih se pogosto odlo~ajo za simptomatsko zdravljenje s transfuzijami, nizkimi odmerki kortikosteroidov, purinetola, metotreksata ali alkerana. Zaradi novih antibio- tikov, antimikotikov, citokinov in imunosupresivnih zdravil se pre`ivetje bolnikov v zadnjih letih pove~uje. [e vedno pa je umrljivost bolnikov, starej{ih od 65 let, velika, predvsem zaradi sep- ti~nih oku`b in so~asnih bolezni srca ter plju~. V retrospektivni analizi bolnikov, zdravljenih pri nas v letih 2000–2007, se je izkazalo, da smo pri 41 bolnikih z ALL v starosti od 17 do 68 let s protokolom UKALL XII dosegli remisijo bolezni pri 81 %; petletno pre`ivetje teh bolnikov je bilo 48%. V tej skupini bolnikov smo kasneje naredili 5 sorodnih alogeni~nih presaditev, 4 nesorodne alogeni~ne presaditve in 9 avtolognih presaditev krvotvornih mati~nih celic. Hoelzer D, Thiel E, Loffler H, Buchner T , Ganser A, Heilet G, et al. Prognostic factors in a multicenter study for treatment of acute lymphoblasic leukemia in adults. Blood 1988; 86: 123–31. Modic M. Zdravljenje akutne limfoblastne levkemije odraslih s protokolom UKALL XII. Med Razgl 2000; 39 S5: 109–16. Modic M, Skerget M. Uspeh zdravljenja akutne limfoblastne levkemije odraslih s protokolom UKALL XII na Hematolo{kem oddelku v Ljubljani. Zdrav Vestn 2008; 77: I-37–42. Moorman AV, Harrison CJ, Buck GAN, Richards SM, Secker-Walker LM, Martineau M, et al. Karyotype is an independent prognostic factor in adult acute lymphoblasic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical research Council (MRC) UKALL XII/Eastern Cooperative Oncology Group (ECOG) 2993 Trial. Blood 2007; 105: 3189–97. Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richardset SM, et al. Induction therapy for adults with acute lymphoblasic leukaemia: results of more than 1500 patients from the international ALL trial: MRC UKALL-XII/ECOG E2993. Blood 2005; 103: 3760–7. 272 AKUTNA LIMFOBLASTNA LEVKEMIJA VIRI Literature Rak.qxd 22.7.2009 12:39 Page 272 concomitant cardiac and pulmonary diseases, is still high. A retrospective analysis of patients treated in Slovenia in the years 2000–2007 showed that the use of UKALL XII protocol in 41 ALL patients aged 17–68 years resulted in a remission of the disease in 81%, while 5-year survival of these patients was 48%. Afterwards, 5 related allogeneic transplantations, 4 unre- lated allogeneic transplantations and 9 autologous transplantations of stem cells were performed in this group of patients. 273 ACUTE LYMPHOBLASTIC LEUKEMIA 01 02 0 30 40 50 60 70 80 90 100 % Slovensko povpre~je / 2000–2002 (EUROCARE-4) Slovenian average Evropsko povpre~je / 2000–2002 (EUROCARE-4) European average Povpre~je ZDA / 2000–2002 (SEER-13) USA average Slika 4: Petletno relativno pre`ivetje bolnikov z akutno limfoblastno levkemijo (povpre~je in 95-odstotni interval zaupanja), zbolelih v letih 2000–2002 v Sloveniji, Evropi in nekaterih obmo~jih v ZDA. Figure 4: 5-year relative survival of acute lymphoblastic leukaemia patients (average and 95% confidence inter- val) diagnosed in the period 2000–2002 in Slovenia, Europe and in some regions of the USA. Rak.qxd 22.7.2009 12:39 Page 273 V obdobju 1991–2005 je za kroni~no limfocitno levkemijo (KLL) zbolelo 1174 ljudi, 660 mo{- kih in 514 `ensk. Kot je razvidno s Slike 1, se ~asovni trendi inciden~nih in umrljivostnih stopenj razlikujejo. Groba umrljivostna stopnja ka`e rasto~ trend; ve~a se povpre~no za 0,8% letno. V celotnem obdobju se inciden~ni stopnji manj{ata, groba inciden~na stopnja za 0,7 % pov- pre~no letno. Tak{no zmanj{evanje incidence je nekoliko presenetljivo in je verjetno posledica po eni strani pomanjkljivosti v registraciji {tevilnih nezdravljenih bolnikov s KLL, po drugi strani pa tudi natan~nej{e diagnostike, ki je omenjena v klini~nem komentarju. KRONI^NA LIMFOCITNA LEVKEMIJA MKB 10: C91.1 274 0 1 2 3 4 5 1986 1990 1995 2000 2005 Leto / Year Incidenca – groba stopnja / Incidence – crude rate Incidenca – SSS* / Incidence – ASR** Umrljivost – groba stopnja / Mortality – crude rate Umrljivost – SSS* / Mortality – ASR** Stopnja na 100.000 / Rate per 100,000 * SSS – starostno standardizirana stopnja (standard – slovenska populacija leta 1986) ** ASR – age standardized rate (standard Slovenian population in 1986) Slika 1: Groba in starostno standardizirana inciden~na in umrljivostna stopnja kroni~ne limfocitne levkemije, Slovenija 1986–2005. Figure 1: Crude and age-standardized incidence and mortality rate of chronic lymphocytic leukaemia, Slovenia 1986–2005. Mo{ki / Males @enske / Females Obdobje / {tevilo / 20–49 let / 50–74 let / 75+ let / {tevilo / 20–49 let / 50–74 let / 75+ let / Period number years (%) years (%) years (%) number years (%) years (%) years (%) 1991–1995 208 5,3 64,4 30,3 178 5,1 62,4 32,6 1996–2000 238 8,4 68,9 22,7 163 5,5 58,9 35,6 2001–2005 196 8,2 62,2 29,6 155 4,5 46,5 49,0 Tabela 1: [tevilo bolnikov s kroni~no limfocitno levkemijo po spolu in obdobju postavitve diagnoze ter njihovi dele`i po starosti. Table 1: Number of chronic lymphocytic leukaemia patients by sex and period of diagnosis with their propor- tions by age. EPIDEMIOLOGIJA Rak.qxd 22.7.2009 12:39 Page 274 In the period 1991–2005, a total of 1174 persons were diagnosed with chronic lymphocytic leukemia (CLL), of these 660 males and 514 females. As evident from Figure 1, the time trends in incidence and mortality rates differ from each other. Crude mortality rate has an increas- ing trend; it is increasing by 0.8% annually on average. Incidence rates have been decreasing throughout the observation period however, the crude rate by 0.7% annually on average. Such a downward trend in the incidence is somewhat surprising and is probably attributable to lack- ing registration of a number of untreated patients with CLL on the one hand and to more accurate diagnostics, as mentioned in the clinical comment, on the other. The survival analysis included 1138 cases; 36 patients (3.1%) diagnosed only after death, were not considered in the analysis. All cases under analysis were microscopically confirmed. The disease rarely occurs in persons under 50 years of age. Almost two thirds of male patients are aged 50–74 years at diagnosis, the rest of them are mostly aged 75 years and older. In females, in the last period there was a significant increase in the proportion of those diagnosed in the oldest age group, so that currently approximately half of all patients are aged 50–74 years at diagnosis, while the other half are aged 75 years and older (Table 1). The course of disease being benign, patients with CLL are rarely given specific treatment; in the period 2001–2005 25% of patient received such treatment. The proportion of untreated patients has remained approximately the same throughout the period under analysis. Among the patients receiving specific treatment in the period 2001–2005, 49% received cytostatics and corticosteroids, 31% cytostatics alone, while 20% were treated only by radiotherapy or by radio- and chemotherapy. In the period 2001–2005, 31% of patients started their treatment at the IO Ljubljana, 20% in GH Celje, 17% in the UMC Ljubljana and 13% in the UMC Maribor. Individual patients were also treated in the general hospitals of Novo mesto, Slovenj Gradec, Murska Sobota and Nova Gorica. The relative survival rate of patients with CLL has been increasing at a slow rate: in 15 years, the 5-year relative survival increased by 2% (Figure 2), in males more than in females (Table 2). Age is a prognostic factor as well, since the 5-year relative survival in patients aged 75 years and more is lower than in younger patients (Figure 3). The 5-year relative survival of all patients diagnosed in the period 2001–2005 was 62% (Figure 2); patients surviving the first year may expect to survive five years in 72%. According to the results of EUROCARE-4 study of patients diagnosed in 2000–2002, the survival of patients with CLL in Slovenia is below (statistically not significant) the European average (Figure 5). CHRONIC LYMPHOCYTIC LEUKEMIA ICD 10: C91.1 275 CLINICAL COMMENT ARY Peter ^ernel~ Chronic lymphocytic leukemia is a disease that is treated at the IO Ljubljana as well as at the UMC Ljubljana, UMC Maribor and at smaller regional hospitals. The fact that patients are treated in different places throughout the country slightly affects the treatment results. A decrease in the number of patients was to a certain extent expected since new diagnostic methods enable EPIDEMIOLOGY Rak.qxd 22.7.2009 12:39 Page 275 V analizo pre`ivetja je vklju~enih 1138 primerov; 36 primerov (3,1 %) nismo upo{tevali, ker jim je bila diagnoza postavljena po smrti. Vsi v analizo vklju~eni primeri so bili mikroskopsko potrjeni. Bolezen je redka pri mlaj{ih od 50 let. Pri mo{kih je skoraj dve tretjini bolnikov ob diagnozi starih 50–74 let, ve~ina ostalih pa 75 let in ve~. Pri `enskah se je v zadnjem obdobju bistveno pove~al dele` zbolelih v najstarej{i starostni skupini, tako da je sedaj pribli`no polovica vseh bolnic ob diagnozi stara 50–74 let, polovica pa je stara 75 let in ve~ (Tabela 1). Ker je potek bolezni benigen, so bolniki s KLL le redko specifi~no zdravljeni; v letih 2001–2005 je bilo specifi~no zdravljenih 25 % bolnikov. Dele` nezdravljenih ostaja v celotnem obdobju analize pribli`no enak. Med specifi~no zdravljenimi je bilo v letih 2001–2005 49 % bolnikov zdravljenih s citostatiki in kortikosteroidi, 31 % je prejelo samo citostatike, ostalih 20 % pa je bilo samo obsevanih ali pa so bili zdravljeni z radio- in kemoterapijo. V obdobju 2001–2005 se je 31 % bolnikov pri~elo zdraviti na OI Ljubljana, 20 % v SB Celje, 17 % v UKC Ljubljana in 13 % v UKC Maribor. Posamezne bolnike so zdravili {e v splo{nih bolni{nicah v Novem mestu, Slovenj Gradcu, Murski Soboti in v Novi Gorici. Relativno pre`ivetje bolnikov s KLL se le po~asi ve~a; v 15 letih se je petletno relativno pre- `ivetje pove~alo za 2 % (Slika 2), bolj pri mo{kih kot pri `enskah (Tabela 2). Napovedni dejavnik je tudi starost, saj je petletno relativno pre`ivetje starih 75 let in ve~ manj{e od pre`ivetja mlaj- {ih bolnikov (Slika 3). Petletno relativno pre`ivetje vseh zbolelih v obdobju 2001–2005 je bilo 62 % (Slika 2); bolni- ki, ki pre`ivijo prvo leto, pa lahko pri~akujejo 72-odstotno petletno relativno pre`ivetje. Rezultati {tudije EUROCARE-4 za zbolele v obdobju 2000–2002 ka`ejo, da je pre`ivetje slo- venskih bolnikov s KLL statisti~no nezna~ilno manj{e od evropskega povpre~ja (Slika 4). 276 KRONI^NA LIMFOCITNA LEVKEMIJA Tabela 2: Opazovano in relativno pre`ivetje bolnikov s kroni~no limfocitno levkemijo po spolu in obdobju postavitve diagnoze s 95-odstotnim intervalom zaupanja (IZ). Table 2: Observed and relative survival chronic lymphocytic leukaemia patients by sex and period of diagno- sis with 95% confidence interval (CI). Opazovano pre`ivetje / Observed survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 74,0 (68,3–80,2) 49,0 (42,7–56,3) 39,4 (33,3–46,7) 77,0 (71,0–83,4) 62,9 (56,2–70,4) 52,8 (46,0–60,7) 1996–2000 81,5 (76,7–86,6) 66,8 (61,1–73,1) 52,1 (46,1–58,9) 84,7 (79,3–90,4) 63,8 (56,8–71,6) 49,7 (42,6–58,0) 2001–2005 80,6 (75,3–86,3) 59,0 (52,4–66,4) 44,5 (37,3–53,0) 79,4 (73,2–86,0) 61,0 (53,8–69,3) 50,8 (42,9–60,1) Relativno pre`ivetje / Relative survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 78,6 (72,0–85,2) 58,9 (50,2–67,7) 54,0 (44,1–63,9) 80,5 (73,8–87,3) 72,4 (63,7–81,0) 66,9 (56,9–76,9) 1996–2000 85,4 (80,1–90,7) 77,7 (70,4–85,0) 67,7 (58,9–76,5) 88,5 (82,5–94,4) 73,4 (64,4–82,4) 63,0 (52,5–73,6) 2001–2005 85,2 (79,2–91,3) 70,2 (61,4–79,1) 59,9 (48,4–71,5) 83,1 (76,1–90,0) 70,7 (61,2–80,2) 65,5 (53,5–77,6) Rak.qxd 22.7.2009 12:39 Page 276 us to differentiate CLL from other lymphomas more accurately. But nevertheless, the complete diagnosis for differentiation of CLL from other lymphomas is not carried out until progres- sion of the disease, since 50–60% of patients are detected incidentally because of absolute lymphocytosis in the blood, which in most cases does not require treatment. Despite some new medications for the treatment of CLL, such as alemtusumab and rituximab in combination with chemotherapy, their influence on the survival of patients is not reflected in the present survival analyses, since they have been used only in recent years. As for the med- ications used so far, such as fludarabin in combination with other cytostatics, they are known to influence the patients' quality of life, but their impact on their survival is negligible. 277 CHRONIC LYMPHOCYTIC LEUKEMIA 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Slika 2: Deset-, pet-, tri- in enoletno relativno pre`ivetje bolnikov s kroni~no limfocitno levkemijo po obdobju postavitve diagnoze. Figure 2: 10-, 5-, 3- and 1-year relative survival of chronic lymphocytic leukaemia patients by period of diag- nosis. 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 20–49 let / years 50–74 let / years 75+ let / years Vsi / All Slika 3: Petletno relativno pre`ivetje bolnikov s kroni~no limfocitno levkemijo po starosti in obdobju postavitve diagnoze. Figure 3: 5-year relative survival of chronic lymphocytic leukaemia patients by age and period of diagnosis. Rak.qxd 22.7.2009 12:39 Page 277 Kroni~na limfocitna levkemija je bolezen, ki jo zdravijo onkologi na OI Ljubljana in hematologi, ki delujejo v UKC Ljubljana, UKC Maribor in v manj{ih bolni{nicah. Dejstvo, da bolnike obrav- navajo na ve~ mestih v dr`avi, praviloma nekoliko poslab{a uspe{nost zdravljenja. Zmanj{anje {tevila bolnikov je bilo do neke mere pri~akovano, saj lahko z novej{o diagnostiko natan~ne- je razmejimo KLL od drugih limfomov. Kljub temu pa celotne diagnostike za razmejitev KLL od drugih limfomov do napredovanja bolezni ne izvajamo, saj 50–60 % bolnikov odkrijemo slu- ~ajno zaradi absolutne limfocitoze v krvi, ki je pri ve~ini ni treba zdraviti. Kljub temu, da je nekaj novih zdravil za zdravljenje KLL, kot sta alemtuzumab in rituksimab v kombinaciji s kemoterapijo, njihovega vpliva na pre`ivetje bolnikov {e ni zaznati pri tokrat- nih prikazih pre`ivetja, saj jih uporabljamo {ele zadnja leta. Za doslej uporabljena zdravila, kot sta fludarabin v kombinaciji z drugimi citostatiki, pa je znano, da vpliva predvsem na kako- vost `ivljenja, neznatno pa na pre`ivetje. Zaenkrat je najpomembnej{i dejavnik, ki vpliva na ve~je pre`ivetje, predvsem starej{ih bolni- kov s KLL, ki imajo so~asno {e druge bolezni, simptomati~no zdravljenje zapletov, v prvi vrsti oku`b, ki jih je potrebno za~eti zdraviti takoj, `e v osnovnem zdravstvu. ^ernel~ P , Modic M. Pomen novej{ih biolo{kih kazalcev za oceno prognoze pri bolnikih s kroni~no limfocitno levkemijo. In: Kri`man I, ed. Interna medicina 2005 – novosti in aktualnosti: zbornik predavanj. Ljubljana: Slovensko zdravni{ko dru{tvo, Zdru`enje internistov; 2005. Paji~ T, ^ernel~ P . Ugotavljanje mutacijskih sprememb v variabilnih genih preurejenih genov za te`ko verigo imunoglobulina pri bolnikih s kroni~no limfocitno levkemijo. Zdrav Vestn 2008; 77 Suppl 1: I-69–I-74. 278 KRONI^NA LIMFOCITNA LEVKEMIJA KLINI^NI KOMENT AR Peter ^ernel~ VIRI Literature Rak.qxd 22.7.2009 12:39 Page 278 For the time being, the most important factor influencing a better survival – particularly in elderly patients with CLL and concomitant other diseases – is symptomatic treatment for com- plications, particularly infections, which should be started at once, already at the primary healthcare level. 