ADIOLOGY AND NCOLOGY June 2007 Vol. 41 No. 2 Ljubljana ISSN 1318-2099 ADIOLOGY AND NCOLOGY Editorial office Radiologij and Oncologij Institute of Oncology Zaloška 2 SI-1000 Ljubljana Slovenia Phone: +386 1 5879 369 Phone/Fax: +386 1 5879 434 E-mail: gsersa@onko-i.si Aims and scope ]une 2007 Vol. 41 No. 2 Pages 57-98 ISSN 1318-2099 UDC 616-006 CODEN: RONCEM Radiologij and Oncology is a journal devoted to publication of original contributions in diagnostic and interventional radiologij, computerized tomography, ultrasound, magnetic resonance, nuclear medicine, radiotherapy, clinical and experimental oncologij, radiobiology, radiophysics and radiation protection. Editor-in-Chief GregorSerša Ljubljana, Slovenia Executive Editor Viljem Kovac Ljubljana, Slovenia Editorial Board Karl H. Bohuslavizki Hamburg, Germany Maja Cemažar Ljubljana, Slovenia Christian Dittrich Vienna, Austria Metka Filipic Ljubljana, Slovenia Tullio Giraldi Trieste, Italy Maria G6deny Budapest, Hungary Vassil Hadjidekov Sofia, Bulgaria Marko Hocevar Ljubljana, Slovenia Maksimilijan Kadivec Ljubljana, Slovenia Deputy Editors AndrejCiir Ljubljana, Slovenia Igor Kocijancic Ljubljana, Slovenia Mikl6s Ktisler Budapest, Hungary Michael Kirschfink Heidelberg, Germany Janko Kos Ljubljana, Slovenia Tamara Lah 1l1rnšek Ljubljana, Slovenia Damijan Miklavcic Ljubljana, Slovenia LukaMilas Houston, USA Damir Miletic Rijeka, Croatia MajaOsmak Zagreb, Croatia Branko Palcic Vancouver, Canada Dušan Pavcnik Portland, USA Advisory Committee Geoffrey J Pilkington Portsmouth, UK Ervin B. Podgoršak Montreal, Canada Uroš Smrdel Ljubljana, Slovenia Primož Strojan Ljubljana, Slovenia Borut Štabuc Ljubljana, Slovenia Ranka Štern-Padovan Zagreb, Croatia Justin Teissie Tolouse, France Stindor Toth Oroshaza, Hungary Gillian M. Tozer Sheffield, UK Andrea Veronesi Aviano, Italy Branko Zakotnik Ljubljana, Slovenia Marija Auersperg Ljubljana, Slovenia; Tomaž Benulic Ljubljana, Slovenia; Jure Fettich Ljubljana; Valentin Fidler Ljubljana, Slovenia; Berta Jereb Ljubljana, Slovenia; Vladimir Jevtic Ljubljana, Slovenia; Stojan Plesnicar Ljubljana, Slovenia; Živa Zupancic Ljubljana, Slovenia Publisher Association of Radiologij and Oncology Affiliated with Slovenia11 Medica/ Association -Slovenian Association of Radiology, Nuc/ear Medicine Society, 5/ovenian Society far Radiotherapy and Oncologi;, and 5/ovenimz Cancer Society Croatian Medica/ Association -Croatian Society of Radiology Societas Radiologorum Hzmgarorum Friuli-Venezia Giulia regional groups of S.I.R.M. (Italian Society of Medica/ Radiology) Copyright © Radiology and Oncology. Ali rights reserved. Reader for English Vida Kološa Keywords Eva Klemencic Secretary Mira Klemencic Design Monika Fink-Serša Printed by Imprint d.o.o., Ljubljana, Slovenia Published quarterly in 600 copies Beneficiary name: DRUŠTVO RADIOLOGIJE IN ONKOLOGIJE Zaloška cesta 2, 1000 Ljubljana Slovenia Beneficiary bank account number: SI56 02010-0090006751 IBAN: SI56020100090006751 Our bank name: Nova Ljubljanska banka, d.d., Ljubljana, Trg republike 2, 1520 Ljubljana; Slovenia SWIFT: LJBASI2X Subscription fee far institutions EUR 100, individuals EUR 50 The publication of this journal is subsidized by the 5/ovenian Research Agency. Indexed and abstracted by: BIOMEDICINA SLOVENICA CHEMICAL ABSTRACTS EMBASE / Excerpta Medica Sci Base Scopus This journal is printed on acid-free paper Radiologi; and Oncology is available on lhe internet at: http:j /www.onko-i.si/radioloncol and http:j/www.versita.com ISSN 1581-3207 ADIOLOGY Ljubljana, Slovenia ISSN 1318-2099 June 2007 UDC 616-006 Vol. 41 No. 2 CODEN: RONCEM CONTENTS RADIOLOGY Mediastinitis and bilateral pleural empyema caused by an odontogenic infection Juretic M, Belusic-Gobic M, Kukuljan M, Cerovic R, Golubovic V, Gobic D 57 IMAGING IN CLINICAL MEDICINE Basal cell carcinoma on the left cheek Jancar B 63 ONCOLOGY Kidney cancer Rajer M 64 Case report from Mayo Clinic: Locally advanced Bartholin gland carcinoma Pinn ME, Austin LM, Sclwmas DA, Miller RC 72 Triple synchronous cancers: a medical and ethical problem Debevec L, Rok Cesar R, Kern I 80 Adenocarcinoma of the small bowel Šavli M, Jamar B 86 RADIOPHYSICS Functional form comparison between the population and the individual Poisson based TCP models Schinkel C, Stavreva N, Stavrev P, Car/one M, Fallone BG 90 SLOVENIAN ABSTRACTS I NOTICES VII Radiology and Oncology is covered in Biomedicina Slovenica, Chemical Absh'acts, EMBASE / Excerpta Medica, Sci Base and Scopus case report Mediastinitis and bilateral pleural empyema caused by an odontogenic infection Mirna Juretic1, Margita Belusic-Gobic1, Melita Kukuljan3, Robert Cerovic1, Vesna Golubovic2, David Gobic4 1Clinic for Oral and Maxillofacial Surgery, 2Clinic for Anaesthesiology and Reanimatology, 3Department of Radiology, 4Clinic for Internal Medicine, Clinical hospital, Rijeka, Croatia Background. Although odontogenic infections are relatively frequent in the general population, intrathoracic dissemination is a rare complication. Acute purulent mediastinitis, known as descending necrotizing mediastin­itis (DNM), causes high mortality rate, even up to 40%, despite high efficacy of antibiotic therapy and surgical interventions. In rare cases, unilateral or bilateral pleural empyema develops as a complication of DNM. Case report. This case report presents the treatment of a young, previously healthy patient with medias-tinitis and bilateral pleural empyema caused by an odontogenic infection. After a neck and pharynx re-inci­sion, and as CT confirmed propagation of the abscess to the thorax, thoracotomy was performed followed by CT-controlled thoracic drainage with continued antibiotic therapy. The patient was cured, although the recognition of these complications was relatively delayed. Conclusions. Early diagnosis of DNM can save the patient, so if this severe complication is suspected, thoracic CT should be performed. Key words: mediastinitis; empyema, pleural; periapical abscess – complications Introduction Acute suppurative mediastinitis is a life-threatening infection infrequently occur­ring as a result of the propagation of odontogenic infection, and is described as descending necrotizing mediastinitis (DNM). Pleural empyema is reported as a Received 25 May 2007 Accepted 18 June 2007 rare complication of acute mediastinitis.1-6 Clinical manifestations of mediastinitis are frequently nonspecific. If the diagnosis of mediastinitis is suspected, thoracic CT is required regardless of negative chest X-ray. In the treatment of advanced mediastinitis, administration of antibiotic therapy alone is ineffective unless aggressive surgical interventions including wide incisions, de­bridement, excision of necrotic tissue and drainage of all abscessed regions are in­cluded. Correspondence to: Belusic-Gobic Margita, MD, KBC A case of a young patient with mediastin- Rijeka, Department of Oral and Maxillofacial Surgery, itis and bilateral pleural empyema caused Tome Strižica 3, 51 000 Rijeka, Croatia; Phone/Fax: +385 51218279; E-mail: mfk@kbc-rijeka.hr by odontogenic infection is presented. Case report A previously healthy 23-year-old man presented to his dentist complaining of toothache in the region of the right man­dibular third molar. Root trepanation was performed and antibiotic therapy (amoxi­cillin) was initiated but the patient’s con­dition worsened with severe pain and 9th marked swelling. On the day after the occurrence of toothache, the patient was referred to the Clinic of maxillofacial and oral surgery. Physical examination revealed trismus, a firm swelling in the right submandibular and in a portion of supramandibular regions, oedema and ery­thema of retromolar mucosa. Due to an ex­tensive dental caries the crown of the tooth was completely destroyed. The patient was subfebrile to 37.5 0C, had dysphagia and slightly muffled voice. On admission to hospital, initial preoperative procedures were performed. Laboratory tests showed signs of inflammation: (WBC 12.6 x 109/ L, fibrinogen 9.09 g/l, CRP 18.9 mg/dL). Chest X-ray revealed no irregularities. The same evening under general endotracheal anaesthesia external incision was done by opening the submandibular triangle to the mandibular periost and to the buccal region, where purulent content was found to be less than expected. A larger amount of pus was obtained by a wide incision in the retromolar space. Ciprofloxacin 400 mg/12 h i.v. and metronidazole 500 mg/8 h were prescribed till the results of cultures were obtained. On the 1st postoperative day the patient’s condition improved sub­jectively, but he continued to be subfebrile, had dysphagia accompanied by sore throat and suppurative spit. Due to his private problems, he insisted on being discharged that same day. Four days later, the patient returned with worsened general condi­tion and local findings. He complained of severe buccal and retromolar pressure, had severe dysphagia and a muffled voice («hot potato voice»), productive cough, and temperature of 37.80C. Clinical ex­amination of the neck showed an infected induration also in the parotid region of the same side. Chest X-ray was again normal. Laboratory tests revealed further increase of leucocytes (25.0 x 109 / L) and CRP (28.2 mg / dL). The HIV test was negative. On the same day re-incision was performed extensively exploring the submandibultar triangle, parotid region, retromolar, retro-mandibular and pharyngeal spaces, and the infection-causing root of the lower third molar was extracted. The culture of the pus content indicated the presence of Streptococcus viridans and based on the antibiogram cefepime 2g /12 h i.v. was given. Two days after the second incision, tem­perature raised to 38.30C with severe pain below right rib arch, major dysphagia and cough. Neck ultrasound and CT were per­formed then which showed a large forma­tion of thick fluid content and gas distal from the a. carotis bifurcation bilaterally. The thoracic CT scan revealed equal path­ological formation in the mediastinum (Figures 1, 2). Emergency posterolateral left thoracoto-my through the fifth intercostal space was performed and about 550 cm3 of purulent material from the mediastinum was evacu­ated. Drains were placed, one in each of the three compartments of the mediastinum. During the same procedure wide incisions of the neck bilaterally were carried out, in­cluding the carotid spaces, suprasternal, parotid and parapharyngeal regions. Wide drains were placed on the neck bilaterally. The patient was transferred to the inten­sive care unit and attached to mechanical ventilation. Thromboprophylactic therapy was introduced and based on the cultures, 1 g / 12 h + amicacin sulphate 500 mg/12 h were given. In a few postoperative days, Radiol Oncol 2007; 41(2): 57-62. the patient was cardiocirculatory instable, with abnormal coagulogram, haematogram and hepatogram. Daily follow-up chest X-rays were performed, and on the 7th day after thoracotomy the follow-up chest X-ray showed lower transparency of lung lobes, indicating a follow-up thoracic CT was re­quired. The CT scan demonstrated enor­mous bilateral pleural empyemas, with a marked reduction in respiratory space and a paracardial purulence (Figure 3). Due to extremely worsened general con­dition of the patient, percutaneous bilat­eral thoracic CT-controlled drainage was performed, 1800 ml of pus was evacuated and a significant lung re-expansion was ob­tained. A suction drain was placed in each chest (Figure 4). Antibiotic therapy was changed to vanco­mycin 1g /12 h + metronidazole 500 mg / 8 h (based on the cultures of purulent material obtained by drains). The patient’s condition gradually improved. On the 22nd day after percutaneous drainage, chest drains were removed, and on the 25th day mechanical ventilation was removed. The patient was discharged from the intensive care unit after the total stay of 37 days, without any significant consequences except slightly muffled voice. Figure 4. CT of the thorax after drainage: bilateral Figure 3. CT of the thorax: bilateral pleural empyema. drains in the pleural space. Radiol Oncol 2007; 41(2): 57-62. Discussion This case demonstrates potentially disas­trous effects of odontogenic infections. DNM is a rare result of a dental infection, and even more infrequently, bilateral pleu­ral empyema develops as a complication of DNM.1,3-7 In the period 1990-2004, there were no cases of mediastinitis after oro-dental or oropharyngeal infection in our epidemiologic centre which covers the pop­ulation of about 400,000 people. Either due to a long period without serious complica­tions of odontogenic infections (although an average of 50 patients with odontogenic abscess are admitted to hospital annually), or because the young man was previously completely healthy without a history of any disease or addiction, and palpation of the neck did not show a larger induration and relatively low fever considering the severity of the condition, this complication was diagnosed with a delay, which some­times contributes to a high mortality rate of DNM. Estrere et al. report that one third of all cases of mediastinitis are diagnosed at post-mortem examination.8 Symptoms of cough, dysphagia and dyspnoea, swell­ing of the neck and upper part of the chest with crepitance indicate clinical manifesta­tions of mediastinitis, but these are late signs. Early diagnosis requires radiologic evaluation and CT is indispensable because clinical examination alone is reliable in on­ly 55% of cases. Besides, CT is beneficial in postoperative follow-up of DNM.1,6,9-12 The fact is that a delay in diagnosis of several days results in severe complications such as pyothorax, aortopulmonal fistula, sepsis, the erosion of the carotid artery or aorta, purulent pericarditis, DIC and multiple damages to the organs.13 Our patient de­veloped bilateral pleural empyema which is infrequently described as a complication of odontogenic DNM.1,3-5,7 Inadequate surgi­cal drainage can lead to deterioration of the patient’s general condition and can cause new infectious foci in residual abscesses. Therefore, the meticulous drainage of the abscess, coupled with antibiotics and .­globulin as supportive therapy.13,14 is man­datory. For minor infections, most authors recommend penicillin and metronidazole per os for 7 days as the first- line therapy in out-patients. For major infections, authors suggest penicillin G 4 million units every 6 h i.v. together with metronidazole 500 mg every 8 h i.v., and against gram- negative species additional gentamicin 3 mg/kg i.v. every 24 h.15,16,17 Maisel and Karlen rec­ommend simultaneous administration of the third generation of cephalosporin and clindamycin or metronidazole as initial an­timicrobial coverage until the results of the antibiogram are obtained.18 The approach to the drainage of mediasti­num remains a moot point. Nevertheless, in case of a massive infection transthoracic ap­proach is required.1,6,8,10,12,13,19 Posterolateral thoracotomy provides adequate drainage of all portions of the mediastinum, pleural cavity and pericardium. One of the issues is also to perform tracheostomy immediately or to leave a tracheal tube. Our patient had a tube during the whole treatment with me­chanical ventilation. Many authors prefer immediate tracheostomy in major cervical infections, to prevent the risk of additional intubations after accidental dislodgement of endotracheal tube in head movements. Other authors prefer intubation in all cases without respiratory impairment since open­ing of the airway by tracheostomy can re­sult in the propagation of infection to the lungs. Opening cervical fascia in tracheos­tomy exposes the patient to the contamina­tion of pretracheal space and to the risk of caudal spread of the infection to the medi­ astinum.6,8,12,19-22 According to the literature cervical in­fections are more common in immunosup­pressive patients8 but Mathieu at al.23 re- Radiol Oncol 2007; 41(2): 57-62. ported that 58% of cases necrotizing fascitis develop in previously healthy patients like in described case. Although DNM as a complication of den­tal infection is thought to be an infrequent clinical entity, according to Sakamoto et al., DNM strictly related to oral causes accounts for 60-70% of all reported cases.22 Usually it originates in the second or third mandibu­lar molar, which roots lie below the mylo­hyoid muscle providing the infection with a possibility of an immediate access to the submandibular space.8, 24, 25 In our patient, the third molar was involved. With a view to all this, in the case of the patient reported here, there were several pointers which indicated the possibility of this complication. Out- patient treatment in the dental office took some time with questionable need for trepanation of less valuable residual root of the third molar. Even on admission of the patient, the pre­senting clinical signs and laboratory find­ings should be followed by CT scan, which was delayed due to underestimation of the patient’s condition, although he was even­tually successfully managed. Conclusions Early diagnosis, aggressive drainage and antibiotic therapy with adequate postopera­tive care can save a patient with DNM, de­spite a high mortality rate of this disease. Therefore, practitioners who face cases of odontogenic infection must be aware of this severe complication even in previ­ously healthy patients, and together with adequate knowledge of this entity, must be able to recognize prodromal symptoms of the disease and if DNM is suspected to per­form CT examination. References 1. Balkan ME, Oktar GL, Oktar MA. Descending necrotizing mediastinitis: a case report and review of the literature. Int Surg 2001; 86: 62-6. 2. Izadi K, Lazow SK, Berger JR. Mediastinitis sec­ondary to an odontogenic infection. A case report. N Y State Dent J 2003; 69: 28-30. 3. Tung-Yiu W, Jehn-Shyun H, Ching-Hung C, Hung-An C. Cervical necrotizing fasciitis of odontogenic origin: a report of 11 cases. J Oral Maxillofac Surg 2000; 58: 1347-53. 4. Sobolewska E, Skokowski J, Jadezuk E. Pleural empyema as a complication of the descending necrotizing mediastinitis. Pneumonol Alergol Pol 1997; 65: 364-9. 5. Bonapart IE, Stevens HP, Kerver AJ, Rietveld AP. Rare complications of an odontogenic abscess: mediastinitis, thoracic empyema and cardiac tam-ponade. J Oral Maxillofac Surg 1995; 53: 610-3. 6. Biasotto M, Pellis T, Cadenaro M, Bevilacqua L, Berlot G, Di Leonarda R. Odontogenic infections and descending mediastinitis: case report and re­view of the literature. Int Dent J 2004; 54: 97-102. 7. Economopoulos GC, Scherzer HH, GryboskiWA. Successful management of mediastinitis, pleural empyema, and aortopulmonary fistula from odon­togenic infection. Ann Thorac Surg 1983; 35: 184-7. 8. Estrera AS, Landay MJ, Grisham JM, Sinn DP, Platt MR. Descending necrotizing mediastinitis. Surg Gynecol Obstet 1983; 157: 545-52. 9. Miller WD, Furst IM, Sandor GK, Keller A. A pro­spective blinded comparison of clinical exam and computed tomography in deep neck infections. Laryngoscope 1999; 109: 1873-9. 10. Tsunoda R, Suda S, Fukaya T, Saito K. Descending necrotizing mediastinitis caused by an odontogen­ic infection: a case report. J Oral Maxillofac Surg 2000; 58: 240-2. 11. Garcia-Consuegra L, Junquera-Gutierrez L, Albertos-Castro JM, Llorente-Pendas S. Descending necrootizing mediastinitis caused by odontogenic infections. Rev Stomatol Chir Maxillofac 1998; 99: 199-202. 12. Marty-Ane CH, Alauzen M, Alric P, Serres-Cousine O, Mary H. Descending necrotizing mediastinitis: avantage of mediastinal drainage with thoracoto-my. J Thorac Cardiovasc Surg 1994; 107: 55-61. Radiol Oncol 2007; 41(2): 57-62. 13. Iyoda A, Yusa T, Fujisawa T, Mabashi T, Hiroshima K, Ohwada H. Descending necrotizing mediastini-tis: report of a case. Surg Today 1999; 29: 1209-12. 14. Labriola JD, Mascaro J, Alpert B. The microbio-logic flora of orofacial abscesses. J Oral Maxillofac Surg 1983; 41: 711-4. 15. Pynn BR, Sands T, Pharoah MJ. Odontogenic infections: Part one. Anatomy and radiology. Oral Health 1995; 85: 7-10, 13-4, 17-8. 16. Sands T, Pynn BR, Katsikeris N. Odontogenic infections: Part two. Microbiology, antibiotics and management. Oral Health 1995; 85: 11-4, 17-23. 17. Sandor GK, Low DE, Judd PL, Davidson RJ. Antimicrobial treatment options in the manage­ment of odontogenic infections. J Can Dent Assoc 1998; 64: 508-14. 