® Prednosti uporabe Kapanola lajšanje zmerne do mocne kronicne bolecine • enkrat ali dvakrat dnevno odmerjanje izpopolnjena formula s polimeriziranimi peletami, ki omogocajo enakomerno sprošcanje morfina 24 ur široka izbira v odmerjanju in nacinu jemanja 6/axoWellcome Glaxo Wellcome Export Ltd., Podružnica Ljubljana RADIOLOGY AND ONCOLOGY Radiology and Oncology is a journal devoted to publication of original contributions in diagnostic and interventional radiology, computerized tomography, ultrasound, magnetic resonance, nuclear medicine, radiotherapy, clinical and experimental oncology, radiophysics and radiation protection. Editor in chief Tomaž Benulic Ljubljana, Slovenia Associate editors Gregor Serša Ljubljana, Slovenia Viljem Kovac Ljubljana, Slovenia Editorial board Tullio Giraldi Branko Palcic Udine, Italy Vancouver, Canada Marija Auersperg Ljubljana, Slovenia Andrija Hebrang Zagreb, Croatia Jurica Papa Zagreb, Croatia Haris Boko Duraa Horvat Zagreb, Croatia Zagreb, Croatia Dušan Pavcnik Ljubljana, Slovenia Nataša V. Budihna Ltiszlo Horvtith Ljubljana, Slovenia Pecs, Hungary Stojan Plesnicar Ljubljana, Slovenia Malte Clausen Berta Jereb Kiel, Germany Ljubljana, Slovenia Ervin B. Podgoršak Christoph Clemm Vladimir Jevtic Montreal, Canada Miinchen, Germany Ljubljana, Slovenia Jan C. Roos Mario Corsi H. Dieter Kogelnik Amsterdam, The Netherlands Udine, Italy Salzburg, Austria Horst Sack Christian Dittrich Ivan Lovasic Essen, Germany Vienna, Austria Rijeka, Croatia Ivan Drinkovic Zagreb, Croatia Marijan Lovrencic Zagreb, Croatia Slavko Šimunic Zagreb, Croatia Gillian Duchesne Luka Milas Lojze Šmid Melbourne, Australia Houston, USA Ljubljana, Slovenia Bela Pomet Maja Osmak Andrea V eronesi Budapest, H ungary Zagreb, Croatia Gorizia, Italy Publishers Slovenim, Medica/ Society -Section oj Radiology, Section oj Radiotherapy Croatian Medica/ Association -Croatian Society oj Radiology Affiliated with Societas Radiologorum Hungarorum Friuli-Venezia Giulia regional groups of S.l.R.M. (ltalian Society of Medica! Radiology) Correspondence address Radiology and Oncology Institute of Oncology Vrazov trg 4 1000 Ljubljana Slovenia Phone: + 386 61 1320 068 Fax: +386611314180 Readers for English Olga Shrestha Mojca Cakš Design Monika Fillk-Serša Key words und UDC Eva Klemencic Secretaries Milica Harisch Betka Savski Printed by Tiskama Tone Tomšic, Ljubljana, Slovenia Published quarterly Bank account number 5010167848454 Foreign currency account number 50100-620-133-27620-5130/6 LB -Ljubljanska banka d. d. -Ljubljana Subscription fee for institutions 100 USD, individuals 50 USD. Single issue for institutions 30 USD, individuals 20 USD. According to the opinion of the Government of the Republic of Slovenia, Puhlic Relation and Media Office, the journal RADIOLOGY AND ONCOLOGY is a publication of informative value, and as such subject to taxation by 5 % sales tax. Indexed and abstracted by: BIOMEDICINA SLOVENICA CHEMICAL ABSTRACTS EXCERPTA MEDICAIELECTRONIC PUBLISHING DIV/SION ORGAN SPARING TREATMENT IN ONCOLOGY Proceedings of the International Symposium on Organ Sparing Treatment in Oncology 19 -21 June 1997 Ljubljana, Slovenia Organized by: Institute of Oncology, Ljubljana, Slovenia Faculty of Medicine, University of Ljubljana, Chair of Oncology and Radiotherapy, Ljubljana, Slovenia Under the auspices of: Alps-Adriatic Working Community, Commission for Health and Social Affairs Edited by: Marjan Budihna, Tanja Cufer, Rastko Golouh, Jurij Lindtner, Zvonimir Rudolf, Branko Zakotnik Reviewers: Marjan Budihna, Tanja Cufer, Jožica Cervek, Rastko Golouh, Jurij Lindtner, Janez Novak, Zvonimir Rudolf, Primož Strojan, Branko Zakotnik The publication was sponsored by Glaxo Wellcome Ltd., Podružnica v Ljubljani THE SYMPOSIUM WAS SPONSORED BY: ALPS-ADRIATIC WORKING COMMUNITY MINISTRY OF SCIENCE AND TECHNOLOGY OF THE REPUBLIC OF SLOVENJA UNIVERSITY OF LJUBLJANA, FACULTY OF MEDICINE SCHERING-PLOUGH/USA RHONE-POULENC RORER DIBETEC d.o.o. REPRO BLOOD TRANSFUSION CENTRE OF SLOVENJA ELI LILLY (Suisse) S. A. HOFFMANN-LA ROCHE Ltd. SANDOZ PHARMA SERVICES Ltd. ZENECA INTERNATIONAL LIMITED PIVOV ARNA UNION d.d. VARIAN INTERNATIONAL AG TRIGLAV INSURANCE COMPANY Ltd., Krško ASTA MEDICA AG LJUBLJANSKE MLEKARNE d.o.o. VIT ACEL d.d. CONTENTS BREAST CANCER Conservative treatment evolution in breast cancer Veronesi U 97 Conservative surgery of the breast: Ten years of experience at the University Hospital for Tumors, Zagreb, Croatia Orešic V, Petrinec Z, Stanec M, Vrdoljak DV 100 Breast conserving operations, prognostic factors and Iife quality Vikmanis U, Berzu,1š A, Leja D, Purkalne G 103 Ductal carcinoma in situ of the breast: Evaluation of the treatment options Vidali C, Milan V, Mustacchi G, Muggia M, Sandri P 107 Tr.eatment of the intraductal carcinoma of the breast with conservative surgery and radiotherapy: An Italian multicenter retrospective study Amichetti M, Caffo O, Richetti A, Zini G, Rigon A, Lora O, Antonello M, Arcicasa M, Roncadin M, Coghetto F, Zorat P, Valdagni R, Balli M, Panizzon G, Maluta S, Di Marco A, Favretto S, Teodorani N, Neri S, Fasan S 109 Pathological examination for quality assurance in breast conserving therapy for breast cancer Decker T, Ruhnke M, Obenaus R, Kettritz U, Kleina A, Morack G, Schneider W 112 Selection of impalpable breast cancer for conservative surgery Svastics E, Pentek Z, Szerjan E 117 Radiation therapy after conservative surgery in the treatment of early breast cancer Raunik W, Petrovic G, Sabitzer H, Klocker J 119 Long term Iocal control and survival in breast cancer patients stage I and II after breast cancer conserving treatment Majdic E 122 Factors of Iocal recurrence rate after whole breast irradiation with and without boost radiotherapy after breast conserving surgery Nagykalnai T, Lovey K, Nemeskeri Cs, Mayer A SARCOMAS Limb sparing in osteosarcoma of the extremity treated by neoadjuvant chemotherapy. Fifteen-year experience at the Rizzoli Institute Bacci G 125 Organ and function sparing treatment for soft tissue sarcomas: The Memorial Sloan-Kettering experience Raben A 127 Malignant bone tumours of the extremities: The role of limb sparing surgery Cucek-Plenicar M, Novak J, Špiler M, Baebler B, Cervek J, Lamovec J 131 Resections of pelvic bone and sacrum, Ljubljana experience Novak J, Cucek -Plenicar B, Eržen D, Srakar F, Sencar M, Baebler B, Cervek J, Vodnik A, Bracko M, Pohar -Marinšek Ž, Anžic J 134 Tumour surgery in the pelvic region Rah6ty P, Szendroi M 137 Preoperative intraarterial chemotherapy with cisplatin for locally advanced high grade soft tissues sarcomas of the extremities Cervek J, Novak J, Zakotnik B, Golouh R, Šurlan M 139 Update on use of expandable prostheses in limb salvage surgery for children's bone sarcomas of lower limb Delepine N, Delepine G, Desbois J-C 142 "Hand on" prosthesis reconstruction after peri-acetabular resection for malignant bone tumors. Our experience Delepine G 143 Place of bank allograft with patellar tendon in prosthetic reconstructions of the upper tibia after en bloc resection and gastrocnemius flap Delepine G, Delepine F 144 BLADDER CANCER Combined chemo-radiotherapy with organ preservation for invasive bladder cancer Tester W 145 Bladder preservation after radiochemotherapy for muscle invasive bladder cancer Birkenhake S, Martus P, Sauer R 149 Bladder perservation by combined modality treatment in invasive bladder cancer Cufer T, Cervek J, Zakotnik B, Kragelj B, Borštnar S, Žumer-Pregelj M 151 Cytomorphology and flow cytometry in monitoring patients treated for bladder cancer; preliminary results Pogacnik A, Us-Krašovec M 155 HEAD & NECK CARCINOMAS Conservative treatment in head and neck cancer Žargi M 158 Combined chemotherapy and radiotherapy in head and neck cancer: Hopes and facts Jassem J 163 Minimally invasive therapy in carcinomas of the head and neck -an updated overview Iro H, Waldfahrer F, Weidenbecher M, Fietkau R, Gramatzki M 165 Chemo-radiotherapy in the elderly and /or poor performance status patients with advanced head and neck cancer Loreggian L, Chiarion Si/eni V, Fede A, Friso ML, Lora O, Barbara R, Riddi F, Paccagnella A 168 Combined application of cisplatin, vindesine, hyaluronidase and radiation for treatment of advanced squamous cell carcinoma of the head and neck Klocker J, Sabitzer H, Raunik W, Wieser S, Schumer J 171 Concomitant radiotherapy and mitomycin C with bleomycin in inoperable head and neck cancer Zakotnik B, Šmid L, Budihna M, Lešnicar H, Šoba E, Furlan L, Žargi M 173 Treatment of malignant tumors of the oral cavity -state of the art Waldfahrer F, lro H 178 Combined therapy of undifferentiated carcinoma of nasopharyngeal type Došen D, Mršic-Krmpotic Z, Krajina Z, Turic M, Šmalcelj J, Janušic R 181 Surgical treatment of advanced oropharyngeal cancer by preservation of the larynx Balatoni Zs, Eto J, K6tai Zs 186 Early pyriform sinus cancers removed by vertical partial pharyngectomy with preservation of the larynx Eto J, Balatoni Zs, Tar T 187 Comparison of sequential and simultaneous chemo-radiotherapy for advanced hypopharyngeal carcinoma -Results of a randomized study Iro H, Waldfahrer F, Fietkau R, Gramatzki M 188 Carcinoma of the posterior pharyngeal wall-Larynx preservation with the radial forearm flap or transoral resection Steinhart H, lro H 190 Organ-sparing surgery in supraglottic cancer: Functional results and survival in 25 year period Czigner J 192 Supraglottic laryngectomy: Treatment results of two different operation methods Cizmarevic B, Didanovic V, Munda A, Becner D, Cundric F 195 Laser surgery as the organ sparing treatment for vocal cord carcinoma. Cost benefit relation in 100 cases Rov6 L, Savay L, Czigner J Concomitant radio-chemotherapy for layrynx preservation Crispino S, Ghezzi P, Ribecco A, Ponticelli P, Lastrucci L, Coiombo A, Ardizzoia A, Parmigiani F, Krengli M, Gambaro G, Taina R, Simeone F 202 Early glottic cancer: The influence of primary therapy on ultimate organ preservation Lešnicar H, Šmid L, Zakotnik B 205 Treatment of early epilaryngeal tumours by COlaser with preservation of laryngeal function 2 ~~~T W A case of recurrence of the malignant mixed tumor of the palate after 16 years Siavtchev R, Ratchkov /, Karashmaiukov A, Shomov G 210 MISCELLANEOUS TUMORS Treatment of epidermoid anal canal carcinoma Potter R, Dobrowsky W 211 Conservative treatment of anal canal cancer: Retrospective study Friso ML, Loreggian L, Baiocchi C, Cesaro MG, Berti F, Mazzarotto R, Caizavara F Fornasiero A, 215 Conservative treatment of the carcinoma of the anal canal Seewaid DH, Hammer J, Track C, Zaidi JP, Putz E, Gruy B, Labeck W 218 Combined radiation and chemotherapy for squamous celi carcinoma of the anal canal: Results and prognostic variables in a multiinstitutional series of 173 patients Grabenbauer GG, Panzer M, Hiiltenschmidt B, Doker R, Huber K, Kuhne-Veite H-1, Hutter M, Riihl U, Budach V, Wendt TG, Schneider IHF, Druschke J, Meyer M, Dvorak O, Sauer R 219 Local excision of flat adenomas of the rectum in the period from 1987 to 1991 Novak J 227 MR imaging in primary irradiated prostatic carcinoma Mayer R, Ranner G, Simbrunner J, Fock CM, Szoiar D, Stranzl H, Prettenhofer U, Stuecklschweiger GF, Hackl A, Ebner F 229 Adenocarcinoma of the prostate treated by definitive high-dose external radiotherapy Stranzl H, Mayer R, Willfurth P, Pummer K, Preidler KW, Prettenhofer U, Stuecklschweiger GF, Hackl A 231 Preservation of the lung function after thoracic irradiation: Role of transforming growth factor beta (TGF/3) Vujaskovic Z, Groen HJM 233 Lung-sparing resection instead Moroz GS of pneumonectomy in patients with wide spread lung cancer 236 Brachytherapy (Ru 106) in the treatment of malignant melanoma of the choroid Jancar B, Andrejc'ic K, Logar P, Brovet-Zupancic I QUALITY OF LIFE Quality of Iife in oncology: Why and how can we evaluate this aspect in cancer care? Kiebert GM 239 Quality of life after neck-dissection: Comparison of the oncological and functional results of the radical and modified radical neck dissection in patients with head and neck carcinomas K6tai Zs, Elo J, Zamb6 O 244 Voice quality after radiation therapy of early glottic cancer Hocevar Boltežar!, Žargi M 247 Functional results after partial vertical laryngectomy Horvath E, Elo .1 252 Radiology and Oncology is now available on the internet at: http:/www.onko-i.si/radiolog/rno l .htm Preface In recent decades, better understanding of tumor biology enabled us to replace some of the previously used extensive and mutilating surgical procedures by minor surgical interventions combined with irradiation and systemic therapy. Thus organ preservation associated with better quality of life is possible in substantial number of cancer patients without jeopardising their survival. Despite the great advances in the field of combined cancer treatment using organ-sparing approach, a number of questions remain unresolved, such as those related to the optimal combination and sequence of individual treatment modalities, immediate and late sequelae of trcatment, spared organ function, and many others. Considering the great interest of medica) profession in combined, organ-sparing oriented treatment, we have decided to organize an international symposium of the Alps-Adriatic community on organ sparing treatment in oncology. The contributions presented at this meeting, prove that this kind of treatment approach has also found its place in this part of the world. Our first idea was to have the contributions published in a "Book of Proceedings". Later on, however, we accepted the kind offer of the editors of "Radiology and Oncology" journal to have the materials published in one of their regular issues. Due to the tirne pressure we took the liberty of making some editorial changes on the manuscripts in order to adjust them as closely as possible to thc journal's requirements. The authors have been consulted personally only in the cases whcn the occasional error in the original was of such nature