279 CHRONIC LYMPHOCYTIC LEUKEMIA 01 02 0 30 40 50 60 70 80 90 100 % Slovensko povpre~je / 2000–2002 (EUROCARE-4) Slovenian average Evropsko povpre~je / 2000–2002 (EUROCARE-4) European average Povpre~je ZDA / 2000–2002 (SEER-13) USA average Slika 4: Petletno relativno pre`ivetje bolnikov s kroni~no limfocitno levkemijo (povpre~je in 95-odstotni interval zaupanja), zbolelih v letih 2000–2002 v Sloveniji, Evropi in nekaterih obmo~jih v ZDA. Figure 4: 5-year relative survival of chronic lymphocytic leukaemia patients (average and 95% confidence inter- val) diagnosed in the period 2000–2002 in Slovenia, Europe and in some regions of the USA. Rak.qxd 22.7.2009 12:39 Page 279 V obdobju 1991–2005 je za akutno mieloi~no levkemijo (AML) zbolelo 813 ljudi, 417 mo{- kih in 396 `ensk. Kot je razvidno s Slike 1, je ~asovni trend inciden~nih in umrljivostnih stopenj rasto~. Groba inciden~na stopnja raste za povpre~no 4,0 % letno, groba umrljivostna stopnja pa povpre~no za 2,3 % letno. Ker je AML prete`no bolezen starej{ih (Tabela 1), je trend rasti obeh starostno standardiziranih stopenj po~asnej{i; starostno standardizirana inciden~na stop- nja raste povpre~no letno za 2,4 %, umrljivostna pa le za 0,3 % letno. AKUTA MIELOI^NA LEVKEMIJA MKB 10: C92.0, C92.4, C92.5, C93.0, C94.0, C94.2, C94.4, C94.5, C95.0 280 0 1 2 3 4 1986 1990 1995 2000 2005 Leto / Year Incidenca – groba stopnja / Incidence – crude rate Incidenca – SSS* / Incidence – ASR** Umrljivost – groba stopnja / Mortality – crude rate Umrljivost – SSS* / Mortality – ASR** Stopnja na 100.000 / Rate per 100,000 * SSS – starostno standardizirana stopnja (standard – slovenska populacija leta 1986) ** ASR – age standardized rate (standard Slovenian population in 1986) Slika 1: Groba in starostno standardizirana inciden~na in umrljivostna stopnja akutne mieloi~ne levkemije, Slovenija 1986–2005. Figure 1: Crude and age-standardized incidence and mortality rate of acute myeloic leukaemia, Slovenia 1986–2005. Mo{ki / Males @enske / Females Obdobje / {tevilo / 20–49 let / 50–74 let / 75+ let / {tevilo / 20–49 let / 50–74 let / 75+ let / Period number years (%) years (%) years (%) number years (%) years (%) years (%) 1991–1995 112 24,1 54,5 21,4 87 26,4 46,0 27,6 1996–2000 126 14,3 66,7 19,0 118 21,2 51,7 27,1 2001–2005 143 18,2 55,2 26,6 150 14,7 48,7 36,7 Tabela 1: [tevilo bolnikov z akutno mieloi~no levkemijo po spolu in obdobju postavitve diagnoze ter njihovi dele`i po starosti. T able 1: Number of acute myeloid leukaemia patients by sex and period of diagnosis with their proportions by age. V analizo pre`ivetja je vklju~enih 736 primerov; 28 primerov (3,4 %) nismo upo{tevali, ker jim je bila diagnoza postavljena po smrti, 49 mlaj{ih od 20 let ob diagnozi pa obravnavamo v po- glavju o otro{kih levkemijah. EPIDEMIOLOGIJA Rak.qxd 22.7.2009 12:39 Page 280 In the period 1991–2005, a total of 813 persons were diagnosed with acute myeloid leukemia (AML), of these 417 males and 396 females. As evident from Figure 1, the time trend in inci- dence and mortality rates is increasing. Thus crude incidence rate has been increasing by 4.0% and crude mortality rate by 2.3% annually on average. AML being prevailingly a disease of the elderly (Table 1), the upward trend of both age-standardized rates is slower, the age-standardized incidence increasing by 2.4% and the mortality by 0.3% annually on average. The survival analysis included 736 cases; 28 cases (3.4%) diagnosed only after death, were not considered in the analysis; 49 patients under 20 years of age at diagnosis are presented in the chapter on childhood leukemias. All cases under analysis were microscopically confirmed. The cases of unclassified AML (85%) were most frequent, while 7% of patients had AML with typical cytogenetic translocations and 8% undifferentiated acute leukemia. Approximately half of all patients of both genders will develop the disease at an age between 50–74 years. In earlier periods, the proportions of patients that were older or younger from the appointed age group were approximately the same; in the last period, however, the pro- portion of patients aged 75 years and older has increased while the proportion of patients younger than 50 years at diagnosis has decreased (Table 1). In the years 2001–2005, 41% of patients with AML did not receive specific treatment. The proportion of untreated patients has remained comparable throughout the period under analy- sis. In the period 2001–2005, 96% of patients with specific treatment received cytostatics while the remaining ones were irradiated. In the last period, 78% of patients started their treatment in the UMC Ljubljana, 14% in the UMC Maribor, 3% in GH Celje, while one or two patients respectively were treated also in general hospitals of Novo mesto, Izola, Murska Sobota and Nova Gorica. The relative survival of patients with AML has been gradually increasing: in 15 years, the 5-year relative survival increased by 5% (Figure 2), in males slightly more than in females (Table 2). The relevance of age at diagnosis is shown in Figure 3: the 5-year relative survival of patients diagnosed before 50 years of age is 47%, patients diagnosed at an age between 50–74 years had 9% 5-year relative survival in the last period, while those aged 75 years and older do not survive five years from diagnosis. The 5-year relative survival of all patients diagnosed in the period 2001–2005 was 15% (Figure 2); patients surviving the first year may expect to survive five years in 42%. According to the results of EUROCARE-4 study of patients diagnosed in 2000–2002, the survival of Slovenian patients with AML is statistically significantly below the European average (Figure 4). ACUTE MYELOID LEUKEMIA ICD 10: C92.0, C92.4, C92.5, C93.0, C94.0, C94.2, C94.4, C94.5, C95.0 281 CLINICAL COMMENT ARY Uro{ Mlakar The incidence of acute myeloid leukemia is increasing with age. Besides cytogenetic subtype, patient age is the most relevant prognostic factor. Therefore adult patients up to 60 years of age (younger patients) are generally dealt with separately from those who are older. Different stud- ies show that in the last 30 years the survival of younger patients has increased considerably. EPIDEMIOLOGY Rak.qxd 22.7.2009 12:39 Page 281 Vsi v analizo vklju~eni primeri so bili mikroskopsko potrjeni. Najpogostej{i so bili primeri nekate- goriziranih AML (85 %), 7 % bolnikov je imelo AML z zna~ilnimi citogenetskimi translokacijami, 8 % pa nediferencirano akutno levkemijo. Pribli`no polovica vseh bolnikov obeh spolov zboli v starosti 50–74 let. V zgodnej{ih obdob- jih so bili dele`i starej{ih in mlaj{ih od te starostne skupine pribli`no enaki, v zadnjem obdobju pa se je pove~al dele` bolnikov, starih 75 let in ve~, in zmanj{al dele` bolnikov, ki so bili ob diagnozi mlaj{i od 50 let (Tabela 1). V letih 2001–2005 ni bilo specifi~no zdravljenih 41 % bolnikov z AML. Dele` nezdravljenih bol- nikov ostaja vse obdobje analize podoben. Med specifi~no zdravljenimi se je v letih 2001–2005 96 % bolnikov zdravilo le s citostatiki, ostali pa so bili obsevani. V zadnjem obdobju je 78 % bolnikov zdravljenje za~elo v UKC Ljubljana, 14 % v UKC Mari- bor, 3 % v SB Celje, po en ali dva bolnika pa {e v splo{nih bolni{nicah v Novem mestu, Izoli, Murski Soboti in v Novi Gorici. Relativno pre`ivetje bolnikov z AML se postopno pove~uje; v 15 letih se je petletno relativ- no pre`ivetje pove~alo za 5 % (Slika 2), pri mo{kih nekoliko ve~ kot pri `enskah (Tabela 2). Kako pomembna je starost ob diagnozi, ka`e Slika 3: petletno relativno pre`ivetje bolnikov, zbolelih pred 50. letom starosti, je 47 %, bolniki, zboleli med 50. in 74. letom, so imeli v zad- njem obdobju petletno relativno pre`ivetje 9 %, medtem ko bolniki, stari 75 let in ve~, pet let po diagnozi ne pre`ivijo. Petletno relativno pre`ivetje vseh zbolelih v obdobju 2001–2005 je bilo 15 % (Slika 2); bolni- ki, ki pre`ivijo prvo leto, pa lahko pri~akujejo 42-odstotno petletno relativno pre`ivetje. Rezultati {tudije EUROCARE-4 za zbolele v obdobju 2000–2002 ka`ejo, da je pre`ivetje slo- venskih bolnikov z AML statisti~no zna~ilno manj{e od evropskega povpre~ja (Slika 4). 282 AKUTA MIELOI^NA LEVKEMIJA Tabela 2: Opazovano in relativno pre`ivetje bolnikov z akutno mieloi~no levkemijo po spolu in obdobju postavitve diagnoze s 95-odstotnim intervalom zaupanja (IZ). Table 2: Observed and relative survival of acute myeloic leukaemia patients by sex and period of diagnosis with 95% confidence interval (CI). Opazovano pre`ivetje / Observed survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 24,1 (17,4–33,5) 10,7 (6,3–18,3) 7,1 (3,7–13,9) 26,4 (18,6–37,5) 13,8 (8,2–23,3) 10,3 (5,6–19,2) 1996–2000 23,8 (17,4–32,5) 8,7 (5,0–15,4) 6,3 (3,2–12,4) 27,1 (20,2–36,5) 8,5 (4,7–15,3) 5,1 (2,3–11,1) 2001–2005 28,0 (21,5–36,4) 11,7 (7,5–18,5) 11,7 (7,5–18,5) 32,7 (26,0–41,1) 14,6 (9,9–21,5) 12,0 (7,7–18,8) Relativno pre`ivetje / Relative survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 25,2 (15,4–35,0) 12,3 (3,6–21,0) 9,0 (0,5–17,6) 27,3 (15,9–38,8) 15,3 (4,7–25,9) 12,3 (1,8–22,9) 1996–2000 24,8 (15,7–33,9) 10,0 (2,4–17,5) 7,9 (0,4–15,5) 28,0 (18,3–37,6) 9,3 (1,8–16,9) 6,0 (0,0–13,0) 2001–2005 29,4 (20,6–38,2) 13,7 (5,9–21,6) 15,3 (6,6–24,1) 33,9 (25,2–42,7) 16,4 (8,6–24,2) 14,7 (6,4–23,0) Rak.qxd 22.7.2009 12:39 Page 282 This is a result of more intensive chemotherapy, hematopoietic stem-cell transplantation and better supportive therapy. This trend is also observed in Slovenian patients (Figure 3). The results of analysis carried out in patients treated in the years 2003–2007 at the Department of Hematology of the UMC Ljubljana show that the treatment success in younger patients in Slovenia is com- parable with the results of large-scale prospective studies (70% of complete remissions, 53% 4-year survival). The prognosis of older patients (> 60 years of age) is poor, since the majori- ty are not suitable for intensive chemotherapy and because they more frequently present with prognostically unfavorable cytogenetic subtypes of AML. Unfortunately, neither was any progress noted in the last decades in the subgroup of elderly patients who are suitable for intensive chemotherapy. The patients who received intensive treatment at the Department of Hematology of the UMC Ljubljana had 12% 3-year survival. Neither was there any statistically significant difference in the survival of elderly patients receiving either intensive or non-intensive therapy. 283 ACUTE MYELOID LEUKEMIA 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Slika 2: Deset-, pet-, tri- in enoletno relativno pre`ivetje bolnikov z akutno mieloi~no levkemijo po obdobju postavitve diagnoze. Figure 2: 10-, 5-, 3- and 1-year relative survival of acute myeloic leukaemia patients by period of diagnosis. 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 20–49 let / years 50–74 let / years 75+ let / years Vsi / All Slika 3: Petletno relativno pre`ivetje bolnikov z akutno mieloi~no levkemijo po starosti in obdobju postavitve diagnoze. Figure 3: 5-year relative survival of acute myeloic leukaemia patients by age and period of diagnosis. Rak.qxd 22.7.2009 12:39 Page 283 Incidenca akutne mieloi~ne levkemije se s starostjo ve~a. Poleg citogeneti~ne podvrsti bolezni je prav starost bolnika najpomembnej{i napovedni dejavnik. Zato se obi~ajno lo~eno obravna- vajo odrasli bolniki, stari do 60 let (mlaj{i bolniki), od tistih, ki so starej{i. Razli~ne raziskave ka`ejo, da se je pre`ivetje mlaj{ih bolnikov v zadnjih 30 letih znatno pove~alo. Vzrok je bolj intenzivna kemoterapija, presaditev krvotvornih mati~nih celic in bolj{e podporno zdravlje- nje. Ta trend se ka`e tudi pri slovenskih bolnikih (Slika 3). Izsledki analize bolnikov, ki so se v letih 2003–2007 zdravili na Klini~nem oddelku za hematologijo UKC Ljubljana, ka`ejo, da je uspe{nost zdravljenja mlaj{ih bolnikov pri nas primerljiva z izsledki velikih prospektivnih raziskav (70 % popolnih remisij, 4-letno pre`ivetje 53 %). Napoved izida starej{ih bolnikov (nad 60 let) je slaba, ker jih ve~ina ni primerna za intenzivno kemoterapijo in ker so pri njih pogo- stej{e napovedno neugodne citogeneti~ne podvrste AML. Na `alost tudi pri podskupini starej{ih bolnikov, ki so primerni za intenzivno kemoterapijo, v zadnjih desetletjih ni pri{lo do napredka. Pri bolnikih, ki smo jih na Klini~nem oddelku za hematologijo UKC Ljubljana zdravili na inten- ziven na~in, je bilo triletno pre`ivetje 12 %. Prav tako nismo ugotovili statisti~no pomembne razlike v pre`ivetju starej{ih bolnikov, ki so se zdravili na intenziven in neintenziven na~in. Napre- dek v zdravljenju starej{ih bolnikov z AML lahko pri~akujemo, ko bodo odkrili nova, manj toksi~na zdravila, in ko bodo izdelana bolj objektivna merila za izbor bolnikov, ki so primer- ni za intenzivno zdravljenje. Burnett AK. Acute myeloid leukemia: treatment of adults under 60 years. Reviews in clinical and experimental hematology 2002; 6: 26–45. Dombret H, Raffaux E, Degos L. Management of elderly patients with acute myeloid leukemia. Hematology 2007; 1: 193–9. Mlakar U. Zdravljenje akutne mieloi~ne levkemije odraslih – 5-letne izku{nje v UKC Ljubljana. Zdrav Vestn 2008; 77: I-31–5 284 AKUTA MIELOI^NA LEVKEMIJA KLINI^NI KOMENT AR Uro{ Mlakar VIRI Literature Rak.qxd 22.7.2009 12:39 Page 284 Advances in the treatment of elderly patients with AML may be expected by discovery of new, less toxic medications and drawing up of more objective criteria for the selection of patients suit- able for intensive therapy. 