18. Maisel RH, Karlen R. Cervical necrotising fascitis. Laryngoscope 1994; 104: 795-8. 19. Wheatley MJ, Stirling MC, Kirsh MM, Gago O, Orringer MB. Descending necrotizing medias-tinitis: transcervical drainage is not enough. Ann Thorac Surg 1990; 49: 780-4. 20. Brunelli A, Sabbatini A, Catalini G, Fianchini A. Descending necrotizing mediastinitis. Surgical drainage and tracheostomy. Arch Otolaryngol Head Neck Surg 1996; 122: 1326-9. 21. Cordero L, Torre W, Freire D. Descending necro­tizing mediastinitis and respiratory distress syn­drome treated by aggressive surgical treatment. J Cardiovasc Surg 1996; 37: 87-8. 22. Sakamoto H, Aoki T, Kise Y, Watanabe D, Sasaki J. Descending necrotising mediastinitis due to odontogenic infections. Oral Surg Oral Med Oral Path Radiol Endod 2000; 89: 412-9. 23. Mathieu D, Neviere R, Teillon C, Chagnon JL, Lebleu N, Wattel F. Cervical necrotizing fasci-tis: clinical manifestations and management. Clin Infect Dis 1995; 21: 51-6. 24. Sugata T, Fujita Y, Myoken Y, Fujioka Y. Cervical cellulitis with mediastinitis from an odontogenic infection complicated by diabetes mellitus: report of a case. J Oral Maxillofac Surg 1997; 55: 864-9. 25. Rubin MM, Cozzi GM. Fatal necrotizing medias-tinitis as a complication of an odontogenic infec­tion. J Oral Maxillofac Surg 1987; 45: 529-33. Radiol Oncol 2007; 41(2): 57-62. images in clinical medicine Basal cell carcinoma on the left cheek Boris Jancar Department of Radiation Oncology, Institute of Oncology, Ljubljana, Slovenia A 91-year-old female patient was treated with irradiation for histologically confirmed basal cell carcinoma on the left cheek. The tumour, measuring 3 x 3 cm, with the depth of 2 cm, was extending up to the lower lid Received 12 April 2007 Accepted 19 April 2007 Correspondence to: Prim. Boris Jancar, MD, MSc, Department of Radiation Oncology, Institute of Oncology Ljubljana, Zaloška 2, Ljubljana, Slovenia; Phone; + 386 1 5879 295; Fax: + 386 1 5879 295; E-mail: bojancar@onko-i.si of the left eye (Figure1). Due to old age and poor physical condition, the patient was irradiated once a week in altogether three treatment sessions. She received a total equivalent dose of 70 Gy. On the fol- low-up control performed 9 months after the completed radiotherapy, it was noted that the tumour regressed completely. The photo was taken 21 months after irradia­tion (Figure 2). The patient died from heart failure at the age of 94 years, 29 months after the com­pleted therapy. At the time of her death, no recurrence of basalioma was observed. Kidney cancer Mirjana Rajer Department of Radiotherapy, Institute of Oncology Ljubljana, Slovenia Background. The purpose of this paper is to present the epidemiology, diagnostic workup and treatment of renal cell carcinoma (RCC) with an emphasis on the Slovenian epidemiological data. RCC represents 2% of all cancers and is the third most common genitourinary tract tumour. It most frequently occurs among people of ages, between 50 and 60 years. Male patients are more prone to it than female. A number of environmental, occupational and genetic factors have been found to be associated with the development of RCC. Patients often have nonspecific symptoms and this is the reason why for half of them the disease is already metastatic when diagnosed. The most common sites of metastases are lungs (75%), followed by soft tissues (36%), bones (20%), liver (18%), skin (8%) and central nerve system (8%). In the evaluation of RCC multiple diagnostic procedures are needed with obligatory image diagnostics. Conclusions. Radical nephrectomy is still the mainstream treatment of localized disease. Nephron sparing techniques have been used in cases, where radical operation would result in an anephric patient. Efficient adjuvant therapy has not been discovered yet. Until recently interpherone and interleukin were the only known effective treatments for metastatic disease, but now new and more efficient biologic agents are being discovered. The most important prognostic factor for survival is stage at the beginning of treatment. The 5-year survival rate is 95% for patients with stage I disease, 88% for stage II, 59% for stage III and 20% for stage IV. Key words: carcinoma, renal cell – epidemiology – diagnosis – therapy; nephrectomy; survival analysis Epidemiology General notes Renal cell carcinoma RCC (e.g. hyperneph­roma, Grawitz’s tumour) accounts for ap- Received 3 May 2007 Accepted 18 May 2007 Correspondence to: Mirjana Rajer, MD, Department of Radiotherapy, Institute of Oncology Ljubljana, Zaloška 2, 1000 Ljubljana, Slovenia; Phone: + 386 41 26 99 46; Fax.: + 386 1 587 9 400; E-mail: mrajer@ onko-i.si proximately 2% of all cancers. It is the third most common genitourinary cancer. The other two are prostatic and bladder cancer.1 Over the past 65 years its incidence has been constantly growing with an annual rate of 2-4%.2,3,4 The reason for this rise is unknown.3 This type of cancer is more common among people of age between fifty and seventy years. Male patients are more prone to it than female patients.2 The ratio male to female patients is 1.5 : 1.3,4 People in urban environments a have higher inci­dence of RCC than those in rural.4 Figure 1. Newly diagnosed urinary tract tumors by site (1984-2003). Slovenian epidemiological data Data from the Cancer registry of Slovenia show that in the past twenty years the number of kidney cancers has been con­stantly rising as has the number of bladder cancers, while the number of newly diag­nosed tumours of renal pelvis and urether remained approximately the same during this period (Figure 1).5 In the year 2003 there were 9997 newly diagnosed cancers in Slovenia (5026 of them among men and 4971 among women). In the same year the number of new cases of renal cancer was 193 (121 male patients and 72 female). Incidence for 2003 was 12,4 for males and 0,7 for females. Figure 2 shows the number of new renal cancers by gender. 5 Renal cancer is the tenth most common cancer among Slovenian males and ac­counts for 2.4% of all male cancers. Others, in order by incidence, are: lung cancer, colorectal cancer, prostate cancer, head and neck cancer, melanoma, bladder and pan­creatic cancer. Kidney cancer is not among the ten most frequent cancers in females, which are: breast cancer, cancer of the skin, colorectal cancer, cancer of the uterus, lung cancer, cervical cancer, stomach can­cer, ovarian cancer, melanoma and non Hodgkin lymphoma.5 The average age at diagnosis is 55 to 60 years and the ratio of the male to female patients is 1 : 1.5,5 which is the same as the general average reported in litera­ture.3,4 Radiol Oncol 2007; 41(2): 64-71. Figure 2. Number of newly diagnosed kidney cancers by gender (1984-2003). Risk factors A number of risk factors have been associ­ated with RCC.1 One of the most important is tobacco use. It is estimated that 30% of RCC in men and 24% in women are associ­ated with smoking.4 Exposure to some envi­ronmental factors can also lead to the devel­opment of RCC. These factors are exposure to cadmium, thorium dioxide, asbestos and petroleum products. People in certain pro­fessions are more at risk (e.g. leather tan­ners, shoe workers and asbestos workers). Other risk factors are hypertension, obesity, and long term use of analgesics, particularly those containing phenacetin.1,2 A special group of patients are those with end stage renal disease. These patients have a 100-fold greater incidence of RCC which is associated with development of acquired polycystic disease and the hyperplasia of the epithelium in these cysts.4 The relation between these factors and the development of RCC is weak, so that primary prevention seems to be quite inef­fective. An effective screening system has not been developed yet, because of the rela­tively low incidence of RCC and the lack of simple diagnostic procedures.2 RCC occurs in sporadic and hereditary form. The most studied form of heredi­tary RCC occurs as a part of von Hippel-Lindau syndrome (VHL). VHL syndrome is a hereditary cancer syndrome caused by a mutation of the VHL gene. Affected individuals are at risk of developing tu- Radiol Oncol 2007; 41(2): 64-71. mours in a number of organs including the kidney.3,4 As many as 28-45% people with von Hippel-Lindau disease develop RCC.1 In hereditary syndromes, people are af­fected at a younger age and tumours tend to be bilateral. More renal cancer occurs among people with autosomal dominant polycystic kidney disease and with tuber­ous sclerosis.4 Natural history RCC may spread by local infiltration trough the renal capsule to involve the perinephric fat and Gerota’s fascia or may grow directly into the renal vein (21% of cases) or vena cava (4% of cases). Lymph node metastases are most often found in the renal hilar, paraaortic and paracaval nodes.1 At the time of diagnosis, the disease is lo­calized in 45% of patients, locally advanced in 25% of patients and metastatic in 30% of patients.1,4 About half of patients with RCC develop metastases some time in the course of the disease. The most common site of metastases are the lungs (75%), followed by soft tissues (36%), bones (20%) liver (18%), skin (8%) and CNS (8%).1 Spontaneous regression of the tumour has been reported. The reason is probably immunogenic. The same phenomenon was observed with metastases after nephrecto-my. The enthusiasm vanished when the re­view of literature showed that less than 1% of the patients experience it. This is the rea­son why nephrectomy is not recommended for this purpose any more.1,4 Pathologic classification RCC is a tumour of the renal cells which develops from the proximal renal tubular epithelium.4 The most common histologi­cal diagnosis is clear cell carcinoma which represents 85% of tumours.3,4 Others are: papillary carcinoma (10%), chromofobic carcinoma (5%), carcinoma of Belliniy’s duct (<1%) and the extremely rare carci­noma of medullary cells.2,3 Presentation For almost half of patients the disease is advanced at the time of diagnosis. Most of them have some nonspecific symptoms like fatigue, weakness, nausea, night sweating and fever.2,3 The classical triad which con­sists of flank mass, haematuria and pain in the lumbal area is rare, present only in the 1-5% of patients. It is a sign of advanced disease.2,3 The most frequent symptom is either gross or microscopic haematuria.1 In some cases a large tumour growth has been reported. Such tumours can grow to the retroperitoneum without causing any symptoms.4 Lately more and more RCC are being discovered incidentally, while patients have some form of radiological diagnostic proce­dure. These tumours have a better prognosis because of the lower stage at detection.1-4 Less frequently patients present with signs or symptoms resulting from a meta­static disease, like bone pain and pulmo­nary symptoms.3 One of the most common signs is ane­mia due to haematuria or haemolysis. It has been observed in 30-88% of patients with RCC. Other signs are polycitemia, nonmet­astatic hepatic dysfunction and acquired dysfibrinogenemia.4 RCC can also cause paraneoplastic symp­toms. A lot of substances have been detect­ed at an elevated concentration in patients with RCC: parathyroide like hormones, erythropoietin, rennin, gonadotropins, pla­cental lactogen, prolactin, enteroglucagon, insulinlike hormones, adrenocorticotropic hormone and prostaglandins.1 Radiol Oncol 2007; 41(2): 64-71. Diagnostic workup Image diagnostics is a part of the initial workup. Beside ultrasound examination, the mostly recommended are CT (with and without the contrast) or MRI of the abdomen and pelvis. CT is a very good method for the assessment of the lymph node status. The use of CT contrast has improved its sensitivity in detecting very small tumours. MRI is preferred to CT in cases where involvement of the inferior vena cava is suspected or instead of the CT when there are contraindications to the ad­ministration of the contrast material. When there is suspicion of the involvement of the inferior vena cava, an US with colour flow Doppler should be performed to determine the position of the tumour thrombus and to help the surgeon with the surgery plan­ning.3,4 US has replaced the previously used venacavography. Sometimes other studies are needed to asses the tumour, like intravenous pyelogram, renal arteriogram and cyst puncture with fluid cytology.1 For the optimal staging and planning of the surgery multiple diagnostic procedures are recommended.4 Imaging of the chest, either CT or radiog­raphy should be performed for assessment of the stage of disease.3 When a patient complains of bone pain or has an elevated serum alkaline phosphatase, the suggested test is a bone scan which is not performed routinely otherwise. The same holds for the CT or MRI of the brain, which is to be per­formed if brain metastases are suspected. PET is not considered as a routine diagnos­tic procedure.3 Treatment Treatment of localized disease Surgical treatment is considered the only effective treatment for the localized dis­ease. The preferred operation is a radical nephrectomy which consists of removal of the kidney, perirenal fat, regional lymph nodes and ipsilateral adrenal gland. The removal of the regional lymph nodes is not a therapeutic procedure, but is being performed for staging purposes. Patients, who have metastases at their lymph nodes, tend to sub sequentially relapse with a distant metastases despite lymphadenec­tomy.3,6 Nephron sparing surgery (NSS) was originally considered only when radical op­eration would result in a patient requiring dialysis, such situations are:3 - RCC in a solitary kidney, - Bilateral synchronous RCC, - RCC in one kidney and inadequate functioning of the other. Recently NSS gained a role in the treat­ment of small tumours (less than 7 cm in diameter) with equivalent results to the radical nephrectomy. Not all tumours are appropriate for NSS, but only those in the upper or lower pole and in the peripheral location.3 After surgical treatment 20-30% of pa­tients experience a relapse, most commonly in the lungs. The median time to relapse is 1-2 years after surgery. Time to relapse is associated with the length of survival after the relapse.3 Adjuvant systemic treatment proved not to be effective and the same holds for ad-juvant radiation therapy. Patients, to whom adjuvant radiation therapy has been admin­istered, did not have a better survival or lo-coregional disease control compared to the non-irradiated patients despite characteris­tics which in other cancers require adjuvant radiotherapy. These are: incomplete tumour resection or metastatic lymph nodes found at the operation. This leads to the conclu­sion that after the nephrectomy observa­tion of the patients is the only reasonable option.3 Radiol Oncol 2007; 41(2): 64-71. Treatment of advanced disease Advanced disease (stage IV) is incurable and the intent of therapeutic proceedings is to prolong life, to reduce patient’s symp­toms and to improve the quality of life.3 Patients with resectable RCC and a soli­tary resectable metastasis are candidates for nephrectomy and metastasectomy. This holds for patients with synchronous discov­ery of NCC and metastatic site and also for the patients who develop metastases after neprhrectomy. Sites of metastases which are amenable for such management are bone, brain and lung. Most patients treated with metastasectomy experience a relapse at some time. However, some long disease free intervals have been detected.3 Some patients with metastatic disease benefit from cytoreductive surgery before the start of chemotherapy. These are pa­tients with lung metastasis only, patients with a good performance status and those with good prognostic features.3 Kidney cancer is one of the few cancers in which systemic chemotherapy and hor­monal therapy do not have a substantial benefit. The reason for this seems to be a big expression of the p glycoprotein. This is a protein in the membrane of the renal tu­bules and renal cancer. The function of this protein is to expel toxic lypofilic substances from the cell, and only those chemothera­peutics that are not the substrate for this glycoprotein, have some effect.2 Until recently the only effective systemic treatment was with interferone-a or IL-2. In both of these drugs the response rate is 30%, the median survival is 13 and 12 months respectively. These drugs have sub­stantial undesirably side effects, which can be acute or chronic.2 Recently the FDA (Food and drug admin­istration) approved 2 kinase inhibitors su­nitinib and sorafenib for the treatment of metastatic RCC. Escudier et al. presented the results of a phase III study with soraf­enib. Patients who progressed on the im­munotherapy were randomized into two groups, those who received sorafenib and placebo. Progression free survival was 24 versus 12 weeks. Some degree of response was observed in 78% of the patients. Good response rates were also observed with the administration of sunitinib. Motzer et al. reported a 40% partial response rate, when sunitinib was administered as a second line treatment after patients progressed on the cytokine therapy. In another study patient were randomized to receive either a su­nitinib or IFN-a as a first line therapy for methastatic disease. The median progres­sion free survival was 47.3 in the sunitinib group and 24,9 weeks in the IFN group and the objective response rates were 35,7% and 8,8%.3 Other patients not suitable for the sys­temic therapy require a good palliative care which should include good pain manage­ment, and some of the procedures like ra­diation of painful methastatic sites or pal­liative nephrectomy in the cases of severe haematuria.3 Survival and prognostic factors Survival of patients differs according to the initial stage of the disease which is the most important prognostic factor.2 Patients who have tumours confined to the kidney, have much better prognosis than those with lo­cally advanced or methastatic disease at the time of diagnosis. Table 1 presents 5-years survival rates in different stages of the disease.1,4 Metastatic disease is incurable and the duration of survival depends on the number and site of metastases.2 Patients who have bone and CNS metastases, have a shorter survival time than patients with other met­astatic sites. Other factors that influence (shorten) the survival are: Radiol Oncol 2007; 41(2): 64-71. Table 1. 5-year survival of patients with RCC according to stage of the disease Trial Total No. Stage I Stage II Stage III Stage IV of patients 5-years survival rate Robson 88 66 64 42 11 Skinner 309 65 47 51 8 Waters 130 51 59 12 0 Boxer not known 56 100 50 8 McNichols 506 67 51 34 13 Cherrie not known not known not known 50 0 Selli 115 93 63 80 13 Bassil not known 91-100 not known not known 18 Golimbu 326 88 67 40 2 Javidan 381 95 80 59 20 Dinney 314 73 68 51 20 Guinan 337 100 96 59 13 Kinouchi 350 96 95 70 24 Tsui 643 91 74 67 32 - bad patient performance status - high degree of weight loss - short disease free interval from the begin­ ning of the treatment to the manifestation of metastases and - some laboratory findings like high LDH values or low haemoglobin level.2,4 Another prognostic factor is the grade of the tumour. As expected tumours of the lower grade have a better prognosis.2,3 Incidentally found tumours have a gener­ally better prognosis as they are being dis­covered at a lower stage. Five year survival rate of these patients is close to 100%.1 Conclusions Survival statistics for RCC have not changed for the last 25 years. This is due to the fact Radiol Oncol 2007; 41(2): 64-71. that an effective adjuvant therapy for the locoregional disease has not been discov­ered yet, and that until recently there were only few possibilities of an effective systemic treatment for metastatic disease.1 With the progression in diagnostics, sur­gery, new radiotherapy techniques and the discovery of the new biological therapies which are more effective and less toxic, ma­jor changes of the therapeutic results are expected. In spite of this, RCC still remains a big challenge for future research. References 1. Michalski JM. Urinary tract tumors. In: Perez CA, Brady LW, Halperin EC, Schmidt- Ulrich RK, editors. Principles and practice of Radiation oncology 4th edition. Philadelphia: Lippincott Williams & Wilkins; 2004. p. 1649-63. 