that only the author himself could correct it. However, in spite of ali our efforts, the journal's requirements often could not bc met, but the Editorial Board of Radiology and Oncology kindly decided to overlook those inconsistencies, for which we feel very obliged. We wish to thank the authors for their interesting papcrs and ideas contributed to the topic discussed. We should also appreciate their consent to thc editorial changes that had to be made in their manuscripts. Thanks are due to ali the invited speakers for their valuable papers. And last but not least, we want to thank our two language proof-readers and to the staff of our special library for their editorial work. Tanja Cufer, Marjan Budihna Radio! Oncol 1997; 31: 97-9. Conservative treatment evolution in breast cancer Umberto Veronesi European Institute of Oncology, Milan, Italy In the late 1960s, we became interested in the pos­sibility of preserving the breast in patients with small breast carcinomas for a number of reasons: new information on the natura! course of this dis­ease, tendency that smaller tumors are being detect­ed on diagnosis, and the fact that aggressive local­regional treatments have failed to improve progno­sis. For example, at the end of the 1960s an interna­ti ona! randomised tria!, comparing traditional Halsted mastectomy with Halsted mastectomy plus dissection of the interna! mammary nodes, showed that the more aggressive approach had no advan­tage over the traditional surgery. The objectives in conserving the breast are to achieve effective local control and at the same tirne produce a good cosmetic result. To this end we developed an extensive surgical excision called "quadrantectomy", whose main characteristic was a radially directed incision by which the resection encompassed the whole dueta! tree from the retro­areolar region downwards and to the periphery. We were convinced that intraductal permeation was an important mechanism of tumor spread, and that therefore ali branches to the involved duet had to be removed. The main duet and its associated tree is often referred to as a breast lobe and the operation could have been designated "lobectomy"; however we chose the name quadrantectomy since the quad­rant concept was simpler to explain. After quadran­tectomy we planned radiotherapeutic treatment con­sisting of 50 Gy delivered to two tangentially op­posed fields, using high energy equipment, plus a Correspondence to: Prof. Umberto Veronesi, MD, Euro­pean Institute of Oncology, Via Ripamonti 435, 20141 Milano, Italy. Key words: breast neoplasms; mastectomy, segmenta! re­section UDC: 618.19-006.6-089.87 boost of 1 O Gy on the scar with orthovoltage equip­ment. The procedure was completed by total axil­lary lymph node dissection (ali three levels). We considered that this intervention, which we called QUART, was radical, although at the beginning we applied it only to TI tumors (less than 2 cm). In 1973 we began a randomized tria! (the Milan I Tria!) to compare small size breast cancer patients treated by Halsted mastectomy with those receiving QUART. The tria! was concluded by the beginning of 1980, after 701 cases had been recruited: 349 underwent mutilating surgical intervention while in 352 the breast was conserved. The preliminary re­sults1 indicated similar survival in both groups. Af­ter 20 years this trend was confirmed,2 and also demonstrated that local recurrences treated by sal­vage mastectomy did not affect the prognosis. The thirteen year survival data showed that QUART gave identical results as Halsted mastectomy, and that subdivision of patients by tumor size, site and age stili did not reveal any difference between the treatments. Subdivision by lymph node involve­ment showed that QUART was superior to Halsted, although the difference was not statistically signifi­cant. Furthermore, the fear that radiotherapy might entail a late oncogenic effect was not confirmed. There were nine new ipsilateral cancers in patients with heavily irradiated breasts, and 19 new cases in the contralateral breasts, the same number that oc­curred in the contralateral non-irradiated breasts of Halsted patients. It appeared therefore that breast irradiation, at the doses we used, might protect the breast, either by destroying occult foci of in situ lesions or by inactivating any proliferative precan­cerous lesions. The conclusion that breast conservation is as safe a procedure as traditional mastectomy in small breast carcinoma was confirmed in subsequent pub­lications. 3"6 Veronesi U The question arose, however, as to whether better cosmetic results could be achieved by an even less aggressive surgical approach. Following a number of second generation trials implemented in various centers,7•9 studying different surgical ap­proaches and types of radiotherapy, we initiated a new tria! which compared classic quadrantectomy, axillary dissection and radiotherapy with a more limited surgical treatment consisting of a lumpecto­my ("tumorectomy") plus axillary dissection, fol­lowed by external radiotherapy and a boost with 192lr implantation (TART). Lumpectomy consisted of excision of the primary tumor with a 1 cm mar­gin of normal breast tissue, without including the overlying skin except for a very small portion for histologic confirmation. Axillary dissection was al­ways total, and was performed by separate incision, as ·defined. Radiotherapy was both external and in­terstitial. External irradiation began four weeks af­ter surgery and the technique was the same as that used after quadrantectomy, with the difference that the total dose (45 Gy) was given over five weeks. After 2-3 weeks 192Ir wires were implanted intersti­tially to give a boost of 15 Gy directly to the tumor bed. A total of 60 Gy was thus given to both groups of patients. Radiation was never applied to the axil­lary or supraclavicular regions. Seven hundred five patients were admitted, 360 received QUART and 345 received TART, the groups being comparable clinically and in terms of the adjuvant treatment received. Local failures in the area of the previous surgery (i.e. cutaneous, subcutaneous and paren­chymal lesions) appearing three to five cm from the quadrantectomy/lumpectomy scar were considered trne local recurrences. At the tirne of last review there were 15 local recurrences in the QUART group and 34 in the TART group. Survival was the same in both groups. The results of this tria! will pose a very delicate dilemma to the surgeon as he has to decide whether the better cosmetic result obtained by tumerectomy and radiotherapy could counterbalance the greater incidence of local recurrences taking into account the fact that recurrences are traumatic for patients, in whom intense anxiety often appears or reap­pears. Since local recurrences are in some cases treated by mastectomy, an excessive number of salvage operations would compromise the original objectives of the procedure. In more recent years new trials have been un­dertaken in an attempt to verify whether radiothera­py is necessary after breast conservative procedures. In Sweden, the Uppsala-Orebro Breast Cancer Study Group10 showed that women who underwent con­servative surgery without radiotherapy had a signif­icantly higher rate of local recurrences than those in whom radiotherapy was used. Between 1987 and 1989 in Milan we randomly assigned 567 women with small breast cancers to quadrantectomy followed by radiotherapy or to quadrantectomy without radiotherapy. 11 As usual, ali patients underwent total axillary dissection and regular follow-up (for a mean period of 39 months). Two hundred ninety nine patients received QUART and 280 received quadrantectomy plus axillary dis­section without radiotherapy (QUAD). There was no significant difference between the two groups with respect to age, site and size of the primary, histological characteristics, or leve! of axillary in­vasion; neither was there any difference with regard to leve! of nodular involvement broken down by adjuvant treatment administered. We did, however, observe a marked difference between the two groups with respect to recurrences. Only three of the 294 QUART patients (1 % ) developed a local recurrence, compared with 28 local recurrences among the 280 patients (10%) of the QUAD group. This tria! clearly showed that postoperative ra­diotherapy administered directly after quadrantec­tomy has a protective effect against local recur­rences and new primary carcinomas. That there was a difference between the two groups did not sur­prise us; what was a surprise was the magnitude of the difference between them: 28 local recurrences and four new carcinomas after quadrantectomy alone, compared with three recurrences and no new tumors when quadrantectomy was combined with radiotherapy. In the QUAD group local recurrences occurred mainly in patients under 55 years of age, but rarely in patients older than that. The presence of an extensive intraductal component was also con­firmed as an important predictor of local recurrenc­es. This tria! definitively established quadrantecto­my plus axillary dissection and radiotherapy as an effective conservative treatment that does not ex­pose patients to increased risk of local recurrence, notwithstanding the fact that in older women con­servative surgery without radiotherapy may result in a low rate of local recurrences, provided that the surgery is an extensive one, removing two to three cm of normal tissue around the primary carcinoma. In a more recent analysis of breast cancer pa­tients uniformly treated by quadrantectomy, axil­lary dissection and subsequent radiotherapy, we evaluated local and distant recurrences according to Conservative treatment evolution in breast cancer demographic, biological and pathological variables in 2233 women. 12 Young age was an important risk factor for recurrence, with peritumoral lymphatic invasion also predictive for local and distant events. Tumor size and axillary lymphnode involvement were not related to local recurrences but were im­portant predictors of distant metastases. Extensive intraductal component was only a risk factor for local recurrence. Finally, women up to the age of 35 at first diagnosis, who had initial peritumoral lymphatic invasion and local recurrence within two years of surgery, were at high risk for distant spread. More recent developments of the conservative approach to breast cancer are directed to the avoid­ance of the axillary dissection in cases with clinical­ly negative nodes. 13 In fact, the axillary dissection is presently performed for staging purposes and any method that would identify the presence of occult metastases without the need of such an extensive total axillary dissection, would greatly improve the quality of life of breast cancer patients. Following this line of thought we developed the "sentinel node" technique, consisting in an injection of a minimal quantity of colloid albumin labelled with 99Tc around the primary carcinoma which would be captured via the lymphatic route by the first axillary node (senti­nel node) which would drain the lymph from that area. In a series of 163 patients we discovered that the predictive value of the sentinel node histology is very high, superior to 95%. When the sentinel node is negative for metastases the chances that other axillary lymph nodes are involved by metastatic can­cer cells are very low. We hope that if the ~ 1 0.85 u :::, 0.8 0-1 1 -2 2-3 3-4 4-5 Follow-up years -+-lobular -lfl--dueta! -t,,-other ] Figure 2. Corrclation between histological typc and sur­vival. 1.000 ~ 0.950 -~ 0.900 ]i :::, 0.850 § O.BOO U 0.750 O-1 1 -2 2·3 3-4 4-5 Follow-up years l-+-<40 ·····lll ...... 41.50 -··fi"·-51-60 -X->611 Figure 3. Survival in different age groups. 1.000 2 ~ 0.950 "' > ~ 1 0.850 :::, ·u 0-1 1 -2 2-3 3-4 4-5 Follow-up years -+-Ouadrantectomy -1\!-Mastectomy -t,,-Arrputation Figure 4. Correlation between the type of surgical treat­ment and survival. "' -~ -·-i !,,:D:±±d 1,~;==~ :::, 0.8. , i -­ u t l 0-1 1 -2 2-3 3-4 4-5 -·~ :,.~==~ l; 0.9 --.. _ , ' "' ,. :i 0.85 --.. · § 08 u . O-1 1 -2 2-3 3-4 4-5 Follow-up years Figure 6. Survival rale in paticnts with adjuvant chcmo­thcrapy. Discussion and conclusions Tumor localization plays a role in the choice of surgical treatment, i.e. the extent of surgery. At present there is a tendency to use breast conserving operations in the case of a small tumor. Around 1990, lhe attitude of oncologists in Latvia towards this tendency was very cautious. There was an opin­ion that only classical mastectomy after Halsted can give good results. Little by little, the attitude has changed. Local recurrences in the scar after breast conserving operations were observed in 0.4% of cases only, but we must admit that the number of patients was srna!!. Veronesi et al.6 found 2.8% local recurrences after quadrantectomy. In large ret­rospective studies the rate of local recurrence was even higher -7% in 5 years of follow up.7 In our study the patients, who died within 5-year follow­up period had distant metastases, mainly pleural and pulmonal. Tumor localization also plays an important prognostic role. According to our data, long-term results are worse in patients with tumor localization in the areolar area, central part and medial quad­rant. With respect to the histological form, better survival was observed in the case of lobular cancer in the 2nd and 3rd year, but no difference was observed in the 5th year. In choosing the type of surgery according to tumor localization, histologi­cal form and the patient' s age, we must take into account that small tumors tend to spread through the dueta! system. Santini et al.5 describe the growth type of such tumors and their presence in the areo­lar complex. Comparing different types of surgical treatments, according to our data there is no differ­ Follow-up years ence between quadrante~tomy and mastectomy. Figure 5. Survival rate in patients with radiotherapy. Five-year survival rate was practically the same. l06 Vikmanis Vet al. Therefore, conserving operations (such as quadran­tectomy) in the case of small tumors are reasona­ble. But the surgeon must be very cautious to per­form an adequate operation. In the case of central localization or localization in the areolar area, we perform histological examination of the incision margin to ensure that no tumor cells have remained around the incision. completeness of surgery. Ac­cording to our data, the worst results were ob­served in postmenopausal women in the age group 51 -60 years and older. The use of additionai radiotherapy in patients without metastases in lymph nodes is questionable. In our center radiation therapy was performed in 1 O 1 cases -in patients with tumor localization in the central part and in the areola or in the medial quadrant. After surgery, patients received radio­therapy with 45 Gy to infra and supra clavicular regions and parasternal area, 50 Gy to the breast, and additional 10 Gy as a boost. After consultation and individual assessment, chemotherapy was per­formed in 17 patients according to CMF regimen. Data from large randomized trials suggest that adjuvant chemotherapy increases disease-free sur­vival, as well as overall survival in node-negative breast cancer patients. 