285 ACUTE MYELOID LEUKEMIA 01 02 0 30 40 50 60 70 80 90 100 % Slovensko povpre~je / 2000–2002 (EUROCARE-4) Slovenian average Evropsko povpre~je / 2000–2002 (EUROCARE-4) European average Povpre~je ZDA** / 2000–2002 (SEER-13) USA average** Slika 4: Petletno relativno pre`ivetje bolnikov z akutno mieloi~no levkemijo* (povpre~je in 95-odstotni interval zaupanja), zbolelih v letih 2000–2002 v Sloveniji, Evropi in nekaterih obmo~jih v ZDA. Figure 4: 5-year relative survival of acute myeloic leukaemia patients* (average and 95% confidence interval) diagnosed in the period 2000–2002 in Slovenia, Europe and in some regions of the USA. * Nabor MKB10 kod v {tudiji EUROCARE-4 je nekoliko druga~en kot smo ga uporabili pri ostalih analizah predstavljenih v tem poglavju: v {tudiji EURCARE-4 so iz analize izvzete akutna promielocitna levkemija (MKB10: C924), akutna mielomonocitna levkemija (MKB10: C925), akutna eritremija in eritrolevkemija (MKB10: C940), akutna panmieloza (MKB10: C945) in akutna levkemija z neopredeljeno vrsto celic (MKB10: C950). ** podatki niso dosegljivi * The ICD10 code selection in EUROCARE-4 study is slightly different in comparison to the selection applied in other analysis in this chapter: in EUROCARE-4 study the acute promyelocytic leukaemia (MKB10: C924), acute myelomonocytic leukaemia (MKB10: C925), acute erythraemia in erythroleukaemia (MKB10: C940), acute panmyelosis (MKB10: C945) in acute leukaemia of unspecified cell type (MKB10: C950) are excluded. ** data not available Rak.qxd 22.7.2009 12:39 Page 285 V obdobju 1991–2005 je za katero koli vrsto raka zbolelo 128.406 ljudi, 65.611 mo{kih in 62.795 `ensk. Med njimi je imelo 13.654 bolnikov (6401 mo{ki in 7253 `ensk) nemelanomskega ko`nega raka. Ker je nemelanomski ko`ni rak zelo pogosta, a prakti~no popolnoma ozdravljiva bolezen, smo te bolnike izvzeli iz analize ~asovnega trenda incidence in umrljivosti, pa tudi iz vseh nadalj- njih izra~unov pre`ivetja. Kot je razvidno s Slike 1, sta se inciden~ni stopnji pove~evali hitreje od umrljivostnih stopenj. Groba inciden~na stopnja se je ve~ala povpre~no za 3,2 % letno, gro- ba umrljivostna stopnja pa bistveno manj, povpre~no za 1,1 % letno. Ker je rak pogostej{i med starej{imi (Tabela 1), se starostno standardizirana inciden~na stopnja ve~a le za povpre~no 1,5 % letno, starostno standardizirana umrljivostna stopnja pa se v opazovanem petnajstletnem obdob- ju manj{a povpre~no za 0,8 % letno. VSE RAKAVE BOLEZNI PRI ODRASLIH (brez ko`nega raka) MKB 10: C00–C96 brez C44 286 0 100 200 300 400 500 1986 1990 1995 2000 2005 Leto / Year Incidenca – groba stopnja / Incidence – crude rate Incidenca – SSS* / Incidence – ASR** Umrljivost – groba stopnja / Mortality – crude rate Umrljivost – SSS* / Mortality – ASR** Stopnja na 100.000 / Rate per 100,000 * SSS – starostno standardizirana stopnja (standard – slovenska populacija leta 1986) ** ASR – age standardized rate (standard Slovenian population in 1986) Slika 1: Groba in starostno standardizirana inciden~na in umrljivostna stopnja vseh rakov (brez ko`nega), Slovenija 1986–2005. Figure 1: Crude and age-standardized incidence and mortality rate of all cancer (except skin), Slovenia 1986–2005. Mo{ki / Males @enske / Females Obdobje / {tevilo / 20–49 let / 50–74 let / 75+ let / {tevilo / 20–49 let / 50–74 let / 75+ let / Period number years (%) years (%) years (%) number years (%) years (%) years (%) 1991–1995 15.818 13,7 68,7 17,6 14.805 19,3 59,7 21,0 1996–2000 18.506 13,2 68,9 17,9 17.734 19,4 57,9 22,7 2001–2005 21.909 11,6 67,6 20,8 20.328 17,5 55,3 27,2 Tabela 1: [tevilo odraslih bolnikov z rakom (brez ko`nega) po spolu in obdobju postavitve diagnoze ter njihovi dele`i po starosti. Table 1: Number of adult cancer (except skin) patients by sex and period of diagnosis with their proportions by age. EPIDEMIOLOGIJA Rak.qxd 22.7.2009 12:39 Page 286 In the period 1991–2005, a total of 128,406 persons were diagnosed with any type of cancer, of these 65,611 males and 62,795 females. Among these, 13,654 patients (6401 males and 7253 females) had non-melanoma skin cancer. As non-melanoma skin cancer is a very fre- quent but practically fully curable disease, these patients were excluded from the incidence and mortality time-trend analysis as well as from all other survival statistics. As evident from Figure 1, the incidence rates have been increasing faster than the mortality rates. The estimated annu- al percentage increase in crude incidence rate was 3.2% and in crude mortality rate 1.0%. Cancer being more frequent in the elderly (Table 1), the age-standardized incidence rate has been increas- ing only by 1.5% annually on average while in the observed 15-year period the age standardized mortality rate has been decreasing by 0.8% annually on average. The survival analysis included 109,100 cases; 13,654 (10.6%) patients with non-melanoma skin cancer and 4585 (3.6%) patients diagnosed only after death were not considered in the analy- sis; 1067 children and adolescents (0.8%) are presented in a separate chapter. In all three periods, 92% of cases were microscopically verified. Among these, 14% were defined as malignant tumors, as unspecified carcinomas or as sarcomas. Among others, there were 49% adenocarcinomas, 14% planocellular carcinomas and 4% malignant melanomas. Other histo- logical types were established in less than 3% of patients. ALL CANCER SITES IN ADULTS (but skin) ICD 10: C00–C96 without C44 287 Tabela 2: [tevilo odraslih bolnikov z rakom (brez ko`nega) po spolu in obdobju postavitve diagnoze ter njihovi dele`i po stadiju. Table 2: Number of adult cancer (except skin) patients by sex and period of diagnosis with their proportions by stage. Mo{ki / Males @enske / Females Obdobje / {tevilo / omejen / raz{irjen / razsejan / neznan / {tevilo / omejen / raz{irjen / razsejan / neznan / Period number localized regional distant unknown number localized regional distant unknown (%) (%) (%) (%) (%) (%) (%) (%) 1991–1995 15.818 30,3 34,4 27,7 7,7 14.805 36,0 33,0 25,2 5,9 1996–2000 18.506 32,3 34,0 27,1 6,6 17.734 38,2 32,8 24,3 4,6 2001–2005 21.909 33,3 33,7 27,6 5,5 20.328 38,3 32,6 25,0 4,1 Mlaj{i od 75 let / Younger than 75 years Stari 75 let in ve~ / 75 years and older Obdobje / {tevilo / omejen / raz{irjen / razsejan / neznan / {tevilo / omejen / raz{irjen / razsejan / neznan / Period number localized regional distant unknown number localized regional distant unknown (%) (%) (%) (%) (%) (%) (%) (%) 1991–1995 24.732 33,7 35,5 26,1 4,7 5891 30,3 26,3 27,9 15,6 1996–2000 28.913 36,6 34,6 25,0 3,8 7327 29,6 28,7 28,7 13,0 2001–2005 32.144 37,6 33,8 25,4 3,2 10.093 29,8 31,1 29,1 10,0 Tabela 3: [tevilo odraslih bolnikov z rakom (brez ko`nega) po starosti in obdobju postavitve diagnoze ter njihovi dele`i po stadiju. Table 3: Number of adult cancer (except skin) patients by age and period of diagnosis with their proportions by stage. EPIDEMIOLOGY Rak.qxd 22.7.2009 12:39 Page 287 288 VSE RAKAVE BOLEZNI PRI ODRASLIH (BREZ KO@NEGA RAKA) 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Slika 2: Deset-, pet-, tri- in enoletno relativno pre`ivetje odraslih bolnikov z rakom (brez ko`nega) po obdobju postavitve diagnoze. Figure 2: 10-, 5-, 3- and 1-year relative survival of adult cancer (except skin) patients by period of diagnosis. Tabela 4: Opazovano in relativno pre`ivetje odraslih bolnikov z rakom (brez ko`nega) po spolu in obdobju postavitve diagnoze s 95-odstotnim intervalom zaupanja (IZ). Table 4: Observed and relative survival of adult cancer (except skin) patients by sex and period of diagnosis with 95% confidence interval (CI). Opazovano pre`ivetje / Observed survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 50,1 (49,4–50,9) 30,5 (29,8–31,3) 23,6 (23,0–24,3) 66,5 (65,8–67,3) 49,9 (49,1–50,7) 42,3 (41,5–43,1) 1996–2000 54,6 (53,8–55,3) 36,2 (35,5–36,9) 29,1 (28,4–29,8) 69,6 (68,9–70,2) 54,7 (54,0–55,5) 47,6 (46,8–48,3) 2001–2005 60,4 (59,8–61,1) 42,4 (41,7–43,0) 35,0 (34,4–35,7) 72,0 (71,3–72,6) 57,5 (56,8–58,2) 50,7 (49,9–51,4) Relativno pre`ivetje / Relative survival (%) Mo{ki / Males @enske / Females Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 52,4 (51,6–53,2) 35,0 (34,1–35,8) 29,7 (28,9–30,6) 68,6 (67,8–69,3) 54,7 (53,8–55,6) 49,4 (48,5–50,4) 1996–2000 57,0 (56,2–57,7) 41,3 (40,5–42,1) 36,5 (35,6–37,3) 71,6 (70,9–72,3) 59,7 (58,9–60,5) 55,2 (54,4–56,1) 2001–2005 63,1 (62,4–63,8) 48,5 (47,7–49,2) 44,3 (43,4–45,2) 74,1 (73,4–74,7) 62,9 (62,1–63,6) 59,2 (58,4–60,1) V analizo pre`ivetja je vklju~enih 109.100 primerov; 13.654 (10,6 %) bolnikov nismo upo{te- vali, ker so imeli nemelanomskega ko`nega raka, 4585 bolnikov (3,6 %) nismo upo{tevali, ker jim je bila diagnoza postavljena po smrti, 1067 otrok in mladostnikov (0,8 %) pa obravnava- mo v posebnem poglavju. V vseh treh obdobjih je bilo mikroskopsko potrjenih 92 % primerov. Med njimi je bilo 14 % opredeljenih le kot maligni tumor ali pa neopredeljen karcinom oziroma sarkom. Adenokar- cinomov je bilo 49 %, plo{~atoceli~nih karcinomov 14 % in malignih melanomov 4 %. Ostale histolo{ke vrste so bile dolo~ene pri manj kot 3 % bolnikov. Rak.qxd 22.7.2009 12:39 Page 288 Approximately two thirds of males were aged between 50–74 years at diagnosis, while in the period 2001–2005 slightly over a half of females belonged to this age group. Cancer is rela- tively rare before the age of 50 years, however, the proportion of patients aged 75 years and older, particularly females, has been increasing (Table 1). In the observed period there were 5% of patients with undefined stage at diagnosis, their per- centage has been slightly decreasing with time. In the period 2001–2005, approximately one third of males had the disease diagnosed in a localized or regional stage, and slightly less in a disseminated stage. The proportion of females with localized disease at diagnosis was by 5% higher than the proportion of those with regional disease; in all three periods, approximately one fourth of females had disseminated disease (Table 2). The higher proportion of localized stage was evident mostly in patients diagnosed before age 75 and not in patients aged 75 or more at the time of diagnosis (Table 3). 289 ALL CANCER SITES BUT SKIN IN ADULTS 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 Omejen / Localized Raz{irjen / Regional Razsejan / Distant Vsi / All Slika 3: Petletno relativno pre`ivetje odraslih bolnikov z rakom (brez ko`nega) po stadiju in obdobju postavitve diagnoze. Figure 3: 5-year relative survival of adult cancer (except skin) patients by stage and period of diagnosis. 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 20–49 let / years 50–74 let / years 75+ let / years Vsi / All Slika 4: Petletno relativno pre`ivetje odraslih bolnikov z rakom (brez ko`nega) po starosti in obdobju postavitve diagnoze. Figure 4: 5-year relative survival of adult cancer (except skin) patients by age and period of diagnosis. Rak.qxd 22.7.2009 12:39 Page 289 Pribli`no dve tretjini mo{kih sta bili ob diagnozi stari med 50 in 74 let, `ensk je bilo v le- tih 2001–2005 v tej starosti dobra polovica. Pred 50. letom starosti je rak razmeroma redka bolezen, ve~a pa se dele` starih 75 let in ve~, predvsem pri `enskah (Tabela 1). V opazovanem obdobju okrog 5 % bolnikov ni imelo dolo~enega stadija ob diagnozi; ta dele` se je s ~asom nekoliko zmanj{al. V letih 2001–2005 je imela med mo{kimi pribli`no tretjina bolezen odkrito v omejenem ali raz{irjenem stadiju, nekaj manj pa v razsejanem. Med `enska- mi je bil dele` tistih z omejeno boleznijo ob diagnozi za 5 % ve~ji od dele`a tistih z raz{irjeno boleznijo; v vseh treh obdobjih je imela pribli`no ~etrtina `ensk razsejano bolezen (Tabela 2). Dele` bolnikov z omejenim stadijem ob diagnozi se je ve~al predvsem pri mlaj{ih bolnikih, ne pa pri starih 75 let in ve~ (Tabela 3). V letih 2001–2005 ni bilo specifi~no zdravljenih 21 % bolnikov. Dele` nezdravljenih bolnikov se je v opazovanem 15-letnem obdobju zmanj{al za 4 %. Med specifi~no zdravljenimi je bilo v letih 2001–2005 34 % bolnikov samo operiranih, 9 % jih je poleg operacije prejelo {e kemo- terapijo, po 7 % so jih samo obsevali ali pa so bili zdravljeni s kombinacijo operacije, radio- in kemoterapije, 6 % bolnikov so operirali in obsevali, po 5 % bolnikov pa je prejelo kombinaci- jo operacije s hormonsko terapijo ali kombinacijo radio- in kemoterapije ali pa samo kemo- ali hormonsko terapijo. Ostale kombinacije zdravljenj so uporabili pri treh ali manj odstotkih bolnikov. V obdobju 2001–2005 so se bolniki z rakom za~eli zdraviti v vseh slovenskih bolni{nicah. Naj- ve~ se jih je za~elo zdraviti na OI Ljubljana (32 %) in v UKC Ljubljana (28 %), 14 % so jih za~eli zdraviti v UKC Maribor, 7 % v SB Celje, po 3 % v SB Nova Gorica, SB Slovenj Gradec in SB Novo mesto, po 2 % v SB Murska Sobota in SB Izola, po 1 % pa v SB Jesenice in na Golni- ku. Manj kot pol odstotka bolnikov se je za~elo zdraviti na Ptuju, v Trbovljah in v Bre`icah. Pre`ivetje bolnikov z rakom se postopno pove~uje; v 15 letih se je petletno relativno pre`ivetje pove~alo za 12 % (Slika 2), za 14 % pri mo{kih in za 10 % pri `enskah (Tabela 4). Kako pomem- ben je stadij ob diagnozi, ka`e Slika 2: v zadnjem obdobju je bilo petletno relativno pre`ivetje bolnikov z omejenim stadijem `e ve~ kot 80-odstotno in se je v primerjavi z leti 1991–1995 pove~alo za 15 %; za 12 % se je pove~alo tudi petletno relativno pre`ivetje bolnikov z raz{irje- no boleznijo in je v zadnjem obdobju `e preseglo 50 %. Petletno relativno pre`ivetje bolnikov, odkritih v razsejanem stadiju, se je v 15 letih pove~alo le za 4 % in je {e vedno manj{e od 20 %. Napovedni dejavnik je tudi starost, saj je bilo petletno relativno pre`ivetje bolnikov, ki so zbo- leli pred 50. letom, v zadnjem obdobju 70 %, tistih, ki so zboleli med 50. in 74. letom, 50 %, tistih, ki so bili stari 75 let in ve~, pa le 38 % (Slika 4). Petletno relativno pre`ivetje vseh zbolelih v obdobju 2001–2005 je bilo 52 % (Slika 2); bolni- ki, ki pre`ivijo prvo leto, pa lahko pri~akujejo 74-odstotno petletno relativno pre`ivetje. Petletno relativno pre`ivetje bolnikov, ki so zboleli samo za eno rakavo boleznijo, je bilo 54 %. Rezultati {tudije EUROCARE-4 za zbolele v obdobju 2000–2002 ka`ejo, da je pre`ivetje slo- venskih bolnikov z rakom statisti~no zna~ilno manj{e od evropskega povpre~ja (Slika 5). 290 VSE RAKAVE BOLEZNI PRI ODRASLIH (BREZ KO@NEGA RAKA) Rak.qxd 22.7.2009 12:39 Page 290 In the years 2001–2005, 21% of patients did not receive specific treatment. In the observed 15-year period the proportion of untreated patients has decreased by 4%. Among those receiving spe- cific treatment in the period 2001–2005, 34% were treated by surgery alone, 9% received chemotherapy in addition to surgery, 7% each were either irradiated only, or treated with a com- bination of surgery plus radio- and chemotherapy, 6% had surgery and irradiation, 5% each received a combination of surgery plus hormone therapy or a combination of radio- and chemother- apy or either chemo- or hormone therapy alone. Other combinations of treatment were used in three or less than three percent of patients. In the period 2001–2005, cancer patients started their treatment in all Slovenian hospitals. In the period 2001–2005, the majority of them started their treatment at the IO Ljubljana (32%) and in the UMC Ljubljana (28%), 14% in the UMC Maribor, 7% in GH Celje, 3% each in general hospitals of Nova Gorica, Slovenj Gradec and Novo mesto, 2% each in general hos- pitals of Murska Sobota and Izola, and 1% each in GH Jesenice and at Golnik. Less than a half percent of patients started their treatment in GH Ptuj, GH Trbovlje and GH Bre`ice. The relative survival of cancer patients has been gradually increasing: in 15 years, the 5-year relative survival increased by 12% (Figure 2), in males by 14% and in females by 10% (Table 4). The relevance of stage at diagnosis is shown in Figure 2: compared to the period 1991–1995, in the last period the 5-year relative survival of patients with localized stage was already above 80%, thus having increased by 15%, while the 5-year relative survival of patients with regio- nal disease has increased by 12%, already exceeding 50% in the last period. However, in 15 years, the relative survival of patients diagnosed in a disseminated stage has increased only by 4% and is still lower than 20%. Age is a prognostic factor as well, since in the last period the 5-year relative survival of patients aged less than 50 years at diagnosis was 70%, while the rate in those aged between 50–74 years was 50%, and in those aged 75and older it was only 38% (Figure 4). The 5-year relative survival of all patients diagnosed in the period 2001–2005 was 52% (Figure 2); patients surviving the first year may expect to survive five years in 74%. The 5-year relative survival of patients diagnosed with one type of cancer only was 54%. According to the results of EUROCARE-4 study of patients diagnosed in 2000–2002, the sur- vival of cancer patients in Slovenia is statistically significantly below the European average (Figure 5). 