2. Cufer T. Rak ledvic. Onkologija 2005; 9: 76-9. 3. Motzer RJ, Bolger GB, Boston B, Carducci MA, Fishman M, Hancoc SL, et al. NCCN Clinical Pracitce guidlines in Oncology: Kidney cancer; 2007. 4. DeVita TV, Hellman S, Rosenberg AS, editors. Principles and practice of Oncology 7th edition. Philadelphia: Lippincott Williams & Wilkins; 2005. 5. Cancer incidence in Slovenia 2003. Ljubljana: Institute of Oncology, Cancer registry of Slovenia; 2006. 6. Cohen HT, McGovern FJ. Renal-cell carcinoma. N Engl J Med 2005; 353: 2477-90. Radiol Oncol 2007; 41(2): 64-71. case report Case report from Mayo Clinic: Locally advanced Bartholin gland carcinoma Melva E. Pinn*, Laura M. Austin*, David A. Schomas, Robert C. Miller Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA Tumors of the Bartholin gland are rare, comprising less than 5% of all vulvar malignancies. Treatment is largely based on that of vulvar and anal squamous cell carcinomas. A case of invasive, grade 4, poorly dif­ferentiated squamous cell carcinoma of the Bartholin gland is presented. Our patient, a 47-year-old woman, had a history significant for cervical intraepithelial neoplasia treated with conization, type 2 diabetes mellitus, and tobacco use. The course of treatment included preoperative radiotherapy plus 5-fluorouracil and cisplatin chemotherapy, followed by restaging and posterior exenteration in combination with vaginal reconstruction. Key words: vulvar neoplasms – radiotherapy – drug therapy – surgery – Bartholin gland Introduction Case Report Accounting for less than 5% of all vulvar malignancies, primary carcinoma of the Bartholin gland is rare. Cancers arising in the Bartholin duct are most commonly adenocarcinomas or squamous cell carcino­mas; occasionally transitional cell, adeno-squamous, and adenoid cystic carcinomas may develop. A case of locally advanced Bartholin gland carcinoma was seen re­cently at Mayo Clinic. Received 6 June 2007 Accepted 23 June 2007 *Visiting medical students at the Department of Radiation Oncology. Correspondence to: Robert C. Miller, MD, MS, Division of Radiation Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail: miller. robert@mayo.edu. A 47-year-old woman first noted a lump in the region of the introitus and labia majora in February 2006 and was evaluated by her local gynecologist. Her only symptom, other than mass effect, was minor constipation. On examination under anesthesia, the patient was found to have a 5- to 7-cm by 7­cm mass that was believed clinically to arise from the region of the left-sided Bartholin duct. It was located anterior to the rectum and posterior and lateral to the vagina and extended to the region of the rectal sphinc­ter. There was no involvement of the vulva, vaginal mucosa, or cervix on physical ex­amination. A 2-cm mass was palpable in the left groin. The patient underwent an extensive multimodality and multispecialty evalua­tion. Magnetic resonance imaging showed a 5.1×3.8×4.5-cm lobu-lated enhancing mass arising between the va­gina and rectum which appeared to encase the anterior and left lat­eral walls of the rectum (Figure 1). Perirectal lymph nodes of up to 1.6 cm were noted, as was a 2.0×1.5-cm en­hancing lymph node in the left inguinal region, consistent with meta­static disease. Compu­ted tomography (CT), chest radiography, and positron emission tom­ography (PET)/CT indi- Figure 2. Lateral 18fluorodeoxyglucose (FDG)–positron emission tomography. A, Image before treatment. Arrows show location of the left inguinal nodal metastases superiorly and primary tumor inferiorly. B, Image 1 month after radiotherapy and chemotherapy showing a complete response by FDG signal. Radiol Oncol 2007; 41(2): 72-79. Table 1. Intensity-Modulated Radiotherapy Prescription Tumor dose Description Normal tissue constraints PTV 51.25 Gy in 2.05-Gy fractions Gross tumor volume (including primary tumor, gross perirectal adenopathy, and gross inguinal adenopathy) + 13- to 15-mm margin Bladder V51.25Gy <2% V40Gy <30% PTV 45.00 Gy in 1.80-Gy fractions Radiographically uninvolved pelvis (excluding bladder and small bowel) and presacrum below the level of the bifurcation of the iliac vessels, and bilateral inguinal and external iliac lymph nodes Small bowel V51.25Gy <2% V45Gy <15% V30Gy <20% PTV 42.50 Gy in 1.70-Gy fractions Common iliacs and presacrum to the mid L5 level Perineum V52Gy <2% V20Gy <20% Femoral heads V45Gy <2% V35Gy <20% Uterus (used as an avoidance structure to conform dose to pelvis and nodal structures) V51.25Gy <2% V40Gy <30% PTV, planning target volume; V, volume. cated no evidence of distant metastases (Figure 2 A). Endoscopic ultrasonography showed numerous abnormal perirectal nodes that were round and echopoor and measured from a few millimeters to 1.2 cm in diameter. The tumor involved the anterior portion of the anal sphincter mechanism. Transrectal biopsy of the primary tumor in February 2006 indicated invasive, grade 4 (of 4), poorly differentiated squamous cell carcinoma. The neoplastic cells were strongly reactive for CK7 and showed nor­mal staining for MLH1, MSH2, MSH6, and PMS2. The tumor lacked staining for CK20, CDX2, and estrogen receptor. The patient’s medical history was signifi­cant for cervical intraepithelial neoplasia treated with cervical conization in 1981. Additionally, the patient had a history of tobacco use and type 2 diabetes mellitus controlled with oral medications. She had never received radiotherapy or chemother­apy. The departments of radiation oncology, medical oncology, gynecologic surgery, and gastroenterology were consulted regarding treatment; it was believed that the optimal course of treatment would involve preop­erative radiotherapy and 5-fluorouracil (5­FU) and cisplatin chemotherapy, followed by restaging and posterior exenteration in combination with vaginal reconstruction. In March 2006, the patient began con­current chemotherapy and intensity-modu­lated radiotherapy (IMRT) to a total dose of 51.25 Gy in 25 fractions to regions of gross Radiol Oncol 2007; 41(2): 72-79. Figure 3. Intensity-modulated radiotherapy isodose curves showing relative sparing of the perineum (A) and sparing of the bladder and central pelvis (B). (Planning target volume [PTV] 45.00 Gy and femur volumes deleted for clarity of illustration.) GTV, gross tumor volume. Radiol Oncol 2007; 41(2): 72-79. tumor, with margins involving the Bartholin gland region and the perirectal and left in­guinal adenopathy. IMRT was delivered with 6-MV photons after a CT simulation of the patient in a supine, frog-legged position with a full bladder. Full technical details of the IMRT prescription are shown in Table 1. All 3 planning target volume (PTV) dose levels were treated simultaneously (Figure 3). The patient received 2 cycles of cisplatin and 5-FU chemotherapy intravenously over 4 days in weeks 1 and 4 of radiotherapy. Cisplatin was given at 75 mg/m2 on day 1 of each chemotherapy cycle, and 5-FU, by ambulatory continuous venous infusion over days 1 through 4 at 225 mg/m2 per day. The patient had radiation toxicity (by the Common Terminology Criteria for Adverse Events v3.0) consisting of grade 3 dermati­tis, grade 2 leukopenia, grade 2 dysuria and frequency, and grade 3 enteritis and proc­titis. She was able to complete the prescribed course of radiotherapy and chemotherapy within 32 days total time, despite the acute toxicity. The patient returned for re-evalu­ation approximately 4 weeks after comple­tion of radiotherapy and chemotherapy, at which time the acute toxicity had resolved. Physical examination showed complete resolution of the primary tumor, and pel­vic examination showed no evidence of ab­normalities. A PET/CT study indicated no 18fluorodeoxyglucose uptake at the site of the primary tumor and lymph nodes, no ev­idence of the left inguinal adenopathy, and near resolution of the primary tumor and perirectal lymphadenopathy by PET tracer uptake (Figure 2 B). The patient then underwent posterior ex-enteration and vaginal reconstruction with a vertical rectus abdominis muscle flap. Pathologic review of the resected specimen showed no residual tumor. An ill-defined submucosal mass was seen in the region of the anterior rectal wall showing fibrosis and histiocytic inflammation but no evidence of tumor. Nine lymph nodes were negative for tumor. The groin was not dissected at the time of surgery. The patient returned for re-evaluation 5 months after surgery. Her postopera­tive course had been unremarkable. She reported no pain or gastrointestinal tract, skin, or genitourinary symptoms. Physical examination showed no evidence of recur­rent tumor, in either the groin or the pelvis. No lower extremity edema was present. CT performed 1 month after surgery showed no evidence of pathologic processes other than postoperative changes associated with the resection and muscle flap. She will undergo re-examination in our clinic approximately every 12 weeks for 2 years, then every 6 months for 3 years, and yearly thereafter. Discussion The incidence of Bartholin gland tumors is highest among women in their 60s, with the median age of diagnosis being 57 years. Most patients with a Bartholin gland malignancy do not have a history of other Bartholin gland disorders. Bartholin gland enlargement in a postmenopausal woman should raise suspicions of malignancy be­cause benign inflammatory disease typi­cally does not occur in this age group. A biopsy should be performed for any abnor­mal growth of the Bartholin gland if the patient is older than 40 years. The differential diagnosis for a Bartholin gland tumor most commonly includes cysts and abscesses, which occur in 2% of women, and other vulvovaginal disorders, such as vulvar carcinoma, acrochordons, hidradenomas, other dermatoses, and con-dyloma acuminata. The Bartholin gland is composed of columnar epithelium, and the ducts are lined by stratified squamous epithelium, which changes to transitional Radiol Oncol 2007; 41(2): 72-79. cell epithelium toward the terminal ducts. Squamous cell carcinoma is the only lesion of the Bartholin gland linked to human pap-illomavirus. Metastases are common as a result of the copious supply of vascular and lymphatic networks in the area. The most common presentation of a Bartholin gland carcinoma is a painless vulvar mass.1,2 Few data are available on the associated treatment of Bartholin gland carcinoma; such treatment is largely based on that of vulvar and anal squamous cell carcino­mas. No large randomized controlled trials have been published on the treatment of advanced vulvar cancer. Moore et al. 3 re­ported a phase II study by the Gynecologic Oncology Group examining the use of pre­operative chemoradiotherapy to avert the need for more radical surgery. In this study, 73 evaluable patients with clinical stage III­IV squamous cell vulvar carcinoma were treated with a planned split course: twice-daily concurrent cisplatin (50 mg/m2) and 5-FU (1,000 mg/m2) on days 1 through 4 and radiotherapy (to 47.6 Gy), followed by surgical excision of the residual primary tumor plus bilateral inguinofemoral lymph node dissection. A total of 33 patients had no visible vulvar cancer after combined chemoradiotherapy.3 The authors conclud­ed that preoperative chemoradiotherapy in advanced squamous cell carcinoma of the vulva is feasible and may decrease the need for more radical surgery.3 In another study, Han et al. 4 concluded that concur­rent chemoradiotherapy as primary treat­ment for locally advanced vulvar cancer decreases local relapse rate and improves disease-specific and overall survival versus radiotherapy alone. Unlike vulvar cancers, treatment of anal cancer has been evaluated in several rand­omized controlled trials. At one time, ab-dominoperineal resection was considered the treatment of choice for anal cancer.5 However, the standard of care has since be­come infusion chemotherapy with 5-FU and mitomycin C (MMC) along with radiothera­py (45-50 Gy). Surgery is now reserved as a last resort.5 A phase III randomized control­led trial assigned 110 patients to either de­finitive radiotherapy alone or radiotherapy combined with 5-FU/MMC.6 The patients received 45 Gy given in 5 weeks, followed by a 6-week rest period and then a 15- to 20-Gy boost to a total dose of 60 to 65 Gy. The chemotherapy regimen consisted of 750 mg/m2 of 5-FU on days 1 through 5 and 29 through 33 and a single dose of MMC (15 mg/m2) on day 1. Concurrent 5-FU/MMC with radiotherapy significantly improved the locoregional control rate and signifi­cantly decreased the need for colostomy.6 A study by the UK Co-ordinating Committee on Cancer Research had a simi­lar design; 585 patients were randomly as­signed to 45 Gy over 4 to 5 weeks alone or combined with chemotherapy (5-FU [1,000 mg/m2 for 4 days or 750 mg/m2 for 5 days by continuous infusion] during the first and final weeks of therapy and MMC [12 mg/ m2] on day 1).7 The combined chemother­apy and radiotherapy arm had a significant increase in local control rate. The authors concluded that standard treatment for anal cancer should be a combination of radio­therapy and infusion of 5-FU and MMC.7 A phase III randomized trial reported by Flam et al. 8 aimed to determine the importance of MMC in the combined treatment of anal cancer. The study showed significantly in­creased colostomy-free survival, disease-free survival, and local control rates. The authors concluded that despite greater tox­icity, the use of MMC is justified.8 Our patient was treated with combined-modality therapy similiar to that used for patients in the study of squamous cell vul-var carcinoma by Moore et al. 3 One notable difference, however, was our use of IMRT. IMRT of the pelvis has been shown by nu­merous investigators to be safe, feasible, Radiol Oncol 2007; 41(2): 72-79. and effective in terms of acute and chronic toxicities, as well as clinical outcomes.8­12 Specifically, Garofalo et al. 13 evaluated IMRT planning in patients with vulvar can­cer undergoing treatment to both the pelvic and inguinal fields. As compared with con­ventional techniques, IMRT was associated with a decreased volume of small bowel, bladder, rectum, and femoral heads receiv­ing the prescription dose. Recently, investi­gators from the University of Chicago and Mayo Clinic Rochester have published their experience with IMRT and anal cancer, which showed favorable toxicity and clini­cal outcomes.14-15 With successful completion of aggres­sive combined-modality therapy using con­current chemotherapy and radiotherapy, a surgically verified complete pathologic response was obtained in the patient pre­sented here. However, metastases of the abdomen and liver eventually developed. At this time, decisions regarding salvage chemotherapy and other potential pallia­tive measures are being considered for this patient. Acknowledgment Editing, proofreading, and reference veri­fication were provided by the Section of Scientific Publications, Mayo Clinic. References 1. Elkas JC, Berek JS. Clinical manifestations, diag­nosis, pathology, and staging of vulvar cancer. UpToDate Patient Information [homepage on the Internet]. UpToDate, Inc.; c2007 [cited 2007 Mar 5]. Available from: http://uptodate.com. 2. Chen KT. Disorders of Bartholin’s gland. UpToDate Patient Information [homepage on the Internet]. UpToDate, Inc.; c2007 [cited 2007 Mar 5]. Available from: http://uptodate.com. 3. Moore DH, Thomas GM, Montana GS, Saxer A, Gallup DG, Olt G. Preoperative chemoradiation for advanced vulvar cancer: a phase II study of the Gynecologic Oncology Group. Int J Radiat Oncol Biol Phys 1998; 42: 79-85. 4. Han SC, Kim DH, Higgins SA, Carcangiu M-L, Kacinski BM. Chemoradiation as primary or ad-juvant treatment for locally advanced carcinoma of the vulva. Int J Radiat Oncol Biol Phys 2000; 47: 1235-44. 5. Rotman M, Lange CS. Anal cancer: radiation and concomitant continuous infusion chemotherapy. Int J Radiat Oncol Biol Phys 1991; 21: 1385-7. 6. Bartelink H, Roelofsen F, Eschwege F, Rougier P, Bosset JF, Gonzalez Gonzalez D, et al. Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III ran­domized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups. J Clin Oncol 1997; 15: 2040-9. 7. UKCCCR Anal Cancer Trial Working Party, UK Co-ordinating Committee on Cancer Research. Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus ra­diotherapy, 5-fluorouracil, and mitomycin. Lancet 1996; 348: 1049-54. 8. Flam M, John M, Pajak TF, Petrelli N, Myerson R, Doggett S, et al. Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treat­ment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study. J Clin Oncol 1996; 14: 2527-39. 9. Mundt AJ, Lujan AE, Rotmensch J, Waggoner SE, Yamada SD, Fleming G, et al. Intensity-modulated whole pelvic radiotherapy in women with gyne­cologic malignancies. Int J Radiat Oncol Biol Phys 2002; 52: 1330-7. 10. Mundt AJ, Roeske JC, Lujan AE. Intensity-modu­lated radiation therapy in gynecologic malignan­cies. Med Dosim 2002; 27: 131-6. 11. Mundt AJ, Roeske JC, Lujan AE, Yamada SD, Waggoner SE, Fleming G, et al. Initial clinical experience with intensity-modulated whole-pelvis radiation therapy in women with gynecologic ma­lignancies. Gynecol Oncol 2001; 82: 456-63. 12. Roeske JC, Lujan A, Rotmensch J, Waggoner SE, Yamada D, Mundt AJ. Intensity-modulated whole pelvis radiation therapy in patients with gyne­cologic malignancies. Int J Radiat Oncol Biol Phys 2000; 48: 1613-21. Radiol Oncol 2007; 41(2): 72-79. 13. Garofalo MC, Lujan AE, Mundt AJ. Intensity-mod­ulated radiation therapy in the treatment of vulvar carcinoma: a feasibility study [abstract]. Radiology 2002; 225 Suppl: 597. 14. Mell LK, Schomas DA, Salama JK, et al. Multi-institutional analysis of dosimetric predictors of acute hematologic toxicity in anal cancer patients treated with concurrent chemotherapy and in­tensity modulated radiation therapy (IMRT). Int J Radiat Oncol Biol Phys In press. 