8• 9.w Yet, the question about the need of adjuvant chemotherapy or radiotherapy in high-risk patients remains to be solved. Breast conserving operations have clear advan­tages in terms of the quality of life, at least with respect to psychological factors. There were no coinplications observed after breast conserving op­erations and chemotherapy. Edema of the arm and movement restriction occurred mainly after classi­cal mastectomy and after radiation following radi­cal mastectomy. Radiation therapy in high-risk pa­tients increased the possibility of late complica­tions which affected the quality of life. Severa] other studies have given similar data. 12•13 Results of our study suggest that in the case of early breast cancer (T1) breast conserving surgery -quadrantectomy should be performed. Additional therapy is required in high risk patients. Taking into account the quality of life, adjuvant chemotherapy is the method of choice. Yet more investigations are necessary to evaluate additional risk factors that could be easily applied in the practical work, as well as to increase the number of patients under study. References l. Fisher B. A biological perspective of breast cancer: contributions of the national surgical adjuvant breast and bowel project clinical trials. Ca 1991; 41: 97-111. 2. Kinne D. The surgical management of primary breast cancer. Ca 1991; 41: 71-84. 3. Hellniegel K. Brusterhiltende Therapie beim Mam­makarzinom: Indikation und Konsequenzen -Ergeb­misse einer Multidisziplinaren Konsensustagung. Chir Prax 1991; 43: 103-7. 4. Higgins NO. Quality control in axillary lymph node dissection. Breast 1994; 3: 7-72. 5. Santini D, Taffurelli M, Gelli MC et al. Neoplastic in­volvment of nipple-areolar complex in invasive breast cancer. Am Surg 1989; 158: 399-403. 6. Veronesi U, Salvadori B, Luini A et al. Conservative treatment of early breast cancer: long term results of 1232 cases treated with quadrantectomy, axillary dis­section and radiotherapy. Am Surg 1990; 211: 250-9. 7. Kurtz IM, Amalric R, Brandone H et al. Local recur­rence after breast conserving surgery and radiotherapy: frequency, tirne course and prognosis. Cancer 1989; 63: 1912-7. 8. Fisher B, Redmond C, Dimitrov N et al. A randomized controlled tria! evaluating sequential methotrexate and fluorouracil in the treatment of patients with node-neg­ative breast cancer who have estrogen receptor-nega­tive tumors. N Engl J Med 1989; 320: 473-8. 9. Mansour E, Gray R, Shatila A et al. Efficasy of adju­vant chemotherapy in high risk node-negative breast cancer. An intergroup study. N Engl J Med 1983; 320: 485-90. 10. Bonadonna G, Valagussa P. Role of chemotherapy in stage I breast cancer. In: de Vita VT Jr, Hellman S, Rosenberg SA, eds. Important advances in oncology. Philadelphia: Lippincott, 1989; 151-60. 11. Ryttou N, Holm N, Ovist N et al. Influence of adjuvant irradiation on the development of late arm lymphede­ma and impaired shoulder mobility after mastectomy for carcinoma of the breast. Acta Oncol 1989; 21: 667­70. 12. Tasmuth T, von Smitten K, Kalso E. Quality of life after two types of surgery in the treatment of breast cancer. 1st Baltic congress of oncology and radiology. Tallin, 1994; 56. 13. Pecking A. Traitment de lymphedeme sequellaire du membre superieur. Buli Cancer 1991; 78: 373-7. Radio/ Oncol 1997; 31: 107-8. Ductal carcinoma in situ of the breast: Evaluation of the treatment options Cristina Vidali,1 V. Milan,1 G. Mustacchi,2 M. Muggia,2 P. Sandri2 1 Istituto di Radioterapia Oncologica A. O. "Ospedali Riuniti" di Trieste, 2 Centra Oncologico A.S.S., Trieste, Italy From January 1978 to December 1994, 87 patients with dueta/ carcinoma in situ (DCIS) oj the breast were obsenied at the Centra Oncologico oj Trieste. 43/87 (49.5%) patients underwent mastectomy; 42187 (48.2%) quadrantectomy and radiation therapy and 2187 (2.3%) lumpectomy alone. The local recurrence rate was 3.4% (3187 cases), with a medianjollow-up oj 69 months. The 3 patients who relapsed had been treatecl by conservative surgery and radiation therapy; they had a salvage mastectomy and are alive and jree oj disease. The 15-year actuarial overall and disease-free su111ivals are 100% and 89.9% respectively. In our retrospective study the conservative treatment proved to be a good alternative to mastectomy in patients with DCJS. Key words: breast neoplasms; dueta! carcinoma in situ; treatment options; treatment outcome Introduction Dueta! carcinoma in situ represents almost 15% of ali breast cancer in the United States and almost 40% of those screening detected. 1 Historically, mastectomy has been the tradi­tional treatment for DCIS. Based on the success of conserving surgery in patients with early invasive breast cancer, this ap­proach would appear to be a logical choice for treating DCIS. During the last clecade, patients with DCIS have been acceptecl for conservative surgery with or without radiation therapy, ancl the results of severa! studies have alreacly been pub­lished. 2•5 In this study we have evaluated the results of treatment in patients with DCIS observecl at the Centro Oncologico of Trieste from January 1978 to December 1994. Correspondence to: Dr. Cristina Vidali, Ospedale Maggiore, Isti tu to di Radioterapia , Via della Pieta 19, 34100 Trieste, ltaly. Patients and methods From January 1978 to December 1994, 87 patients with DCIS of the breast were observed at the Centro Oncologico of Trieste; patients with syn­chronous or metachronous invasive carcinoma of the breast were excluded from analysis. The medi­an age was 57 years (range: 31-84 years). Ali pa­tients unclerwent preoperative mammography: 5/87 cases (5.8%) were detected only clinically; 51/87 (58.6%) clinically and by mammography, ancl 31/ 87 (35.6%) by mammography alone. Mastectomy was performed in 43/87 (49.5%) patients; quadrantectomy and racliation therapy in 42/87 (48.2%) and lumpectomy alone in 2/87 (2.3%). Ali cases treated by conservative surgery had negative resection margins. Ali patients, except those treated by lumpectomy, underwent axillary dissection; in ali cases lymph nodes were negative for metastatic involvement. Patients who unclerwent quaclrantectomy re­ceived postoperative radiation therapy at the Istitu­to di Raclioterapia Oncologica of Trieste. They wcre treated with tangential fields delivered by a Cobalt UDC: 618. l 9-006.66-08-036 Unit; the prescribed dose was 50 Gy in 25 fractions, 108 Vidali C et al. followed by a boost of 1 O Gy to the primary tumour bed with electrons from a Linear Accelerator. Since 1984, the treatment planning was performed on CT seans using a 2-D planning system. Twelve patients were receiving hormona! ther­apy with tamoxifen for 5 years after surgery. The follow-up schedule included clinical ex­amination every 3 months for 3 years, every 6 months for the following 3 years, and later on once yearly; mammography was carried out once a year while other radiological and laboratory examina­tions were done only in specific cases. Actuarial survival curves were calculated using the Kaplan-Meier method. Results The median follow up was 69 months (range 16­227 months). Local failure occurred in 3/87 patients (3.4%) in the group treated with quadrantectomy and radi­otherapy. Time from surgical treatment to relapse ranged from 9 to 85 months. These patients under­went salvage mastectomy and adjuvant therapy with tamoxifen (estrogen receptors were positive at the tirne of recurrence). They are alive and free of any distant failure or further local recurrence. In our series, 15-year actuarial disease-free sur­vival was 89.9%, and the overall survival was 100%. Cosmetic results in patients treated by conserv­ati ve surgery and radiotherapy were satisfactory. Discussion and conclusions The optimal management for the patients with DCIS remains controversial. Mastectomy cures almost ali patients and is the standard by which other thera­peutic options are measured.6 Recurrence rate after conservative surgery with­out irradiation is high: 23-75%,3 whereas in series using radiotherapy after conservative approach, lo­cal failure rates range from 4% to 10% at 3-5 year follow up.7 In the randomized study published by Fisher et al. 8 the local control following lumpectomy with irradiation is higher in comparison with lumpecto­my alone. The majority of breast recurrences after con­servative treatment occur near the original tumor and approximately 50% are invasive.3 The outcome of salvage treatment must be regarded as an impor­tant issue in the treatment of DCIS because of the risk of local relapse. Virtually ali patients who de­velop a non-invasive recurrence and almost 75% of those with an invasive recurrence are salvaged.3 The risk of axillary nodal metastases is very low4 and therefore axillary dissection is no longer recommended. In our series there were no nodal metastases in the patients who underwent axillary dissection. The results of our retrospective study showed an incidence of relapse at 3.4% (3/87 cases) after quadrantectomy and radiotherapy; while there were no recurrences in the group treated with mastecto­my. There was no difference, however, in the sur­vival rate after salvage treatment. The conservative approach proved to be a good alternative to mastec­tomy in patients with DCIS. Ongoing randomized clinical trials comparing conservative surgery ver­sus conservative surgery and radiation therapy are expected to add more information on the therapeu­tic approach and will clarify the optimal manage­ment for the patients with DCIS. References 1. Silverstein MJ, Barth A, Poller DN et al. Ten-year results eomparing masteetomy to exeision and radiation thera­py for dueta! eareinoma in situ of the breast. Eur J Cancer 1995; 31A: 1425-7. 2. Amiehetti M, Caffo O, Riehetti A et al. Radioterapia e ehirurgia eonservativa ne! eareinoma intraduttale della mammella: studio multieentrieo. Radio/ Med 1995; 90 Suppl.1: 23-5. 3. Fowble B. Dueta! eareinoma in situ evaluation of treat­ment oplions. ASCO 29th Annual meeting; 1993: 73­9. 4. Frykberg ER, Bland KI. Overview of the biology and management of dueta! eareinoma in situ. Cancer 1994; 74: 350-61. 5. Solin LJ, Fowble BL, Sehultz DJ et al. Definitive irradia­tion for intraduetal eareinoma of the breast. Int J Radi­at Oncol Biol Phys 1990; 19: 843-50. 6. Frykberg ER, Masood S, Copeland EM et al. Dueta! eareinoma in situ of the breast. Surg Gynecol Obstet 1993; 177: 425-40. 7. Me Cormiek B, Rosen PP, Kinne Det al. Duet earcinoma in situ of the breast: an analysis of loeal eontrol after eonservation surgery and radiotherapy. Int J Radiat Oncol Biol Phys 1991; 21: 289-92. 8. Fisher B, Costantino J, Redmond C et al. Lumpeetomy eompared with lumpeetomy and radiation therapy for the treatment of intraduetal breast eaneer. N Engl J Med 1993; 328:1581-6. Radio! Oncol 1997; 31: 109-11. Treatment of intraductal carcinoma of the breast with conserva­tive surgery and radiotherapy: An Italian multicenter retrospective study M. Amichetti,1 O. Caffo,1 A. Richetti,2 G. Zini,3 A. Rigon,4 O. Lora,4 M. Antonello,5 · M. Arcicasa,6 M. Roncadin,6 F. Coghetto,7 P. Zorat,7 R. Valdagni,8 M. Balli,9 G. Panizzon,9 S. Maluta,10 A. Di Marco,10 S. Favretto,10 N. Teodorani,11 S. Neri,11 S. Fasan12 From the Departments oj Radiation Oncology of 'Trento, 2Varese, 3Reggio Emilia, 4Padova, 5Mestre, 6Aviano, 7Treviso, RMilano, 9 Vicenza, 10Verona, 11 Bologna, 12 Venezia, Italy A collaborative multi-institutional study on intraductal carcinoma (!DC) oj the breast in twelve Radiation Oncology Departments oj the north Italy was conducted. The study population comprised 206 women with !DC oj the breast treatecl between 1982 and 1992. Surgical procedures were as jollows: quadrantectomy in 158, lumpectomy in 34, and wide excision in 14 cases. The axilla was surgically staged in 141 cases: alt the palients were node negaLive. Radiation Lherapy was delivered with 6°Co units (73%) or 6 MV linear accelerators (27%) for a median total dose to the entire breast oj 50 Gy ( mean, 49.52 Gy ). The tumour bed was boosted in 137 cases at a median dose of JO Gy. Medianjollow-up is 72 months. Nineteen local recurrences were recorded. All recurrent patients had a salvage mastectomy and are alive and free oj disease. Actuarial overall-, cause­specific-, and recurrence-jree survivals at JO years were 93.5%, 100%, and 84%, respectively. The results oj this retrospective multicentric study confirm the favourable data reported in the literature about the ejflcacy oj breast conse111ing treatment of !DC with co11se1vative surgery mul adjuvant radiation therapy. Key words: breast neoplasms; intraductal carcinoma; treatment options; treatment outcomc; multicentcr studies Introduction After its recognition in 1907, intraductal carcinoma (IDC) of the brcast was rarely diagnosed, exccpt as an incidenta! finding or as a palpable mass, until the 80's. 1 During the past dccade, thc diffusion of mammographic screening increased the frequency of the diagnosis of IDC in a preclinical stage.2 Currently, IDC represents about l 0% of ali newly diagnosed breast cancers. 