291 ALL CANCER SITES BUT SKIN IN ADULTS 01 02 0 30 40 50 60 70 80 90 100 % Slovensko povpre~je / 2000–2002 (EUROCARE-4) Slovenian average Evropsko povpre~je / 2000–2002 (EUROCARE-4) European average Povpre~je ZDA / 2000–2002 (SEER-13) USA average Slika 5: Petletno relativno pre`ivetje odraslih bolnikov z rakom – brez ko`nega – (povpre~je in 95-odstotni interval zaupanja), zbolelih v letih 2000–2002 v Sloveniji, Evropi in nekaterih obmo~jih v ZDA. Figure 5: 5-year relative survival of adult cancer (except skin) patients (average and 95% confidence interval) diagnosed in the period 2000–2002 in Slovenia, Europe and in some regions of the USA. Rak.qxd 22.7.2009 12:39 Page 291 V obdobju 1991–2005 je za rakom zbolelo 1067 otrok in mladostnikov, 600 de~kov in 467 de- klic. Med njimi je bilo 243 primerov levkemij, 154 primerov tumorjev centralnega `iv~nega sistema (C@S), 115 primerov Hodgkinovih limfomov (HL) in 95 primerov ne-Hodgkinovih limfomov (NHL). Kot je razvidno s Slike 1, se groba inciden~na stopnja raka pri otrocih in mladostni- kih ves ~as opazovanja ve~a, povpre~no za 1,8 % letno, medtem ko se groba umrljivostna stopnja zmanj{uje, povpre~no za 2,7 % letno. ^asovne trende inciden~nih stopenj posameznih vrst raka je te`ko ocenjevati, saj je {tevilo primerov majhno; trendi najpogostej{ih vrst so prikazani na Sliki 2. Najbolj se ve~a incidenca levkemij (1,6-odstotni povpre~ni letni porast) in NHL (1,2-od- stotni povpre~ni letni porast). RAK PRI OTROCIH IN MLADOSTNIKIH 292 0 2 4 6 8 10 12 14 16 18 20 1986 1990 1995 2000 2005 Leto / Year Incidenca – groba stopnja / Incidence – crude rate Umrljivost – groba stopnja / Mortality – crude rate Stopnja na 100.000 / Rate per 100,000 Slika 1: Groba inciden~na in umrljivostna stopnja raka pri mlaj{ih od 20 let, Slovenija 1986–2005. Figure 1: Crude incidence and mortality rate of cancer in patients younger then 20 years, Slovenia 1986–2005. De~ki / Boys Deklice / Girls Obdobje / {tevilo / 0–14 let / 15–19 let / {tevilo / 0–14 let / 15–19 let / Period number years (%) years (%) number years (%) years (%) 1991–1995 200 62,5 37,5 161 70,2 29,8 1996–2000 204 58,8 41,2 148 66,2 33,8 2001–2005 189 61,4 38,6 155 58,7 41,3 Tabela 1: [tevilo bolnikov z rakom pri mlaj{ih od 20 let po spolu in obdobju postavitve diagnoze ter njihovi dele`i po starosti. Table 1: Number of cancer in patients younger then 20 years by sex and period of diagnosis with their proportions by age. V analizo pre`ivetja je vklju~enih 1057 primerov; 10 bolnikov (0,9 %) nismo upo{tevali, ker jim je bila diagnoza postavljena po smrti. Med njimi je bilo 6 primerov raka krvotvornih in limfati~nih organov ter 4 primeri raka C@S. Med vsemi v analizo vklju~enimi primeri pet bolnikov ni imelo mikroskopsko potrjene bolezni. EPIDEMIOLOGIJA Rak.qxd 22.7.2009 12:39 Page 292 In the period 1991–2005, a total of 1067 children and adolescents were diagnosed with can- cer, of these 600 boys and 467 girls. Among these, there were 243 cases of leukemias, 154 tumors of the central nervous system (CNS), 115 cases of Hodgkin's lymphoma (HL) and 95 cases of non-Hodgkin lymphoma (NHL). As evident from Figure 1, the crude incidence rate of can- cer in children and adolescents has been increasing throughout the observation period, by 1.8% annually on average, while the crude mortality rate has been decreasing, by 2.7% annually on average. The time trends in the incidence rates of individual cancer types are difficult to eval- uate since the number of cases is small; the trends for the most frequent types are shown in Figure 2. The highest increase has been noted in leukemias (1.6% average annual increase) and in NHL (1.2% average annual increase). The survival analysis included 1057 cases; 10 patients (0.9%) diagnosed only after death, were not considered in the analysis. Among these, there were 6 cases of hematopoietic and lym- phatic cancers and 4 cases of CNS cancers. Out of all cases included in the analysis, five patients did not have microscopically confirmed disease. CANCER IN CHILDREN AND ADOLESCENTS 293 Tabela 2: [tevilo bolnikov z rakom pri mlaj{ih od 20 let po spolu in obdobju postavitve diagnoze ter njihovi dele`i po stadiju. Table 2: Number of cancer patients younger then 20 years by sex and period of diagnosis with their propor- tions by stage. De~ki / Boys Deklice / Girls Obdobje / {tevilo / omejen / raz{irjen / razsejan / neznan / {tevilo / omejen / raz{irjen / razsejan / neznan / Period number localized regional distant unknown number localized regional distant unknown (%) (%) (%) (%) (%) (%) (%) (%) 1991–1995 200 34,5 25,5 39,5 0,5 161 37,3 19,9 41,6 1,2 1996–2000 204 43,1 18,6 36,8 1,5 148 34,5 25,7 39,2 0,7 2001–2005 189 37,6 26,5 35,4 0,5 155 36,1 23,9 39,4 0,6 Tabela 3: [tevilo bolnikov z najpogostej{imi raki pri mlaj{ih od 20 let po spolu, stadiju in starosti. Table 3: Number of most common cancers in patients younger then 20 years by sex, stage and age. Levkemije / Tumorji centralnega Hodgkinov neHodgkinovi Leukaemias `iv~nega sistema / limfom / limfomi / Tumors of central Hodgkin nonHodgkin nervous system limfoma limfoma Spol/Sex de~ki / boys 41 29 20 22 deklice / girls 37 17 16 10 Stadij/Stage omejen / localized (%) – 32 3 6 raz{irjen / regional (%) – 2 16 5 razsejan / distant (%) – 2 8 20 neznan / unknown (%) – 0 0 1 Starost/Age 0–14 let / years 56 37 15 22 15–19 let / years 22 9 17 10 EPIDEMIOLOGY Rak.qxd 22.7.2009 12:39 Page 293 V obdobju 2001–2005 je bilo med bolniki, mlaj{imi od 20 let, pribli`no 60 % otrok, mlaj{ih od 15 let, in 40 % mladostnikov, starih od 15 do 19 let. Razmerje med otroki in mladostniki je pri de~kih ves ~as opazovanja pribli`no enako, manj{a pa se dele` bolnic, mlaj{ih od 15 let, na ra~un ve~anja dele`a zbolelih mladostnic (Tabela 1). V vseh treh obdobjih je imelo pribli`no enak dele` bolnikov (dobra tretjina) ob diagnozi bolezen v omejeni ali pa `e v razsejani obliki. Raz{irjeno bolezen je imela pribli`no ~etrtina bolnikov, le redkim otrokom in mladostnikom pa stadij bolezni ob diagnozi ni dolo~en. Dele`i posameznih stadijev se z leti niso bistveno spreminjali (Tabela 2). [tevilo otrok in mladostnikov z najpogo- stej{imi vrstami raka po starosti in stadijih, zbolelih v obdobju 2001–2005, prikazuje Tabela 3. 294 RAK PRI OTROCIH IN MLADOSTNIKIH 0 1 2 3 4 5 6 1986 1990 1995 2000 2005 Leto / Year ne-Hodgkinovi limfomi / non-Hodgkin's limfoma Hodgkinov limfom / Hodgkin's limfoma Levkemije / Leukaemias Tumorji centralnega `iv~nega sistema / Tumors of central nervous system Stopnja na 100.000 / Rate per 100,000 Slika 2: Groba inciden~na stopnja najpogostej{ih rakov pri mlaj{ih od 20 let, Slovenija 1986–2005. Figure 2: Crude incidence rate of most common cancers in patients younger then 20 years, Slovenia 1986–2005. Tabela 4: Opazovano in relativno pre`ivetje bolnikov z rakom pri mlaj{ih od 20 let po spolu in obdobju postavitve diagnoze s 95-odstotnim intervalom zaupanja (IZ). Table 4: Observed and relative survival of cancer patients younger then 20 years by sex and period of diag- nosis with 95% confidence interval (CI). Opazovano pre`ivetje / Observed survival (%) De~ki / Boys Deklice / Girls Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 83,5 (78,5–88,8) 72,0 (66.0–78,5) 69,0 (62,9–75,7) 87,6 (82,6–92,8) 76,4 (70,1–83,2) 72,1 (65,4–79,3) 1996–2000 89,7 (85,6–94.0) 75,0 (69,3–81,2) 71,6 (65,6–78,0) 91,9 (87,6–96,4) 83,8 (78,1–89,9) 79,7 (73,5–86,5) 2001–2005 87,8 (83,3–92,6) 80,4 (75.0–86,3) 79,6 (74,0–85,7) 92,3 (88,1–96,6) 89,0 (84,2–94,1) 86,2 (80,7–92,1) Relativno pre`ivetje / Relative survival (%) De~ki / Boys Deklice / Girls Obdobje / 1-letno / 3-letno / 5-letno / 1-letno / 3-letno / 5-letno / Period -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) -year (IZ/CI) 1991–1995 83,6 (78,3–88,9) 72,2 (65,7–78,7) 69,3 (62,5–76.0) 87,6 (82,4–92,9) 76,5 (69,6–83,3) 72,2 (64,9–79,4) 1996–2000 89,8 (85,5–94,0) 75,1 (68,9–81,3) 71,8 (65,3–78,3) 91,9 (87,4–96,4) 83,8 (77,7–90,0) 79,8 (73,1–86,6) 2001–2005 87,9 (83,1–92,7) 80,6 (74,7–86,4) 79,9 (73,8–85,9) 92,3 (88,0–96,6) 89,1 (84,0–94,1) 86,3 (80,4–92,2) Rak.qxd 22.7.2009 12:39 Page 294 In the period 2001–2005, approximately 60% of patients younger than 20 years were children under 15 years of age and 40% adolescents aged 15–19 years. In boys, the ratio between chil- dren and adolescents has been approximately the same throughout the observation period, while in girls the proportion of patients under 15 years of age has been decreasing on the account of a higher proportion of adolescent patients (Table 1). In all three periods, approximately the same proportion of patients (over one third) presented with localized or disseminated disease at diagnosis. Regional disease was found in approxi- mately one fourth of patients; there were only few children and adolescents without stage determined at diagnosis. The proportions of individual stages did not change significantly with time (Table 2). The number of children and adolescents with the most frequent cancers diag- nosed in the period 2001–2005 by age and stage are presented in Table 3. 295 CANCER IN CHILDREN AND ADOLESCENTS 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Slika 3: Deset-, pet-, tri- in enoletno relativno pre`ivetje bolnikov z rakom pri mlaj{ih od 20 let po obdobju postavitve diagnoze. Figure 3: 10-, 5-, 3- and 1-year relative survival of cancer patients younger then 20 years by period of diag- nosis. 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 Omejen / Localized Raz{irjen / Regional Razsejan / Distant Vsi / All Slika 4: Petletno relativno pre`ivetje bolnikov z rakom pri mlaj{ih od 20 let po stadiju in obdobju postavitve diagnoze. Figure 4: 5-year relative survival of cancer patients younger then 20 years by stage and period of diagnosis. Rak.qxd 22.7.2009 12:39 Page 295 V obdobju 2001–2005 ni bilo specifi~no zdravljenih 3,5 % otrok in mladostnikov. Dele` nez- dravljenih bolnikov se v vsem obdobju analize ni bistveno spreminjal. Vsi zdravljeni bolniki z rakom krvotvornih in limfati~nih organov so prejeli citostatike. Pribli`no 80 % teh bolnikov je kot dopolnilno zdravljenje prejelo {e kortikosteroide, dodatno obsevanih pa je bilo 18 % bol- nikov z levkemijami, 78 % bolnikov s HL in 20 % bolnikov z NHL. Med bolniki s tumorji C@S jih je bilo 93 % operiranih, polovica med njimi je prejela tudi kemoterapijo, operaciji pa je bila v 38 % dodana {e radioterapija. V obdobju 2001–2005 se je slaba polovica bolnikov za~ela zdraviti na Pediatri~ni kliniki v Ljub- ljani, 27 % v UKC Ljubljana, 13 % na OI Ljubljana in 4 % v UKC Maribor. Posamezni bolniki so se pri~eli zdraviti {e v splo{nih bolni{nicah v Celju, Izoli, Murski Soboti, Novi Gorici, Novem mestu in na Jesenicah. Skoraj vsi, ki so pri~eli z zdravljenjem v UKC Ljubljana, so imeli tumor C@S in so bili tam operirani, na OI Ljubljana pa so ve~inoma z zdravljenjem pri~eli bolniki s HL. Relativno pre`ivetje otrok in mladostnikov z rakom se ve~a; v 15 letih se je petletno relativno pre`ivetje pove~alo za 12 % (Slika 3), pri deklicah nekaj ve~ kot pri de~kih (Tabela 4). Najmanj{e pre`ivetje imajo bolniki z razsejano boleznijo (Slika 4); petletno relativno pre`ivetje bolnikov, zbolelih v obdobju 2001–2005 z razsejano boleznijo, je bilo 72 %, medtem ko je bilo pre`ivet- je bolnikov z raz{irjeno boleznijo 90-odstotno. Pre`ivetje otrok se bistveno ne razlikuje od pre`ivetja mladostnikov (Slika 5). Pri primerjavi pre`ivetja najpogostej{ih rakov pri otrocih in mladostnikih (Tabela 5) vidimo, da se je petlet- no relativno pre`ivetje v 15 letih najbolj pove~alo pri bolnikih s tumorji C@S in pri bolnikih s HL – pri njih je v zadnjem obdobju tudi doseglo 100 %. Pre`ivetje je pri levkemijah in HL zelo podobno pri obeh spolih, medtem ko so pri bolnikih z NHL v zadnjem obdobju bolje pre`ivljale deklice, med bolniki s tumorji C@S pa de~ki. Prikaz pre`ivetja po stadijih pri najpogostej{ih vrstah raka otrok in mladostnikov je zaradi majh- nega {tevila bolnikov v posameznem stadiju nezanesljiv. Pri primerjavi pre`ivetij otrok s pre`ivetji mladostnikov pa pri najpogostej{ih anatomskih mestih opa`amo bolj{e pre`ivetje mlaj{ih od 15 let pri levkemijah, tumorjih C@S in NHL. Petletno relativno pre`ivetje vseh zbolelih v obdobju 2001–2005 je bilo 83 % (Slika 3); bolni- ki, ki pre`ivijo prvo leto, pa lahko pri~akujejo 92-odstotno petletno relativno pre`ivetje. Podobno se pove~a pri~akovano pre`ivetje, ~e bolnik pre`ivi prvo leto tudi pri posameznih vrstah raka; pri levkemijah s 74 % na 86 %, pri tumorjih C@S s 69 % na 83 % in pri NHL s 75 % na 96 %. Rezultati {tudije EUROCARE-4 za zbolele v obdobju 1995–2002 ka`ejo, da je pre`ivetje slo- venskih otrok in mladostnikov z rakom statisti~no nezna~ilno manj{e od evropskega povpre~ja (Slika 6). 296 RAK PRI OTROCIH IN MLADOSTNIKIH KLINI^NI KOMENT AR Janez Jazbec Za Slovenijo velja na~elni dogovor, naj se vsi otroci do dopolnjenega 18. leta starosti, pri kate- rih je postavljen utemeljen sum na raka, diagnosti~no obdelajo in zdravijo v nacionalnem centru za otro{ko onkologijo na Pediatri~ni kliniki v Ljubljani, ki deluje v sklopu UKC Ljubljana in tesno sodeluje z OI Ljubljana. Ker so v sedanjo analizo vklju~eni mladostniki do 20. leta sta- rosti, je lahko dele` bolnikov, ki so specifi~no zdravljenje za~eli v drugih bolni{nicah, posledica obravnave bolnikov med 18. in 20. letom. Ker so maligne bolezni pri otrocih heterogena skupina, je natan~nej{a analiza dejavnikov, ki so vzrok opazovanemu izbolj{anju pre`ivetja, zelo te`ka. Otroci z levkemijami se v Sloveniji zdravijo po shemah zdravljenja, ki izvirajo iz tako imenovane sheme BFM (Berlin-Frankfurt-Münster). V zadnjih letih so vsi bolniki z akutno limfoblastno Rak.qxd 22.7.2009 12:39 Page 296 In the period 2001–2005, 3.5% of children and adolescents did not receive specific treatment. The proportion of untreated patients has not changed significantly throughout the period under analysis. All the patients with cancers of hematopoietic and lymphatic organs received cytosta- tics. Approximately 80% of these patients also received an adjuvant therapy with corticosteroids, while 18% of patients with leukemias, 78% with HL and 20% with NHL were additionally irradiated. Among the patients with CNS tumors, 93% underwent surgery, and half of these also received chemotherapy; in 38% surgery was combined with radiotherapy. In the period 2001–2005, slightly less than half of the patients started their treatment at the University Children's Hospital in Ljubljana, 27% in the UMC Ljubljana, 13% at the IO Ljubljana and 4% in the UMC Maribor. Individual patients also started their treatment in the GH of Celje, Izola, Murska Sobota, Nova Gorica, Novo mesto and Jesenice. Nearly all those who start- ed their treatment in the UMC Ljubljana had CNS tumors and underwent surgery there, while patients with HL mostly started their treatment at the IO Ljubljana. The relative survival of children and adolescents with cancer has been increasing: in 15 years, the 5-year relative survival increased by 12% (Figure 3), in girls slightly more than in boys (Table 4). The lowest survival was observed in patients with disseminated disease (Figure 4); the 5-year relative survival of patients with disseminated disease diagnosed in the peri- od 2001–2005 was 72%, while the survival rate of patients with regional disease was 90%. The survival of children does not significantly differ from that of adolescents (Figure 5). When com- paring the survival of children and adolescents with the most frequent cancers (Table 5), in 15 years the highest increase in 5-year relative survival is seen in patients with CNS tumors and in patients with HL, in the latter being 100% in the last period. The survival in leukemias and HL is similar in both genders; in the last period, however, better survivors among NHL patients were girls and among patients with CNS tumors boys. The results of survival by stage in the most frequent cancers of children and adolescents are unreliable owing to a small num- ber of patients in individual stages. When comparing the survivals of children with those of adolescents, we note better survivals with leukemias, CNS tumors and NHL in children fewer than 15 years of age. The 5-year relative survival rate of all patients diagnosed in the period 2001–2005 was 83% (Figure 3); patients surviving the first year may expect to survive five years in 92%. If the patient survives the first year, a similar increase in the expected survival is noted in individual cancer 297 CANCER IN CHILDREN AND ADOLESCENTS 0 20 40 60 80 100 % 1986–1990 1991–1995 1996–2000 2001–2005 0–14 let / years 15–19 let / years Slika 5: Petletno relativno pre`ivetje bolnikov z rakom pri mlaj{ih od 20 let po starosti in obdobju postavitve diagnoze. Figure 5: 5-year relative survival of cancer patients younger then 20 years by age and period of diagnosis. Rak.qxd 22.7.2009 12:39 Page 297 levkemijo vklju~eni v medcelinsko raziskavo ALL-IC 2002. Po nekaterih ocenah otro{kih levke- mologov je 90-odstotno pre`ivetje verjetno zgornja meja, ki jo je mogo~e dose~i pri zdravljenju levkemije s trenutnim konceptom zdravljenja. Nakazano zmanj{anje pre`ivetja v zadnjem obdob- ju je zato treba tolma~iti z zadr`kom, saj gre pri njem lahko tudi za naklju~no nihanje. [tevilo bolnikov s tumorjem C@S v otro{kem obdobju je sorazmerno stalno. Osnovni na~in zdravljenja ostaja nevrokirurgija. Delno gre pove~anje pre`ivetja verjetno pripisati izbolj{anim metodam diagnostike in uvajanju intenzivnej{ih shem pooperativne kemoterapije, vklju~no s ke- moterapijo z visokimi odmerki s podporo avtolognih mati~nih krvotvornih celic. Dele` bolnikov, ki se je zaradi HL zdravil zunaj Pediatri~ne klinike, je 25 %. Vsi ti bolniki so se zdravili na OI Ljubljana. Ve~inoma gre za bolnike, starej{e od 18 let. Komentar pre`ivetja verjetno ni potreben, saj {tevilke govorijo, da je s sodobnimi na~ini diagnostike in zdravljenja HL v obdobju otroka in mladostnika ozdravljiva bolezen. 