15. Salama JK, Mell LK, Schomas DA, et al. Concurrent chemotherapy and intensity-modulated radiation therapy for anal canal cancer patients: a multi-center experience. Int J Radiat Oncol Biol Phys In press. Radiol Oncol 2007; 41(2): 72-79. case report Triple synchronous cancers: a medical and ethical problem Lucka Debevec, Rok Cesar, Izidor Kern University Clinic of Respiratory and Allergic Diseases Golnik, Golnik, Slovenia Background. In a patient with suspicious synchronous multiple tumours, there are limited possibilities for effective therapy. Therefore, the decision for invasive diagnostics and precise staging of tumours is question­able, especially in elderly patients suitable only for symptomatic therapy. Case report. A 78-year-old man with hypertension and angina pectoris was admitted to the hospital due to syncope. Two primary lung tumours and a kidney tumour were detected by imaging investigation. The patient refused invasive diagnostics and left the hospital. After 19 months he was readmitted in an impaired clinical condition and subsequently died of bronchopneumonia. The autopsy revealed squamous cell carci­noma of the right upper lobe with metastases to regional lymph nodes and to the brain, small-cell carcinoma of the left upper lobe with metastases to regional lymph nodes and to the spleen, and clear-cell kidney carcinoma with multiple metastases to the lungs. All tumours were necrotizing, and therefore we assumed that any attempt at specific therapy would have been ineffective. Conclusions. In an elderly patient with advanced lung tumors and suspicious synchronous triple cancers, the “wait and see” option can be suitable. Key words: neoplasms, multiple primary; prognosis; ethics, medical Introduction Multiple synchronous cancers in the same organ or in various organs are rather unu­sual. Sometimes this condition is diag­nosed during the staging process of the tumour, by postoperative histology of a re-sected organ, but it is mostly identified by autopsy. During the diagnostic procedure Received 16 April 2007 Accepted 23 April 2007 Correspondence to: Assist. Lucka Debevec, MD, PhD, University Clinic of Respiratory and Allergic Diseases Golnik, SI-4204 Golnik, Slovenia; Phone: +386 4 2569 100; Fax: +386 4 2569 117; E-mail: lucka.debevec@ klinika-golnik.si involving the patient with suspicious mul­tiple tumours, a dilemma appears relative to the precise staging of each of all prob­able tumours in a patient suitable only for symptomatic therapy. A case of synchronous triple tumours is presented in which noninvasive diagnostic procedures were performed and suspicion of triple primary cancer was established. The patient refused invasive diagnostics and left the hospital. Fortunately, the course of the disease was rather favorable, and none of the three tumours caused symptoms requir­ing urgent invasive diagnostics or attempts at any specific therapies. Despite three dis­seminated carcinomas, the patient survived at home, i.e. without specific or symptomatic therapy needing hospi­talization, for 19 months after the diagnosis of two lung tumours and a kidney tumour. Case report A 78-year-old man with hypertension and angina pectoris was brought to the hos­pital due to syncope without convulsions in June 2005. At the time of admittance he had no fever but a dry cough. Laboratory tests indicat­ed anemia (Hb 9.2 g/dL), leucocytosis (WBC 16.5 x 103/µL), hypokalemia (potassium 3.4 mmol/ L), slightly elevated BUN and creatinine, and low serum iron (2.7 µmol/L). A CT scan of the brain showed diffuse atrophy without signs of metastasis. On the chest X-ray, tumours in­filtrating in both upper lobes were visible. The lesion on the left side was excavated (Figure 1). A CT scan of the tho­rax and upper abdomen showed – in addition to tumour lesions in the left and right lung – also a tumour-enlarged right kidney (Figure 2). The conclusion after the im- Radiol Oncol 2007; 41(2): 80-85. aging procedures was the probability of three synchronous primary tumours: a tumour in the right upper lobe in­filtrating the mediasti­num, a tumour in the left upper lobe with me­tastases to hilar and me-diastinal lymph nodes, and a tumour in the right kidney. The patient did not agree to further invasive diagnostics for verifica­tion of the tumours, and despite some persuasion he left the hospital with advice for a urological examination. By the end of Decem­ber 2006, the patient was admitted bedrid­den, dehydrated, som­nolent, with respiratory insufficiency, anisocoria and anamnesis of fre­quent vomiting during the previous few days. Laboratory tests showed high inflammatory pa­rameters (CRP 97.2 mg/ dL, WBC 16.6 x 103/µL), and elevated BUN (50.8 mmol urea /L) and cre­atinine (149 µmol/L), but there was no anemia (he­moglobin was currently 15.9 g/dL). A brain CT showed cerebral atrophy and a coliquated round lesion in the right occipital re­gion without surround­ing oedema (Figure 3). On the chest X-ray, the Radiol Oncol 2007; 41(2): 80-85. known tumours of the upper lobes and diffuse infiltrates in both lungs appeared (Figure 4). The patient received antibiotics and parenteral hydration, and died four days af­ter admittance. The autopsy revealed the excavated tu­mour of the left upper lobe, 7 cm in diam­eter, infiltrating the left main bronchus, to be a necrotizing small-cell carcinoma with metastases to ipsilateral hilar and ipsilat­eral mediastinal lymph nodes, and with necrotizing spleen metastasis of 3 cm. The tumour of the right upper lobe, 10 cm in diameter, was also necrotizing. Due to en­larged and coliquated hilar and mediastinal lymph nodes, there was an impression of tuberculosis. But histology showed a necro­tizing squamous cell carcinoma of the right lung and lymph nodes, and a necrotizing me­tastasis of the same histology was revealed in the right occipital region of the brain. The right kidney was entirely trans­formed by a 13 cm tumour infiltrating the renal capsule and perirenal fat tissue. Histology revealed a necrotizing well differ­entiated clear-cell carcinoma with multiple metastases to both lungs. All three primary tumours as well the metastases of the brain, spleen, right hilar and mediastinal lymph nodes, were necro­tizing. The cause of death was bronchop­neumonia. Discussion In patients with two or more tumour lesions detected in various organs, one reasons that it is a primary tumour with metas­tases, which is statistically most probable. Synchronous triple tumours are uncom­mon. In the annual reports of the Cancer Registry of Slovenia it is not possible to de­termine the number of patients with mul­tiple cancers, since these are registered as different single tumours, i.e. cancer cases, irrespective of the number of patients.1 So, a triple cancer would be registered three times, despite involving the same patient. In the literature it is difficult to obtain data on synchronous cancers. Hamada et al.2 re­ported a gradual increase of triple primary cancers in Japan in the period 1994-1996. The incidence of triple cancers represented 0.81% of all autopsy cases reported. There are interesting site combinations of triple cancers. The most frequently re­ported were all tumours in the same organ or organ system: lung,3-9 digestive organs,10­ 13 and urogenital organs.14-19 Lung cancer appeared in combination with tumours of two various organs: urinary bladder and es-ophagus,20 breast and stomach,21 pancreas and duodenum,22 and stomach and thyroid.2 Kidney cancer was seen in combination with tumours of the liver and oral floor,23 sigmoid colon and thyroid.24 On PubMed one can find articles on synchronous triple tumours, for all successfully resected ones, but mostly published in Japanese without an English abstract. Therefore, the many cases of synchronous triple cancers estab­lished in Japan raise the possibility of the influence of atomic bomb radiation on can­ 17 cer incidence. Hakada et al.mentioned that there had been a patient with synchro­nous cancers of the kidney, urinary bladder and prostate exposed to the atomic bomb explosion in Hiroshima in 1945. In our patient presented above, it is ques­tionable whether the disease could have progressed otherwise, even with the pa­tient’s agreement to invasive diagnostics at the time of first admittance to the hospital. Probably one or both lung tumours could have been established by bronchoscopy. A needle aspiration biopsy under ultrasound guidance would have been necessary for verification of the kidney tumour. Had there been successful definition of all primary tu- Radiol Oncol 2007; 41(2): 80-85. mours, carefully dosed chemotherapy for lung cancer would parhaps have been ap­plied. The kidney tumour would certainly not have responded to chemotherapy, and embolization of the renal artery would have been indicated, especially in the case of haematuria. Concerning the necrosis of all primary tumours and their metastases to the brain, spleen and thoracic lymph nodes, as established by the autopsy, chemother­apy would probably not have influenced survival, but certainly would have impaired the patient’s quality of life. The patient de­cided on “wait and see” management and lived at home to the age of 80, thus saving the physicians the dilemma of performing invasive investigation and staging of the tu­mours. Considering that at the time of first admittance a lack of the possibility of effec­tive therapy was already evident, even the objection to bronchoscopy could be consid­ered reasonable. In conclusion, in the case of synchro­nous triple cancers in an elderly patient the possibilities of effective therapy are limited. Therefore, invasive diagnostics and accurate staging may not be indicated in pa­tients with bilateral advanced primary lung tumours. A “wait and see” decision can be quite a reasonable option. References 1. Cancer Registry of Slovenia. Cancer incidence in Slovenia 2003. Report No 45. Ljubljana: Institute of Oncology, Epidemiology and cancer Registry; 2006. 2. Hamada Y, Takise A, Uno D, Itoh H, Ichikawa H, Morishta Y. Synchronous primary triple cancers including the lung, stomach, and thyroid: a case report. Kyobu Geka 2000: 53: 101-5. 3. Tokuchi Y, Kamachi M, Harada M, Hasegawa M, Mishina T, Yamashiro K, et al. Synchronous triple lung cancers after treatment for non-Hodgkin’s lymphoma: metachronous quadruple cancers. Intern Med 2003; 42: 1031-4. 4. Nishino R, Daga H, Sasaki R, Moritani C, Ohashi N, Arita K, et al. A case of severe pneumoco­niosis with synchronous triple lung cancer. Nihon Kokyuki Gakkai Zasshi 2003; 41: 491-5. 5. Brun S, Paparelli C, Sinnona N, Venuti VM. Synchronous lung cancer; clinical case of triple lung carcinoma. G Chir 2002; 23: 43-4. 6. Motohiro A, Matsumoto T, Ienaga S. Synchronous growth of triple lung cancer. Surg Today 1995; 25: 1054-6. 7. Hoshi E, Aoyama K, Takayanagi N. A case of a synchronous triple primary lung cancer with hamartoma. Kyobu Geka 1995; 48: 251-5. 8. Dalton ML, Warner RL. Triple synchronous pri­mary lung carcinomas treated with simultaneous resection. J Med Assoc Ga 1991; 80: 287-90. 9. Badiali P, Alloisio M, Lombardi L. Synchronous triple carcinoma of the lung in one patient. Tumori 1987; 73: 525-9. 10. Sato K, Maekawa T, Yabuki K, Tamasaki Y, Maekawa H, Kudo K, et al. A case of triple syn­chronous cancers occurring in the gallbladder, common bile duct, and pancreas. J Gastroenterol 2003; 38: 97-100. 11. Tamura M, Shinagawa M, Funaki Y. Synchronous triple early cancers occurring in the stomach, co­lon and gallbladder. Asian J Surg 2003; 26: 46-8. 12. Chang YT, Tsai CI, Yang TH, Shih CW, Wu MS, Lin JT. Synchronous triple cancers at middle and lower esophagus and stomach with differ­ent histological feature and genetic alterations. J Gastroenterol Hepatol 2002; 17: 724-7. 13. Chen JH, Chen CC, Tzeng LM, Tsay SH, Chiang JH, Lu CC, et al. Resection of triple synchronous tumors: gastric adenocarcinoma, gallbladder ad-enocarcinoma and stroma tumor of the stomach. Zhonghua Yi Xue Za Zhi 2001; 64: 655-60. 14. Isin Dogan Ekici A, Kucukali T, Coskun Salman M, Ayhan A. Triple simultaneous primary gynae­cological malignancies in a 56-year-old patient. Int J Gynecol Cancer 2006; 16: 1947-50. 15. Jun SY, Cho KJ, Kim CS, Ayala AG, Ro JY. Triple synchronous neoplasms in one kidney: report of a case and review of the literature. Ann Diagn Pathol 2003; 7: 374-80. 16. Satoh H, Momma T, Saito S, Hirose S. A case of synchronous triple primary carcinomas of the kidney, bladder and prostate. Hinyokika Kiyo 2003; 49: 261-4. Radiol Oncol 2007; 41(2): 80-85. 17. Takada T, Honda M, Momohara C, Komori K, Fujioka H. Synchronous triple urogenital cancer (renal cancer, bladder cancer, prostatic cancer): a case report. Hinyokika Kiyo 2002; 48: 239-42. 18. Vallejo Herrador J, Sanchez de la Muela P, Diz Rodrigez R, Martin-Laborda F. Synchronous pri­mary urologic triple neoplasia. Report of a new case and review of the literature. Actas Urol Esp 2002; 26: 57-9. 19. Harima M, Narita K, Kobayakawa H, Tsujino T, Yamamoto S, Fukushima S, et al. A case of syn­chronous triple primary cancers of prostate, kid­ney and bladder. Hinyokika Kiyo 1998; 44: 675-8. 20. Tamura K, Inoue K, Fukata S, Kamada M, Shuin T. Small cell carcinoma of the urinary bladder with synchronous esophageal cancer and incidental lung cancer: a case report. Hinyokika Kiyo 2001; 47: 273-6. 21. Patel S, Alfonso AE. Landis J, Suarez J. Three syn­chronous multiorgan primary cancers. All stage I. Arch Surg 1985; 120: 1182-4. 22. Taira K, Shiraishi M, Sunagawa H, Takushi Y, Shimoji H, Tomita S, et al. Resection of triple synchronous cancers: a case report. Hepatogastroenterology 1999; 46: 199-203. 23. Okajima E, Ozono S, Nagayoshi J, Uemura H, Hirao Y, Nakajima Y, et al. A case report of syn­chronous triple cancer resected simultaneously. Jpn J Clin Oncol 1994; 24: 166-70. 24. Kurihara T, Ishida T, Miyamoto Y, Mishima T, Suda A, Izuo M. A case of quartet cancer: a carcinoma of the breast followed by three synchronous cancers (kidney, thyroid and colon). Gan No Rinsho 1989; 35: 955-62. Radiol Oncol 2007; 41(2): 80-85. case report Adenocarcinoma of the small bowel Metka Šavli, Breda Jamar Institute of Clinical Radiology, University Medical Centre, Ljubljana, Slovenia Background. Adenocarcinoma of small bowel is generally a rather rare primary tumour of small bowel with a prevalence rate of 0.5 – 3.0 / 100.000 population, but the most frequent tumour of small intestine. It more often involves the duodenum and jejunum than the ileum. The aim of this paper is also to point out the value of small bowel follow through (SBFT) in the diagnosis of stenosing lesions. Case report. An 83 – year old male patient suffered from abdominal pain, malaise, vomiting, cachexia and diarrhoea for 3 months. The result of occult blood testing was negative. Haemoglobin level was nor­mal. Proctoscopy, colonoscopy, upper gastrointestinal (GI) endoscopy, and ultrasonography (US) did not explain the patient’s problems. Ileus of the small bowel was established with abdominal plain film. Small bowel follow through (SBFT) and computer tomography (CT) showed a stenosing tumour in the jejunum. Adenocarcinoma of the small bowel was established with histological examination after resection of the tumor. Conclusions. SBFT, with manual compression of all segments of the small bowel, can be a very accurate diagnostic investigation for evaluation of stenosing lesions in this part of the intestine. Key words: intestinal obstruction; jejunal neoplasms; adenocarcinoma - radiography Introduction Comprising about 2 % of all gastrointesti­nal malignancies, malignant tumors of the small bowel are relatively rare 1, adenocar­cinomas being the most frequent among them. Their peak incidence, slightly higher in males than in females, is in the 7 th decade.2 More often they are found in the jejunum or duodenum. In the jejunum, ad-enocarcinomas are usually located within Received 14 May 2007 Accepted 5 June 2007 Correspondence to: Breda Jamar MD, Institute of Clinical Radiology, University Medical Centre, Zaloška 7, SI-1000 Ljubljana, Slovenia. Tel. +386 1 522 8530; Fax: +386 1 522 2497; E-mail: breda.jamar@kclj.si the first 30 cm distally of the ligament of Treitz.3 Lymphatic spread to the regional lymph nodes and through the portal sys­tem to the liver are frequent. Peritoneal metastases can also be found, or there may be direct progression of the tumor into the adjoining structures.4 Adult coeliac dis­ease, Crohn‘s disease and Peutz – Jeghers syndrome are precancerous conditions.5-7 More specific symptoms are preceded by a period of vague abdominal discomfort, dyspepsia and malaise, often not alarming enough for the patient to seek medical ad­vice. The more specific clinical presentation is associated with obstruction and ulcera­tion of the cancer. Since the small bowel contents are liquid, obstructive symptoms are somewhat late and may diminish to conservative treatment. Because of its anatomy, small bowel is difficult to examine. The proximal jejunum and terminal ileum can be examined with enteroscopy, while for the stenosing proc­esses in the mesenteric small intestine, ra­diologic examinations, especially dedicated SBFT and CT, are dominant diagnostic procedures.8,9 On SBFT, the typical image of primary adenocarcinoma of the small in­testine is an annular lesion of the » apple core » type.2 It is usually symmetric, with a centrally positioned stricture. It is rigid and its shape is not significantly changed dur­ing compression of the abdomen.10 Case report An 83-year-old man with arterial hyperten­sion was first referred to the proctologist because of difficult defecation, abdominal pain and diarrhoea lasting for about one month. On proctoscopy, polyp of 5 – times 5 mm was found in the rectum. It was resected at a later colonoscopy and sent for histological examination. Some diver-ticula were also observed. With the upper GI endoscopy signs of chronic atrophic gastritis were found. With abdominal ul­trasonography small cysts in the right kid­ney were revealed. However, the results of all examinations could not explain the patient’s problems. Two months later the patient returned to the emergency depart­ment, for the third time in one month, because of severe vomiting and weight loss. Haemoglobin level was found nor­mal. Dilated small bowel was observed on abdominal plain film (Figure 1), while no signs of acute abdomen were seen on physical examination, leading abdominal surgeons at the first two patient’s visits to conclusion that there was no indication for surgery. At the third patient’s visit to the emergency department, the gastroenterolo-gist referred him to SBFT. On SBFT, the jejunum was found dilat­ed, and an oval formation, approximately 3 – times 3 cm in size in the distal jejunum, causing relative obstruction, was revealed. Proximally to the formation, in a length of about 30 cm, thickened mucosal folds and irregular bowel wall were seen (Figure 2). The shape of the segment did not sig­nificantly change during compression of the abdomen. The process was obviously malignant, not inflammatory. As definite diagnosis could not be established, CT scan of the abdomen was done. It showed a solid tumour in the jejunum, 3 – times 3 cm in size (Figure 3, 4). There were no signs of spread into adjacent mesenteric fat. Radiologic signs of mechanical obstruction (dilated small bowel) could still be seen. No lymphadenopathy was found. With the ex­ception of right cystic kidney, parenchymal organs were normal. There was some free fluid in the Proust’s pouch. Radiol Oncol 2007; 41(2): 86-89. The patient was admitted to surgery. Implantation of pace maker for his ar­rhythmia was needed before he could be operated upon (5 days later). A 30 cm long segment of the jejunum was resected. Appendectomy was also performed. The histopathologic diagnosis was adenocar­cinoma of the small bowel. One out of 17 nodes in the mesentery was found malig­nant. Lymphangiocarcinomatosis of the mesentery was also established. Discussion The performed examinations of the proxi­mal and distal part of the alimentary tract – proctoscopy, colonoscopy, upper GI en­doscopy – could not explain the patient’s problems. Abdominal US revealed small cysts in the right kidney. The small bowel and colon attracted no attention of the ultrasonographist. It should be born in mind, however, that the interpretation of the bowel US is highly operator – depend­ent. Vast experience is needed to achieve accuracy rates comparable with those from the literature.6 On the three patient’s visits of the emer­gency department in just one month be­cause of the clinical progression of his state (severe vomiting, abdominal pain and loss of weight), signs of the small bowel me­chanical ileus could be demonstrated with plain film of the abdomen, while no signs of acute abdomen could be seen on physi­cal examination. The levels of haemoglobin were normal. Figure 3 and 4. Computed tomography: A solid tumour in the jejunum. Dilated small bowel loops proximally. Radiol Oncol 2007; 41(2): 86-89. In order to examine the mesenteric small bowel, a dedicated investigation, the SBFT, was indicated. The revealed oval formation, approximately 3 – times 3 cm in size, in the distal part of the jejunum, causing relative obstruction and thickened mucosal folds as well as irregular bowel wall proximally to the obstruction not changing during ab­dominal compression, could be recognised as malignant. As the changes were not typi­cal of the small bowel adenocarcinoma, CT scan of the abdomen was performed for the differential diagnosis of lymphoma. CT disclosed a solid tumour in the je­junum causing a relative obstruction and, proximally, dilatation of a small bowel loop. There was some free fluid in the pouch of Proust, but no signs of distal spread. The question whether it was a primary tumour or a direct progression from surroundings could not be answered. Because of the radiologic signs of ob­structive ileus, the results of SBFT and CT, the patent was admitted for surgery. A 30 cm long segment of the jejunum was re-sected. Appendectomy was also performed. The final diagnosis of adenocarcinoma of the small bowel was established with his-topathologic examination. Conclusion Abdominal pain, vomiting, anaemia, and the presence of dilated proximal jejunum should suggest an obstructing neoplasm of the small bowel in older patients, and indicate the need for further diagnostic procedure with fluoroscopic small bowel study. The demonstration of a small bow­el stenosing lesion depends primarily on SBFT. In most cases, the differentiation between malign or benign (e.g. inflamma­tory) lesion can be made, although the final diagnosis of the type of malignancy is done by histopathology. References 1. Barclay THC, Shapira DV. Malignant tumors of the small intestine. Cancer 1983; 51: 878-81. 