3 Correspondence to: Dr. Maurizio Amichetti, Ospedale Santa Chiara, Centro Oncologico, Largo Medaglie d'Oro, 38100 Trento, Italy. UDC: 618.19-006.6-089 .87-036 The treatment employed for DCIS of the breast varics widely, and the best treatment option bas not yct been clearly defined. Experience with conserva­tive managcment of IDC with surgery and radio­therapy (XRT) is limited in terms of both patients number reported from single Institution series and the duration of follow-up. In this study, an analysis of 206 women with IDC of the breast treated with this conservative approach in twelve Italian institutions, is reported. Patients and methods A collaborative, multi-institutional retrospective study of patients affected by IDC of the breast Amichetti Metal. treated with breast-conserving therapy (excision and radiation therapy) was performed, analyzing data from 12 Institutions of the north Italy for the period 1982 to 1992. A total of 206 sequential evaluable cases were collected. Their median age was 49 years (range 23-88 years), 92 patients had post-menopausal sta­tus; twenty-nine patients had a family history of breast cancer. Of the 126 patients with known clini­cal status, 103 (54%) had a palpable lump. Preoper­ative mammography was performed in 177 patients: 77 (43.5% of the total) were due to microcalcifica­tions alone, 60 (34%) to mass effect alone, and 18 (10.2%) to mass plus calcification. In 112 patients a measurement of the extent of the disease in the surgical specimen was available: the median patho­logic tumor size was 1.2 cm (range 0.2-5.5 cm). The surgical treatment consisted of quadrantecto­my in 158 cases, wide excision in 14, and tumourecto­my in 34. An axillary dissection was performed in 141 out of 206 cases with a median of 15 lymph nodes dissected (mean 14, range 3 -36): ali the cases were pathologically negative for metastatic disease. The tumor diagnoses were reviewed and con­firmed as IDC by institutional pathologists, central pathology review being unfeasible. The cases were classified according to the estab­Iished histological criteria with respect to the domi­nant growth pattern; the structural features were cat­egorized as follows: comedo (61), solid (8), cribri­form (42), papillary and micropapillary (29), and cases associated with lobular carcinoma in situ (13). Irradiation with curative intent was delivered with cobalt-60 (151 cases; 73%) or 6-MV photons (55 cases; 27% ), by tangential fields, encompassing the entire breast, up to doses of 45-60 Gy (mean, 49.52 Gy; median, 50 Gy) delivered in 2 Gy dose fractions in ali but 2 patients. A boost consisting of an addi­tional median dose of 10 Gy to the primary site was delivered after treatment of the whole breast in 137 cases. Neither regional nodal irradiation nor adju­vant systemic treatments were used. Overall survival, cause-specific survival and re­lapse-free survival were calculated using the Kaplan­Meier method,4 starting from the tirne of surgery. Results The median follow-up for the group was 72 months from the date of surgery, with a range of 31-167 months. Local failure was recorded in 19 patients, at an interval of 7-109 months after surgi­cal treatment. Ten cases were invasive carcinoma and 9 intraductal carcinoma. One patient developed an axillary nodal relapse after invasive local recur­rence. No distant metastases were observed. In 12 women, both the first and the second tumors were trne recurrences, occurring either at the site of pre­vious excision or on the border of the same quad­rant. Eight of the 19 patients with relapse had re­ceived a tumor-bed dose of 50 Gy, and 11 had had a supplemental external boost of 10 Gy. The initial surgical intervention had been quadrantectomy in 14 cases, tumourectomy in 4 and wide excision in one. Salvage mastectomy was performed in ali the patients. One patient was also treated with adjuvant tamoxifen at the tirne of recurrence. Ali the patients with breast failure are alive without evidence of disease. None of them has subsequently failed with distant metastases. Five-and ten-year actuarial breast recurrence­free rate is 93.5% and 84% respectively, overall survival is 98% and 93% respectively; while cause­specific survival and freedom from distant metas­tases is 100% at five and ten years. Subsequently, 7 patients developed a contralateral carcinoma of the breast, of these 3 intraductal and 4 infiltrating. The cosmetic outcome was separately assessed at the last follow-up in 175 cases: 87% of them had an excellent or good result. Discussion The surgical approach to IDC of the breast changed during the second half of the eighties by increasing use of breast conserving treatments with or without radiotherapy; thus, better cosmesis can be achieved than with mastectomy. The results of Iimited surgery alone are rather unsatisfactory: local recurrence has been reported at a cumulative average rate of 19.7%, ranging from 0% to 66%, calculated from about a thousand cases reported in the literature. A comparison of these data with the reported results of conservative surgery plus definitive irradiation suggests that ra­diotherapy can reduce the breast cancer recurrence rate to an acceptable leve! but does not eliminate it. This suggests that a combination of excision and radiotherapy provides acceptable Iocal control while ensuring excellent survival and cosmetic results.5•10 The only published randomized study is the NSABP B-17 trial1 1 comparing Iimited excision fol­ Treatmen of intraductal carcinoma r!f the breast with conservative surge,y and radiotherapy lowed by irradiation or observation. There were 790 women evaluable for analysis; the addition of radiation decreased the risk of breast cancer recur­rence and subsequently, the development of inva­sive breast cancer. The current study is the largest series of IDC treated by conservative surgery and irradiation reported in Italy. Our results are closely comparable with those reported for a series with a similar follow-up, 12-16 according to which the prob­ability of breast preservation at 10 years was 84%. In our series eause-speeific survival was 100% at 1 O years, ali the 19 patients with local recurrence being salvaged by mastectomy. The majority of breast recurrences in our study were observed at or near the site of primary IDC suggesting a persist­ence rather than a new second tumor: 12/15 known sites of recurrence were in the same quadrant as the first lesion. From these data it can be concluded that multicentric cancers rarely evolve into clinical cancer. The clinical size of the measurable palpable primary tumours in our series was relatively small, with about 80% of lesions smaller than 2 cm, and 65 patients in our study had non-palpable, mammo­graphically discovered lesions. Recently, White et al. reported a low rate of local recurrences in pa­tients treated by surgery and irradiation for mam­mographically detected lesions.8 An axillary dissection was performed in 141 patients: ali the cases were pathologically negative. In the literature on conservatively treated and irra­diated patients, axillary invasion was reported in 2 cases only, confirming the results reported in pa­tients treated with mastectomy. 17 Our study, al­though involving numerous Institutions, indicates that clinically or mammographically detected IDC can be succesfully treated by conservative surgery and definitive irradiation. References 1. Frykberg ER, Bland KI. Ovcrview of the biology and management of dueta! eareinoma in situ of the breast. Cancer 1994; 74: 350-61. 2. Lagios MD. Duet earcinoma in situ. Surg Ciin North Am 1990; 4: 859-71. 3. Frykberg ER, Bland KI. In situ breast earcinoma. In: Cameron JL ed. Advances in surge,y. St. Louis: Mos­by, 1993: 29-72 (Year Book Med Pubi). 4. Kaplan EL, Meier P. Non parametrie estimation from incomplete observation. J Am Stat Assoc 1953; 53: 457-81. 5. Silverstein MJ, Cohlan BF, Gierson ED et al. Duet earei­noma in situ: 227 eases without microinvasion. Eur J Cancer 1992; 28: 630-4. 6. Forquet A, Zafrani B, Campana F, Durand JL, Vilcoq JR. Breast-conserving treatment of dueta! earcinoma in situ. Semin Radiat Oncol 1992; 2: 116-24. 7. Cutuli B, Teissier E, Piat JM et al. Radieal surgery and eonservative treatment of dueta! eareinoma in situ of the breast. Eur J Cancer 1992; 28: 649-54. 8. White J, Levine A, Gustafson G et al. Outcome and prognostie faetors for loeal reeurrenee in mammograph­ieally deteeted dueta! earcinoma in situ of the breast treated with eonservative surgery and radiotherapy. Int J Radiat Oncol Biol Phys 1995; 35: 791-7. 9. Warneke J, Grossklaus D, Davis J et al. Influence of loeal treatment on the recurrenee rale of dueta! earcinoma in situ. J Am Col/ Surg 1995; 180: 683-8. 10. Solin LJ, Kurtz J, Forquet A et al. Fifteen-year results of breast-eonserving surgery and definitive breast irradia­tion for dueta! earcinoma in situ of the breast. J Ciin Oncol 1996; 14: 754-63. 1 l. Fisher B, Costantino J, Redmond C et al. Lumpeetomy eompared with lumpectomy and radiation therapy for the treatment of intraduetal breast eaneer. N Engl J Med 1993; 328: 1581-6. 12. Stotter AT, MeNeese M, Oswald MJ, Ames FC, Roms­dahl MM. The role of limited surgery with irradiation inprimary treatment of dueta! in situ breast cancer. Jnt J Radia! Oncol Biol Phys 1990; 18: 283-7. 13. Solin LJ, Fowble BL, Sehultz OJ, Yeh IT, Kowalyshyn MJ, Goodman RL. Definitive irradiation for intraduetal eareinoma of the breast. Int J Radiat Oncol Biol Phys 1990; 19: 843-50. 14. Me Cormiek B, Rosen PP, Kinne D, Cox L, Yahalom J. Duet careinoma in situ of the breast: an analysis of local control after eonservation surgery and radiothera­py. lnt J Radiat Oncol Biol Phys 1991; 21: 289-92. 15. Sneige N, MeNeese MD, Atkinson EN et al. Dueta! eareinoma in situ treated with lumpeetomy and irradia­tion: histopathologieal analysis of 49 specimens with emphasis on risk faetors and long term results. Hum Patlwl 1995; 26: 642-9. 16. Silverstein MJ, Barth A, Poller DN et al. Ten-year re­sults eomparing masteetomy to excision and radiation therapy for dueta! eareinoma in situ of the breast. Eur J Cancer 1995; 31A: 1425-7. 17. Silverstein MJ, Rosser RJ, Gierson ED et al. Axillary lymph node dissection for intraductal breast carcinoma -is it indieated? Cancer 1987; 59: 1819-24. Radio/ Oncol 1997; 31: 112-6. Pathological examination for quality assurance in breast co:nserving therapy f or breast cancer Thomas Decker,1 Monika Ruhnke,1 Rainer Obenaus,2 Ute Kettritz,3 Andreas Kleina,2 Gtinther Morack2 and Wolfgang Schneider1 1/nstitute of Pathology, 2Department of Gynaecology and 3Department of Diagnostic Radiology, Berlin-Buch Medica! Centre, Berlin, Gennany Lang-term survival in patients ajter breast conserving therapy (BCT) is similar to that ajter mastectomy. Nevertheless, there is a significant risk oj local recurrence. Although local recurrence does not appear to affect the survival, there certainly is associated morbidity and attendant emotional trauma present. The margin status was shown to be a risk jactor jor local recurrence. Microscopic evaluation oj the margins oj lumpectomy specimens is the only way to dejine the extent oj the tumour, especially oj its intraductal component, and the adequacy oj resection. We intended to check the influence oj a standardised protocoljor pathological examination on the results oj histological margin assessment. Moreove,~ we wanted to investi­gate the effects oj margin status and size oj the area oj the DCIS-component on the choice oj treatment. Between February 1994 and Februa,y 1996, 582 women had an unilateral breast excision at the Berlin-Buch Medica! Centre. In 233 patients (71.8%) there were no clinical or mammographic contraindications jor BCT and their carcinomas were treated by conservative surge,y and irradiation. The aim oj all tumour excisions was the complete removal oj the tumour. As a result oj our standardised margin investigation, in 28% oj cases there was microscopic evidence oj tumour tissue in the margins oj 100 consecutive BCT specimens although the margins looked clear macroscopically. In two periods when histological investigations were not carried out on non suspicious-looking margins and the margin assessment was non-standardised, the evidence oj tumour could be jound in only 2% and 12% oj the patients respectively. in each case with invasive carcinoma or DCIS detected in paraffin slides oj the margins, either directly at the resection line or within a distance oj 5 mm jrom it, a second operation followed. Finally, 100 women out oj the primary BCT group of 323 patients were advised to undergo mastectomy, and thus 132 / 323 (40.8%) patients with malignancies were treated by dejinitive BCT. The importance oj standardised evaluation oj BCT specimens is to select patients jor re-excision or jor treatment with conversion to mastectomy, and thus reduce local recurrence. Key words: breast cancer; breast conserving therapy; margin investigation; treatment outcome Introduction The efficacy of breast conserving therapy (BCT) and mastectomy in breast cancer has been com­pared in severa! randomised clinical trials. The long- Correspondence to: Dr. Decker, Institut fuer Pathologie, Klinikurn Berlin-Buch, Karower strasse 11, D-13122 Ber­lin, Gerrnany. UDC: 618.19-006.6-089 .87-036 term disease free survival in patients treated by BCT is similar to that of patients treated by mastec­tomy .1·7 Nevertheless, long-term survival should not be the only gauge of treatment efficacy. There is a significant risk of Iocal recurrence.x-11 Although Io­cal recurrence does not appear to affect the surviv­al, it is certainly associated with morbidity and attendant emotional trauma. Dueta! carcinoma in situ (DCIS) has implications for breast conserving therapy regardless whether it Pathological exami11ation.fi1r quality assurance in breast co11sen1ing therapy.ft1r breast cancer is associated with invasive carcinoma or not. DCIS •15 significantly affects local control rates. 