298 RAK PRI OTROCIH IN MLADOSTNIKIH ST AROST / AGE 0–14 Slovenija / Slovenia Malta / Malta ^e{ka / Czech Republic Islandija / Iceland [kotska / Scotland Nizozemska / Netherlands Severna Irska / Northern Ireland Poljska / Poland Anglija in Wales / England and Wales Danska / Denmark Portugalska / Portugal [panija / Spain Italija / Italy Norve{ka / Norway Francija / France Irska / Ireland [vedska / Sweden Belgija / Belgium [vica / Switzerland Nem~ija / Germany Finska / Finland Avstrija / Austria 01 02 0 30 40 50 60 70 80 90 100 % Evropa / Europe Slika 6: Petletno relativno pre`ivetije bolnikov z rakom (povpre~je in 95-odstotni interval zaupanja) starih od 0–14 in od 15–24 let, zbolelih v letih 1995–2002, v Sloveniji in izbranih evropskih dr`avah (EUROCARE-4)*. * Vir: Gatta G., @igon G., Capocaccia R., Coebergh J. W., Desandes E., Kaatsch P ., Pastore G., et al. Survival of European children and young adults with cancer diagnosed 1995–2002. Eur J Cancer 2009; 45: 992–1005. Rak.qxd 22.7.2009 12:39 Page 298 types: in leukemias from 74% to 86%, in CNS tumors from 69% to 83% and in NHL from 75% to 96%. According to the results of EUROCARE-4 study of patients diagnosed in 2000–2002, the survival of children and adolescents with cancer in Slovenia is below (statistically not signifi- cant) the European average (Figure 6). 299 CANCER IN CHILDREN AND ADOLESCENTS CLINICAL COMMENT ARY Janez Jazbec ST AROST / AGE 15–24 Evropa / Europe Malta / Malta ^e{ka / Czech Republic Islandija / Iceland [kotska / Scotland Nizozemska / Netherlands Severna Irska / Northern Ireland Poljska / Poland Anglija / England Wales / Wales Danska / Denmark Portugalska / Portugal [panija / Spain Italija / Italy Norve{ka / Norway Francija / France Irska / Ireland [vedska / Sweden Belgija / Belgium [vica / Switzerland Nem~ija / Germany Finska / Finland Avstrija / Austria 01 02 0 30 40 50 60 70 80 90 100 % Slovenija / Slovenia Figure 6: 5-year relative survival of cancer patients (average and 95% confidence interval) aged 0–14 and 15–24, diagnosed in the period 1995–2002 in Slovenia and in European countries (EUROCARE-4)*. * Source: Gatta G., @igon G., Capocaccia R., Coebergh J. W., Desandes E., Kaatsch P ., Pastore G., et al. Survival of European children and young adults with cancer diagnosed 1995–2002. Eur J Cancer 2009; 45: 992–1005. It has been agreed in principle that in Slovenia all children up to their 18 years of age justifi- ably suspected of having cancer, should undergo a diagnostic workup and treatment at the National Centre for Pediatric Oncology of the University Children's Hospital in Ljubljana func- tioning within the framework of the UMC Ljubljana and closely cooperating with the IO Ljubljana. As the present analysis includes adolescents up to 20 years of age, the proportion Rak.qxd 22.7.2009 12:39 Page 299 V zadnjem petletnem obdobju se je zmanj{alo pre`ivetje mo{kih bolnikov z NHL. Pri dekle- tih je v isti starostni skupini pre`ivetje v zadnjem obdobju 100 %. Glede na to, da je pristop k diagnostiki in zdravljenju pri obeh spolih enak, bo treba rezultat natan~nej{e analizirati, saj iz podatkov, ki so trenutno na voljo, razlage za razliko v pre`ivetju med spoloma ni. Jazbec J, Raji} V, Karas-Ku`eli~ki N. Levkemije otro{ke dobe. Zdrav Vestn 2008; 77 Suppl 1: I-25–30. Jazbec J, An`i~ J, Benedik-Dolni~ar M, Kitanovski L, Velen{ek-Prestor V, Raji} V, Pretnar J. Presaditev krvo- tvornih mati~nih celic pri otrocih v Sloveniji – stanje in perspektive. In: Kr`i{nik C, Battelino T. Izbrana poglavja iz pediatrije 19: novosti v klini~ni pediatriji, obnovitvena rehabilitacija, pediatri~na alergologija. Ljubljana: Katedra za pediatrijo, 2007; 61–7. Jazbec J, E}imovi} P , Jereb B. Second neoplasms after treatment of childhood cancer in Slovenia. Pediatr Blood Cancer 2004; 42: 574–81. Velen{ek-Prestor V, Jazbec J. Pre`ivetje otrok in mladostnikov s solidnimi tumorji v Sloveniji v obdobju 1990–2000. Slov Pediatr 2002; 9: 94–9. Mali P , Jazbec J. Pre`ivetje otrok in mladostnikov z nehodgkinovim limfomom v Sloveniji v obdobju 1990–1999. Slov Pediatr 2002; 9: 90–3. Mali P, Jazbec J. Pre`ivetje otrok in mladostnikov z akutno levkemijo v Sloveniji v obdobju 1990–1999. Slov Pediatr 2002; 9: 86–9. 300 RAK PRI OTROCIH IN MLADOSTNIKIH Tabela 5: Deset-, pet-, tri- in enoletno relativno pre`ivetje bolnikov, mlaj{ih od 20 let, pri {tirih najpogostej{ih lokacijah raka po obdobju postavitve diagnoze s 95-odstotnim intervalom zaupanja. Table 5: 10-, 5-, 3- and 1-year relative survival of cancer patients younger then 20 years by four most common cancer locations and period of diagnosis with 95% confidence interval. Relativno pre`ivetje / Relative survival (%) Obdobje / Period 1-letno / -year 3-letno / -year 5-letno / -year 10-letno / -year Levkemije / Leukaemias 1991–1995 86,3 (78,4–94,2) 70,1 (59,3–80,9) 62,6 (51,0–74,2) 60,2 (48,4–72,0) 1996–2000 92,8 (87,1–98,6) 79,6 (70,4–88,8) 77,3 (67,7–86,9) 76,2 (66,4–86,0) 2001–2005 85,9 (77,8–94,0) 78,3 (68,6–88,0) 74,2 (63,1–85,3) – Tumorji centralnega 1991–1995 70,6 (56,9–84,3) 64,8 (50,2–79,4) 59,0 (43,8–74,2) 55,2 (39,6–70,8) `iv~nega sistema / 1996–2000 75,5 (63,0–88,0) 58,6 (43,7–73,5) 54,8 (39,6–70,1) 49,3 (33,7–64,9) Tumors of central 2001–2005 82,6 (70,9–94,4) 71,8 (57,5–86,1) 68,9 (53,7–84,1) – nervous system Hodgkinov limfom / 1991–1995 95,6 (91,2–100,0) 91,3 (82,6–100,0 ) 89,2 (79,5–98,9) 87,3 (76,7–97,8) Hodgkin's limfoma 1996–2000 100,0 97,1 (94,1–100,0) 91,1 (82,0–100,0) 88,3 (76,4–100,0) 2001–2005 100,0 100,0 100,0 – ne-Hodgkinovi limfomi / 1991–1995 75,8 (59,7–91,9) 72,8 (55,9–89,8) 73,0 (56,0–89,9) 67,1 (48,8–85,4) non-Hodgkin's limfoma 1996–2000 92,6 (85,2–100,0) 81,6 (65,5–97,6) 81,7 (65,6–97,8) 81,9 (65,8–98,0) 2001–2005 78,2 (62,4–93,9) 75,1 (58,5–91,7) 75,2 (58,5–91,8) – VIRI Literature Rak.qxd 22.7.2009 12:39 Page 300 of patients starting specific treatment in other hospitals could represent the patients treated at an age between 18–20 years. The fact that malignant diseases in children make a heterogeneous group renders an exact analy- sis of factors contributing to the observed improvement in survival very difficult. Children with leukemias in Slovenia are treated according to the schedules derived from the so-called BFM (Berlin-Frankfurt-Münster) schedule. In recent years, all patients with acute lymphoblastic leukemia are included into the intercontinental ALL-IC 2002 study. According to some assessments of pediatric leukemologists, 90% survival is probably the upper limit attain- able in leukemia treatment by means of present treatment approach. Therefore, the indicated downward trend in the survival in the last observation period should be interpreted with cau- tion, as it may be a result of random fluctuation. The number of patients with CNS tumors in childhood is relatively stable. Neurosurgery still remains the basic treatment approach. An increase in the survival could partly be ascribed to the improved diagnostic methods and to the implementation of more intensive postoperative chemotherapeutic schedules, including megatherapy with autologous hematopoietic stem-cell support. The proportion of patients treated for HL outside the University Children's Hospital amounts to 25%. All these patients, the majority of them being older than 18 years, were treated at the IO Ljubljana. There is probably no need to add any comment on the survival since the rates themselves clearly show that – by means of up-to-date diagnosis and treatment – HL in child- hood and adolescence is a curable disease. In the last 5-year period, the survival of male patients with NHL has decreased. In the same period, the survival of girls in the same age group was 100%. Considering that the same diag- nostic and treatment approach is used in both genders, the result calls for a detailed analysis, since on the basis of currently available data the gender-related difference in the survival can- not be explained. 301 CANCER IN CHILDREN AND ADOLESCENTS Rak.qxd 22.7.2009 12:39 Page 301 UVOD Rak je bolezen, s katero se moderna civilizacija vse pogosteje sre~uje. Z vi{jim `ivljenjskim stan- dardom, higienskimi in drugimi javnozdravstvenimi ukrepi se je pri~akovana `ivljenjska doba mo~no podalj{ala. Starost je eden glavnih nevarnostnih dejavnikov raka, bolezni, ki je bila v pre- teklosti redka in v ve~ini primerov smrtna. Z razvojem znanosti in tehnologije imamo danes vrsto oro`ij, da se z njo spopademo in jo v visokem odstotku obvladamo. Brez merjenja u~in- ka na{ih intervencij, ki izhajajo iz predklini~nih in klini~nih raziskav na celotni populaciji, pa bi bila borba in uspehi jalovi. V medicini se namre~ nemalokrat izka`e, da uspe{en eksperi- ment v laboratoriju ali na izbrani skupini ljudi ne ka`e enakega u~inka na celotni populaciji bolnikov. Kako uspe{ni smo pri obvladovanju raka, merimo med drugim tudi s populacijskim pre`ivetjem. S spremljanjem tega kazalca v dalj{em ~asovnem obdobju lahko dokaj zanesljivo ugotovimo, kak{ne posledice imajo ukrepi, ki dokazano vplivajo na zgodnje odkrivanje in zdrav- ljenje raka. Izredno pomembno bi bilo, ~e bi lahko merili tudi kakovost `ivljenja teh bolnikov, vendar so metodologije za to trenutno prezapletene in tudi dana{nji zajem podatkov tega ne omogo~a. [TEVILO IN KAKOVOST PODATKOV, ZBRANIH V REGISTRU RAKA REPUBLIKE SLOVENIJE Pravzaprav bi moral biti rak preprosto ozdravljiva bolezen, ~e vemo, da vznikne iz ene same celice. @al dejstva ka`ejo ravno obratno. Ve~ kot vemo o biologiji celice, bolj postaja jasno, da je rak bolezen, s katero se bo treba spopasti intenzivno na vseh ravneh (primarna, sekundar- na preventiva, zdravljenje, rehabilitacija), da jo bomo uspeli obvladovati, verjetno pa je v celoti ne bomo obvladali nikoli. Ker se v obvladovanje raka vklju~ujejo {tevilni dejavniki, postaja jasno, da so stro{ki teh naporov visoki; pri~akujemo, da se bodo v prihodnje strmo ve~ali. ^e ne bomo sprejemali dokazano u~inkovitih ukrepov pravo~asno in na pravem mestu, raka ne bomo mogli obvladovati kljub vedno ve~jemu vlaganju v to podro~je. Za na~rtovanje u~inkovitih ukrepov na podro~ju raka so zato potrebne analize, kot je ta, ki pa morajo seveda temeljiti na vrsti rele- vantnih podatkov. Kaj bi bilo potrebno v zajemu na{ih podatkov v RRS dopolniti ali izbolj{ati, da bi bile te analize {e bolj verodostojne in natan~ne? ^e razumemo, da je glavni namen zajema podatkov na~rtovanje z dokazi podprtih ukrepov in da njihov u~inek lahko vrednotimo, potrebujemo danes pri vrednotenju obvladovanja raka nasled- nje podatke: histolo{ko/citolo{ko diagnozo, zamejitev raka (stadij) in plan ter izvedbo prvega zdravljenja. Za zajem teh podatkov se bo seveda potrebno poslu`iti vseh mo`nosti, ki jih lah- ko nudi sodobna informacijska tehnologija. Registri raka so dragoceno podatkovno skladi{~e za {tevilne analize bremena raka v dr`avi, {tevilo in kakovost podatkov, ki jih potrebujemo za natan~nej{e analize pre`ivetja, pa z dana{njo tehnologijo zbiranja podatkov, kakovostjo posre- dovanih podatkov in s {tevilom osebja, ki jih obdeluje, ne sledijo potrebam klinikov. Nujno bo, da v prihodnje skupaj s stroko dore~emo in raz{irimo nabor podatkov, ki bo omogo~il {e dodat- ne, bolj usmerjene analize. Vse te dopolnitve seveda narekujejo posodobitev tehnologije zbiranja in obdelave podatkov RRS, ne nazadnje tudi ve~ osebja; zagotovo pa bo taka investicija stro{- kovno u~inkovita in smiselna. KAJ VSE POVEDO PRIKAZANI REZULTATI 302 Rak.qxd 22.7.2009 12:39 Page 302 INTRODUCTION Cancer is a disease that modern civilization has to face more and more frequently. A higher standard of life as well as hygienic and other public health measures contributed to a conside- rable increase in life expectancy. Consequently, the number of cases is increasing, as age is one of the main risk factors for cancer, the disease that used to be quite rare and in most cases fatal in the past. The development in science and technology produced a number of tools, which help us to combat and quite successfully control the disease. However, without evaluating the effects of our interventions, derived from population-based preclinical and clinical research, this fight and its results would be worthless. Namely, in medicine it often turns out that a suc- cessful experiment carried out in vitro or in a selected group of people does not yield the same result when applied to the whole population of patients. The success in cancer control is meas- ured among other things by population survival. By following this indicator over a longer period, it is possible to assess quite reliably the results of interventions known to influence early detec- tion and treatment of cancer. It would be very important if we could also measure the quality of patients' life, however the relevant methodologies are presently too complex, and the cur- rent data collection does not enable that either. THE NUMBER AND QUALITY OF DAT A COLLECTED BY THE CANCER REGISTRY OF REPUBLIC OF SLOVENIA Actually, cancer should be an easily curable disease, considering that it originates from a sin- gle cell. Unfortunately, the facts show just the opposite, and more that we know about cell biology, more clear it becomes that, in order to control cancer successfully, the disease should be approached intensively at all levels (primary and secondary