2. Dean DT, Maglinte MD. Malignant tumors of the small bowel: In Gore RM, Levine MS, editors. Textbook of gastrointestinal radiology. Philadelphia: WB Saunders Company; 2000. p. 792-9. 3. Herbsman H, Wetstein L. Tumors of the small intestine. Curr Probl Surg 1980; 17: 121-82. 4. Lightdale CJ, Sherlock P. Small intestinal tumors (other than lymphoma and carcinoid). In Berk JE, editor. Bockus Gastroenterology. Philadelphia: WB Saunders Company 1985; p.1887-99. 5. Berstein D, Rogers A. Malignancy in Crohn’s dis­ease. Am J Gastroenterol 1996; 91: 434-40. 6. Lashner BA. Risk factors for small bowel cancer in Crohn’s disease. Dig Dis Sci 1992; 37: 1179-84. 7. Spigelman AD, Murday V, Phillips RKS. Cancer and the Peutz – Jeghers syndrome. Gut 1989; 30: 1588-90. 8. Bessette JR, Maglint DDT, Kelvin FM, et al. Primary malignant tumors in the small bowel: a comparison of the small bowel enema and conventional follow – through examination. Am J Roentgenol 1989; 153: 741-4. 9. Hulnick DH, Megibow AJ. Computed tomogra­phy of the small bowel. In: Herlinger H, Maglinte D, eds. Clinical Radiology of the Small Intestine. Philadelphia: WB Saunders; 1989: p.161-200. 10. Papadopoulos VD, Nolan DJ. Carcinoma of the small intestine. Clin Radiol 1985; 36: 409-13. Radiol Oncol 2007; 41(2): 86-89. Functional form comparison between the population and the individual Poisson based TCP models Colleen Schinkel1,2, Nadia Stavreva2, Pavel Stavrev2, Marco Carlone2,3 and B. Gino Fallone1-3 1 Department of Physics, University of Alberta, 2 Department of Medical Physics, Cross Cancer Institute; 3 Department of Oncology, University of Alberta, Edmonton, Alberta, Canada In this work, the functional form similarity between the individual and fundamental population TCP models is investigated. Using the fact that both models can be expressed in terms of the geometric parameters .50 and D50, we show that they have almost identical functional form for values of .50 = 1. The conceptual inadequacy of applying an individual model to clinical data is also discussed. A general individual response TCP expression is given, parameterized by Df and .f – the dose corresponding to a control level of f, and the normalized slope at that point. It is shown that the dose-response may be interpreted as an individual response only if .50 is sufficiently high. Based on the functional form equivalency between the individual and the population TCP models, we discuss the possibility of applying the individual TCP model for the case of heterogeneous irradiations. Due to the fact that the fundamental population TCP model is derived for homogeneous irradiations only, we propose the use of the EUD, given by the generalized mean dose, when the fundamental population TCP model is used to fit clinical data. Key words: radiotherapy dosage; Poisson distribution; dose-response relationship, models, statistical, TCP Introduction In the decades following the introduc­tion of the first individual TCP model by Munro and Gilbert,1 the distinction between the individual and population response has often been disregarded and individual TCP models have been fit to clinical datasets. The necessity of describ- Received 01 June 2007 Accepted 20 June 2007 Correspondence to: B. Gino Fallone, Ph.D., Department of Medical Physics, Cross Cancer Institute, 11560 University Ave., Edmonton, Alberta, T6G 1Z2, Canada. Tel: (780) 432-8750, Fax: (780) 432-8615; E­mail: ginofall@cancerboard.ab.ca, ing the impact of population heteroge­neity on dose-response has lead to the development, by a number of authors, of population-based tumour control prob­ability (TCP) models.2-5 It has been shown that the presence of population heterogeneity leads to a dose-response curve that is flattened relative to the individual dose-response curve. If an individual TCP model is fit to a popula­tion dataset, the biological meaning of the parameter estimates is lost – the radiobio-logical parameters take on unrealistically low values.6 Nevertheless, although it is conceptually incorrect, the individual TCP model has been fit to clinical datasets and parameters obtained from these fits have Background and method been assumed to have radiobiologically meaningful values.4,7-10 On the other hand, The general form of the population-based it has also been shown that these fits are Poisson TCP model has eight parameters. characterized by an acceptable goodness However, it has previously been shown6,11 of fit. that the parameters of such a model are It has been expected that the population interrelated; many different combinations TCP models would allow for the estima-of parameters lead to one and the same tion of biologically meaningful population TCP curve. Thus, it may seem difficult to parameters. Unfortunately, it is impossible directly compare the functional forms of to obtain a unique set of parameter val-the individual and population-based TCP ues when a population TCP model is fit to models. On the other hand, Carlone et al.11 clinical data.6,11 This is due to the fact that have specified (based on a certain approxi-different sets of population parameter val-mation, of course, but a clinically valid ues produce almost identical TCP curves. one) what these interrelations actually are, Carlone et al.11 analytically demonstrated and have shown that there are only two based TCP models. On the other hand Carlon that when the dominant source of inter-independent population model parameters patient heterogeneity is that of tumour – D50 and .50. Fortunately, the individual radiosensitivity, the population TCP func-Pooison-based TCP module can also be pa- clinically valid one) what these interrelations based TCP models. On the other hand Carlone et al.11 have specified (based on a certain approximation, of c tion has only two independent parameters rameterized by these parameters. This fact model parameters – D50 and 50. Fortunately, – the dose t 50% TCP, D50, which deter-makes the comparison of both models an clinically va lid one) what these interrelations actually are, and have shown that there are only two independen based TCP model could be parameterised too. mines the position of the TCP curve, and easier task. the normalized slope of the curve, .50. model parameters – D50 and 50. Fortunately, these two parameters are also the parameters in which the individ 5 These parameters have geometric mean- The Poisson-based individual TCP model ing. Since it is also true that the individual TCP model may be expressed in terms of This common form of the individual TCP based TCP model could be parameterised too. Hence making the comparison of both models an easier task. The Poisson-based individual TCP model 5 the same two parameters,3,12 it is possible model is based on Poisson statistics com-that, for a given range of parameter values, bined with a simplified description of This common form of the individual TCP mo both models will exh bit almost identical clonogen repopulation.4,10,11,13-26 In the The Poisson-based indi vidual TCP model functional form. In this work, we inves-case where a tumour undergoes homogene­ clonogen repopulation.4,10,11,13-26 In the case where tigate the similarities between these two ous irradiation to a total dose D, split into models expressed in terms of D50 and .50 n fractions with equal dose per fraction, d, This common form of the individual TCP model is based on Poisson statistics combined with a simplified de n fractions with equal dose per fraction, d, the by plotting them for identical values of the individual Poisson TCP model may be clonogen repopulation.4,10,11,13-26 In the case where a tumour undergoes homogeneous irradiation to a total dose these geometric parameters. written as:11  NS D E d D O T n fractions with equal dose per fraction, d, the individual Poisson TCP model may b 10 [1] TCP written as: 11 Ne e exp > ind 0 Ş § ş E d D  NS E d D O T © d ą [1] ind 00 0 10 [1] TCP e exp  Ne @ exp  Ne » exp  N exp c D @ , where N0 is the initial number of clonogens, N » Ľ where N0 is the initial number of clonogens, NS is the mean number of clonogens surviving linear quadratic (LQ) radiosensitivity param where N0 is the initial number of clonogens, NS is the mean number of clonogens surviving the treatment, D a the treatment, a and ß are the linear quadratic (LQ) radiosensitivity parameters, . is the tumour repopulation rate, T is the total treatment time and c Tn . Note as as an equal dose linear quadratic (LQ) radiosensitivity parameters, O is the tumour repopulation rate, T is the total treatmen Note that as long as an equal dose is given during each fraction of the treatment (which is common clinical practice), the parameters , E and c can be co practice), the parameters a, ß and .' can be combined into one single parameter: c T n . Note that as long as an equal dose is given during each fraction of the treatment (which is com 15 [2] c E d  c . d practice), the parameters , E and c can be combined into one single parameter: Radiol Oncol 2007; 41(2): 90-98. c The validity of the Poisson TCP model was 15 [2] c E d  . d 5 5 20 5 5 5 5 10 10 10 10 10 10 15 15 15 15 15 15 c T n . Note that as long as an equal dose is given during each fraction of the treatment (which is comm practice), the parameters , E and c can be combined into one single parameter: 92 Schinkel et al. / Functional form comparison of TCP models Ş 2 J § D ş exp « 50 ¨ 1  » [2[] 2] c E d  « 2ln J 2. ¨ DD 50 » 50 [3a] TCPind 0.5exp « d ¨ 1  » . ¨ ln 2 D oisson Ş 2 J 50 § CP TD ş The validity of the Pmodel was questioned by Tucker and Travis,21 and others27­ [3a] TCPind 0.5 « © 50 » . ln 2 D © 50 » [3a] TCPind 0.5exp Ş 2 J § 1  D ş . val dity of the Poisson TCP model was questioned by Tucker and Travis,21 and others27-31 who explore 31 who explored the non-Poisson nature of the TCP in the case where tumour repopulation T h e noti on of normalized slope, , was first introduced by Brahme33 for the purpose of dosimetric precision qua 50 « conditions, ln 2 D » occurs. Under certain however, it has been shown27,32 that the distribution of exp ¨ 1 ¸ The notion of normalized slope, [3a] 0.5 « ¨ 50 Ľ , was first introduced by Brahme. 33 for the purpose of dosimetric precision qua Poisson nature of the TCP in the case where tumour repopulation occurs. Under certain conditions, however, the number of clonogen cells remaining at the end of a treatment is well-approximated by TCPind Later, Kallman et al.34 used the maximum value of at the inflection point of the TCP curve and derived an the Poisson distribution. In view of these results, and also because of the relative complex- The notion of normalized slope, n , was first introduced by Brahme33 for the purpose of dosimetric precision qua Later, Kallman et al.34 Ş used the maximum value of § ş at the inflection point of the TCP curve and derived an 2 J D shown27,32 that the distribution of the number of clonogen cells remaining at the end of a treatment is well-approx CP D models, , was firsthe t intindividual roduced by TBCP rahfunction me33 for thpre esentpurposed e oin f dEq. osim[1] etric is precision qua ity of the non-Poissonian T exp « 50 ¨ 1  » The notion of normalized slope, « ln 2 © 50 » similar to Eq. [3a], but as pointed out by Bentzen and Tucker,35 a slight inconsistency is present in their formula. [3a] TCPind 0.5 Ľ . ofstien milused. ar to Eq. [3a], but as pointed out by Bentzen and Tucker,35 a slight inconsistency is present in their formula. Later, Kallman et al.34 used the maximum value of at the inflection point of the TCP curve and derived an the Poisson distribution. In view of these results, and also because of the relative complexity of the non-Poiss A form of the individual TCP model3,12 that is equivalent to Eq. [1], but written in terms Later, Kallman et al.34 used the maximum value of at the inflection point of th TCP curve and derived an the Poisson TCP expression given by Eq. [1], may be transformed and parameterize d in terms of the normalized models, the individual TCP function presented in Eq. [1] is often used. of the geomethe Poisson Ttric parCP expameressitoern s, gi.ven and by EDq. 50[, is giv1], may en bbe tyr: ansformed and parameterize d in term s of the normalized 50, was first introduc d by Brahme33 for the purpos of dosi etric precision qua similar to Eq. [3a], but as pointed out by Bentzen and Tucker,35 a slight inconsistency is present in their formula. The notion of normalized slope, similar to Eq. [3a], but as pointed out by Bentzen and Tucker,35 a slight inconsistency is present in their formula. any dose point Df: Ş 2 § D ş exp « 50 ¨ 1  » the Poisson TCP expression given by Eq. [1], may be transformed and parameterized in terms of the normalized [3[3a]a] Later, Kallman TCPind et al0.5.34 ¬ used the maximum value of 50 Ľ . at the inflection point of the TCP curve and derived an any dose point Df: « ln 2 ¨ D » the Poisson TCP expressi on gi ven by Eq. [1], may be transformed an d parameterized in terms of the normalized A form of the ndiv dual TCP model3,12 that is equivale t to Eq. [1], but written in t rms of the any dose point Df: J § D ş The notion of normalized slope, «  f J ln ff ¨ Df » .., was first introduced by Brahme33 for the purpose of exp ¨ 1 » similar to Eq. [3a], but as pointed out by Bentzen and Tucker,35 a slight inconsistency is present in their formula. ¬ f © D Ľ ¸ paramet rs, 50 and D50, is given by: dosime[3b] any do e pproinecision t TCPindDf: f ¨ , was first introduced by Brahme33 for the purpose of dosimetric precision qua squantification. » f Later, Kallman et al. The n tion of normalized slope, « f ln fD 34 used the maximum value of . at [3b] TCP f exp ¨ 1 » © Ľ the inflection point of the TCP curve and derived an expression similar to Eq. [3a], but as ind Ş J f § D ş the Poisson TCP expression given by Eq. [1], may be transformed and parameterized in terms of the normalized point[3b] bout TCPy ind en  f uckş ed Bentzand Ter,35 a slight inconsistency is present in their formula. In exp ¨ 1 » Later, Kallman et alf .34 Ş f used the maximum value of ln J ff § DD » at the inflection point of the TCP curve and derived an © Ľ From Eqs. [1] and [3b], the following relationships between the two different sets of parameters (f, Df) and (N0, exp ¨ 1 » © ession xprĽ general, the Poisson TCP egiven by Eq. [1], may be transformed and parameter- any dose point Df: « f ln f ¨ Df » From Eqs. [1] and [3b], the following relationships between the two different sets of parameters (f, Df) and (N0, [3b] TCPind f ¸ similar to Eq. [3a], but as pointed out by Bentzen and Tucker,35 a slight inconsistency is present in their formula. ized in terms of the normalized slope .f at any dose point Df: derived: From Eqs. [1] and [3b], the following relationships between the two different sets of parameters (f, Df) and (N0, D derived: J § D ş f exp ¨ 1 » the Poisson TCP expression given by Eq. [1], may be transformed and parameterized in terms of the normalized « f ln fD » [3[3b] b] TCPind f ¨ f ¸ From Eqs. [1] and [3b], the following relationships between the two different sets of parameters (f, Df) and (N0, © Ľ derived: 1  N 0 · [4a] Df ln ¸ any dose point D1 f: ¨  N 0 ¸ From Eqs. [1] and [3b], the following relationships between the two different sets of pa­ derived: c ln f [4a] Df ln © ą ¸ From Eqs. [1] and [3b], the following relationships between the two different sets of parameters (f, Df) and (N0, rameters (.f, Df) and ( 1 ©  N 0 , a') may be derived: c ln f [4a] Df ln ¨ J f § D ş © expln « f ¨ 1  » D 1  N f ln0 fD derived: « © N 0 f » [4a] Df ¸ a ¬ Ľ 3 TCP  f ln f ¨ ln ¸ ¸ . [ 4b ] J f f ind c © ln ¨ f ą N 0 ¸ [4b]  f ln f ln © ln f ą . f ¸ ln f  N 0 · From Eqs. [1] and [3b], the following relationships between the two different sets of parameters (ln ¸ f, Df) and (N0, D 4a f ¨ [ 4[4b] b]  1 f ln § f  ln N © 0 · ą . . Df ¨ ln ¸ f and for (50, D50D ) in particular: c ln © f  N 0 · [4b] J f  f ln © f ln ą ¸ . derived: ą and for (.50, D50) in particular: and for (50, D50) in particular: ¨ ln f ¸ and for (50, D50) in particular: 1 § N 0 · [5a] D 50 ln ¨ N 0 · [4b] J f D 1 f c ln § fN · ¸ . and for (50, D50) in particular: ln 0 ¨ 2 ¸ [4a] Df c ln © ln 2 ¸ ą [5[5a] a] D 50 1ln  N 0 ą ln · f ¸ D 1 § ln Nf · [5a] D ln ¨ 0 ą 50 c © ln 2 ą ln12 § N · a J ln ¨ [5b] 50 ln2 § N · . and for ([ 5 b] 50D , D50) in particular: ¨ 00 . D 2 c © ln 202 ą [5b] J 50 ln ¨ N .0 · [4b] J f  2 f ln f © ln ¨ 2 ¸ . ln 2 § N · ¸ [5b] J 50 1ln ¨ N 0 © 0 · ln . f ą [5a] D 50 2ln © ln 2 ą ln 2 § N · [5b] J 50 c ln ¨ ln 20 . The population-based TCP model 2 © ln 2 ą and for (50, D50) in particular: The population-based TCP model Carlone et al.11 showed that the population TCP model for the case of dominant heterogene- The population-based TCP model [5b] J 50 ln ¨ 0 . 12 © N ln02 ą ln 2 § N · ity in radiosensitivity may be written as: Carlone et al.11 showed that the population TCP model for the case of dominant heterogeneity in radiosensitiv 1 § D ş The population-based TCP mod l 5a] D ln 50 Carlone et al.11 showed that the population TCP model for the case of dominant heterogeneity in radiosensitiv « [ 6[6] ]50 TCPerfc pop c ln 2 J 50 1 . 2 D ą The population-based TCP model Ľ written as: Carlone et al.11 showed that the population TCP model for the case of dominant heterogeneity in radiosensitivi written as: ln 2 § N · Carlone et al.11 showed that the population TCP model for the case of do inant heterogeneity in radiosensitiv Radiol Oncol 2007; 41(2): 90-98. [5b] The parameters in Eq. J 50 ln ¨ 0 . [6] – D50 and 50 – have the same geometric m eaning as the corresponding parame written as: The population-based TCP model 2 © ln 2 ą written as: [3a]. The geometric parameters may be expressed in terms of the population-based radiobiological parameters, D Carlone et al.11 showed that the population TCP model for the case of dominant heterogeneity in radiosensitiv D h e p a ra e te 2 ¬ in © q . 6 – Ľ a nd –h av e th e a eg e o e tic e a n ig a th e co ep o nd in g p r e ar etrs i tr s i .[] [ ] –– D 50 an a n d J J 50 –– h a v e th e s am e g e om e tr ic m e an in g as th e c or r es p o n d in g pa a e t e sa e eo etric t tr i eani i 1 as t ec res on i s t Ş r s § D i ş ar a T h e pa r am e ter s in E q . .[ 6] s [6] TCPerfc J ¨ 50 1 . [3 a ] . T h e g eo m e t r i c p a r am e t e r s m ay b e ex p r e ss ed in t e rm s o f th e p o p u l a t io n -b a []. e e tri r tr a e e re s e it e rs r pop i tr « ft e 50 la ti l ti ­ [ a ]. e tric a ra e te rs f t ­ The parameters in Eq. [6] – D50 and 50 – have the sam geometric meaning as he corresponding parame 2 © D Ľ 3 a . h e g eo e t ic a a e te ay b e ex p e ed in te o th e p o p u la tio n -b a ed ad io b io l g i a l p a a e te r [a]. e e etric ar r etrs a e r i tr lati lti r il il ical ar r etrsr [ 3 a] . T h e g e om e tr ic p a r am e ter s m a y be e x pr e s e d in term s of th e p o p u la t io n - b as e d r a d io b io lo g ic a l pa r am e te tr i res e i ter s s f t e -ase ra i i i l t [ ] . tr s f t s e parameters in Eq. [6] – D50 and 50 – have the same geometric meaning as the corresponding parame Schinkel et al. / Functional form comparison of TCP models . :11 93 ln N [3a]. The geometric parameters may be expressed in terms of the population-based radiobiological parameters, D 0 00 :: :11 The parameters in Eq. [6] – D50 and ln N 000 :0: : The parameters in Eq. [6] – D50 and .50 – have the same geometric meaning as the cor- [3a]. The geometric parameters may be expressed in terms of the population-based radiobiological parameters, D :11 lnN 0 * ln N responding parameters in Eq. [3a]. The geometric parameters may be expressed in terms of h a v e t h e s a m e g e o m e t r i c m e a n i n g a s t h e c o r r e s p o n d i n g p a r a m e t e r s i n E q . d J 50 – :11 5 [a ] [ D 50 0 00 [3a]. The geometric parameters may be expre [7 a ] ] lnN 0 * ln N 0 D c c 0 0 0 7 a D 5 [a] [ ] 50 [ 7 a] : 11 the population-based radiobiological paramet  lnN D 0 c c s, and lnN 0 r e s s e d i n t e r m s o f t h e p o p u l a t i o n - b a s e d r a d i o b i o l o g i c a l p a r a m e ter s , D c , V c a n d 5 [7a] D 50 * lnc N D c c 5 [7[7a] a] D 50 0 [7 b ] [ ] JJ 50 [] c D c c SV c c  lnN 0 7 b J [ ] [ ] J 50 [ 7 b] 5 [7a] D 50 c 2 SV c c c [7[7b] b] J 50 2 V c 2 22 O c c 2 22 2 22 2 22 2 22 V O c c [7b] J 50 e re r c c D d  a V  V where D , ,, E , ,, O c c a n a n H e r e D c E an d c V d  c 2 DD E E 2 c 2 2 2 2 22 O c c 222 2 222 2 222 2 222 2 d V O O c c D d c Her He r e er re D c c D E d d  a and an d a n d V c V  d d V  where where [7b] D ,,, E ,,, , O c c a and a n d n d ln N are are the are population av a D E E 2 222 2 50 000 0 c d d 2 222 V c d d 2 c Here c E d  and  d  where D , E , c and lnN are the population avera population averages of the corresponding individual parame er O d c e s D ii V d ii 2 a l a ra e te rs a V DD , V E E , , V O c c and lnln NN 0 a re t e irs r t ir co rr e sp o n d in g in d iv id u a l p a r am et e r s an d c r i E i ii 2 lrtr , , 0 an d a V a r e th e i r s t 2 222 c H re c or re s p o n d in g in d iv idu a l pa r am e te r s a n d D E d i d i id and V et rsan V t  d d  ,, aan d d are t eir stan ar lnt N are the population avera ev iatio n s. i ti 00 . h e sy co r esp o n in g in iv u al p ar a r e the ir s ta n da rd de v ia t io n s . T he s ym b th i iii i l t D V D D ,, V E E 2 E ,, V O c c lnln NN ti 0 iti . are their st d del viations. The symbol c d G reprwhere ,esents V Euler’s t ant, has , V , E gamma , c anconsd d d b o o d d 000 0 E u l e r ’ sg amm a co n s t an t ,w h i ch h a s an a pr o x im a t ev a lu eo f0 .5 7 . m tt, ic i a s a a p r ia te a le f i t O f. . 