12Micro­scopic evaluation of the margins of lumpectomy specimens is the only way to define the extent of the tumour, especially of its intraductal component, and the adequacy of resection. 11 •10•20 We intended to check the influence of a standardised protocol for pathological examination on the results of histolog­ical margin assessment. Moreover, we wanted to investigate the effects of margin status and the size of DCIS-component area on the choice of treat­ment. Materials and methods Patients Between February 1994 and February 1996, 582 women had an unilateral breast excision parformed at the Berlin-Buch Medica! Centre. The malignan­cy yield in our centre was 55.5% (327/582). In 4 of these 327 malignancies lobular carcinoma in situ was diagnosed. Out of the remaining 323 women, 91 (28.2%) underwent primary mastectomy for var­ious reasons. In 233 patients (71.8%) there were no clinical or mammographic contraindications for BCT and their pT i.s.; pTl, and pT2 carcinomas were treated by conservative surgery and irradia­tion. They had been evaluated by a team of breast surgeons, radiologists and pathologists before they were given the option of breast conserving therapy. 205 (88.0%) of the tumours treated by BCT were invasive (ali but 6 invasive lobular carcinomas had an invasive dueta! histology). Except for two tu­mours with diameters of 22 and 24 mm respective­ly, ali the invasive carcinomas were in stage pTl (mean diameter 13 mm); 28 (12.0%) of the 233 tumours treated by BCT were "pure" DCIS without invasion (pTi.s.). Surgery Ali tumour excisions were performed by the same team of gynaecologists under supervision of an ex­perienced breast surgeon. The aim was complete tumour removal by wide excision with an attempt­ed margin of 1 O mm, which would ensure at least 5 mm of macroscopically healthy tissue. In the cases of positive margins on gross inspection or a macroscopic distance less than 5 mm between the tumour and excision margin, the site of the margin involved was re-excised unless an indication for mastectomy was given. The data for this study have been derived from the primary excision specimens. In every case with invasive carcinoma or DCIS detected in paraffin slides of the margins, either directly at the resection line or within a distance of 5 mm to it, a second operation followed. Taking into consideration the surgical possibilities, re-re­section was performed always when the diameter of the DCIS ("pure" or as an component of invasive carcinoma) was less than 40 mm; in ali other cases, especially such with DCIS diameters exceeding 40 mm, the patients are advised to undergo mastecto­my. In ali patients with invasive tumours axillary dissection was performed, which was not done for DCIS. Pathology protocol In order to ensure standardization, we base our his­topathological investigations of BCT specimens on a practice protocol.21 This protocol includes eight steps: 1. Review of the preoperative clinical checklist. 2. Preoperative interdisciplinary consultation with gynaecologists, radiologists and pathologists. 3. Wide excision of the lesion (see above), after mammographic hook wire localisation if neces­sary. 4. Orientation of the BCT specimen on a drawn form showing the nipple -by the surgeon (addition­ally, the margins are marked with sutures). 5. Review of the intraoperative clinical checklist. 6. Conducting a gross examination and selecting the tissue for microscopic examination, after speci­men radiography with needle localisation, if neces­sary. 7. Review of the pathological checklist compris­ing gross examination, microscopic evaluation and diagnoses. 8. Postoperative interdisciplinary consultation. Handling instructions for gross examination and tissue sampling l. Determination of specimen dimensions. 2. Marking of the margins with Latex. 3. Serial slicing of the specimen at 4 mm inter­vals in a plane perpendicular to the mammillar­peripheral axis and, of course, perpendicular to the dueta! system. 4. Determination of location, dimension, and con­figuration of the tumour, and measuring its distance to the margins, determination of location and dis­ Decker Tet al. tance of the radiographic needle, marking as appro­priate. 5. Blocking of any suspicious area of the inner part. 6. Blocking of margins: As the slices are made perpendicular to the mammillar-peripheral axis, it is clear that the mammillar and peripheral slices contain margins which can be seen as a plane and can be submitted in toto for blocking. The other four margins are sampled from the edges of the tumour-bearing slices and the neighbouring ones (so-called radia! sampling). Dejinition oj positive margins and measuring oj macroscopically invisible tumour Any tumour in mammillary and peripheral tissue blocks is considered as evidence of positive mar­gin. In radia! tissue blocks only the presence of tumour in the definitive margins themselves is tak­en as evidence of positive margin. The distance to the margins of invasive carcinoma as well as of DCIS were determined by ocular micrometry from the slides for measuring smaller spaces. For larger distances, a combination of direct measuring and estimation by reconstruction, based on the stand­ardised handling protocol, was used. Evaluation oj the sensitivity oj the standardised procedure We compared the results of our standardised mar­gin investigation of 100 cases with the analysis of the margin status of 100 BCT specimens, each from two different tirne periods with different handling. Before 1989 only margins where tumour tissue was suspected on macroscopic examination were inves­tigated microscopically. From 1989 to 1991, mar­gins were evaluated more systematically, but the evaluations were not standardised and did not con­sider the orientation of the dueta! system. Results Margin status In 28% of cases, tumour tissue was found upon the investigation under the microscope, in the margins of 100 consecutive BCT specimens where the mar­gins Iooked clear macroscopically. In the periods when histological investigations were not carried out on non suspicious-looking margins and when margin assessment was non-standardised, tumour could be found in only 2% and 12% respectively. Based on our standardised practice protocol we dis­covered invasive carcinoma in 8% of cases investi­gated under the microscope exclusively as invasive carcinoma, 14% of the tumours discovered were only carcinomas in situ, and in 5% were combined invasive and intraductal carcinomas. Therapeutic consequences Primary in 233 (71.8%) of 323 women with malig­nancies there were neither clinical nor mammo­graphic contraindications for BCT. DCIS was found much more frequently than invasive carcinoma within a 5 mm distance to the surgical margin or transsected at the resection line. There were 144 secondary operations (re-excisions or secondary mastectomies) performed because of the positive margin status or because the extent of the DCIS­area was more than 40 mm. Finally, 100 women out of the primary BCT group of 323 patients were advised to undergo mastectomy, and thus 132/323 (40.8%) patients with malignancies were treated by definitive BCT. Discussion and conclusions Initial studies on recurrence rates following wide local excision used a margin of excision of 5 cm, but the cosmetic results were poor. 22 Subsequently, the trend has been towards taking Iess and less tissue. Better cosmetic results has been achieved, but a Iumpectomy alone is associated with a high incidence of local recurrence.23 The hypothesis that recurrence is due to residual tumour is supported by patterns of failure studies. 10• 24 The margin status is shown to be a risk factor for local recurrence. 14•25 Though excision may be clinically adequate, mi­croscopic examination may reveal tumour at the specimen edge, 1•25•27 and therefore confirmation of clearance by pathological examination must be sought. Our results verify a strong influence of our prac­tice protocol on the results of the examination of BCT specimens: Firstly, there is a higher sensitivi­ty for tumour bearing margins compared with ran­dom sampling of margin tissue. Moreover, based on the consideration of the dueta! orientation, our protocol offers a better chance to detect in situ components of tumour in the margins. With our method we are able to define exactly the tumour Pathological examinationfor quality assurance in breast conserving therapy j<1r breast cancer bearing margin and thus also the site of re-excision, if necessary. Finally, based on our protocol, it is possible to determine the size of the area involved by DCIS. The proximity of DCIS to a marked margin is de­termined by direct measuring and ocular microme­try. Based on the standardised sampling, we esti­mated the diameter of DCIS by combining direct measuring and reconstruction in a manner similar to _that of the Van Nuys group.28 This has got very strong implications for BCT: Recent results by the group of Schnitt et al. have shown that an extensive intraductal component (EIC) as defined by Conolly and Schnitt29 significantly affects local control rates only when the non invasive component contributes to the residual tumour load in the breast. 14 With complete excision for EIC-positive invasive breast carcinomas, irradiation provides a local control rate equal to that of EIC-negative lesions. Therefore EIC per se should not be considered a contraindica­tion to BCT unless substantial DCIS remains in the breast.26 The standardised practice protocol for the han­dling of BCT specimens provides the clinical team with more detailed information about margin status and the size of DCIS component of the tumour than was available before. The aim of standardised evaluation of BCT spec­imens is to select patients for a re-excision, or for treatment with conversion to mastectomy. We think that such careful planning of treatment assures bet­ter tumour control rates and cosmetic outcome than more aggressive surgery. References 1. Fisher B, Bauer M, Margolese R, Poisson R, Pilch Y, Redmond C. Five year results of a randomized clinical tria! comparing total mastectomy and segmenta! mas­tectomy with or without radiation in the treatment of breast cancer. N Engl J Med 1985; 312: 665-73. 2. Fisher B, Redmond C. Lumpectomy for breast cancer; an update of the NSABP experience: National Surgical Adjuvant Breast Project. Monogr Natl Cancer Jnst 1992; 11: 7-13. 3. Veronesi U, Banfi A, Salvadori B, Luini A, Saccozzi R, Zucali R. Breast conservation is the treatment of choice in small breast cancer: longterm results of a randomised clinical tria!. Eur J Cancer 1990; 26: 668-70. 4. van Dongen JA, Bartelink H, Fentiman IS, Lerut T, Mignolet F, Olthnis G. Randomized clinical tria! to access the valne of breast conserving therapy in stage I and II breast cancer. EORTC 10801 tria!. Monogr Natl Cancer Jnst 1992; 11: 15-8. 5. Blichert-Toft M, Brincker H, Andersen JA, Andersen KW, Axelsson CK, Mouridsen HT. A Danish rand­omized tria! comparing breast preserving therapy with mastectomy in mammary carcinoma. Acta Oncol 1988; 27: 671-6. 6. Lichter A, Lippman M, Danforth D, d'Angelo T, Stein­berg SM, deMoss E. Mastectomy versus breast con­serving therapy in the treatment of stage I and II carci­noma of the breast: a randomized tria! at the National Cancer Institute. J Ciin Oncol 1992; 10: 976-83. 7. Sarrazin D, Le MG, Arriagada R, Contesso G, Fontaine F, Spielmann M. Ten-year results of a randomized tria! comparing a conservative treatment to mastectomy in early breast cancer. Radiother Oncol 1989; 14: 177­84. 8. Silverstein MJ, Gierson ED, Colburn WJ, Cope LM, Furmanski M. Can intraductal breast carcinoma be ex­cised completeley by local excision? Cancer 1994; 73: 2985-9. 9. Fowble BL, Solin LJ, Schultz DJ, Goodman RL. Ten year results of conservative surgery and irradiation for stage I and II breast cancer. Jnt J Radia/ Oncol Biol Phys 1991; 21: 269-77. 10. Recht A, Silen W, Schnitt SJ. Time-course of local recurrence following conservative surgery and radio­therapy for early stage breast cancer. lnt J Radiat On­col Biol Phys 1988; 15: 255-61. 11. Veronesi U, Volterrani F, Luini A. Quadrantectomy versus lumpectomy for small size breast cancer. Eur J Cancer 1990; 6: 671-3. 12. Gelman R, Osteen RT, Schnitt SJ. Recurrence in the breast following conservative surgery and radiation therapy for early-stage breast cancer. Monogr Natl Can­cer lnst 1992; 11: 33-9. 13. Kurtz JM. Factors influencing the risk of local recur­rence in the breast. Eur J Cancer 1992; 28: 660-6. 14. Schnitt SJ, Abner A, Gelman R. The relationship be­tween microscopic margins of resection and the risk of local recurrence in patients with breast cancer treated with breast conserving surgery and radiation therapy. Cancer 1994; 74: 1746-51. 15. Lagios MD. Duet carcinoma in situ: biological implica­tions for clinical practice. Se min Oncol 1996; 23: 6-11. 16. Anscher MS, Jones P, Prosnitz LR, Blackstock W, Her­bert M, Reddick R. Local failure and margin status in early-stage breast carcinoma treated with conservation tsurgery and radiation therapy. Ann Surg 1993; 218: 22-8. 17. Boyages J, Recht A, Connolly JL, Schnitt SJ, Gelman R, Kooy H. Early breast cancer: predictors of breast recurrence for patients treated with conservative sur­gery and radiation therapy. Radiother Oncol 1990; 19: 29-41. 18. Fourquet A, Campana F, Zafrani B. Prognostic factors of breast recurrence in the conservative management of early breast cancer: a 25 year follow-up. /nt J Radiat Oncol Phys 1989; 7: 719-25. 