prevention, treatment and rehabilitation), though a complete control can probably never be attained. Since cancer control includes several fac- tors, obviously, these efforts are associated with high costs, which are expected to increase even more rapidly in the future. If the proven effective measures are not going to be adopted in due time and where necessary, cancer would remain out of control, despite the ever higher invest- ments into this area. Therefore, effective intervention planning in the area of cancer requires analyses such as the present one; however, these must be based on a range of relevant data. What in the CRS's data collection should be upgraded or improved so as to render those analy- ses even more valid and accurate? Considering that the main objective of data collection is to plan evidence-based interventions and to facilitate the evaluation of the effect of these interventions, presently the following data are needed for the evaluation of cancer control: histological/cytological diagnosis, cancer stag- ing, treatment planning and primary treatment implementation. In order to collect all these data, it will be necessary to make use of all the facilities offered by current information tech- nology. Cancer registries represent valuable data pools for several analyses of national cancer burden, however, the current technology of data collecting, the quality of the data provided and the number of personnel involved in the data processing are not able to ensure that the scope and quality of data needed for more accurate survival analyses would be consistent with the needs of clinicians. In the future, it will be necessary to define and expand – together with WHAT CAN BE DERIVED FROM THE PRESENTED RESULTS 303 Survival of cancer patients, diagnosed in 1991–2005 in Slovenia Rak.qxd 22.7.2009 12:39 Page 303 Pri {irjenju {tevila podatkov, ki se zbirajo in obdelujejo v RRS, bo treba misliti predvsem na naslednje: Histolo{ka/citolo{ka diagnoza @e danes, predvsem pa v prihodnje, bo molekularni profil raka odlo~al o na~rtovanju zdrav- ljenja, zato bo potrebno v RRS bele`iti histolo{ko/citolo{ko diagnozo na na~in, da bo mogo~e kadar koli preveriti, ali je bilo zdravljenje izvedeno v skladu s smernicami, ki bodo temeljile na genskem podpisu raka. Samo velik dele` histolo{ko/citolo{ko potrjenih rakov, za kar gre veli- ka zasluga RRS v preteklosti, bo postal le nujen predpogoj, saj bo moral biti na voljo tudi genski podpis (terapevtske tar~e) pri vseh rakavih boleznih, ki se bodo zdravile, da bomo lahko sprem- ljali, ali je bilo predpisano zdravljenje primerno in tudi stro{kovno u~inkovito. Stadij Bele`enje stadija raka bo {e vedno potrebno, morda {e bolj zaradi spremljanja u~inkovitosti pre- sejalnih programov, a tudi zaradi ugotavljanja primernosti zdravljenja. Ravno zaradi slednjega in zaradi upo{tevanja smernic, ki temeljijo na stadiju TNM, bo treba poleg registrskega upora- biti tudi za vsako anatomsko mesto raka priporo~en stadij (TNM ali po kaki drugi klasifikaciji); seveda pa je od poro~evalcev RRS odvisno, kako popoln je ta podatek. RRS stadij bolezni po TNM oz. po drugih klasifikacijah bele`i `e sedaj, vendar preve~krat v prijavnici ni zapisan. Velikokrat pa je bila nenatan~na postavitev stadija tudi povezana z nedostopnostjo diagnosti~nih naprav (CT, MRI). Kako je to pomembno, se vidi v slab{em pre`ivetju v primerjavi z zahod- noevropskimi dr`avami, npr. pri urolo{kih rakih, kjer je bila dostopnost do diagnosti~nih mo`nosti neprimerno bolj{a. Na~rt in izvedba prvega zdravljenja Na tem podro~ju bo treba v zajemu podatkov RRS najve~ dopolniti. Bele`iti bo treba odlo~i- tev multidisciplinarnega konzilija o predlaganem prvem zdravljenju in nato zabele`iti tudi prejeto zdravljenje (s podatki o operativnem posegu, obsevanju, sistemskem zdravljenju in o tem, kje in kdo je zdravljenje izvedel). Le na ta na~in bomo lahko zares vrednotili vzroke za ugotov- ljene rezultate zdravljenja in na njih vplivali, kjer bo to potrebno. Le pravilno na~rtovano in izvedeno prvo zdravljenje je lahko u~inkovito, s tem pa tudi najbolj stro{kovno u~inkovito. KAJ DELAMO DOBRO, KAJ SLABO IN KAJ MORAMO IZBOLJ[ATI Primarna preventiva Merilo za uspeh primarne preventive je zmanj{evanje incidence, kar praviloma spremlja tudi zmanj{anje umrljivosti. Kot je razvidno iz prikazov v posameznih poglavjih in pri vseh rakavih boleznih skupaj, se pri ve~ini incidenca ve~a, umrljivost pa ostaja enaka (starostno standardi- zirana se celo zmanj{uje), kar ka`e, da smo bolj uspe{ni pri zdravljenju, ki je seveda neprimerno dra`ji ukrep z neprimerno ve~ sopojavi kot prepre~evanje, npr. z zdravo hrano, s primerno tele- sno dejavnostjo, z nekajenjem, omejevanjem alkoholnih pija~ in izogibanjem karcinogenom v delovnem in bivalnem okolju. Edini rak, kjer se incidenca vztrajno manj{a pri obeh spolih, je `elod~ni rak, pa {e tu je trend zmanj{evanja v Sloveniji po~asnej{i kot drugod po svetu. Pri mo{kih sta se incidenca in umrljivost za plju~nim rakom na ra~un manj{anja dele`a kadilcev ustalila, medtem ko se pri `enskah strmo ve~ata. O~itno so ukrepi na podro~ju omejevanja kaje- nja vplivale predvsem na odrasle mo{ke, zato bo treba najti nove poti, kako vplivati tudi na `enske in mlade. 304 Pre`ivetje bolnikov z rakom, zbolelih v letih 1991–2005 v Sloveniji Rak.qxd 22.7.2009 12:39 Page 304 the competent profession – the range of data that would facilitate additional, more directed analyses. Of course, all these amendments require that the data collecting and processing tech- nologies of the CRS be updated and more personnel employed, but undoubtedly such an investment would prove cost-effective. When expanding the range of data to be collected and processed by the CRS, particularly the following should be considered: Histological/cytological diagnosis Already today, but even more so in the future, treatment planning will depend on the molec- ular profile of cancer, and therefore in the CRS histological/cytological diagnosis should be registered in such a way that it will be possible to check at any time whether the treatment was carried out in accordance with the guidelines based on cancer gene transcript. A large pro- portion of histologically/cytologically confirmed cancers – which is definitely the result of the CRS's efforts in the past – will become an ultimate prerequisite only, since gene transcripts (therapeutic targets) will also have to be available in all cancers treated, thus enabling us to assess whether the prescribed treatment was both suitable and cost-effective. Stage Stage registration will still be necessary, perhaps even more so, to facilitate the surveillance of the effectiveness of screening programs rather than to assess the adequacy of therapy. For that very reason, as well as for taking account of the guidelines based on the TNM staging system, apart from the registry's also a staging (according to TNM or any other classification) rec- ommended for each cancer site in accordance with the pathologist's definition will have to be used; the completeness of these data, however, depends on the reporters to CRS. So far, stage according to TNM or some other classifications has already been registered by the CRS, how- ever, too often this information is lacking on the notification form. Stage registration will have to be improved particularly in urological cancers, where inaccurate staging was also associat- ed with lacking access to diagnostic facilities (CT, MRI). The importance of this is reflected in a lower survival in comparison with West European countries, where the accessibility of diag- nostic facilities is much better. Primary treatment planning and performance This segment of CRS's data acquisition requires major upgrading. Registration will have to include the decision by a multidisciplinary team counsel on the proposed primary treatment as well as the therapy received (including information on surgical interventions, irradiation, systemic therapy and specifying where and who performed the treatment). All these data will enable us to actually evaluate the reasons for the obtained treatment results and influence them as necessary. Only a correctly planned and performed primary treatment may be successful and thus also cost-effective. WHAT ARE WE DOING WELL, WHAT ARE OUR WEAKNESSES AND WHAT SHOULD BE IMPROVED Primary prevention In primary prevention, the measure of success is a decreasing incidence, generally also accom- panied by a decreasing mortality. As evident from the presentations in individual chapters and for all cancers combined, in the majority of them the incidence rates are increasing while the 305 Survival of cancer patients, diagnosed in 1991–2005 in Slovenia Rak.qxd 22.7.2009 12:39 Page 305 Sekundarna preventiva Merilo za u~inkovitost presejalnih programov je zmanj{anje umrljivosti za rakom; pri rakavih boleznih, pri katerih s presejanjem zdravimo predrakave spremembe, pa tudi incidence (npr. pri raku materni~nega vratu, debelega ~revesa in danke). Tako se pri nas `e ka`ejo u~inki pre- sejalnega programa za raka materni~nega vratu ZORA. Pri raku dojk se po~asi ve~a dele` bolnic z omejenim stadijem (brez prizadetih pazdu{nih bezgavk ob diagnozi), verjetno na ra~un ve~je skrbi `ensk za svoje zdravje in oportunisti~nega presejanja. Starostno standardizirana umrlji- vost se manj{a, delno na ra~un zgodnej{e diagnoze, predvsem pa na ra~un bolj{ega dopolnilnega zdravljenja. Glede na podatek, da je petletno relativno pre`ivetje bolnic z rakom dojk, ki nima- jo prizadetih pazdu{nih bezgavk ob diagnozi, ve~ kot 95-odstotno (govori o odli~no izvedenih postopkih zdravljenja raka dojke v na{i dr`avi!), bi s kakovostnim presejalnim programom lah- ko {e zmanj{ali umrljivost. Pri raku debelega ~revesa in danke pa odkrijemo manj kot 15% bolnikov z omejenim stadijem, pri njih pa je petletno relativno pre`ivetje ve~ kot 90-odstot- no. S kakovostnim presejalnim programom bi z odstranjevanjem predrakastih polipov zmanj{ali incidenco, raka pa bi v skoraj treh ~etrtinah odkrili v omejenem stadiju. Zdravljenje Merilo za uspeh terapevtskih ukrepov je pre`ivetje, seveda je pri tem treba upo{tevati stadij bolezni in starost bolnikov, saj imajo starej{i bolniki vrsto spremljajo~ih bolezni, pri katerih je potrebno zdravljenje prilagoditi ali pa ga sploh ni mo`no izvesti. Ravno zato je zelo pomemb- no, da specifi~no zdravljenje izvajajo za to usposobljeni strokovnjaki onkologi, ki se prete`ni del svojega ~asa ukvarjajo z bolniki z rakom in obravnavajo zadostno {tevilo bolnikov. Tak{ne so tudi mednarodne zahteve in definicije*. Kako se teh na~el dr`imo v Sloveniji? Kot je razvid- no iz posameznih poglavij, se bolniki z rakom zdravijo prakti~no v vseh slovenskih bolni{nicah. To je tudi pri~akovati, saj pomembnej{ih ukrepov na tem podro~ju, ki bi kaj spremenili, v teh obdobjih prakti~no ni bilo. Verjetno pa je to podro~je, kjer bo moralo priti do dodatnih spre- memb predvsem pri redkih rakavih boleznih, ki jih morajo zdraviti v enem centru; pogostej{e pa v ve~, vendar v tistih, ki so za to dodatno usposobljeni. Podatek iz pri~ujo~e publikacije, ki to podpira, je razlika v pre`ivetju bolnikov z NHL, zdravljenih na OI Ljubljana, kjer se zdra- vi 80 % slovenskih bolnikov, v primerjavi z ostalimi 20 %, ki se zdravijo v ostalih bolni{nicah. Ob upo{tevanju ostalih dejavnikov (stadij, starost), ki so bili vklju~eni v multivariatni model, je tveganje smrti kar 2,5-krat manj{e pri bolnikih, zdravljenih na OI Ljubljana. Iz dostopnih podatkov seveda ne moremo izlu{~iti natan~nih vzrokov. Ker so NHL {e vedno relativno red- ka bolezen, je nedvomno bolj smotrno, da se ti bolniki zdravijo tam, kjer so zaradi ve~jih izku{enj mo`nosti ozdravitve ve~je. Na podoben na~in bo treba napraviti natan~nej{e analize, ki presegajo obseg te publikacije, tudi za druge rakave bolezni in na ta na~in ugotoviti centre, ki bodo bolj usmerjeni v zdravljenje dolo~enih bolezni. Ob tem bo treba upo{tevati tudi pogostost bolezni in dostopnost posamez- nih na~inov zdravljenja. Kirurgija ostaja {e vedno najpogostej{i na~in zdravljenja raka pri bolnikih vseh starosti, saj so jo kot edini na~in zdravljenja uporabili v zadnjem obdobju pri 43 % bolnikov, kot sestavni del pa {e pri nadaljnjih 33 % bolnikov. Odstotek bolnikov, ki je bil zdravljen z obsevanjem, je bil v obdobju 1991–1995 43 %, v obdobju 2001–2005 se je zmanj{al za ve~ kot ~etrtino, na 31 %. Potrebno je analizirati, ali gre dejansko za manj{i odstotek indikacij za obsevanje pri posameznih 306 Pre`ivetje bolnikov z rakom, zbolelih v letih 1991–2005 v Sloveniji * Onkolog je zdravnik ali zdravnica, ki polni delovni ~as zdravi bolnike z rakom. Je dodatno usposobljen/-a na podro~ju internisti~ne, obsevalne ali kirur{ke onkologije. Zna uporabljati specifi~no onkolo{ko zdravljenje in simptomatsko, psiholo{ko, podporno in paliativno zdravljenje, ki ga izvaja dnevno za izbolj{anje kakovosti `ivljenja bolnikov z rakom. Je usposobljen/-a in se {e naprej izobra`uje za upo- rabo takih postopkov, ki najbolj koristijo bolniku, ob tem, da zna upo{tevati psiholo{ke in socialne potrebe bolnikov z rakom in njihovih dru`in. (http://www.esmo.org/about-esmo/bylaws.htmlc1006) Rak.qxd 22.7.2009 12:39 Page 306 mortality remains the same (the age-standardized is even decreasing), which shows that our treatment is more successful – albeit these measures being much more expensive and entail- ing much more adverse effects – than prevention, e. g. by means of healthy nutrition, adequate physical activity, non-smoking, reduced alcohol drinking and avoiding exposure to carcino- gens in workplace and living environment. Stomach cancer is the only cancer with a persistent downward trend in the incidence in both genders, but even there the decreasing trend in Slovenia is slower than elsewhere in the world. While the incidence and mortality for lung cancer in males have become stable on the account of a decreasing proportion of smokers among them, the relevant rates in females are undergoing a steep increase. Obviously, smoking restriction measures have exerted a prevailing influence on adult males, and therefore new ways should be sought to influence women and adolescents as well. Secondary prevention A measure of the effectiveness of screening programs is a reduced cancer mortality and – in cancers where screening is intended to detect precancerous changes – also a reduced incidence (e. g. in cervical and colorectal cancers). Thus we can already witness the effects of our ZORA screening program for cervical cancer. In breast cancer the proportion of patients with locali- zed stage (without lymph node involvement at diagnosis) is slowly increasing, probably on the account of greater awareness of women regarding their health, and also as a result of oppor- tunistic screening. Age-standardized mortality is decreasing, partly due to earlier detection, but mainly due to better adjuvant therapy. Considering the fact that the five-year relative sur- vival of breast cancer patients without lymph node involvement at diagnosis is over 95% (which speaks for an excellent approach to the treatment of breast cancer in Slovenia!), a quality screen- ing program may further reduce the relevant mortality rates. In colorectal cancer, less than 15% of patients are diagnosed in a localized stage, where the five-year relative survival exceeds 90%. A quality screening program may reduce the incidence as a result of detected and removed