22 le r’s a lr’ a c s ta t, r l . 7 . 2 corresponding individual parameters and D , E , c and V re thei stand rd deviations. The symbol * an approximate value of 0.577. c ln N 0 Here c E d  and D  d le ’ g a a co n tn t, h ich a an a o x i a t v a lu e 0 .5 . d asaap rxi atevalueof .7 . ler’s am ac nstant, s ta t, ic s i l . . e s r 2 correspondin l ’individual parameters i nd D , V r E , O tc and V lnf N . are their standard deviations. The symbol * The general form of the Carlone et al.11 population TCP model takes both heterogeneity E u ler ’sg a m a c o ns ta n t ,w h ich h as a n ap pr o x im a te v a lu eo f 0 .57 7 . 22 V O c Euler’sgammaconstant,whichhasanapproximatvuef0.577. T h eg en e ra l fo rm o f th eC a r lo n e e rlfr fte rl e e t a le t . l11 . p o p u l a t io n T C P m o d e l t ak e la ti l t in radiosensitivity and heterogeneity in clonogen number into account. However, this form 10 h e e ra lf r ft 0 a rl tl. lti e lta e VE  where D , E , O c a n d ln N 0 are the population a v era g es of the d corresponding individual parameters and D 2 of the population TCP model has three parameters, and was shown11 to be almost identical 10 fte le p o p u la tio n lt it i T h e g e n er a l f orm of th e C ar lo ne h e g en e a l o e e eral f r f t arl a r lo n e e t a ltet a l t ..11 po p u la t io n T C P m o d e l tak es b o th he ter o g e n e i ty in r a d io lati l ti o d e l ta e b o th el ta es s t et r e te o g en e ity in ad i t r e eit i ra i se r r lf r o th e l. l. ti Euler’sgammaconstant,whichhasanapp ximaevalue f0.577. h e t e ro g en e i ty in c lo n o g en n u mb e r in to a cc o u n t . Ho w ev e r , th i s fo rm o f th e p o p u e te r e e it i c l e rit a c e e r,tis fr tr iti l e m rit t. t. H r,tifr fte ft to the one that only takes heterogeneity in radiosensitivity into account. Hence, the latter 10 The general form of the Carlone et al.11 population TCP model takes both heterogeneity in radiosens , a n d V a r e t h e i r s t a n d a r d d e v i a t i o n s . T h e s y m b o l * r e p r e s e n t s c e D , VE c e teo g en ity in lo n o g en u eeiticl l e in to o u n t. t. t. eer,th is fr o Euler’sgammaconstant,whichhasnapprox o tep o p u la tio n lati lti o l s tr t h etr iti b eritac o ev e ,ti r ,tis d elh asth re will be used for this analysis. he ter o g e n e i ty in c lo n o g en n um b er in to ac c o u n t . H ow e v er , th is f orm of th e p o p u la t io n T C P m od e l ha s th re e p VO ln t r N e r it r fth e t l a 10 The general form of the Carlone 0 s et alt . t 11 population TCP m del tak s bo h he erogen i y in radiosens e a l l s t i e tic a l t t e t i t t l ta e s l t te r was sh o w n 11 to b e a lm o s t id en t i c a l to th e o ne th a t o n ly t ak e s he t e roge neity in ra n tiltt ta t t r heterogeneity in clonogen number into account. However, this form of the population TCP model has three param h o n tob e a l o tid e n tia lto th e on e th a to n ly tak h te n to eal ostienticaltoteoetatonl taes etr was s h ow n11 to b e a lm os t id e n t ic a l to th e o n e th a t o n ly ta ke s he teroge neity in ra diose nsitivity into account. He ss n t l s ti tic ltt tt lt se tr n elected to use th e latter for our an alysis. heterogeneity in clonogen number into account. However, this form of the population TCP model has three param o x i m a t e v a l u e o f 0 . 5 7 7 . 10 The general form of the Carlone et Functional form comparison between individual and population-based TCP models te ta was shown11 to be almost identical to the one that only takes heterogeneity in radiosensitivity into account. Hence, elected to use th e latter for our a nalysis. e te t a th an Since both the individual and the population TCP models may be written in terms of the heterogeneity in clonogen number into accou was shown11 to be a lmost identical to the one tha t only takes heterogeneity in radiosensitivity into account. Hence, e t a l . 11 p o p u l a t i o n T C P m o d e l t k e s b o t h h e t e r o g e n i t y i n r d i o se n s i t i v i t y a n d elected to use the latter for our analysis. same two parameters, .50 and D50, it seems natural to assume that the two models may was shown11 to be almost identical to the one display similarity in functional form. In order to explore the functional similarity of these elected to use t h e latter for our analysis. u n t . H o w e v e r , t h i s f o r m o f p o p u l a t i o n T C P m o d e l h a s t h r e e p a r a m e t e r s , a n d F u n c t io n a l fo rm co m p a r iso n b e tw ee n in d i v id u a l a n d p o p u la t io n -b a s ed T C P m o 15 ti lfr lf r i b t e iiv i ii l lti lti -s e o models, Eqs. [3a] and [6] are evaluated for a given range of .50 and D50 values. Subsequently, c ti c ie t il -d e t h a t o n l y t a k e s h e t e r oge neity in ra diose n sitivity into account. He nce, we have elected to use the latter for our analysis. the individual and population TCP curves obtained for equal sets of .50 and D50 values are n c tio n a l fo co p a i n b e t n in d iv id u a l a n d p o p u la tio n -b a ed o d e l cti ti lfr c ri r i et e iiiv ll lti --se ls 15 F u n c t io n a l form c om p ar iso n b e tw e e n in d iv id u a l a n d p o p u la t io n -b as e d T C P m o d e ls lfr t i i lti s els 15 S in c e b o th th e in d iv idu al an d th e p o p u l a t io n T C P m o d e l s m ay b e w r i tt en in t e r t t pop ii a la t la ti a it t te i l plotted for visual comparison. Functional form comparison betwee The functional closeness of i i the ls ves ely be more c e individual a i ii and athe ttTd esab-population ionClP Ti tmCP oedcurl e e s rie rit i te tt i i ala t ls aay b e rite iters itr s o th e a e to p a a e t ftesaet f t t etr t Si n c e bo th th e in d iv id u a l a n d th e p o p u la t io n T C P m o d e ls ma y b e w r it t e n in term s of th e s am e tw o pa r am e te 15 Funct o al f rm compar son between individual and population-b s d TCP models r e e a e c o rigoriby ed s erence beareas the i b i e cously n e b h h i i ed n d ivi d u an d h e p o p u la o n o d fe ii t twt en n s ar r i t s ee m s n a tu r a l to a ss u m e th a t t h e tw o m o d e l s m ay d i sp l ay s im i l a r i ty in fu n c t i its e a tra lt e ta tte t a i l c t t Since both the individual and the population TCP models may be written in terms of the same two parameters, J two TCP curves, it s trlt a s t t t e ls lm is la s iila ritif iilritif A  A 15 Functional form comparison between individu itse its s ' A at ralt t r lt as TCP t et t o d e l a isla is l si ilarit i f cti ti alfr ..n o d e to ex p lo . rert r e lre lr it i t se em s n a tur a l to a s um e th at th e tw o m o d e ls m a y d is p la y s im i lar i ty in f u nc t io n a l f orm . sn a tu a l to a u e th a t th e t o e t at TCP t els ls ay d i p lay i ila ity in u n tio n a l o s i il r it i f l f r II n or d er to e x p lor e I s r t pop ind Since both the individual and the popu at on TCP models may be written i terms of the same two param ters, J it seems natural to assume that the two models may display similarity in functional form. In order to explore the [[8] 8] s im i lar i ty o f th e s e m o d e ls, E q s . [3 a ] an d [6 ] a r e ev a lu a ted fo r a g ive n r an g s i il i t i il it f t e s e f t l s . [ a ] a . [ ] r l t f r a i ra , e l []a re e a la t [] fr ie r A J 50 A , TCP TCP pop pop q . 3 a t f J an d v a lu es . S u ftes s s.[a]a r fra o i ra fJ al es. s . u b d u a l a n d p o p u l a t i o n - b a s e d T C P m o d e l s si il it s im i lar i ty of the s e m o d e ls, E qs . [ 3 a] a n d [ 6] ar e e v a lu a ted f or a g iv e n r a n g e of i il ity o s i il it f t th e e o d e l el l s . [ ] n d 6 a e ev a lu a t [ ] are e al at [ ] l f r a g iv en i e an g e o r e J50 aa nd D 50 v a lu e . l Since both the individual an the population it seems natural to assume that the two models may display similarity in functional form. In order to explore the in d iv id u a l an d p o p u l a t io n T C P cu rv e s o b t a in ed fo r eq u a l s e t s o f la ti f  J  50 an d D 50 val ii l ta ie fre l similarity of these models, Eqs. [3a] and [6] are evaluated for a given range of50 and D50 values. Subsequ as a function of .50. ii ii a la lti P c re s r ti fr a ls e ts f t J a ii ala lati lti cu v eo b ta in ed o eq u a l s taiefre f r alsets f J aan d u a e r u p in iv id u a lan d p o p u ltio n ind iv d u a la n d p o p u la t io nT C P c ur v es o b ta in e df or e q u a ls e ts of r J50 a n d D 50 val ues ar e plotted for vis ual com p ii i l cres ti ls ts f to  J are as a functi on of 50. it seems natural to assume that the two mode n T C P m o d e l a y b e w r i t e n i n t e r m s o f t h e s a m e t w o p a r a m e t e r s , J 50 a n d D 50 , and D50 s im ilarity of t hese models, Eqs. [3a] and [6] are evaluated for a given range of50 values. Subsequ individualandpopulationTCPcurvesobtained orequalsets f 50 and D50 values are plotted for visual comparison. 20 T h e f u n c t io n a l c lo s en e ss o f th e in d iv idu a l an d th e p o p u l a t io n T C P c u h f e f ti a lc ls e e s fte i ft i iid a la t la ti lti c c ti ll ii l te c similarity of these models, Eqs. [3a] and [ e l s m a y d i s p l a y s i m i l a r i t y i n f u n c t i o n a l f o r m . h e u n c tio a l c lo e f ct i o al cl senes o f t e in i TCP curv l l s I o r d e r o x p l o r t h e f u c i o n a l f t i i l a nd t e p op u la tion sets of t 50 o and l ti D50 values a e plotted for visual comparison. cu ves s y b e e r r u y r 20 T h ef u n c t ion a lc los en e s oft he in d iv idu a l an d th e p o p u la t io nT C P c ur v esm a y b em o r er igo r o usl u alan l th e aa e ig o u y individualandpopla ef ti so th e ind iv id btaindfore q i latio c u v e r oreri r i Results their work of 50 Gy, with values ranging c a l cu l a t in g th e n o rm a l i z ed d i ff e r en c eb e tw ee n th e a r e a su n d e r th e two T C P cu r v c a lc la ti l lti te r a liz e r ifr t te a re a s t r rt tw c r r t li i e re c e e t e rte t 20 The functional closeness of the individual and the population TCP curves may be more rigorously est from 10 to 90 Gy. We therefore chose a calclti te te a n d if er D 50 t n th e a e au n e th e to r t li teareas r cres, [ 6 ] a r e e v a l u a t ed f o r c a lcu la tin g th n o c a lc u la t in g then orm a l iz ed d if fe r e n c e b e tw e e n the are as u nd er th e tw oT C P c ur v es , lti g i v e n r a g e o f r alize r liz ed i e en c eb e t  J 50 if r ce et e v a l u e s . S u b s q u n t l y , t h e t s ertet t cu v e , s , lThe individual and the population TCP individualand population TCP curvesobtaine r value of D50 = 50 Gy for our investigation. 20 The functional closeness of the individual and the population TCP curves may be more rigorously est calculating thenormalized differencebetween the areas under the two TCP curves, curves were calculated according to Eqs. Figure 1 shows eight pairs of individual n e d f o r e q u a l s e t s o f  J 50 a n d D 50 val u es a r e plotted for vis u al com p arison. 20 The functional closeness of the ind [3a] and [6] for values of the parameters .50 and population TCP curves calculated for calculating thenormalized differencebetween the areas under the two TCP curves, 5 Results Eqs. [3a] and and [6] Dfor eporrues tof ed the Okuniefmeters 50 valby paraf et al.36 Based the following parameter values: D50= 50 Gy calculating thenormalized differencebetween d i v i d u a l a n d t h e p o p u l a t i o n T C P c u r v e s m a y b e m o r e r i g o r o u sl y e s t i m a t e d b y on their estimates of .50, we chose a range and .50 = [0.5, 1, 1.5, 2, 2.5, 3, 4, 6]. This fig- The individual and the population TCP curves were calculated according to Eqs. [3a] and [6] for values of the 0.5, 6@ These authors ose a range of J 50 . These authors also reported ure was reproduced for different values of e n t h e a r e a s u n d e r t h e t w o T C P c u r v e s , a mean D50 for all tumours investigated in D50, to determine whether this parameter with values ranging from 10 to 90 Gy. We 50 and D50 reported by Okunieff et al.36 Based on their estimates of 50, we chose a range of J 50 0.5, 6@ . Th Radiol Oncol 2007; 41(2): 90-98. also reported a mean D50 for all tumours investigated in their work of 50 Gy, with values ranging from 10 to 5 culated for the following para meter values: therefore chose value of D50 = 50 Gy for our investigation. so reported a mean D50 for all tumours investigated in their work of 50 Gy, with values ranging from 10 to 90 Gy. We therefore chose a value of D50 = 50 Gy for our investi ation. umours investigated in their work of 50 Gy, with values rang ing from 10 to 90 Gy. We therefore chose a value of D50 = 50 Gy for our investigation. therefore chose a value of D50 = 50 Gy for our investigation. tigated in their work of 50 Gy, with values ranging from 10 to 90 Gy. We therefore chose a value of D50 = 50 Gy for our investigation. 0 Gy for our investigation. 10 Figure 1 shows eight pairs of individual and population TCP curves calculated for the following parameter va Figure 1 shows eight pairs of individual and population TCP curves cal 94 10 10 Figure 1 shows eight pairs of individual and population TCP curves calculated for the following parameter vSchinkel et al. / Functional form comparison of TCP models a nvestigation. high dose range. The individual and population models Figure 1 shows eight pairs of individual and population TCP curves calculated for the following parameter values: s of individual and population TCP curves calculated for the following para meter value s: D50=50 Gyand 50 = [0.5, 1, 1.5, 2, 2.5, 3, 4, 6]. This figure w s reproduc d for different values of D50, to dete D50 D50= 50 Gyand 50 = 50 Gy and 50 = [0.5, 1, 1.5, 2, 2.5, 3, 4, 6]. This figure was reproduced for different values of = [0.5, 1, 1.5, 2, 2.5, 3, 4, 6]. This figure was reprod uce D50,to et r had any influence on functional equiva-The considerable closeness in functional al and population TCP curves calculated for the following parameter values: whether this parameter had any influence on functional equivalency. It was found th t the location of he TCP curves lency. It was found that the location of the for m of both models expla ins the observat ion whether this paramete had any influence on functional equivalency. It was foun 5, 2, 2.5, 3, 4, 6]. This figure was reproduce d for different value 50 whether this parameter had any influ nce on funct onal equivalency. It was fou d that the location of the TCP curves = of D50, to determin = 50 Gy and 50 [0.5, 1, 1.5, 2, 2.5, 3, 4, 6]. This fi gure was reproduced for diffe rent values of D50, to determine seen from Figure 1, for 50 less than 2.5 the individual TCP curves along the dose-axis did not in-that the individual TCP model produces a rea­ the dose-axis did not influence the shapes of the curves or their positions relative to each other. Hence, th locatio results shown hether this parameter had any influence on funct ional e quivalen cy. It was found that the location of the TCP curve s along 4, 6]. This figure was reproduced for different values of D50, to determine fluence the shapes of curves or their sonable fit to clinical datasets.4,10 In spite of the dose-axis did not influence the shapes of the curves or their positions relative the dose-axis did not influence the shapes of the curves or their positions relative to each other. Hence, the results shown fluence on functional equivalency. It was found hat th of the TCP curves along compared with the population-based TCP curves. For norm  positions relative to each other. Hence, the this, the observed equivalence in functional the dose-axis did not influence the shapes of the curves or their positions relative to each other. Hence, the results shown in shapes of the curves or their positions relative to each other. Hence, the results shown in nctional equivalency. It was found that the location of the TCP curves along figure 1 are applicable for any D50 value. J results shown in Figure 1 are applicable for form of the two TCP models should not be figure 1 are applicable for any D50 value. figure 1 are applicable for any D50 value. slightly underread the population TCP. The overreading a value. any D50 value. the curves or their positions relative to each other. Hence, the results shown in 15 (Eq. [8]) is plot ed in Fig. 2. The conside rable closeness in functional form The quantit J 50 (Eq. [8]) is plot -The quantity (Eq. [8]) is plotted in Fig. 2. The largest are 15 The quantity J 50 (Eq. [8]) is plotted in Fig. 2. The largest area difference between the two TCP curves J 50 15 figure 1 are applicable for any D50 value. regarded as an endorsement to use the indi-The quantity AA 5 viduT e P t sel r ato a fidifferet clinincce al dbeattween a. al hClramgoedthe two TCP curves A ATCP ATCPpop ATCPpop However, a very steep dose response is (Eq. [8]) is plot ed in Fig. 2. The largest ararea ea differdiffere tween the two TCP curves is ence ce beunusual for clinical data sets. Shallower re- The ed tquant in ity Fig. 2. The larges (Eq. [8]) is plotted in Fig. 2. The largest area difference between the two TCP curves is pop between the two TCP curves is -17.7% ob- ATCP J 50 model produces a reasonable fit to clinical datasets.4,10 In plotted in Fig. 2. The largest area difference between the two TCP curves is -17.7% obtained at pop 50 = 0.5. -17.7% obtained at 50 = 0.5. -17.7% obtained at 50 = 0.5. sponses are much more typical for popula- tained at .50 = 0.5. tions of patients. Therefore, it would con- two TCP models should not be regarded as an endorsemen 17.7% obtained at 50 = 0.5. ceptually be more correct to use the popula­tion TCP model, which accounts for inter- patient heterogeneity to fit such data. If, However, a very steep dose response is unusual Discussion Discussion Discussion Discussion however, the individual TCP model is used, for populations of patients. Therefore, it would concep Based on Figures 1(d) – 1(h) and Figure 2, one should bear in mind that the obtained Discussion Discussion Based on Figs. 1(d) – 1(h) and Figure 2, one may conclude that the functional forms of the in ividual and the popu– l Based on Figs. 1(d) 1(h) and Figure 2, one may conclud e that the functional Based on Figs. 1(d) – 1(h) and Figure 2, one may conclude that he functional forms of the individual and the popu paramet er values have lost their biological one may conclude that the functional forms 10 accounts for inter-patient heterogeneity to fit such data. Discussion meaning and should be interpreted simply of the individual and the population models ased on Figs. 1(d) – 1(h) and Figure 2, one may conclude that the functional fo rms of the individual and the population gure 2, one may conclude that the functional forms of th individual and the p pulation A ATCPpop 2, 6@ . Indeed, for this ra ge of 50 the index models are almo st identical for Indeed, f r this range of J 50 the index 20 me arodels almosare almt ost identical for for 20 J 2, 6@ . Indeed, 50 2, 6@ . Indeed, for thi s range of 50 the inde as phenomenological coefficients. is less than 0.5%. Alth 20 models are almost identical for J 50 min d that the obtained parameter values have lost less than 0.5%. Alth A ATCP pop may conclude that the functional forms of the individual and the population 50 Ź As can be seen from Figures 1(a) and m50 2, 6@ . Inor fdeethis d, for rtange his raof nge .o50 f J 50 the 502inde ,the i 6@ ex odels are almost identical for . In d eed, for this range of 50 the index is less than 0.5%. Although is less t a 0.5%. Although pop A ATCP 1(b), both models start to differ in function­ ph en omenological coefficients. A ATCP is higher ( ' A ATCP pop A A TCP pop of 50 th e index A ATCP  0.5 ,  6.7% pop ) is less g ihs ithan ' ( re0.5%. A ATCP > Although pop 0.A 5, A TCP 6.7pop % is ) is higher ( for the interval ' A ATCP J 50 1, 02. 