19. Silverstein MJ, Waisman JR, Gamagami P. Intraductal carcinoma of the breast (208 cases): clinical factors influencing treatment choice. Cancer 1990; 55: 102-8. Decker Tet al. 20. Solin LJ, Yeh 1-T, Kurtz JM, Fourquet A, Recht A, Kuske R et al. Dueta! carcinoma in situ (intraductal carcinoma) of the breast treated with breast conserving surgery and definitive irradiation: correlation of patho­logic parameters with outcome of treatment. Cancer 1993; 71: 2532-42. 21. Decker T, Ruhnke M, Schneider W. Standardisierte pa-thologische Untersuchung von Mamma-Exzisionsprapa­raten: Relevanz innerhalb eines interdisziplinaren Prax­isprotokolls fiir 2cm 44% 52% 'Silverstein et al.2 2Unpublished 04 ' i ' d.+ . ------. p„o,29 ! 02 L. 0,2 0,1 -hemlpelvectomios(15) o.o~---------=----~ -··· rosoctions{59) O 12 24 36 48 60 72 84 96 108120132144156168180192 =•• Figure 3. Overall survival of ali patients with malignant tumors of the pel vic regi on treated by resection (n=59) and those treated by hemipelvectomy (n=l5) Conclusion The quality of life after anterior and posterior re­sections is from good to excellent, when no major nerves have been sacrificed. The functioning of the limb after real inner hemipelvectomy is worse, but the majority of the patients gain some active mobility of the newly formed fibrous joint as well as full weight bearing. Even after a resection of one major nerve these patients live better than after a hemipelvectomy. Patients with high bilat­eral sacrum resections have problems with mictu­rition and rarely with defecation. In terms of sur­vival, the results of resections are not considera­bly worse than those after a mutilating procedure. Many of the medially lying tumors can not be treated by the latter. No matter how demanding resection procedures can be for ali members of the surgical team, the effort seems to be justified by the results obtained. Table l. Recurrence rate in 50 M0 patients resected for tumors in the pelvic region (NED=no evidence of disease, LR=local recurrence, M= metastases) NED LR LR+M M Ali R0 resection 20(51%) 2(5%) 8(21%) 9(23%) 39(100%) RI resection 6(55%) 0(0%) 3(27%) 2 (18%) 11 (100%) Ali 26(52%) 2(4%) 12 (24%) 11 (22%) 50 (100%) References 1. Enneking WF. A system of staging musculosceletal neo­plasms. Ciin Ortlwp 1996; 204: 9-24. 2. Heare TC, Enneking WF, Heare MM. Staging techniques and biopsy of bone tumors. Orthop Ciin North Am 1989; 20: 273-85. Radio/ Oncol 1997; 31: 137-8. Tumour surgery in the pelvic region Pal Rah6ty1 and M. Szendroi2 1Dept. of Surgery, National Institute of Oncology, 2Dept. of Orthopedics, SOTE, Budapest, Hungary During the past ten years the authors operated on 27 tumours oj the pelvic reg ion, 12 oj them involving the pelvic hlade, 6 the periacetabular region, further 9 the os pubis and ischii, respectively. Most oj the cases (16) were chondrosarcomas. The mean age oj the patients -13 male and 14 Jemale -was 41 years. As to surgical radicality, 11 wide, 10 marginal and 6 intralesional resections were performed. After a mean follow-up period oj 3 years (0.5-11 years) 19 patients are alive and tumour-free, 2 with tumour, 4 have died and 2 have been lost to follow-up. As postsurgical complication a wound-healing disorder and inguinal hernia occurred in 5 cases, surgical field thrombosis with secondary compartment syndrome and renal insufficiency developed in one case. The authors draw attention to the difficulties and indications for pelvic resections (internat hemipelvectomies). Key words: bone neoplasms; pelvic bones-surgery; hemipelvectomy Introduction One of the greatest challenges for tumour surgeons is to operate osseal tumours originating from the pelvic region or soft tissue tumours destructing pel­vic bones. The reconstruction following "interna! hemipelvectomy", i.e. partial pelvic resection, may be particularly difficult for restoring the walking ability of the patient and for achieving an adequate quality of life. 1 Methods Between 1986 and 1995 we performed "interna! hemipelvectomy" thus saving the extremity in a total of 27 cases. In our series we had 13 male and 14 female patients; their mean age was 41 years, ranging from 18 to 78 years. In our materi­al an overwhelming majority of tumours was rep- Correspondence to: Dr. Pal Rah6ty, National Oncological Institute, Surgical Department, Rath Gyorgy u 7-9, 1125 Budapest, Hungary. resented by chondrosarcoma (16 patients). In oth­er 4 patients we were compelled to perform a partial pelvic resection due to a giant celi bone tumour. As to surgical radicality, the interven­tion was wide in 11 cases, in 8 cases at least one surface of the resection was marginal, while in other 2 cases the tumour could only be extirpated in two parts due to its large size, which meant that contaminated marginal resection took place. Intralesional intervention was performed in 6 pa­tients. Reconstruction was done in 3 patients: one patient had pelvic endoprosthesis implanted, while in the other 2 patients we fixed the femoral head to the ileal stump of the acetabular defect by cerclage, and then secured the site with a pel vic plaster. Results Local recurrence was observed in 6 patients. Com­plications occurred in 8 cases. After a mean follow­up of 3 years, 18 (66%). of our 27 patients are alive and tumour-free; in 6 patients the follow-up period UDC: 616.718.19-006.6-089.87 has exceeded 5 years. Ralu5ty Pand Szendriii M Discussion Conclusion While one should attempt a eomplete tumour re­moval, we should not eommenee on an operation if the prerequisites are not present. For a proper judge­ment the up-to-date imaging teehniques should be used. In our opinion, hemipelveetomy is indieated in the following eases: 1) if the tumour has invaded along the isehiadie nerve into the gluteal muscles, or the posterior surfaee of the thigh; 2) if the tu­mour involves the iliae externa, or the femoral ar­tery and vein and if it extended to the adduetors via the adduetal eanal; 3) if the tumour equally infil­trntes the E/I, E/II and E/III regions. Although in this ease interna! hemipelveetomy ean be earried out, there is no possibility of a reeonstruetion, and the flail hip offers an extremely poor rehabilitation outeome; 4) the age and general eondition of the patient should be eonsidered individually. Opinions in the literature are eontroversial as regards the reeonstruetion of the defeets. The defeet need not be reeonstrueted if the pelvie are remains intaet, i.e. the 2-finger-thiek osseal are above the isehiadic incision and the aeetabulum are not dam­aged. 2·3 Among our 27 patients operated on during 1 O years, 20 are alive, 18 without a tumour at present. This is an eneouraging figure! The prerequisite for the favourable results is to perform surgery for pelvie tumours in well-equipped eentres, with ex­perieneed multidisciplinary surgieal teams includ­ing orthopedie, abdominal surgeons, possibly gyneeologists and/or urologists as well. References 1. Enneking WF, Menendez LR. Functional evaluation of various reconstructions after periacetabular resection of iliac lesions. In: Enneking WF, ed. Limb salvage in musculoskeletal oncology. Edinburgh: Churchill Liv­ingstone, 1987: 117. 2. Grimer RJ, Carter SR. Reconstruction after tumor sur­gery, Curr Opin Ortlwp 1993; 4:73. 3. Monticelli G, Santori FS, Ghera S, Folliero A, Manili M. Surgical problems in the treatment of pelvic tu­mours. In: Oosterom AT, van Unnik JAM, eds. Man­agement 4,0001mm', PLT count > 100,000/mm', Hb > 10 g/dl; patients with good !iver function with AST, ALT, LDH, gamma-GT <2.5 times the upper limit of normal values; creatinine leve! < 1,2 mg/dl or cre­atinine clearance > 60 ml/min. Staging was performed according to the Ameri­can Joint Committee on Cancer Staging (AJCC) 1989 classification. Before entering the study, ali patients underwent physical examination, and a laryngoscopy under Iocal anesthesia. General check­up included Jung and esophageal endoscopy, chest x-ray, !iver echography, complete blood count and blood chemistry. Ali patients received Carboplatin (AUC 3 mg/ml/ min) i.v. over I hour, 5FU 375 mg/mq i.v. bolus, Leucovorin 100 mg/mq i.v. over 30 minutes, on day one, for a total of 4 courses, each course was repeat every two weeks. During radiotherapy Carboplatin was adminstered at 20 mg/m2/day, 5 days/week with a portable bat­tery pump (Pharmacia Deltec CADD-1) connected to venous access port, recharged every week till the end of the radiotherapy treatment. In the case of severe toxicity (> grade 2), Iasting until the scheduled treatment day the course was postponed for one week. If recovery of the toxicity was stili incomplete, dose modification was per­formed. In the case of hematologic toxicity, both drugs were reduced to 50% in granulocyte count between 1,000/µL and 2,000/µL or platelet count between 50,000/µL and 100,000/µL; in renal toxic­ity, the dose of Carboplatin was reduced to 75%; in mucosal toxicity, the dose of 5FU was reduced to 50% for grade > 2. A first clinical evaluation of response was per­formed after the fourth chemotherapy cycle. The fina! evaluation was assessed by a clinical exami­nation and a laryngoscopy under local anesthesia with biopsies for primary tumor, and by echogra­phy for neck nodes. The response was defined as progressive disease (PD), stable disease (SD), par­tial response (PR), and complete response (CR), according to World Health Organization (WHO) guidelines. The pathologic complete response (PCR) for primary tumor was defined as macroscopic dis­appeararice of the lesion with negative biopsy. The response was scored separately for primary tumor and lymph nodes. Standard external beam radiotherapy program consisted of 1.8-2.0 Gy daily fractions and a total dose of 70 Gy in seven weeks for primary lesion (T) (a I to 2 week split was performed when necessary) and 60 Gy to regional lymph nodes. Radiotherapy was delivered by a LINAC 6 MeV. The target vol­ume varied according to tumor localization and stage. Whenever possible, the therapy was planned from CT scan images at severa! different levels. In the case of retreatment, the dose was 60 Gy (1.8 Gy/fraction) with weekly control of toxicity. Treat­ment fields of photons were combined with elec­tron fields (6-15 MeV) and/or brachytherapy treat­ment with Ir 192 as boost. Results Ali 9 patients who entered the study, were evalua­ble for response to induction chemotherapy, Iocal treatment toxicity and survival. Three patients stopped the treatment after the fourth cycle of in­ Loreggian Letal. duction chemotherapy due to disease progression with worsening of the clinical condition. Six pa­tients completed the planned treatment obtaining 2 CRs, 2 PRs and 2 SDs. In responding patients the shrinkage of the tumor started after the second cycle of induction chemo­therapy in 3, and after the first cycle in l. Ali the responding patients had the primary lesion located in the oropharynx. Lymph node response was ob­tained only in 1 case; another patient with CR of the primary Iesion is now disease free, after a neck dissection. The toxicity of induction chemotherapy was mild without renal or !iver damage, only 3 cycles were delayed by seven days to allow platelet recovery, and vomiting was observed only in 7 out of 35 cycles. During radiochemotherapy 4 patients expe­rienced grade III mucositis and 2 grade II. The median dose of radiotherapy delivered was 61 Gy (range 60-70) in 8 weeks (range 6-10) with a medi­an split of one week (range 0-3). One patient expe­rienced a central catheter line thrombosis. Up to now, 8 patients are alive, 2 without disease and 6 with persistent disease. One died two months from the start of induction chemotherapy due to neoplastic cachexia. Discussion With Cisplatin and 5FU infusions (PF) given for four cycles before definitive local therapy a signifi­cant survival advantage in a Iarge subgroup of inop­erable stage III and IV patients was found. 9 More than 35% of the patients with advanced head and neck tumor, seen at our department could not be treated with PF since they did not fulfill the inclu­sion criteria. It is important to stress that there is no known way how to modify a curative treatment for the elderly to be associated with fewer side effects without compromising the chance for cure. Nevertheless, renal, gastrointestinal and neural toxicities of Cisplatin limit its dosage, especially in old or debilitated head and neck cancer patients.4 lnduction chemotherapy decreases distant metas­tases but does not improve Iocal disease control.9•10 Carboplatin, besides being less toxic than Cisplatin with similar activity in head and neck patients,6 induces potentiation of moderate-dose radiation cy­totoxicity in human Jung cancer celi Iines.7 It could be safely administered by continuous infusion over 6 weeks at 20 mg/m2/day in combination with Ioco-regional fractionated radiation therapy 30 x 2 Gy, with mild toxicity.8 However, due to the small number of patients in our study, it is difficult to draw any definitive conclusion. Nevertheless, we can say that 4 cy­cles of Carboplatin-5-fluorouracil and Leucov­orin even at Iow, well tolerated doses, seem to have some effect upon the tumor in e!derly pa­tients and could be followed without additional toxicity by radiotherapy with combined systemic Carboplatin infusion. The overall response in 4 out of 9 patients, with only 2 CRs is not signifi­cant. This protocol needs further evaluation, and if efficacious, it has to be compared with radio­therapy alone in a randomized study. References l. Ausili-Cefaro G, Olmi P. Tumori in eta seni/e. Ed Art­grafica-Firenze 1995; 3-24. 2. Scalliet P. Radiotherapy in the elderly. Eur J Cancer 1991; 27: 3-5. 3. Stupp R, Weichselhaum RR, Vokes EE. Combined mo­dality therapy of head and neck cancer. Semin Oncol 1994; 21: 49-58. 4. Vokes EE, Athanasiadis l. Chemotherapy for squamous celi carcinoma of head and neck: the future is now. Ann Oncol 1996; 7:15-29. 5. Zagone! V, Fratino L, Sacco C et al. Reducing chemo­therapy-associated toxicity in elderly cancer patients. Cancer Treat Rev 1996; 22: 223-44. 