pre- malignant polyps, while in almost three fourths of cases cancer could be detected in a localized stage. Treatment Although survival is the measure of therapeutic success, stage of disease and patients' age should be taken into account as well, since elderly patients present with a number of concomitant dis- eases, so their treatment has to be adjusted or is not feasible at all. Therefore it is of particular importance that specific treatment be carried out by adequately qualified experts-oncologists, prevailingly involved in the management of cancer patients and thus having sufficient expe- rience in this area of expertise. This is consistent with the international requirements and definitions too*. And how are these principles respected in Slovenia? As evident from indi- vidual chapters of this report, cancer patients are treated in practically all general hospitals of Slovenia. Such situation is not surprising since practically no major interventions to change it in any way have been undertaken in this respect in the past 15 years. Probably this is an area where certain additional changes will have to be made particularly as regards rare cancers, which should be treated in a single center, while more frequent cancers may be treated in several insti- tutions, however these should be additionally qualified to do that. Further evidence that supports this view can be found in the present publication showing the difference between the survival 307 Survival of cancer patients, diagnosed in 1991–2005 in Slovenia * An oncologist is a physician taking care of cancer patients full-time. He/she has training in Medical Oncology or Radiation Oncology or Surgical Oncology. He/she is able to use the respective therapies and symptomatic, psychological, supportive, palliative, and after care in daily clinical practice to improve the quality-of-life of cancer patients. He/she will be trained and continue to update his/her knowledge in the application of such interventions for optimal benefit, taking into account the psychological and social needs of cancer patients and their families. (http://www.esmo.org/about-esmo/bylaws.htmlc1006) Rak.qxd 22.7.2009 12:39 Page 307 rakavih boleznih (npr. pri Hodgkinovi bolezni, drugih limfomih in seminomih) ali pa niso prav postavljene indikacije za obsevanje (v obdobju 2001–2005 je bilo obsevanih samo 7 % bolni- kov z rakom prostate). Pri zdravljenju s kemoterapijo vidimo ravno obratno; v letih 1991–1995 jo je prejelo 26 % bolnikov kot prvo zdravljenje samo ali v kombinaciji z ostalimi na~ini, v ob- dobju 2001–2005 pa 3 % ve~. Zavedati pa se moramo, da tu ni upo{tevano hormonsko in tar~no zdravljenje, ki je v zadnjem ~asu v strmem porastu, tako po indikacijah kot po trajanju (ve~ let, do`ivljenjsko). Zato bo treba pri racionalnem na~rtovanju potreb po posameznih profilih specialistov v prihodnje te trende upo{tevati, da bo kakovost zdravljenja primerna in zares u~in- kovita. 308 Pre`ivetje bolnikov z rakom, zbolelih v letih 1991–2005 v Sloveniji Rak.qxd 22.7.2009 12:39 Page 308 of patients with NHL treated at the IO Ljubljana (80% of NHL patients in Slovenia) and the remaining 20% treated in other hospitals. Taking into account other factors (stage, age) includ- ed in the multivariate model, patients treated at the IO Ljubljana have as much as 2.5-fold lower risk of death. The available data do not provide conclusive information on the exact rea- sons for such results, however. As NHL is a relatively rare disease, it seems definitely more reasonable that the patients are treated there where their chances of cure are, because of more experienced stuff, better. Similar, more detailed analyses, which exceed the scope of this publication, will also have to be carried out for other cancers in order to identify the centers that would be most competent for treatment of particular diseases. At the same time it will be necessary to take into account the frequency of diseases and the accessibility of individual treatment modalities. Surgery still remains the most important method of cancer treatment in patients of all ages; thus, in the last period it was used as monotherapy in 43% of patients and as part of combined therapy in another 33%. In the period 1991–1995, the proportion of patients treated by irra- diation represented 43%, whereas in the period 2001–2005 this percentage decreased by more than one-fourth, being 31%. It would be necessary to analyze whether the decrease is actual- ly due to a lower percentage of indications for irradiation in individual cancers (e. g. in Hodgkin's disease, other lymphomas and seminomas) or perhaps the indications for irradiation are not established correctly (in the period 2001–2005 irradiation treatment was used in only 7% of patients with prostate cancer!). The opposite situation is observed as regards chemotherapy: in the period 1991–1995, 26% of patients received it in the course of their primary treatment either alone or in combination with other methods, whereas in the period 2001–2005 this per- centage increased by 3%. It should be kept in mind, however, that this score does not include the use of hormone and targeted therapy, which has been recently on the steep increase so in terms of indications as well as the duration of treatment (several years or lifelong). Therefore, these trends should be taken into account in order to rationally plan the need for individual profiles of specialists in the future and thus ensure an adequate quality and effectiveness of therapy. 309 Survival of cancer patients, diagnosed in 1991–2005 in Slovenia Rak.qxd 22.7.2009 12:39 Page 309 1. Pre`ivetje odraslih bolnikov z rakom (brez ko`nega) se s ~asom pri ve~ini rakavih bolezni pomembno izbolj{uje; v desetih letih (1991–1995 in 2001–2005) se je petletno relativno pre`ivetje vseh bolnikov izbolj{alo za 12 % (s 40 % na 52 %), mo{kih za 14 % (s 30 % na 44 %) in `ensk za 10 % (z 49 % na 59 %). 2. Pri pogostej{ih rakavih boleznih, ki v obdobju 2001–2005 posami~no predstavljajo 3 % ali ve~ skupnega bremena raka pri odraslih, skupaj pa 61 %, se je pre`ivetje v 10 letih pove~a- lo za 10 % ali ve~ pri vseh rakavih boleznih, razen pri dveh, kjer tudi v Evropi ni ve~jega napredka (plju~a, materni~no telo); najbolj se je pre`ivetje pove~alo pri raku prostate (za 26 %), sledijo debelo ~revo (16 %), dojka (14 %), ko`ni melanom (12 %), danka (11 %) in `elodec (10 %) (Tabela 1). 3. Po rezultatih raziskave EUROCARE-4 za bolnike, zbolele v letih 2000–2002, pri vseh v to~- ki 2 omenjenih rakavih boleznih pre`ivetje slovenskih bolnikov zaostaja za evropskim povpre~jem, najve~ pri raku prostate, za 16 % (Tabela 1). 4. Skupina redkej{ih rakavih bolezni, ki v obdobju 2001–2005 posamezno predstavljajo manj kot 3 % skupnega bremena raka pri odraslih, je heterogena. V prvi skupini so rakave bolezni, pri katerih je pre`ivetje slovenskih bolnikov enako ali celo bolj{e od evropskega povpre~ja (Tabela 2). Med njimi z najbolj{im pre`ivetjem izstopajo bolniki z rakom mod, {~itnice in Hodgkinovo boleznijo, ki se `e sedaj zdravijo v zato usmerjenih centrih. V drugi skupini redkej{ih rakov (Tabela 3) so bolniki, katerih pre`ivetje zaostaja za evropskim povpre~jem (urolo{ki in hematolo{ki raki ter ve~ina rakov glave in vratu). 5. Nekatere od rakavih bolezni z najslab{im pre`ivetjem (plju~ni rak, rak `rela in po`iralni- ka) so kot opomin narave ~love{ki neumnosti; zdravljenje ni uspe{no, z zdravim `ivljenjskim slogom pa bi jih ve~ino lahko prepre~ili! 6. Ker se prebivalstvo stara, zboli za rakom vse ve~ starej{ih. V zadnjem obdobju je bila `e peti- na odraslih mo{kih z rakom (brez ko`nega) in skoraj tretjina `ensk ob diagnozi stara 75 let ali ve~ – Tabela 1, poglavje Vse rakave bolezni pri odraslih (brez ko`nega). V primerjavi z mlaj- {imi je njihovo petletno relativno pre`ivetje statisti~no zna~ilno manj{e, vendar se ravno tako s ~asom izbolj{uje – Slika 4, poglavje Vse rakave bolezni pri odraslih (brez ko`nega). Eden od razlogov za slab{e pre`ivetje je zanesljivo ta, da se s ~asom ni ve~al dele` bolnikov z ome- jenim stadijem, kot se je pri mlaj{ih bolnikih – Tabela 3, poglavje Vse rakave bolezni pri odraslih (brez ko`nega). V omejenem stadiju je namre~ pre`ivetje tudi pri starej{ih bolnikih statisti~- no zna~ilno bolj{e kot pri ostalih stadijih. Drug razlog pa je ta, da imajo starej{i bolniki vrsto spremljajo~ih bolezni in niso vedno sposobni za specifi~no onkolo{ko zdravljenje oziroma ga ni mogo~e izpeljati do konca. Kljub temu pa je ravno specifi~no in bolj{e podporno zdrav- ljenje lahko glavni razlog, da se je petletno relativno pre`ivetje bolnikov, starih 75 let in ve~, v opazovanem obdobju pove~alo z 29 % na 38 %. 7. Med bolniki z rakom je manj kot 1 % otrok in mladostnikov; zbolevajo predvsem za lev- kemijami, tumorji osrednjega `iv~nega sistema in limfomi in imajo bolj{e petletno relativno pre`ivetje kot odrasli; tisti, zboleli v letih 2001–2005, 83-odstotno, za 12 % ve~je od tistih, zbolelih deset let prej. Rezultati raziskave EUROCARE-4 za zbolele v obdobju 1995–2002 ka`ejo, da je pre`ivetje slovenskih otrok in mladostnikov v evropskem povpre~ju. PREGLED NAJPOMEMB- NEJ[IH UGOTOVITEV 310 Rak.qxd 22.7.2009 12:39 Page 310 1. In the majority of cancers (other than cutaneous), the survival of adult patients has gra- dually undergone a significant improvement; in ten years (1991–1995 and 2001–2005), the 5-year relative survival of all patients increased by 12% (from 40% to 52%), in males by 14% (from 30% to 44%) and in females by 10% (from 49% to 59%). 2. In more frequent cancers, in the period 2001–2005 individually representing 3% or more and altogether 61% of total cancer burden in adults, in ten years, the survival increased by 10% or more in all but two cancers, where no significant improvement has been achieved in other European countries either (lung, corpus uteri); the highest increase in the survival was observed in prostate cancer (by 26%), followed by colon (16%), breast (14%), cutaneous melanoma (12%), rectum (11%) and stomach (10%) (Table 1). 3. According to the results of EUROCARE-4 study of patients diagnosed in the pe- riod 2000–2002, the survival of Slovenian patients in all more frequent cancers is lagging behind the European average, most apparently in prostate cancer – by 16% (Table 1). 4. The group of less frequent cancers, in the period 2001–2005 representing individually less than 3% of total cancer burden in adults, is heterogeneous. The first group consists of can- cer diseases in which the survival of Slovenian patients is equal or even better than the European average (Table 2). Among these, the best survival is observed in patients with testicular and thyroid cancer and Hodgkin's disease, who are already now treated in ade- quately specialized centers. The second group consists of rare cancers (Table 3), where the survival of patients lags behind the European average (urological and hematological can- cer and most of the head and neck cancers). 5. Certain cancers with the worst prognosis (cancers of the lung, larynx and esophagus) appear as nature's warning to human stupidity; treatment is not successful but a healthy lifestyle could prevent most of them! 6. As population is ageing, the number of cancer cases increases especially among the elder- ly. In the last period, a fifth of adult males with cancer (but skin) and nearly a third of females were aged 75 years or more at diagnosis – Table 1, chapter All cancers other than cutaneous in adults. Their survival is statistically significantly below the survival of younger patients, but is improving with time – Figure 4, chapter All cancers other than cutaneous in adults. One of the reasons for lower survival in the elderly may be the fact that the proportion of patients with localized stage of the disease at diagnosis has not increased with time as in younger patients – Table 3, chapter All cancers other than cutaneous in adults. The survival of the el- derly with localized disease is statistically significantly better than in more advanced stages. The second reason may be the presence of many concomittant diseases in the elderly, which render specific oncological treatment more difficult or impossible to carry out. Nevertheless, better palliative and specific oncological treatment are probably the main reasons for the 9% increase in 5-year relative survival of patients aged 75 years or more (from 29% to 38%) in the period studied. 7. There are less than 1% of children and adolescents among cancer patients; they prevail- ingly present with leukemias, tumors of the central nervous system and lymphomas and have better 5-year relative survival than adults; in those diagnosed in the period 2001–2005 the 5-year relative survival is 83%, i. e. by 12% better than in patients diagnosed ten years earlier. According to the results of EUROCARE-4 study of patients diagnosed in the peri- od 1995–2002, the survival of Slovenian children and adolescents is comparable with the European average. OVERWIEV OF THE MOST IMPORTANT FINDINGS 311 Rak.qxd 22.7.2009 12:39 Page 311 312 Mesto raka / Cancer site [tevilo novih Dele` (%) 5-letno relat. 5-letno relat. Razlika med Petletno relat. Evropsko povpre~je Razlika med primerov vseh novih pre`ivetje zbolelih pre`ivetje zbolelih pre`ivetjem pre`ivetje slovenskih 2000–2002 / slovenskim 2001–2005 / primerov 1991–1995 / 2001–2005 / 2001/5 in 1991/5 / bolnikov 2000–2002 / European average pre`ivetjem Number of new 2001–2005 / 5-year relative 5-year relative Difference 5-year relative survival 2000–2002 in evropskim cases 2001–2005 % of all new survival of patients survival of patients in survival of Slovenian patients (EUROCARE-4) povpre~jem* / cases 2001–2005 diagnosed in diagnosed in 2001–2005 2000–2002 Difference between 1991–1995 2001–2005 vs. 1991–2005 (EUROCARE-4) Slovenian and European average survival* Prostata / Prostate 3615 8,6 52,4 78,2 25,8 63,3 79,7 –16,4* Debelo ~revo / Colon 3256 7,7 41,6 57,7 16,2 51,5 56,7 –5,2* Dojka / Breast 5236 12,4 69 83,3 14,3 75,2 82,2 –7,0* Ko`ni melanom / 1526 3,6 69,3 81,4 12 79,2 86,3 –7,1* Cutaneous melanoma Danka / Rectum 2709 6,4 34 45,4 11,4 49,5 57,1 –7,6* @elodec / Stomach 2278 5,4 18,6 28,3 9,7 23,2 23,4 –0,2 Materni~no telo / 1488 3,5 78,4 82,6 4,2 78,7 78,1 0,6 Corpus uteri Plju~a / Lung 5453 12,9 10,2 12,4 2,2 9,9 12 –2,1* * Razlika je statisti~no zna~ilna (p < 0,05). / The difference is statistically significant (p < 0.05). Tabela 1: Primerjava petletnih relativnih pre`ivetij bolnikov z najpogostej{imi vrstami raka. Table 1: Comparison of 5-year relative survivals of patients with most frequent cancer sites. Rak.qxd 22.7.2009 12:39 Page 312 313 Mesto raka / Cancer site [tevilo novih Dele` (%) 5-letno relat. 