5,  6.7% ) for the interval J 50 ,d 1, 2 , the plots in Figures 1(b) and 1(c) ind eed, for this range A ATCP is less than 0.5%. Although for the interval J 50 Ź >  , the plots in Figures 1(b) and 1(c) in1, 2 al forfor the clinically observable range of pop pop that the individual and population TCP curves are still sufficiently close to each other, especially for the clinically-relevan .50 < 1. In addition, for these values of .50, ) for the interval A ATCPpop  500Ź .5pop ,1 , 26 .7, the plots in Figures 1(b) and 1(c) indicate % ) for the interval for the 50 J the ht, 1, 2 individual s tolpe model ugiFn ileads rteo 1s T) b(CP a> n0 d f(1or c) indicate D As can be seen from Figures 1(a) and 1(b), b  0.5,  6i7% higher s higher ( .' A ATCP pop that the individual and population TCP curves are still sufficiently close to each 7 % ) for the v al that the individual and population TCP curves are still sufficiently close to each other, especially for the clinically-relevan inter interv, e htthe s tolpploits Fn in s erugiFigur1es na) b(1(b) d 1(c) indicate 0. Therefore, fits to very shallow curves 50 Ź 1, 2 = that the individual and population TCP curves are still sufficiently close to each other, especially for the clinically-relevant TCP curves are still sufficiently close to each other, especially for the clinically-relevant using the individual model may distort the observable range of 50 < 1. In addition, for these values and 1(c) indicate that the individual and are still sufficiently close to each other, especially for the clinically-relevant best-fit estimates of .50 and D50. 6 The authors advocate the use of the pop-close to each other, especially for the clini-ulation model in regards to clinical data. 6 population TCP curves are still sufficiently fits to very shallow curves using the individual model may 15 cally-relevant high dose range. The individ-6 However, the demonstrated equivalence in The authors advocate the use of the population functional form of the individual and popu­ual and population models differ consider-lation models can be utilized for the case of equivalence in functional form of the individual and popu 17.7% ) As can be As In this . heterogeneous tumour irradiation. ably at differ considerably at 50 = 0.5 ( ' A A TCP pop case, the individual TCP model with exist- irradiation. In this case, the individual TCP model with e can be seen from Figure 1, for .50 less than ing {.50, D50} estimates (e.g. Okunieff et al.36) vidual curves overread TCP everywhere except at 50% control when normalized slopes above 50 = 2.5, the individual curves tend to can be used for the evaluation of TCP37 ac-everywhere except at 50% control when cording to the following expression:38 2.5 the individual curves overread TCP the evaluation of TCP37 according to the following expres 2 D 50 i 1 compared with the population-based TCP Ş ş ¨ · v exp i « » ¸ ln2 D 50 nd underreading tendencies are clearly demonstrated by Figure 2. curves. For normalized slopes above .50 20 = [9][9] TCP 0.5 i 2.5, the individual curves tend to slightly Equation [9] is a simple, straightforward of both models explains the observation that the individual TCP Equation [9] is a simple, s raightforward generalizati generalization of Eq. [3] for t he case of het- underread the population TCP. The over- erogeneous irradiation. The generalization n spite of this, the observed equivalence in functional form of the reading and underreading tendencies are generalizati n of Eq. [6] for the cas of heterogeneous ir of Eq. [6] fo r the case of heterogene ous irra- clearly demonstrated by Figure 2. nt to use the individual TCP model to fit clinical data. diation, without introducing extra model pa-complicated mathematical problem, and has not yet been s Radiol Oncol 2007; 41(2): 90-98. al for clinical data sets. Shallower responses are much more typical ptually be more correct to use the population TCP model, which If h h idi id lTCP dli d h ldb i Figures 20 40 60 20 40 60 and knowledge of its value for each tumour (%) (%) 20 40 60 20 40 60 mour. Therefore, until 1 more comprehensive (f) 50 = 3.0 parameter estimates are produced through fits of the population 0.5 2 2 TCP model to clinical 0 data for the case of het­ 20 40 60 20 40 60 0 0 erogeneous irradiation, 1 (h) we propose that Eq. [9] -2 -2 50 = 6.0 be used for evaluation 0.5 of treatment plans in -4 -4 terms of TCP, based on the functional form 0 -6 20 40 60 20 40 60 -6 equivalency of both A/A TCPpop A/A TCPpop 1 (e) 50 = 2.5 0.5 A/A (%) TCPpop 0 1 (g) 50 = 4.0 0.5 0 Dose (Gy) Dose (Gy) -8 -8 Figure 1. Individual (solid) and population-averaged (dotted) TCP curves for D50 ure 1. Individual (solid) and population-averaged (dotted) TCP curves for D50 = 50 Gy and the 50 values shown in each Gy and the .50 values shown in each sub-plot. -10 -10 2 0 -12 -12 -2 rameters, presents a complicated mathemat- -14 -4 -14 ical problem, and has not yet been solved. -6 -16 Strictly speaking, the ability to use Eq. -8 -16 [9] as a population TCP descriptor has not -10 -18 yet been proven theoretically. Nevertheless, -12 2 -18 0 1 our experience with the TCP/NTCP estima­01 tion module37 shows that it produces rea--14 models. = 50 12 3 4 5 2 3 4 50 -16 50 -18 012345 6 -plot. 6 5 the population TCP model is to replace the Figure 2. The ratio of the area difference, ' A ATCPpop  ATCPind , between the two TCP curves, to the to Figure 2. The ratio of the area difference, ' AA  A , between the two TCP curve homogeneous dose, D' TCPpop TCPind under the population TCP curve ( ATCPpop ), plotted for the values of 50 used to generate the curves show under the population TCP curve ( ) plotte for the values of 50 used to generate the cu ATCPpop , plotted for the values of .50 used to 1. generate the curves shown in Figure 1. 1. Radiol Oncol 2007; 41(2): 90-98. sonable TCP estimates. Another approach to the problem of taking dose heterogeneity into account for Conclusions It is thus concluded that: • The population and the individual TCP re­sponses are almost identical in functional form for .50 belonging to the interval [1, 6]. If each of these models were fit to the same clinical dataset, they would produce statistically indistinguishable values of the parameters D50 and .50. • It is conceptually incorrect to use the indi­vidual TCP model to fit clinical data. • Until reliable estimates of the population TCP parameters for the case of heteroge­neous tumour irradiation are obtained, the individual TCP model (Eq. [9]) with exist­ing D50 and .50 estimates could be used for TCP evaluations in this situation. • The case of a shallow dose-response relationship, which is usually observed clinically, can be explained by the pres­ence of significant inter-patient heteroge­neity. The population TCP model should be used to fit such data, as it accounts for this heterogeneity. If, however, the individual TCP model is used, the esti­mated parameter values should be in­terpreted simply as phenomenological coefficients. • A steep dose-response relationship indi­cates the presence of a relatively small inter-patient heterogeneity. Though it is highly improbable to observe such dose-responses clinically, the individual TCP model may be applied to such data for the purpose of estimating biological parameters, as the individual parameters would retain some biological meaning in this case. Acknowledgements This research was supported by student­ships from the Alberta Foundation for Medical Research, the Alberta Cancer Board and the Translational Research Training in Cancer program (the Canadian Institutes for Health Research), as well as the Alberta Cancer Board Research Initiative Program Grant RI-218. References 1 Munro TR, Gilbert CW. The relation between tumour lethal doses and the radiosensitivity of tumour cells. Br J Radio 1961; 34: 246-51. 2 Fenwick JD. 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A TCP-NTCP estimation module using DVHs and known radiobiological models and parameter sets. J Appl Clin Med Phys 2004; 5: 50-63. Radiol Oncol 2007; 41(2): 90-98. 38 Niemierko A. Radiobiological models of tissue re­sponse to radiation in treatment planning systems. Tumori 1998; 84: 140-3. 39 Choi B, Deasy JO. The generalized equivalent uni­form dose function as a basis for intensity-modu­lated treatment planning. Phys Med Biol 2002; 47: 3579-89. 40 Wu Q, Mohan R, Niemierko A, Schmidt-Ullrich R. Optimization of intensity-modulated radiotherapy plans based on the equivalent uniform dose. Int J Radiat Oncol Biol Phys 2002; 52: 224-35. Radiol Oncol 2007; 41(2): 90-98. Radio/ Oncol 2007; 41(2): 57-62. Mediastinitis in empiem plevre zaradi širjenja zobnega vnetja Juretic M, Belusic-Gobic M, Kukuljan M, Cerovic R, Golubovic V, Gobic D Izhodišca. Zobna vnetja so pogosta, vendar se redko širijo v vrat in v podorcje prsnega koša. Akutni gnojni mediastinitis (spušcajoci se nekrozantni mediastinitis) je bolezen, ki ima kljub zdravljenju z antibiotiki in kirurškim posegom do 40% smrtni izhod. Izjemno redko se kot posledica mediastinitsa razvije plevralni empiem. Prikaz primera. Prikazan je primer mladega, predhodno zdravega bolnika z mediastinitisom in obojestranskim plevralnim empiemom, ki je nastal kot posledica širjenja zobnega vnetja. V zacetku je bil zdravljen s kirurškima posegoma na vratu. Po CT preiskavi prsnega koša, ki je pokazala širjenje vnetja v prsni koš, je bila narejena torakotomija in drenaža obojestran­skega empiema plevre z antibiotskim zdravljenjem. Bolnik je ozdravel, kljub zakasnelem spoznanju zapleta zobnega vnetja. Zakljucki. Pri zgodnji diagnostiki spušcajocega se nekrotizantnega mediastinitisa, ki nas­tane zaradi zobnega vnetja, je CT preiskava prsnega koša pomembna diagnosticna metoda saj omogoca ustrezno zdravljenje bolnika. Radio/ 011col 2007; 41(2): I-VI. Radio/ Oncol 2007; 41(2): 64-71. Rak ledvic Rajer M Izhodišca. Namen prispevka je prikazati trenutno stanje na podrocju diagnostike in zdrav­ljenja raka ledvic (RL), s poudarkom na slovenskih epidemioloških podatkih. Rak ledvic predstavlja 2% vseh rakov in je tretji najpogostejši rak genitourinarnega podrocja. V ve­liki vecini prizadene ljudi med 50 in 60 letom starosti. Pogostejši je pri moških kakor pri ženskah. Z nastankom RL naj bi bili povezani številni dejavniki tveganja. Še najmocneje je dokazana povezava s kajenjem tobaka. Ostali pomembni dejavniki tveganja so še hiperten­zija, debelost in kronicna ledvicna odpoved. V polovici primerov pridejo bolniki na prvi pregled k zdravniku, ko je bolezen že napredovala, saj RL pogosto ne spremljajo znacilni simptomi. RL najpogosteje metastazira v pljuca (75%), nato v mehka tkiva (36%), kosti (20%), jetra (18%), kožo (8%) in centralni živcni sistem (8%). V diagnostiki prevladujejo slikovne metode. Zakljucki. Lokalizirano bolezen zdravimo kirurško z radikalno nefrektomijo. Ohranitvena operacija je indicirana, ko bi odstranitev celotne ledvice privedla bolnika do dialize. Do danes še ni bila odkrita ucinkovita dopolnilna terapija po operaciji. Metastatsko bolezen zdravimo z interferonom in interlevkinom, prihajajo pa vedno nova in ucinkovitejša biološka zdravila. Najpomembnejši prognosticni dejavnik za preživetje je stadij bolezni ob zacetku zdravljenja. Petletno preživetje bolnikov z RL je 95% za stadij I, 88% za stadij II, 59% za stadij III in 20% za stadij IV. Radio/ Oncol 2007; 41(2): I-VI. Radio/ On col 2007; 41 (2): 72-9. Prikaz primera z Mayo Clinic: Lokalno napredovali karcinom Bartholinijeve žleze Pinn ME, Austin LM, Schomas DA, Miller RC Tumorji Bertholinijeve žleze so redki, predstavljajo manj kot 5% malignomov vulve. Zdravljenje poteka v najvecji meri po nacelih za zdravljenje karcinomov vulve ali analnega kanala. Predstavljen je primer invazivnega, slabo diferenciranega skvamoznega karcinoma Bartholinijeve žleze. V anamnezi 47. letne bolnice izstopa predhodna cervikalna intraepitel­ijska neoplazija, zdravljen s konizacijo, sladkorna bolezen tipa 2, in kajenje. Zdravljena je bila s predoperativno radioterapijo v kombinaciji s 5-fluorouracilom in cisplatinom, cemur je sledila ponovna ocena razširjenosti bolezni ter operacija z rekonstrukcijo vagine. Radio/ Oncol 2007; 41(2): I-VI. Radio/ Oncol 2007; 41(2): 80-5. Trojni socasni rak: medicinski in eticni problem Debevec L, Cesar R, Kern I Izhodišca. Pri bolniku, pri katerem sumimo na socasni rak, so možnosti za ucinkovito zdravljenje omejene. Zato se postavlja vprašanje invazivne diagnostike in natancne zame­jitve, posebno pri starejših bolnikih s slabo telesno zmogljivostjo, ki so primerni le za simptomatsko zdravljenje. Opis primera. 78-letni bolnik z arterijsko hipertenzijo in angino pektoris je bil sprejet v bolnišnico zaradi sinkope. S slikovnimi preiskavami smo ugotovili dva primarna tumorja pljuc in tumor ledvice. Bolnik je odklonil invazivno diagnostiko in po nekaj dneh smo ga odpustili domov. 19 mesecev kasneje je bil ponovno sprejet v slabem klinicnem stanju in je umrl zaradi pljucnice. Avtopsija je pokazala: plošcatocelicni rak desnega zgornjega pljucnega režnja z zasevki v regionalne bezgavke in možgane, drobnocelicni rak levega zgornjega pljucnega režnja z zasevki v regionalne bezgavke in vranico ter svetlocelicni rak desne ledvice s številnimi zasevki v obeh pljucnih krilih. Vsi tumorji so bili nekroticni. Zaradi tega sklepamo, da poskus specificnega zdravljenja verjetno ne bi bil uspešen. Zakljucki. Pri starejšem bolniku z napredovalim pljucnim rakom, pri katerem sumimo na trojni socasni rak, je lahko najbolj ustrezna odlocitev spremljanje bolnika. Radio/ 011col 2007; 41(2): I-VI. Radio/ On col 2007; 41 (2): 86-9. Adenokarcinom ozkega crevesa Šavli M, Jamar B Izhodišca. Adenokarcinom ozkega crevesa je redko maligno obolenje, s prevalenco 0.5­3.0/100.000. Pogosteje prizadene dvanajstnik in jejunum kot ileum. Prikaz primera. 83 letni moški je imel bolecine v trebuhu 3 mesece. Navajal je slabo pocutje, bruhanje in driske, bil je kahekticen. Krvne preiskave so bile v mejah normalnih. Izvidi koloskopije, gastrokopije in ultrazvocnega pregleda so bili prav tako še v mejah normalnih. Pri dvakratnem pregledu v urgentnem bloku abdominalni kirurg ni odkril znakov za akutno kirirurško oboblenje. Pri obeh pregledih so bile na rentgenskem posnetku trebuha vidna razširjene vijuge ozkega crevesa, rentgenski znak ileusa. Ob tretjem pregledu v urgentnem bloku je intrenist napotil bolnika na rentgenski pregled ozkega crevesa, kjer je bila opažena stenozantna sprememba v jejunumu, po videzu maligna. Bolnik je opravil še racunalniško tomografijo trebuha. Pri operaciji so resecirali 30 cm jejunuma, histološko je bil dokazan adenokarcinom. Zakljucek. Jejunoileografija je zanesljiva diagnosticna metoda za prikaz stenozantnih spre­memb ozkega crevesa, v vecini primerov tudi za razlikovanje med benignimi in malignimi spremembami. Radio/ 011col 2007; 41(2): !-VI. Radio/ Oncol 2007; 41 (2): 90-8. Primerjava Poissonovih TCP modelov za posameznika in populacijo Schinkel C, Stavreva N, Stavrev P, Carlone M, Fallone BG Raziskali smo podobnost TCP modelov za posameznika in populacijo. Z ozirom na to, da lahko oba modela opišemo z geometrijskima parametroma y50 in D50, smo pokazali, da dobita skoraj enako obliko pri vrednostih y50 :2c l. Obravnavali smo neprimernost uporabe modela za posameznika na klinicnih podatkih. Podali smo splošen izraz za TCP in ga para­metrizirali z Dr in Yr -z dozo, kjer TCP zavzame vrednost fin z normaliziranim naklonom v tej tocki. Izkazalo se je, da lahko krivuljo interpretiramo kot odziv posameznika le ob dovolj velikem y50. Na osnovi podobnosti TCP modelov za posameznika in populacijo smo obravnavali možnost uporabe slednjega v primeru neenakomernega obsevanja. Ker osnovni TCP model za populacijo predpostavlja enakomerno obsevanje, smo predlagali, da se pri uporabi na klinicnih podatkih vrednost parametra EUD izenaci s povprecno dozo. Radio/ Oncol 2007; 41(2): I-VI. Notices Natices submitted far publicatian shauld cantain a mailing address, phane and/ or fax number and/ar e-mail af a Contact person ar department. Oncology July 5-8, 2007 The "ESMO Conference Lugano" will take place in Lugano, Switzerland. Contact ESMO Head Office, Congress Department, Via La Santa 7, CH-6962 Viganello-Lugano, Switzerland; or +41 (0)91 973 19 19; or fax +41 (0)91 973 19 18; or e-mail congress@esmo.org; or see http://www.esmo. org/activities/ecluconference/ Radiotherapy July 1-5, 2007 The ESTRO teaching course "IMRT and Other Conformal Techniques in Practice" will take place in Vienna, Austria. Contact ESTRO office, Avenue E. Mounierlaan, 83/12, B-1200 Brussels, Belgium; or call +32 2 775 93 40; or fax +32 2 779 54 94; or e-mail info@estro.be; or see http://www.estro.be Radiation oncology July 1-6, 2007 The ESTRO teaching course "Evidence Based Radiation Oncology: Methodological Basis & Clinical Application (extra edition)" will take place in Krakow, Poland. Contact ESTRO office, Avenue E. Mounierlaan, 83/12, B-1200 Brussels, Belgium; or call +32 2 775 93 40; or fax +32 2 779 54 94; or e-mail info@estro.be; or see http://www.estro.be Toxicology July 15-19, 2007 The "11 th International Congress of Toxicology" will be offered in Montreal, Canada. Contact Congress Secretariat, e-mail: ict2007@nrc­cnrc.gc.ca; or see http://www.ict2007.org Radiotherapy August 22-25, 2007 The ESTRO teaching course "30 Planning and Imaging (special edition)" will take place in St Petersburg, Russia. Contact ESTRO office, Avenue E. Mounierlaan, 83/12, B-1200 Brussels, Belgium; or call +32 2 775 93 40; or fax +32 2 779 54 94; or e-mail info@estro.be; or see http:/ jv.,,v,v.estro. be Gynaecology August 30 -September 1, 2007 The ESTRO teaching course "3D Image-based Brachytherapy in Gynaecological Malignancies" will take place in Copenhagen, Denmark. Contact ESTRO office, Avenue E. Mounierlaan, 83/12, B-1200 Brussels, Belgium; or call +32 2 775 93 40; or fax +32 2 779 54 94; or e-mail info@estro.be; or see http://www·.estro.be Lung cancer September 2-6, 2007 The "12th World Conference on Lung Cancer" will be offered in Seoul, Korea. Contact Conference Secretariat; e-mail WCLC2007@ ncc.re.kr; or see http://www.iaslc.org!umages/ 12worldconfannounce. pdf Oncology September 7, 2007 The EORTC annual course "One-Day Introduction to EORTC Trials" will take place in Brussels, Belgium. Contact Mr. Danielle Zimmermann; EORTC Education Office, Avenue E. Mounier, 83, bte 11, B-1200 Brussels, Belgium; or call +32 2 774 16 02; or fax +32 2 772 61 33; or e-mail Danielle.zimmermann@eortc.be; or see http://www.eortc.be Radio/ On col 2007; 41 (2): VII-IX. Radiotherapy September 8-13, 2007 "9th The Biennial ESTRO Meeting on physics and Radiation Technology far Clinical Radiotherapy will take place in Barcelona, Spain. Contact ESTRO office, Avenue E. Mounierlaan, 83/12, B-1200 Brussels, Belgium; or call +32 2 775 93 40; or fax +32 2 779 54 94; or e-mail info@estro.be; or see http://www.estro.be Hematologic malignancies September 14-15, 2007 The NCCN 2nd Annual Congress: "Hematologic Malignancies " will take place in New York, USA. Contact National Comprehensive Cancer Network, 500 Old York Road, Suite 250 Jenkintown, PA 19046, USA; or call +l 215.690.0300; or fax +l 215.690.0280; or e-mail support@nccn.ecimail.net; or see