6. Gregoire V, Beaduin M, Humblet Y et al. A phase I-II tria! of induction chemotherapy with carboplatin and fluouracil in locally advanced head and neck squa­mous celi carcinoma: a report from the UCL-Oncology Group, Belgium. J Ciin Oncol 1991; 9:1385-92. 7. Groen HJM, Slaijfe S, Meije C et al. Carboplatin-and cisplatin-induced potentation of moderate-dose radia­tion cytotoxicity in human lung cancer celi lines. Br J Cancer 1995; 72: 1406-11. 8. Groen HJM, Van deer List ADH, De Vries EGE et al. Continuous carboplatin infusion during 6 weeks' radi­otherapy in locally inoperable non-small-cell lung can­cer: a phase I and pharmacokinetic study. Br J Cancer 1995; 72: 992-7. 9. Paccagnella A, Orlando A, Marchiori C et al. Phase III tria! of initial chemotherapy in stage III or IV head and neck cancers: a study by the Gruppo di studio dei tumori della testa e del collo. J Nat. Cancer 1994; 86: 265-72. 1 O. Laramore GE, Scott CB, Al-Saraff M: Adjuvant chemo­therapy for resectable squamous cell carcinomas of the head and neck: report on intergroup study 0034. Int J Radiat Oncol Biol Phys 1992; 23: 705. Radio! Oncol 1997; 31: 171-2. Combined application of dsplatin, vindesine, hyaluronidase and radiation for treatment of advanced squamous celi carcinoma of the head and neck J. Klocker,1 H. Sabitzer,2 W. Raunik,2 S. Wieser,3 J. Schumer1 Klagenjurt General Hospital: 1 1st Medica! Department, 2Dept. oj Radiotherapy, 3 Dept. oj Otholaryngology, Klagenjurt, Austria Forty eight patients with advanced head and neck tumours were treated with irradiation and concomitant chemotherapy with cisplatin, vindesine and hyaluronidase. The disease-free survival rate at 5 years was 47%. The toxic effects were mucositis (48 patients), nausea (25 patients -in 6 patients vomiting), bone marrow depression ( 15 patients ), and peripheral neuropathy ( 14 patients ). The results warrant a randomised tria!. Key words: head and neck neoplasms-therapy; radiotherapy; cisplatin; vindesine; hyaluronidase; treatment outcome Introduction Advanced, unresectable epithelial cancer of the head and neck is a challenging problem in oncology. Standard radiation therapy is suboptimal because of a comparatively high risk of recurrence and long term survival is only achieved in less than I 0% of the cases. Recent studies have shown that simulta­neous radiochemotheray can prolong the recurrence­free interval as well as the patient' s survival time. 1 Also, the radiosensitizing effect of Cisplatin has been observed.2•3•4 The tumor-celi synchronizing ef­fect of vinca alcaloids is well known.5 The combi­nation of Vindesine and Cisplatin was tested in severa! clinical studies.6•7 The sensitizing effect of Hyaluronidase on polychemotherapy has already been demonstrated in separate studies, also as addi­tive to the regimen with Cisplatin and Vindesine.8•9 The purpose of the present study is to evaluate the effect of radiation therapy in combination with Correspondence to: Dr. J. Klocker, 1st Medica! Depart­ment, Klagenfurt General Hospital, St. Veiter-Strasse, A­9026 Klagenfurt, A ustria. chemotherapy consisting of Vindesine, Cisplatin and additional Hyaluronidase. Material and methods The chemotherapy scheme was as follows: on day I (5 mg Vindesine) and day 2 (80 mg/sqm Cisplatin), with 200.000 IU Hyaluronidase ad­ministered i.v. over 20 min. on each of these two days before initiation of chemotherapy, and on 12 radiation days 3 -5, 8 -12 and 15 -18. Rena! function was protected by infusions before and after chemotherapy. This therapy regimen was repeated twice starting with chemotherapy on days 22 and 43. The irradiation treatment was given by 6 MeV photon beam unit, 5 x 2 Gy per week, to the mid­plane tumour dose 72 Gy with shrinking field tech­nique. If the radiomucositis was severe, the irradia­tion treatment was interrupted for a week. The response to the treatment was evaluated after each cycle and after every month and finally three months after completion of treatment (according to WHO-guidelines). Mean observation tirne was 62 UDC: 617.52/.53-08 months (range: 32 -85 months). Klocker J et al. Results To date, 48 patients were treated. No one was !ost to follow-up. The survival of patients at 5 years was 47%. Sixteen patients are stili in complete remis­sion without relapse. The complete and partial re­mission was achieved in 40/48 patients and 3/48, respectively; in 1 patient, the condition remained unchanged. In 4 patients, tumor progression was evident under therapy and they died 3, 5, 6 and 8 months after therapy. In 12 cases relapses occurred after complete remission and ali died because of cancer. Those who did not achieve complete remis­sion died as well. Nine patients with stage T4 N2 and T4 N3 tumor died from tumor progression or recurrent disease. One patient died of pneumonia 5 months after achieving complete remission; anoth­er died of sudden heart failure 25 months after achieving complete remission. One patient died from secondary !iver carcinoma. Toxic effects: nausea occurred in 25 cases (WHO­grade 1 -2); only 6 patients suffered from vomiting (WHO-grade 1 -2). In 15 patients, signs of myelo­toxicity (in 13 patients with WHO-grade 1, and in 2 patients with WHO-grade 2) and in 14 cases pe­ripheral neuropathy (WHO-grade 1) developed. Twenty seven patients suffered from moderate/se­vere mucositis (WHO-grade 1 -2) caused by radia­tion, and 12 patients experienced mucositis WHO­grade 3. Nine patients developed mucositis WHO­grade 4 and at this point radiation therapy was stopped for about a week. However, chemotherapy was administered according to the protocol in these patients as well. Conclusion Encouraged by the promising results of the pre­sented tria!, a randomized tria! is being made with unchanged combined radiochemotherapy plus or minus additional hyaluronidase to evalu­ate the impact of this enzyme on the effective­ness of the therapy. References l. Wustrow TP et al. Grundlagen der simultanen Radio­Polychemotherapie bei fortge-schrittenem Kopf-und Hal­skarzinom. La,yngol Rhinol Oto/ 1987; 66: 366 -72. 2. Talyor SG et al. Improved control in advanced head and neck cancer with simultaneous radiation and cispl­atin/5-FU chemotherapy. Cancer Treat Rep 1985; 69: 937-9. 3. Marcial V, Pajak TF, Al Sarraf M, Kinzie J, Velez­Garcia E. Concurrent radiotherapy and cisplatinum in inoperable mucosal squamous celi carcinoma of the head and neck: a Radiation Therapy Oncology Group report. lnt J Radiat Oncol Biol Phys 1985; 11 Suppl 1: 89. 4. Richmond RC. Toxic variability and radiation sensiti­zation by dichlor-diamine platinum (11): complexes in S. thyphimurium cells. Radiat Res 1984; 99: 596-608. 5. Camplejohn RS. A critical review of the use of vincis­tine (VCR) as a tumor celi synchronizing agent in can­cer therapy. Cel/ Tissue Kinet 1980;13: 327-35. 6. Ruttmann R. Chemotherapeutische Behandlung von Plattenepithel-Karzinomen im Kopf-und Halsbereich mit einer Kombination von Vindesine und Cisplatin. Lwyngol Rhinol Otol 1982; 61: 406-10. 7. Leitner SP et al. A pilot study of cisplatin -vinblastine as the initial treatment of advanced head and neck cancer. Cancer 1986; 58: 1014-7. 8. Baumgartner G et al. Die Hyaluronidase in der cysto­statischen Therapie von HNO-Tumoren. La1yngol Rhi­nol Oto/ 1987; 66:195-9. 9. Klocker J et al. Hyaluronidase als Zusatz zur palliativ­en cystostatischen Therapie von Plattenepithelkarzi­nomen im Kopf-und Halsbereich. Wien Klin Wochen­schr 1988; 100 Suppl 17: 8-15. Radio/ Oncol 1997; 31: 173-7. Concomitant radiotherapy and mitomycin C with bleomycin in inoperable head and neck cancer Branko Zakotnik,1 L. Šmid,2 M. Budihna,1 H. Lešnicar,1 E. Šoba,1 L. Furlan,1 M. Žargi2 1 Institute of Oncology, 2 University Department of Otorhinolaryngology and Cervicofacial Surgery, Ljubljana, Slovenia In a prospective randomized study the efjicacy oj simultaneous irradiation with Mitomycin C and Bleomycin in patients with inoperable head and neck carcinoma was assessed. Between March 1991 and December 1994, 64 patients with inoperable head and neck carcinoma were randomly assigned to receive either radiation therapy alone (group A) or radiotherapy combined with simultaneous Mitomycin C and Bleomycin ( group B ). The disease-jree survival ( DFS) at 4 years jor group B was 37%, and jor group A 8%. ( P=0.016), and the overall survival (OS) was 26% jor group Band 7% jor group A (p=0.09). The DFS jor patients with oropharyngeal carcinoma in group B was 48% and in Group A 10% (p=0.0009) and the OS was 38% in group Band 10% in group A (p=0.024). In patients with nonoropharyngeal carcinoma, there were practi­cally no differences in DFS and OS between groups B and A.The concomitant treatment (radiotherapy, Mitomycin C, Bleomycin) significantly improved DFS and OS in patients with orophmyngeal carcinoma. Key words: head and neck neoplasms-therapy; radiotherapy; bleomycin; mitomycin C; treatment outcome Introduction During the past 20 years, the incidence of carcino­ma of the oral cavity and pharynx has been increas­ing considerably in our country.1 At diagnosis, more than half of the tumors are in advanced, inoperable stage. Various combinations of treatment modali­ties tested so far have failed to provide significant improvement of survival. Chemotherapy, applied as induction treatment has not yielded significant survival benefit.2 In contrast to this, simultaneous application of combined radio-and chemotherapy has proved to be more effective in the treatment of advanced head and neck carcinomas.3-6 Yet, the question of the most suitable chemotherapeutic combination stili remains to be solved.7 The aim of our prospective randomized clinical study was to compare radiotherapy (arm A) and Correspondence to: Dr. Branko Zakotnik, M.D., Institute of Oncology, Zaloška 2, 1105 Ljubljana, Slovenia. radiotherapy combined with simultaneous applica­tion of Mitomycin C, Bleomycin, Nicotinamid, Chlorpromazine, and Dicoumarol (arm B). Rationale jor selection oj chemotherapeutic scheme According to some basic experimental studies that bioreductive alkylating agent Mitomycin C is se­lectively toxic to radioresistant hypoxic cells8•9 and considering clinical studies of Weisberg6 and Do­browsky,10 it appears that its use in patients with advanced head and neck carcinoma is justified. Namely, in a majority of these patients, a high percentage of hypoxic cells due to large tumor mass can be expected. Since more than only additive effect of combination of Mitomycin C and irradia­tion was speculated,11·12 we decided to apply Mito­mycin C and two irradiation fractions (2 Gy each) in the same day, after patients had received a dose of I O Gy. Some studies6•13 indicate that the repeated application of Mitomycin C improves the treatment UDC: 617.52/.53-006.6-08 effect. In accordance with this observation, a re­ Zakotnik B et al. peated dose of Mitomycin C before the end of ther­apy was planned. It seems that Dicoumarol significantly enhances the effect of Mitomycin C on hypoxic tumor cells. 14 Therefore, the application of Mitomycin C was com­bined with Dicoumarol. In contrast to Mitomycin C, Bleomycin prevailingly acts on oxygenated cells. Due to its radiosensitizing effect, Bleomycin has been tested in severa! clinical studies. 2.4·5•15 In the treatment of carcinoma of the oral cavity, a simul­taneous combination of irradiation and Bleomycin­based chemotherapy improved survival in some ran­domized studies.4•5 Some studies in vitro have confirmed the resist­ance of certain tumor celi lines to Bleomycin.16 It seems possible that this resistance could be further enhanced by mutagens such as ionizing irradiation and Mitomycin C. In attempt to avoid the appear­ance of resistant celi lines, our patients received Bleomycin in combination with Nicotinamid, as suggested by the results of a corresponding basic study. 16 According to the findings of Hait and cowork­ers17 that simultaneous application of Bleomycin and Chlorpromazine significantly enhances the ef­fect of Bleomycin on tumor cells and, at the same tirne, reduces the appearance of pulmonary fibrosis, Chlorpromazine was also incorporated in our chem­otherapeutic scheme. Combination of both, Mitomycin C and Bleomy­cin proved to be effective in the treatment of ad­vanced squamous celi carcinoma of the cervix uteri. 