5-letno relat. Razlika med Petletno relat. Evropsko povpre~je Razlika med primerov vseh novih pre`ivetje zbolelih pre`ivetje zbolelih pre`ivetjem pre`ivetje slovenskih 2000–2002 / slovenskim 2001–2005 / primerov 1991–1995 / 2001–2005 / 2001/5 in 1991/5 / bolnikov 2000–2002 / European average pre`ivetjem Number of new 2001–2005 / 5-year relative 5-year relative Difference 5-year relative survival 2000–2002 in evropskim cases 2001–2005 % of all new survival of patients survival of patients in survival of Slovenian patients (EUROCARE-4) povpre~jem* / cases 2001–2005 diagnosed in diagnosed in 2001–2005 2000–2002 Difference between 1991–1995 2001–2005 vs. 1991–2005 (EUROCARE-4) Slovenian and European average survival* Materni~ni vrat / Cervix uteri 971 2,3 65 78,6 13,6 65,2 65,2 0 Ne-Hodgkinovi limfomi / 1165 2,8 50,1 60,7 10,6 55,3 53,6 1,7 Non-Hodgkin lymphoma Akutna limfoblastna levkemija / 59 0,1 12,4 22,5 10,1 30,1 27,2 2,9 Acute lymphoblastic leukemia Jaj~nik / Ovary 863 2 34,2 44,2 10 36,8 36,5 0,3 [~itnica / Thyroid 557 1,3 82,1 91,3 9,2 93,3 85,5 7,8 Hodgkinov limfom / 204 0,5 80,8 89,5 8,6 84,2 81,4 2,8 Hodgkin’s lymphoma Grlo / Larynx 536 1,3 58,4 62,8 4,4 69 67,3 1,7 Trebu{na slinavka / Pancreas 1210 2,9 2,5 5,2 2,8 4,8 4,7 0,1 Mehka tkiva (sarkomi) / 302 0,7 52,9 55 2,1 64 60,6 3,4 Soft tissues (sarcomas) Modo / Testis 448 1,1 95,2 95 -0,2 96 95,8 0,2 * Nobena od razlik ni statisti~no zna~ilna (p < 0,05). / Non of the difference is statistically significant (p < 0.05). Tabela 2: Primerjava petletnih relativnih pre`ivetij bolnikov z redkej{imi vrstami raka, ki so po petletnem relativnem pre`ivetju primerljiva z evropskim povpre~jem. Table 2: Comparison of 5-year relative survivals of patients with rare cancer sites; the survival of Slovenian patients is in line with the European average or even higher. Rak.qxd 22.7.2009 12:39 Page 313 314 Mesto raka / Cancer site [tevilo novih Dele` (%) 5-letno relat. 5-letno relat. Razlika med Petletno relat. Evropsko povpre~je Razlika med primerov vseh novih pre`ivetje zbolelih pre`ivetje zbolelih pre`ivetjem pre`ivetje slovenskih 2000–2002 / slovenskim 2001–2005 / primerov 1991–1995 / 2001–2005 / 2001/5 in 1991/5 / bolnikov 2000–2002 / European average pre`ivetjem Number of new 2001–2005 / 5-year relative 5-year relative Difference 5-year relative survival 2000–2002 in evropskim cases 2001–2005 % of all new survival of patients survival of patients in survival of Slovenian patients (EUROCARE-4) povpre~jem* / cases 2001–2005 diagnosed in diagnosed in 2001–2005 2000–2002 Difference between 1991–1995 2001–2005 vs. 1991–2005 (EUROCARE-4) Slovenian and European average survival* Ustna votlina / Oral cavity 473 1,1 34,2 48 13,8 29,6 49,8 –20,2* Ledvica / Kidney 1185 2,8 52,6 60,9 8,3 51,6 55,1 –3,5 Ustno `relo / Oropharynx 626 1,5 25,8 31 5,2 31,4 44,5 –13,1* Akutne nelimfoblastne 293 0,7 10,5 14,9 4,4 7,6 15,8 –8,2* levkemije / Acute lymphoblastic leukemia Plazmocitom / Plasmacytoma 429 1 27,1 31,4 4,3 26,5 35,9 –9,4* Spodnje `relo / Hypopharynx 268 0,6 21,1 24,6 3,5 19,4 27,8 –8,4 Se~ni mehur / Urinary bladder 1242 2,9 48,2 50,7 2,5 48,7 67,3 –18,6* Po`iralnik / Esophagus 449 1,1 7 9,3 2,3 5,1 10,3 –5,2* Kroni~na limfocitna 351 0,8 60,3 62,4 2,1 64 70,2 –6,2 levkemija / Chronic lymphocytic leukemia @ol~nik in `ol~ni vodi / 639 1,5 7,4 9 1,7 12,9 14,4 –1,5 Gallbladder and bile ducts Mo`gani / Brain 586 1,4 16,5 17,9 1,3 13,2 17,1 –3,9 Jetra (jetrnoceli~ni karcinom) / 357 0,8 7,6 5,4 –2,2 4,4 9,4 –5 Liver (hepatocellular carcinoma) * Razlika je statisti~no zna~ilna (p < 0,05). / The difference is statistically significant (p < 0.05). Tabela 3: Primerjava petletnih relativnih pre`ivetij bolnikov z redkej{imi vrstami raka, ki po petletnem relativnem pre`ivetju zaostajajo za evropskim povpre~jem. Table 3: Comparison of 5-year relative survivals of patients with rare cancer sites; the survival of Slovenian patients is below the European average. Rak.qxd 22.7.2009 12:39 Page 314 STROKOVNI IN AKADEMSKI NAZIVI TER UST ANOVE ZAPOSLITVE VSEH SODELUJO^IH PROFESSIONAL AND ACADEMIC TITLES WITH AFFILIATIONS OF ALL CONTRIBUTORS Avtorji / Authors izr. prof. dr. Maja Primic-@akelj, dr. med., specialistka epidemiologinja, Epidemiologija in register raka, Onkolo{ki in{titut Ljubljana Assoc. Prof. Maja Primic-@akelj, MD, PhD, Specialist in Epidemiology, Epidemiology and Cancer Registry, Institute of Oncology Ljubljana doc. dr. Vesna Zadnik, dr. med., specialistka javnega zdravja, Epidemiologija in register raka, Onkolo{ki in{titut Ljubljana Assist. Prof. Vesna Zadnik, MD, PhD, Specialist in Public Health, Epidemiology and Cancer Registry, Institute of Oncology Ljubljana Tina @agar, univ. dipl. fiz., mlada raziskovalka, Epidemiologija in register raka, Onkolo{ki in{titut Ljubljana Tina @agar, BSc, Physics, Junior Researcher, Epidemiology and Cancer Registry, Institute of Oncology Ljubljana izr. prof. dr. Branko Zakotnik, dr. med., specialist internist, Sektor internisti~ne onkologije, Onkolo{ki in{titut Ljubljana Assoc. Prof. Branko Zakotnik, MD, PhD, Specialist in Internal Medicine, Division of Medical Oncology, Institute of Oncology Ljubljana Sodelavci / Co-workers asist. Franc Anderluh, dr. med., specialist radioterapevt in onkolog, Sektor radioterapije, Onkolo{ki in{titut Ljubljana Assist. Franc Anderluh, MD, Specialist in Radiotherapyt and Oncology, Division of Radiotherapy, Institute of Oncology Ljubljana izr. prof. dr. Nikola Be{i}, dr. med., specialist kirurg, Sektor operativnih strok, Onkolo{ki in{titut Ljubljana Assoc. Prof. Nikola Be{i}, MD, PhD, Specialist in Surgery, Division of Surgery, Institute of Oncology Ljubljana prof. dr. Peter ^ernel~, dr. med., specialist internist, Klini~ni oddelek za hematologijo, Interna klinika, Univerzitetni klini~ni center Ljubljana Prof. Peter ^ernel~, MD, PhD, Specialist in Internal Medicine, Department of Hematology, Division of Internal Medicine, University Medical Centre Ljubljana prof. dr. Tanja ^ufer, dr. med., specialistka internistka, vi{ja svetnica, Klini~ni oddelek za plju~ne bolezni in alergijo – Bolni{nica Golnik in Medicinska fakulteta Ljubljana Prof. Tanja ^ufer, MD, PhD, Specialist in Internal Medicine, Higher Councillor, University Clinic of Respiratory and Allergic Diseases Golnik izr. prof. dr. Andrej Debeljak, dr. med., specialist internist, svetnik, Klini~ni oddelek za plju~ne bolezni in alergijo – Bolni{nica Golnik Assoc. Prof. Andrej Debeljak, MD, PhD, Specialist in Internal Medicine, Councillor, University Clinic of Respiratory and Allergic Diseases Golnik 315 Rak.qxd 22.7.2009 12:39 Page 315 asist. mag. Ibrahim Edhemovi}, dr. med., specialist kirurg, Sektor operativnih strok, Onkolo{ki in{titut Ljubljana Assist. Ibrahim Edhemovi}, MD, MSc., Specialist in Surgery, Division of Surgery, Institute of Oncology Ljubljana asist. dr. Janez Er`en, dr. med., specialist kirurg, Klini~ni oddelek za torakalno kirurgijo, Univerzitetni klini~ni center Ljubljana Assist. Janez Er`en, MD, PhD, Specialist in Surgery, Department of Thoracic Surgery, Division of Surgery, University Medical Centre Ljubljana doc. dr. Albert Peter Fras, dr. med., specialist ginekolog porodni~ar in specialist radioterapevt, Sektor operativnih strok, Onkolo{ki in{titut Ljubljana Assist. Prof. Albert Peter Fras, MD, PhD, Specialist in Gynecology and Obstetrics, Specialist in Radiotherapyt, Division of Surgery, Institute of Oncology Ljubljana prof. dr. Eldar M. Gad`ijev, dr. med., specialist kirurg, vi{ji svetnik, Sektor operativnih strok, Onkolo{ki in{titut Ljubljana Prof. Eldar M. Gad`ijev, MD, PhD, Specialist in Surgery, Higher Councillor, Division of Surgery, Institute of Oncology Ljubljana doc. dr. Marko Ho~evar, dr. med., specialist kirurg, Sektor operativnih strok, Onkolo{ki in{titut Ljubljana Assist. Prof. Marko Ho~evar, MD, PhD, Specialist in Surgery, Division of Surgery, Institute of Oncology Ljubljana doc. dr. Janez Jazbec, dr. med., specialist pediater, hemato-onkolog, Klini~ni oddelek za otro{ko hematologijo in onkologijo, Pediatri~na klinika Ljubljana, Univerzitetni klini~ni center Ljubljana Assist. Prof. Janez Jazbec, MD, PhD, Specialist in Pediatrics and Hemato-Oncology, Unit of Oncology and Haematology, Division of Pediatrics, University Medical Centre Ljubljana doc. dr. Barbara Jezer{ek Novakovi}, dr. med., specialistka internistka, Sektor internisti~ne onkologije, Onkolo{ki in{titut Ljubljana Assist. Prof. Barbara Jezer{ek Novakovi~, MD, PhD, Specialist in Internal Medicine, Division of Medical Oncology, Institute of Oncology Ljubljana prim. izr. prof. dr. Andrej Kmetec, dr. med., specialist urolog, svetnik, Klini~ni oddelek za urologijo, Kirur{ka klinika, Univerzitetni klini~ni center Ljubljana Assoc. Prof. Andrej Kmetec, MD, PhD, Specialist in Urology, Councillor, Department of Urology, Division of Surgery, University Medical Centre Ljubljana prim. Elga Majdi~, dr. med., specialistka radioterapevtka in onkologinja, Sektor radioterapije, Onkolo{ki in{titut Ljubljana Elga Majdi~, MD, Specialist in Radiotherapy and Oncology, Division of Radiotherapy, Institute of Oncology Ljubljana doc. dr. Uro{ Mlakar, dr. med., specialist internist, Klini~ni oddelek za hematologijo, Interna klinika, Univerzitetni klini~ni center Ljubljana Assist. Prof. Uro{ Mlakar, MD, PhD, Specialist in Internal Medicine, Department of Hematology, Division of Internal Medicine, University Medical Centre Ljubljana mag. Mojca Modic, dr. med., specialistka internistka, Klini~ni oddelek za hematologijo, Interna klinika, Univerzitetni klini~ni center Ljubljana Mojca Modic, MD, MSc, Specialist in Internal Medicine, Department of Hematology, Division of Internal Medicine, University Medical Centre Ljubljana 316 Rak.qxd 22.7.2009 12:39 Page 316 asist. dr. Irena Oblak, dr. med., specialistka radioterapevtka in onkologinja, Sektor radioterapije, Onkolo{ki in{titut Ljubljana Assist. Irena Oblak, MD, PhD, Specialist in Radiotherapy and Oncology, Division of Radiotherapy, Institute of Oncology Ljubljana dr. Janja Ocvirk, dr. med., specialistka internistka, Sektor internisti~ne onkologije, Onkolo{ki in{titut Ljubljana Janja Ocvirk, MD, PhD, Specialist in Internal Medicine, Division of Medical Oncology, Institute of Oncology Ljubljana izr. prof. dr. Mirko Omejc, dr. med., specialist kirurg, Klini~ni oddelek za abdominalno kirurgijo, Kirur{ka klinika, Univerzitetni klini~ni center Ljubljana Assoc. Prof. Mirko Omejc, MD, PhD, Specialist in Surgery, Department of Abdominal Surgery, Division of Surgery, University Medical Centre Ljubljana prof. dr. Stanislav Rep{e, dr. med., specialist kirurg, Klini~ni oddelek za abdominalno kirurgijo, Kirur{ka klinika, Univerzitetni klini~ni center Ljubljana Prof. Stanislav Rep{e, MD, PhD, Specialist in Surgery, Department of Abdominal Surgery, Division of Surgery, University Medical Centre Ljubljana prim. dr. Boris Sedmak, dr. med., specialist urolog, svetnik, Klini~ni oddelek za urologijo, Kirur{ka klinika, Univerzitetni klini~ni center Ljubljana Boris Sedmak, MD, PhD, Specialist in Urology, Dept of Urology, Department of Surgery, University Medical Centre Ljubljana mag. Uro{ Smrdel, dr. med., specialist radioterapevt in onkolog, Sektor radioterapije, Onkolo{ki in{titut Ljubljana Uro{ Smrdel, MD, MSc, Specialist in Radiotherapy and Oncology, Division of Radiotherapy, Institute of Oncology Ljubljana izr. prof. dr. Miha Sok, dr. med., specialist kirurgije, Klini~ni oddelek za torakalno kirurgijo, Kirur{ka klinika, Univerzitetni klini~ni center Ljubljana Assoc. Prof. Miha Sok, MD, PhD, Specialist in Surgery, Department of Thoracic Surgery, Division of Surgery, University Medical Centre Ljubljana izr. prof. dr. Primo` Strojan, dr. med., specialist radioterapevt in onkolog, Sektor radioterapije, Onkolo{ki in{titut Ljubljana Assoc. Prof. Primo` Strojan, MD, PhD, Specialist in Radiotherapy and Oncology, Division of Radiotherapy, Institute of Oncology Ljubljana dr. Breda [krbinc, dr. med., specialistka internistka, Sektor internisti~ne onkologije, Onkolo{ki in{titut Ljubljana Breda [krbinc, MD, PhD, Specialist in Internal Medicine, Division of Medical Oncology, Institute of Oncology Ljubljana prof. dr. Lojze [mid, dr. med., svetnik, specialist otorinolaringolog, Klinika za otorinolaringologijo in cervikofacialno kirurgijo, Univerzitetni klini~ni center Ljubljana Prof. Lojze [mid, MD, PhD, Specialist in Otorhinolaryngology, Councillor, Department of Otorhinolaryngology and Cervicofacial Surgery, University Medical Centre Ljubljana izr. prof. dr. Marjetka Ur{i~-Vr{~aj, dr. med., specialistka ginekologinja in porodni~arka, Sektor operativnih strok, Onkolo{ki in{titut Ljubljana Assoc. Prof. Marjetka Ur{i~-Vr{~aj, MD, PhD, Specialist in Gynecology and Obstetrics, Division of Surgery, Institute of Oncology Ljubljana asist. dr. Vaneja Velenik, dr. med., specialistka radioterapevtka in onkologinja, Sektor radioterapije, Onkolo{ki in{titut Ljubljana 317 Rak.qxd 22.7.2009 12:39 Page 317 Assist. Vaneja Velenik, MD, PhD, Specialist in Radiotherapy and Oncology, Division of Radiotherapy, Institute of Oncology Ljubljana doc. dr. Samo Zver, dr. med., specialist interne medicine, Klini~ni oddelek za hematologijo, Interna klinika, Univerzitetni klini~ni center Ljubljana Assist. Prof. Samo Zver, MD, PhD, Specialist in Internal Medicine, Department of Hematology, Division of Internal medicine, University Medical Centre Ljubljana izr. prof. dr. Matja` Zwitter, dr. med., specialist radioterapevt in onkolog, Sektor radioterapije, Onkolo{ki in{titut Ljubljana Assoc. Prof. Matja` Zwitter, MD, PhD, Specialist in Radiotherapy and Oncology, Division of Radiotherapy, Institute of Oncology Ljubljana doc. dr. Janez @gajnar, dr. med., specialist kirurgije, strokovni direktor, Onkolo{ki in{titut Ljubljana Assist. Prof. Janez @gajnar, MD, PhD, Specialist in Surgery, Medical Director, Institute of Oncology Ljubljana prim. Mirjana @umer-Pregelj, dr. med., specialistka urologinja, Klini~ni oddelek za urologijo, Kirur{ka klinika, Univerzitetni klini~ni center Ljubljana Mirjana @umer Pregelj, MD, Specialist in Urology, Department of Urology, Division of Surgery, University Medical Centre Ljubljana Analiza podatkov EUROCARE-4 in SEER / Analysis of Eurocare-4 and SEER data Silvia Francisci, Enota za onkolo{ko epidemiologijo, Dr`avni center za epidemiologijo, nadzor in promocijo zdravja, Vrhovni in{titut za javno zdravje, Rim, Italija Silvia Francisci, Cancer Epidemiology Unit, National Center for Epidemiology, Surveillance and Health Promotion, Istituto Superiore di Sanita, Rome, Italy Recenzenta / Reviewers Prof. dr. Vera Pompe Kirn, dr. med., specialistka socialne medicine, vi{ja svetnica, Register raka Republike Slovenije, Onkolo{ki in{titut Ljubljana Prof. Vera Pompe Kirn, MD, DSc, Specialist in Social Medicine, Higher Councillor, Cancer Registry of Republic of Slovenia, Institute of Oncology Ljubljana izr. prof. dr. Matja` Zwitter, dr. med., specialist radioterapevt in onkolog, Sektor radioterapije, Onkolo{ki in{titut Ljubljana Assoc. Prof. Matja` Zwitter, MD, PhD, Specialist in Radiotherapy and Oncology, Division of Radiotherapy, Institute of Oncology Ljubljana Lektor za sloven{~ino / Reader for Slovenian language Jo`e Faganel, prof. slov. in franc, vi{ji strokovni sodelavec specialist ZRC SAZU Jo`e Faganel, BA, Specialist on Terminology, ZRC SAZU Prevod / Translation Olga Shrestha, univ. dipl. ang. prev. Olga Shrestha, BA, English Translation Oblikovanje / Design Monika Fink-Ser{a, univ. dipl. in`. arh., Nava d. o. o. Monika Fink-Ser{a, BSc, Architecture, Nava d. o. o. 318 Rak.qxd 22.7.2009 12:39 Page 318 319 Rak.qxd 22.7.2009 12:39 Page 319 320 Rak.qxd 22.7.2009 12:39 Page 320 70let years 6 3 5 1 7 0 6 1 6 9 8 7 9 ISBN 978-961-6071-53-6 PRE@IVETJE BOLNIKOV Z RAKOM, ZBOLELIH V LETIH 1991–2005 V SLOVENIJI SURVIVAL OF CANCER PATIENTS, DIAGNOSED IN 1991–2005 IN SLOVENIA Pre`ivetje bolnikov z rakom, zbolelih v letih 1991–2005 v Sloveniji Survival of cancer patients, diagnosed in 1991–2005 in Slovenia Maja Primic-@akelj Vesna Zadnik Tina @agar Branko Zakotnik register raka republike slovenije cancer registry of republic of slovenia ljubljana 2009 naslovnica.qxd 30.7.2009 14:14 Page 1