13 The same cytotoxic drugs were used by An­dreasson et al. in the treatment of advanced head and neck carcinomas. In this study, severe local adverse reactions due to intraarterial application of Mitomycin C were reported. Considering this, our patients were treated by intravenous application of Mitomycin C, while Bleomycin was given intra­musculary. Patients and methods Between March 1991 and December 1994, 64 pa­tients with previously untreated, histologically con­firmed inoperable squamous celi carcinoma of the head and neck entered the study. The median age of patients was 51 years (range 37-68). Pretreatment assessment consisted of physical examination, en­doscopy with biopsy, radiography of the head and neck with or without computerized tomography, and ultrasonography of the neck and abdomen, complete blood count and blood biochemistry, dif­fusion for CO. For staging, the UICC staging crite­ria were used. Criteria for inoperability were tech­nical unresectability and/or selection based on low surgical curability.4 Eligibility criteria, determined by the multidisciplinary team of radiation oncolo­gist, head and neck surgeon, and medica! oncolo­gist included performance status < 3 (WHO), Hb > 100 g/1, L > 3.5 x 109/1, Tr > 100 x 109/1, normal bilirubin, creatinin, prothrombine tirne, and diffu­sion for CO. Informed consent was obtained from ali patients. Patients with distant metastases, previ­ous or simultaneous other malignancy except cured skin carcinoma, psychotic and senile patients, and those refusing the proposed treatment were exclud­ed from the study. Eligible patients were randomly assigned to one of the two treatment groups using randomization with permuted blocks and stratified according to primary tumor site (Table 1). Sixty patients had Stage IV and four Stage III of disease. Table l. Treatment by site (RT=radiotherapy, ChT=chemo­therapy) Site RT RT+ChT Ali paranasal sinuses 2 4 6 oral cavity 6 4 10 oropharynx 21 20 41 hypopharynx 3 4 7 Ali 32 32 64 Ali patients in both groups received fractionated irradiation five times weekly with 2 Gy to the total dose of 66-70 Gy to the gross disease and 50 Gy to the clinically negative regions of the neck and supr­aclavicular lymph-node areas. On the day of the first application of Mitomycin C, patients in group B were treated with two fractions of 2 Gy with an interval of at least 6 h in between. The radiation dose to the spina! cord was 40 Gy. Chemotherapy regimen included intramuscular ap­plication of Bleomycin 5 units twice a week with the planned total dose being 70 units and Mitomycin C 15 mg/m2 given intravenously after delivery of 10 ­12 Gy of irradiation. The application of Mitomycin C was planned to be repeated on the last day of radiotherapy in a dose of 1 O mg/m2• Throughout the therapy, patients in group B received Nicotinamid (650 mg/day) and Chlorpromazine (200 mg with Bleomycin). Dicoumarol (300 mg) was applied in the evening and morning before Mitomycin C. Concomitant radiotherapy and mitomycin C with bleomycin in inoperable H. & N. cancer The main endpoints of the tria! were tumor response, toxicity, disease-free survival (DSF), and overall survival (OS). The response rate was estimated 2 months after therapy. The difference in response rates was tested with X2 test. If the number of patients was less then 5 in any cel! of the table, a Fischer exact test was used. The sur­vival was calculated after the completed treat­ment using the method of Kaplan -Meier and a logrank test was used to test the differences be­tween groups. Results and conclusions Ali 64 patients who had entered the study, were evaluable for tumor response, toxicity, DFS and OS. Median follow-up was 42 months (range 21 ­63 months). Table 2 shows tumor response 2 months after treatment. Table 2. Response rates in ali, oropharyngeal and nonoropharygeal carcinoma patients (RT=radiotherapy, ChT=chemotherapy, CR=complete remission) All patients RT RT+ChT p CR 10 (31%) 19 (59%) notCR 22 (69%) 13 (41%) 0,04 Oropharynx CR 6 (29%) 15 (75%) notCR 15 (71%) 5 (25%) 0,007 Others CR 4 (36%) 4 (33%) notCR 7 (64%) 8 (67%) 0,33 There was no treatment related death. The fre­quency and severity of early toxic effects due to therapy were more pronounced in patients in treatment group B (Table 3) and sometimes the dose reduction of Bleomycin and/or Mitomycin C was necessary, while there was no reduction of the total irradiation dose. Table 3. Incidence of toxic side-effects by WHO toxicity grade (RT=radiotherapy, ChT=chemotherapy) Grade o 1 2 3 4 mukositis RT o 2 11 17 2 RT+ChT o 1 3 13 15 infection RT 30 1 o 1 o RT+ChT 19 5 4 4 o leucopenia RT 31 1 o o o RT+ChT 18 8 5 1 o Eight patients underwent salvage surgery, 2 from group A and 6 from group B. Surgery was success­ful in two group B patients only. The DFS for group B was 37%, and for group A 8%. (P=0.01) (Figure 1), and the OS was 26% for group B and 7% for group A (p=0.08)(Figure 2). The DFS in patients with oropharyngeal carcino­ma in group B was 48% and in Group A 10% (p=0.001) (Figure 3) and the OS was 38% in group B and 10% in group A (p=0.019) (Figure 4). In patients with nonoropharyngeal carcinoma, there were practically no differences in DFS and OS between groups B and A. ! = ~+la3~32 10011 % 75 s u r 1 p=0,01 1 soj v i v a 1 25 J YEARS Figure l. Disease free survival in ali patients (RT=radiotherapy, KT=chcmotherapy). ........ Rf=32 -RT+Kr = JZ 100 % 75 s r 1 p = 0,08 1 v u 'h 50 ~ i v a 25 .O ... O YEARS Figure 2. Overall survival in ali patients (RT=radiotherapy, KT=chemotherapy). From our study it seems that concomitant radio­chemotherapy improves survival significantly in patients with inoperable oropharyngeal squamous celi carcinoma. Although the number of patients with nonoropharyngeal carcinoma is rather small, it Zakotnik B et al. RT= 21 -Rr+KT-20 100 % 75 5 u r 50 j v 1 p=0,001 I a v JI YEARS Figure 3. Disease free survival of patients with oropharyngeal carcinoma (RT=radiotherapy, KT=chemo­therapy). .. Rf = 21 -RT+KT = 20 100 % 75 s u r ·v 50 j v a I 25~ 1 p=0,0191 o 1 2 3 ~ YEARS Figure 4. Overall survival of patients with oropharyngeal carcinoma (RT=radiotherapy, KT=chemotherapy). seems that this concomitant treatment modality is not profitable for these patients. The intent of our concomitant treatment was to achieve a higher percentage of complete response rates and better survival by enhancing the effect of radiotherapy with severa! additional drugs. The prevalence of complete responders and improved survival in the combined therapy group is therefore not the consequence of only one, but probably of severa! coexisting factors. The choice of chemotherapeutic agents used in our tria! was done on the basis of their effectiveness on hypoxic tumor cells, as well as their radiosensi­tizing effect. The latter is believed to be responsible for marked acute mucositis in patients treated by combined therapy. References 1. Cancer Registry of Slovenia. Cancer incidence in Slov­enia 1990. Ljubljana: Institute of Oncology, 1993. 2. Auersperg M, Šoba E, Vraspir-Porenta O. Intravenous chemotherapy with synchronization in advanced can­cer of oral cavity and oropharynx. Z Kreb.~fi1rsch 1977; 90: 149-59. 3. Adelstein DJ, Vishawa MS, Scott E. Simultaneous ver­sus sequential combined technique therapy for squa­mous celi head and neck cancer. Cancer Res 1990; 65: 1685-91. 4. Fu KK, Phillips TL, Silverberg IJ et al. Combined radi­otherapy and chemotherapy with bleomycin and meth­otrexate for advanced inoperable head and neck can­cer: update of Northern California oncology group ran­domized tria!. I Ciin Oncol 1987; 5: 1410-8. 5. Shanta V, Krishnamurti S. Combined therapy of oral cancer with bleomycin and radiation: a clinical tria!. Ciin Radio/ 1977; 28: 427-9. 6. Weissberg JB, Son YH, Papac RJ et al. Randomized clinical tria! of mitomycin C as an adjunct to radiother­apy in head and neck cancer. Int I Radiat Oncol Biol Phys 1989; 17: 3-9. 7. Vokes EE. Interactions of chemotherapy and radiation. Semin Oncol 1993; 20: 70-9. 8. Kennedy KA, Rockwell S, Sartorelli AC. Preferential activation of mitomycin C to cytotoxic metabolites by hypoxic tumor cells. Cancer Res 1980; 40: 2356-60. 9. Vokes EE, Weichselbaum RR. Concomitant chemora­diotherapy: rationale and clinical experience in patients with solid tumors. I Ciin Oncol 1990; 8: 911-34. 1 O. Dobrowsky W. Unconventional fractionation with or without mitomycin C in advanced head and neck can­cer. Semin Oncol 1992; 2: 45-7. 11. Dobrowsky W, Dobrowsky E, Rauth AM. Mode of interaction of 5-fluorouracil, radiation and mitomycin C: in vitro studies. Int I Radiat Oncol Biol Phys 1992; 22: 875-80. 12. Von der Maase H, Overgaard J. lnteractions of radia­tion and cancer chemotherapeutic drugs in a C3H mouse mammary carcinoma. Acta Radio/ Oncol 1985; 24: 181-7. 13. Miyamoto T, Takabe Y, Watanabe M, Terasima T. Ef­fectiveness of sequential combination ofbleomycin and mytomycin C on an advanced cervical cancer. Cwzcer 1978; 41: 403-14. 14. Rockwell S, Keyes SR, Sartorelli AC. Modulation of the antineoplastic efficacy of mitomycin C by dicou­marol in vivo. Cancer Chemother Pharmacol 1989; 24: 349-53. 15. Eschwege F, Sancho-Garnier H, Gerard JP. Ten-year results of randomized tria! comparing radiotherapy and concomitant bleomycin to radiotherapy alone in epi­dermoid carcinoma of the oropharynx: experience of the European Organization for Research and Treat­ment ofCancer. NCI Monogr 1988; 6: 275-8. Concomitant radiotherapy and mitomycin C with bleomycin in inoperable H. & N. cancer 16. Urade M, Sugi M, Mirna T. High induction of poly 17. Hait WN, Lazo JS, Chen DL, Gallichio VS, Filderman (ADP-ribose) polymerase activity in bleomycin re­AE. Antitumor and toxic effects of combination chem­sistant bela cells. Jpn J Cancer Res 1989; 80: 464-otherapy with bleomycin and anticalmodulin agent. J 8. Natl Cancer Inst 1988; 80: 246-50. Radio! Oncol 1997; 31: 178-80. Treatment of malignant tumors of the oral cavity -sta te of the art F. Waldfahrer and H. Iro Department oj Otorhinolaryngology, Head and Neck Surgery, Saarland University, Homburg, Germany In the past decades minimally invasive surgery and multimodal treatment strategies have gained in impor­tance in the treatment oj oral cancer as well as elsewhere. Within this concept, the primary tumor is resected enorally whenever possible, especially by carbon dioxide laser. The regional lymphatics are treated prejer­entially with junctional neck dissection, preserving the sternocleido-mastoid muscle, accessory nerve and interna[ jugular vein. As a part oj this multimodal treatment concept, percutaneous and interstitial radio­therapy was oj great significance. Interstitial radiotherapy with iridium-seeds in the region oj the (removed) primary tumor allows, on the one hand, local application oj a high radiation dose and, on the other, protection oj the surrounding tissues. The neck may be irradiated percutaneously, if necessary. By using this concept, extensive surgery with disfiguring dejects, impaired swallowing, speech and chewing, and the necessity oj reconstruction measures can be avoided in many cases with equally good treatment results and even improved quality oj lije. Tumours which cannot be resected by organ sparing surgery, will be treated by simultaneous radiochemotherapy. This report discusses the results oj treating oj 614 patients with oral cancer admitted to the Department oj Otolaryngology, Head and Neck Surgery, University Erlangen­NUremberg, during the period oj 1970 to 1994. Key words: mouth neoplasms-therapy; combined modality therapy Introduction Most common etiologic factors for oral cancer are abuse of alcohol and nicotine; recent epidemiologic data have demonstrated an increase in incidence in the last decades. The progress in oncology ali in ali has failed to demonstrate a significant improvement on survival of patients with oral cancer, since most patients ask for medica! help only just in advanced stages of the disease. In the past, a typical treatment of oral cancer was transcutaneous surgery with the resection of the primary tumour and the lymphatics of the neck "en bloc" (commando procedure,'). Therefore, of­ten the continuity of the mandible had to be inter- Correspondence to: Dr. F. Waldfahrer, Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University, D-66421 Homburg (Saar), Germany. rupted. The neck dissection was performed as a radical surgery method with resection of the sterno­cleidomastoid muscle, the interna! jugular vein and the accessory nerve. 1 These jaw-neck procedures either required mandibular reconstructions with ex­tensive flaps for covering the defects or resulted in disfiguring defects with severe functional impair­ment and loss of quality of life. The concept of organ sparing treatment with minimally invasive surgery tries to avoid percuta­neous or transmandibular surgical access to the pri­mary site and instead makes use of the natura! "entrance" through the oral cavity. The primary tumour is resected with high-frequency diathermic knives and needles and carbon dioxide laser.24 The neck is treated discontinously and, if possible, using functional, nerve and muscle sparing surgical techniques. 3 Postoperative radiotherapy proved to be espe­cially beneficial in stages III and IV of the disease. UDC: 616.31-006.6-08 If tumour resection seems unfeasible from the func­ Treatment ofmalignant tumors ofthe oral cavity-state ofthe art tional point of view, simultaneous chemoradiother­apy must nowadays be considered as the treatment policy of choice. We discuss the results in oral cancer treatment obtained in the last two decades, especially by comparing "functional" vs. "radical" therapy. Materials and methods Within a retrospective analysis, the records of all 506 patients, treated for oral cancer at the Depart­ment of Otorhinolaryngology, Head and Neck Sur­gery, University Erlangen, between 1970 and 1990, were reviewed. TNM classification was updated in accordance with the 4th edition. Follow-up 2 (WHO) on day 20, and CDDP was decreased to 75 mg/m2 if calculated creatinin clearance was between 50 and 75 ml/min. Chemotherapy was discontinued if clearance was lower than 50 ml/min or if hematological toxicity was Grade 3 or more by day 35. In both arms, the radiotherapy protocol planned to deliver 65-70 Gy in 6.5-7.5 weeks to the primary tumor, 65 Gy to clinically involved nodes, and 50 Gy to the remaining cervical and supraclavicular nodal area. The fractionation schedule used was five daily fractions of 2 Gy per week. The treatment was performed using photon beam of a 6°Co unit or a 4-5 Me V linear accelerator. The guidelines for irradiation of the primary site and upper cervical chain were as follows: two laterni opposed fields were used up to 42 Gy with an anterior limit of 2-3 cm in front of the pterygoid plane for T2 tumors and, depending on spread, for T3-T4; the inferior limit was above the margin of the hyoid bone; the posterior limit was generally a plane running be­hind the spina! apophysis; the upper limit for T2-T3 was the upper third of sphenoid sinus and above tumor spread to the base of the skull or intracranial for T4 tumors. After 42 Gy, the posterior limit was modified to exclude the spina! cord, and 28 Gy added using a reduced laterni photon fields. The Combined therapy of undifferentiated carcinoma of nasopha,yngeal type posterior fields were treated with 8 Gy if NO, and 23 Gy if palpable nodes were initially present, us­ing 8-10 Me V electron beams. The middle and inferior cervical nodes were treat­ed by an anterior cervical field using photon beams of 6°Co or 4-5 Me V unit and the