http:// www.nccn.org Oncology September 23-27, 2007 The "14th European Cancer Conference ECCO 15/ ESTRO 26" will take place in Barcelona, Spain. Contact Conference Secretariat, ECCO 14, The European Cancer Conference, European Cancer Societies (FECS), Avenue E. Mounier, 83, B-1200 Brussels, Belgium; or call +32 2 775 02 01; or fax +32 2 775 02 00; or e-mail ECC014@fecs.be; or see http://www.fecs.be Radiotherapy September 30 -October 4, 2007 The ESTRO teaching course "Radiotherapy with Protons and Ions" will take place in Heidelberg, Germany. Contact ESTRO office, Avenue E. Mounierlaan, 83/12, B-1200 Brussels, Belgium; or call +32 2 775 93 40; or fax +32 2 779 54 94; or e-mail info@estro.be; or see http://www.estro.be Radiobiology October 14-18, 2007 The ESTRO teaching course "Basic Clinical radiobiol­ogy" will take place in Giardini Naxos, Italy. Contact ESTRO office, Avenue E. Mounierlaan, 83/12, B-1200 Brussels, Belgium; or call +32 2 775 93 40; or fax +32 2 779 54 94; or e-mail info@estro.be; or see http://wvvw.estro.be Radio/ 011col 2007; 41(2): VII-IX. Radiotherapy October21-25, 2007 The ESTRO teaching course "Physics for Clinical ra­diotherapy" will take place in Limassol, Cyprus. Contact ESTRO office, Avenue E. Mounierlaan, 83/12, B-1200 Brussels, Belgium; or call +32 2 775 93 40; or fax +32 2 779 54 94; or e-mail info@estro.be; or see http://www.estro.be Radiation oncology November 11-16, 2007 The ESTRO teaching course "Evidence Based Radiation Oncology: Methodological Basis & Clinical Application" will take place in Athens, Greece. Contact ESTRO office, Avenue E. Mounierlaan, 83/12, B-1200 Brussels, Belgium; or call +32 2 775 93 40; or fax +32 2 779 54 94; or e-mail info@estro.be; or see http://www.estro.be Prostate cancer November 15-17, 2007 The ESTRO multidisciplinary prostate cancer meeting will be offered. Contact ESTRO office, Avenue E. Mounierlaan, 83/12, B-1200 Brussels, Belgium; or call +32 2 775 93 40; or fax +32 2 779 54 94; or e-mail info@estro.be; or see http://www.estro.be Radiotherapy December 9-13, 2007 The ESTRO teaching course "lmage-Guided Radiotherapy in Clinical Practice" will take place in Brussels, Belgium. Contact ESTRO office, Avenue E. Mounierlaan, 83/12, B-1200 Brussels, Belgium; or call +32 2 775 93 40; or fax +32 2 779 54 94; or e-mail info@estro.be; or see http://www.estro.be Lung cancer June 12-14, 2008 The "11 th Central European Lung Cancer Conference" will be offered in Ljubljana, Slovenia. Contact Conference secretariat, Ms. Ksenia Potocnik, Department of Thoracic Surgery, Medica! Centre Ljubljana, Slovenia; or call +386 1 522 2485; or fax +386 1 522 3968; or e-mail ksenia.potocnik @kclj.si; or see http://en.ce-lung2008.org/ Lung cancer August 21-24, 2009 The "13th World Conference on Lung Cancer" will be offered in San Francisco, USA. Contact Conference Secretariat; e-mail WCLC2007@ ncc.re.kr; or see http://www.iaslc.orgiumages/ 12worldconfannounce. pdf Oncology September 4-8, 2009 The "34th ESMO Congress" will take place in Vienna, Austria. Contact ESMO Head Office, Congress Department, Via La Santa 7, CH-6962 Viganello-Lugano, Switzerland; or +41 (0)91 973 19 19; or fax +41 (0)91 973 19 18; or e­mail congress@esmo.org; or see http://w,v1v.esmo.org As a service to our readers, notices oj meetings ar courses will be inserted free o f charge. Please send information to tlze Editorial office, Radiology and Oncology, Zaloška 2, SI-1000 Ljubljana, Slovenia. Radio/ Onco/ 2007; 41(2): VII-IX. FUNDACIJA "DOCENT DR. J. CHOLEWA" JE NEPROFITNO, NEINSTITUCIONALNO IN NESTRANKARSKO ZDRUŽENJE POSAMEZNIKOV, USTANOV IN ORGANIZACIJ, KI ŽELIJO MATERIALNO SPODBUJATI IN POGLABLJATI RAZISKOVALNO DEJAVNOST V ONKOLOGIJI. DUNAJSKA 106 1000 LJUBLJANA ŽR: 02033-001 7879431 Activity of »Dr. J. Cholewa« Foundation for Cancer Research and Education -a report for the second quarter of 2007 The Dr. J. Cholewa Foundation for Cancer Research and Education plans to con­tinue focusing its activities and attention to cancer research and education in Slovenia. In this setting, it plans to promote all the fonns of cancer education in general population, among medical and nursing students and in general popula­tion. The Dr. J. Cholewa Foundation for Cancer Research and Education will also continue to deal carefully and with great attention with the requests and propos­als for research grants and scholarships. The Foundation members with clinical and research experience in cancer and members with important experience in finance will continue to be instrumental in this activity. The Dr. J. Cholewa Foundation for Cancer Research and Education continues to support the regular publication of "Radiology and Oncology" international medical scientific journal in 2007. This journal is edited, published and printed in Ljubljana, Slovenia. This support is in line with the philosophy of the Foundation, emphasizing the spread of information and knowledge among many profession­als in clinical and laboratory cancer research in Slovenia, but it also gives special attention to many interested individuals in lay public and others in Slovenia and elsewhere. In addition, the Dr. J. Cholewa Foundation for Cancer Research and Education bestowed and allocated by a number research and study grants 2006 and will continue with this activity in 2007. The Foundation pays special attention to the support of the publication of the results from cancer research in Slovenia in respectable international scientific journal worldwide. The Dr. J. Cholewa Foundation for Cancer Research and Education respectfully acknowledges the contribution of its members with clinical and research experi­ence in cancer and its members with experience in finance. Without their efforts the Foundation would not be able to continue with its mission. Borut Štabuc, MD, PhD Tomaž Benulic, MD Andrej Plesnicar, MD, MSc Sanolabor SIEMENS S1e111ensMed1cal.com oncology SEEK-FIND-ACT-FOLLOW -the Continuum of Oncology Care™ Siemens oncology portfol10 compr,ses comprehens,ve max1m1zed ut1hzat1on potent,al. and pat1ent-friendly des,gn workflow solut1ons 1ntegrat1ng the full spectrum of care and features from screen1ng/early detect1on and d1agnos,s through therapy and follow-up Ali from one prov1der -w1th over Every day in the Un1ted States alone, 29.000 cancer 100 years h1story of 1nno11at1on 1n medica! technology pat1ents rece111e rad1at,on therapy dehvered by S,emens hnear accelerators As chn1cal protocols trans1t or to Siemens proven chn1cal methods can help vou to ach1eve ,nclude IMRT and IGRT Siemens seamlessly 1ntegrates more successful outcomes HowJ Through ,ndustry­the d1agnost,c and treatment modalit.es That's what we lead,ng technology, increased product1v1ty measures for call Sest Practice Oncology Care Siemens r id1ca S I ut, o that help estava HYCAMTIN 4 mg pra!ek za koncentrat za raztopino za infundiran)e. Vsaka viala YSebu)e 4 mg topotekana (Y obllkl orida) lndikadje Samostojno zdravfjen)e s topotekanom Je indicirano pri bolnicah z rakom )a)lnika z metastazami, le raplja prve Izbire in tudi naaedn)e terapije niso uspele; bolnikih z relapsom drobnocelllnega pl)ulnega raka, pri katerih novno zdravfjenje s terapijo prve Izbire ni primem. Topotekan v komblnacip s cisplatinom Je indlciran pri bolnicah s noYitvijo karcinoma matemllnega vratu pozdravf)enju z obsevanjem in bolnicah s stadijem IVB karcinoma matemllnega ratu. Odmerjanje in naon uporabe Ka«inom Ja//nlko In drobnocelllnl plfuini ka«inam; lo/etnl odmer,Jc Priporoleni merek topotekana Je t,5 mglm' telesne povr!ine na dan, z intravensko lnfuzljo, ki traja po 30 minut dnevno. v ciklih po zaporednih dni in s tritedenskimi pr.edkl med zaletki vsakega cikla zdravljenja. (ega bolnlkl dobro prenala)o, smemo zdravf)en)em nadaljevati, dokler je bolezen , progresiji. Hadalfevalni odmerki Pred naslednjo uporabo topotekana mora ti !teYilo nevtrofilcev 1 x 10'n, ltevilo trombodto, 100x lD'n, vrednost hemoglobina pa 9 g/dl (po transfuziji, leje le-ta trebna).Bolnike s hudo nevtropeni)o (lteYilo nevtrofilcev < 0,5 x lD'n), ki traja 7 ali vel dni, ali hudo nevtropeni)o z mlano telesno temperaturo ali okuibo, ali tiste, ki pm Je bilo treba zdravf)en)e pre!oliti zaradi ne'ltropenlje, zdravimo tako, uporabimo man)li odmeret tj. t,25 mg/m1 na dan (ali ga po potrebi !e dodatno zmanjlamo do 1,0 mg/m' na dan) ali jemo v na.edn)ih ciklih profilaktilno G-CSF za ohranjanje enake jakosti odmerlca. Zalnemo na 6. dan cikla (na.edn)i n po prenehanju vnalanja topotekana). (e se nevtropenl)a z vnalanjem G-C.SF ustrezno ne popravi, je odmerxe treba njlatl. Podobno je treba zrnan)lati odmerlce, le pade ltevilo trombocitov pod 25 x lD'n. Med klinllnimi preskulanji so potekan prenehali uporabljati, le Je bil odmerek le zman)lan na 1,0 mg/m' in bi ga bilo treba zaradi nelelenlh ulinkov dodatno zmanjlati. Kardnam materni/nega vraru; la/ernl odmerek Priporolenl odmerek topo teka na Je 0,75 mglm1/dan. lnlca ga 1., 2. in l. dan prejme, obliki JO-minutne intravenske lnfuzl)e enkrat na dan. 1. dan po prejemu odmerlca potekana bolnica prejme !e intravensko infuzijo cisplatina , odmerlcu 50 mg/m'/dan. Taklna shema zdravfjen)a se po­ vija vsakih 21 dni, 6 ciklov ali dokler je bolezen, progreslji. Naslednji odmerki Bolnica topotekana ne sme prejeti, le evilo nevtrofilcev ni vecje ali enako 1,5 x 1o•n, !teYilo trombodtov vecje ali enako 100 x lD'n in vrednost hemoglobina ja ali enaka 9 g/dl (po transfuziji, le je le-ta potrebna). Pri bolnicah s febrilno nevtropenijo (!teYilo nevtrofilcev man)!e 1 x lD'n In telesna temperatura l8 '( all velja) je pri na.ednjih ciklih priporofijivo odmerek topotekana zrnanjlati 20 '16 na 0,60 mg/m'ldan.V primeru febrilne nevtropeni)e je alternativa zrnanjlanju odmerlca lahko dajanje G-C.SF po aaedn)em ciklu (pred zmanjlan)em odmerlca). Z npm se zalne 4. dan cikla (vsaj 24 ur po koncu dajanja topotekana).(e febrilna ne'ltropenlja pojavi kljub uporabi G-CSF, je pri naaednjih ciklih priporolifivo odmerek topotekana zrnanjlati za adaljn)ih 20 '16 na 0,45 mg/m'ldan. Pri bolnicah pri katerih se !levilo trombodtov zmanjla pod 10 x lD'n Je pri naslednjih ih priporolijivo odmerek topotekana zman)lati za 20 '16 na 0,60 mg/m'ldan. Odmerjanje pri bolnikih z ledvllno okvaro • zdravf)en)e bolnikov z olistkom kreatinlna < 20 ml/min ne moremo priporoliti ustreznih odmerlcov, saj imamo premalo u!en). Omejena kollona podatkov, ki je na volj. kale, da je treba pri zdravljenju bolni kov z zmerno ledvilno okvaro od­erek zmanjlati. Kontraindikadje Topotekan je kontraindiciran pri bolnikih, ki imajo, anamnezi hudo preobcutljlvostno akcijo na topotekan ali katero koli pomožno snov; bolnicah, ki so nosele ali dojijo; bolnikih, ki imajo hudo depresijo kost­ ega mo,ga le pred zaletkom prvega cikla, kar je razYidno iz lzhodl!lnega !levila ne'llrofilcev < 1,5 x lD'n in/ali !teYila mbocitov 100 x lD'n. Posebna opozorila In prtvldnostnl ukrepi Hematolo!ka toksilnost Je odvisna od odmerlca, to Je treba bolnikom redno nadzorovati celotno krvno sliko, Ykljulno s trombodti. Kot pri uporabi drugih citotoksilnlh ravil so tudi pri uporabi topotekana porolall o pojavu mle!osuprea)e. O pojavu hude mlelosupresije In posledilne sepse so rolali pri 5 '16 bolnikov, ki so se zdravili s topotekanom. Huda sepsa se lahko konla smrtno. Uporaba samega topotekana topo teka na v kombinaciji s cisplatinom je pogosto povezana s pojavom klinllno pomembne trombocitopenije. To je treba po!tevati, npr. pri bolnikih, pri katerih obstaja vel)e tveganje za pojav krvavitve tumorja. Kot)e bilo pri la kovati, se bolni ki, aab!em telesnem stanju (PS> 1) slab!e odzivajo na zdravilo in pri njih tudi pogosteje opažamo zaplete, kot so zYilana sna temperatura, okužbe in sepsa. Pomembno je, da se bolnikow telesno stanje ob zaletku zdravtjenja natancno oce zagotovi, da se ne po.abla na l. Z uporabo topo teka na za zdravf)en)e bolnikov s hudimi motnjami delovanja ledvic ( kreatinina < 20 ml/min) ali s hudo okvaro Jetrne funkcije, ki je poaedica ciroze (serumski bilirubin . 10 mg/dl), ni izku!en). Pri teh skupinah bolnikov zdravljenje s topotekanom ni priporolljivo. Le man)!e !levilo bolnikov z jetrno o (vrednost serumslOVZETEK GLAVNIH ZNACILNOSTI ZDRAVILA transdermalne obliže hranite nedosegljive otrokom. Obližev ne smete razdeliti, razrezati ali na kakršenkoli 'entanil Lek 25, 50 in 100 mikrogramih transdermalni obliži SESTAVA: 1 transdermalni obliž vsebuje na in poškodovati. Fentanil lahko povzroci znatno respiratorno depresijo. Fentanil Lek je treba previdno dajati: ..5 mg, 5,0 mg ali 10,0 mg fentanila. TERAPEVTSKE INDIKACIJE: Kronicne bolecine, pri katerih je bolnikom s kronicno pljucno boleznijo, povišanim intrakranialnimtlakom, možganskim tumorjem, boleznimi srca, iotrebno zdravljenje z opioidnimi analgetiki. ODMERJANJE IN NACIN UPORABE: Odmerek zdravila jeter in ledvic, tistim z zvišano telesno temperaturo, pri starejših bolnikih, bolnikih z miastenijo gravis. Odvisno.si irilagodite posameznim bolnikom in po vsaki uporabi ovrednotite njegov ucinek. Izbira zacetnega odmerka. od zdrav;Ja: IIOt posledica ponavljajoce se uporabe se lahko razvijeta toleranca za ucinkovino ter psihološka •išina odmerka naj temelji na predhodni uporabi opioidov. Pri bolnikih, ki nimajo izkušenj z opioidi in ki in/ali tizi na odvisnost od nje. Drugi lahko se pojavijo neepilepticne (mio)klonicne reakcije. MEDSEBOJNO 1pioidov predhodno niso jemali, zacetni odmerek ne sme presegati 25 µg/h. Predhodnega zdravljenja z DELOVANJE Z DRUGIM ZDRAVILI 1N DRUGE OBLIKE INTERAKCIJ:. Opioidi, sedativi, hipnotiki, splošni 1nalgetlki ne smete prekiniti prej kot v 12 urah po namestitvi prvega transdermalnega obliža. Oolocde11 anestetiki, fenotiazini, anksiolitiki, sredstva za sprošcanje mišic, sedativni antihistaminiki in alkoholne pijace, -elikosti odmerka in vzdrževalnega odmerka. Transdermalne obliže menjajte v 72-urnih presledkih. ritonavir, ketokonazol, itrakonazol in nekateri makrolidni antibiotiki, petidin in zaviralci monoaminske oksidaze )dmerek titrirajte, dokler ne dosežete analgeticnega ucinka. ce je analgeticni ucinek ob koncu zacetnega (npr. tranilcipromin), pentazocin, buprenorfin. VPLIV NA SPOSOBNOST VOŽNJE IN UPRAVLJANJA S ,bdobja uporabe neustrezen, lahko odmerek povecujete v tridnevnih presledkih do želenega ucinka. STROJI: Zdravilo Ima mocan ucinek na sposobnost za vožnjo in upravljanje strojev. Bolniki naj se o tem, ali 'rehod na drugo zdravljenje a/iprenehanje zdravljenj'a. ce želite preiti na zdravljenje z drugim oploidom, smejo vozili in upravljati stroje, posvetujejo z zdravnikom. NEŽELENI UCINKI: Najresnejši neželeni ucinek dstranite transdermalni obliž Fentanil Lek in titrirajte odmerek novega analgetika glede na bolnikovo rentanila je respiratorna depresija. Zelo pogosti (> 1/10): zaspanost, glavobol, navzeja, bruhanje, zaprtje, orocanje o bolecini, dokler ne dosežete ustreznega analgeticnega ucinka. Pri nekaterih bolnikih se lahko potenje, pruritus. Pogosti(> 1/100, < 1/10): sedacija, zmedenost, depresija, tesnoba, živcnost, halucinacje, i ojavjo odtegnitveni simptomi. Uporaba pri otrocih. Zaradi jakosti odmerkov tega zdravila se uporaba pri zmanjšan apetit, kserostomija, dispepsija, kožne reakcije na mestu uporabe. Obcasni(> 1/1000, < 1/100): trocih ne priporoca. Uporaba pri stare/Sih. pri starejših bolnikih je treba biti pozoren na znake prevelikega evforija, amnezija, nespecnost, razdražljivost, tremor, parestezija, motnje govora, bradikardija, tahikardija, dmerjanja in odmerek po potrebi zmanjšati. Uporaba pri bolnikih z okVa'ro ledvic ali/eter. pri teh bolnikih hipotenzija, hipertenzija, dispneja, hipoventilacija, hemoptiza, pulmona!na kongestija in faringitis, driska, 1 treba biti pozoren na znake prevelikega odmerjanja in odmerek po potrebi zmanjšati. Uporaba pri izpušcaji, eritem, zadrževanje urina. P reobcut#i"vostne reakcje. anafilakticne reakcije, laringospazem. Drug, IOlnikih s povi§ano telesno temperaturo. med epizodami povišane telesne temperature bo morda potrebno neželeni ucinki pri dolgotrajni uporabi se lahko razvijeta toleranca in psihicna ali fiziološka odvisnost. Pri rilagajanje odmerka. KONTRAINDIKACIJE: Znana preobcutljivost za fentanil, katerokoli pomožno nekaterih bolnikih, ki z drugega opioidnega analgetika preidejo na transdermalne obliže Fentanil Lek, nov ali lepilo transdermalnega ob!lža. Hudo okvarjeno delovanje osrednjega živcevja. Socasna uporaba se lahko pojavijo reakcije, znacilne za prekinitev zdravljenja z opioidi. NACIN IZDAJE ZDRAVILA: Na aviralcev MAO ali uporaba v 14dneh po prenehanju zdravljenja z zaviralci MAO. POSEBNA OPOZORILA zdravniški recept. OPREMA: Škatlice s 5 lransdermalnimi obliži po 25, 50 in 100 mikrogramov/h. IMETNIK >I PREVIDNOSTNI UKREPI: Zaradi razpolovnega casa fentanila morate bolnika po pojavu resnega DOVOLJENJA ZA PROMET Z ZDRAVILOM: Lek farmacevtska družba d.d., Verovškova 57, Ljubljana, eže!enega ucinka nadzorovati še 24 ur po odstranitvi transdermalnega obliža. Uporabljene in neuporabljene Slovenija. INFORMACIJA PRIPRAVLJENA: oktober 2006 .lek clan skupine Sandoz let razvoja Lek farmacevtska družba d.d. Verovškova 57, 1526 Ljubljana, Slovenija• www.lek.si ® rimidex anastrozol Kratka informacija o zdravilu lmezdravlla Arimidex 1 mg filmsko obložene tablete Sestava Ena tableta vsebuje 1 mg anastrozola. Indikacije Adjuvantno zdravljenje žensk po menopavzi, ki imajo zgodnji invazivni rak dojke s pozitivnimi estrogenskimi receptorji. Zdravljenje napredo­valega raka dojke pri ženskah po menopavzi. Ucinkovitost pri bolnicah z negativnimi estrogenskimi receptorji ni bila dokazana razen pri tistih, ki so imele predhodno pozitiven klinicni odgovor na tamoksifen. Odmerjanje In nacin uporabe 1 tableta po 1 mg peroralno, enkrat na dan. Pri zgodnjem raku je priporocljivo trajanje zdravljenja 5 let. Kontraindikacije Arimidex je kontraindiciran pri: ženskah pred menopavzo, nosecnicah in dojecih materah, bolnicah s hujšo ledvicno odpovedjo (ocistek kreatinina manj kot 20 ml/min (oziroma 0,33 mljs)), bolnicah z zmernim do hudim jetrnim obolenjem, bolnicah, ki imajo znano preobcutljivost za anastrozol ali za katerokoli drugo sestavino zdravila. Posebna opozorila in previdnostni ukrepi Menopavzo je potrebno biokemicno dolociti pri vseh bolnicah, kjer obstaja dvom o hormonskem statusu. Ni podatkov o varni uporabi Arimidexa pri bolnicah z zmerno ali hudo jetrno okvaro ali hujšo ledvicno odpovedjo (ocistek kreatinina manj kakor 20 mljmin (oziroma 0,33 ml/s)). Pri ženskah z osteoporozo ali pri ženskah s povecanim tveganjem za razvoj osteoporoze je treba dolociti njihovo mineralno gostoto kosti z denzitometrijo, na primer s slikanjem DEXA na zacetku zdravljenja, pozneje pa v rednih intervalih. Po potrebi je treba zaceti z zdravljenjem ali preprecevanjem osteoporoze in to skrbno nadzorovati. Povzetek glavnih neželenih ucinkov Zelo pogosti (2: 10 %): navali vrocine, obicajno blagi do zmerni Pogosti (2: 1 % in < 10 %): astenija, bolecine / okorelost v sklepih, suhost vagine, razredcenje las, izpušcaji, slabost, diareja, glavobol (vsi obicajno blagi do zmerni) Arimidex znižuje nivo estrogena v obtoku, zato lahko povzroci zmanjšanje mineralne kostne gostote, kar pomeni za nekatere bolnike zvecano tveganje za zlome. Medsebojno delovanje z drugimi zdravili Zdravila, ki vsebujejo estrogen, ne smete dajati socasno z Arimidexom, ker bi se njegovo farmakološko delovanje iznicilo. Tamoksifena se ne sme uporabljati skupaj z Arimidexom, ker lahko pride do zmanjšanja njegovega delovanja. Režim izdajanja zdravila Rp/Spec Datum priprave informacije Februar 2007 Pred predpisovanjem, prosimo, preberite celoten povzetek glavnih znacilnosti zdravila. Dodatne informacije in literatura so na voljo pri: AstraZeneca UK Limlted Podružnica v Sloveniji Verovškova 55, Ljubljana in na spletnih straneh: www.breastcancersource.com www.arimidex.net AstraZeneca emodal 20 mg; 100 mg, 250 mg. Sestava zdravila Vsaka kapsula zdravila Temodal vsebuje 20 mg, 100 mg ali 250 mg temozolamida.Terapevlske indikacije Temodal apsule so indicirane za zdravljenje bolnikov z: -za zdravljenje novo diagnosticiranega glioblastoma multiforme, socasno z radioterapijo in kasneje kot monoterapija, ­1alignim gliomom, na primer multiformnim glioblastomom ali anaplasticnim astrocitomom, ki se po standardnem zdravljenju ponovi ali napreduje. Odmerjanje in nacin porabe Temodal smejo predpisati le zdravniki, ki imajo izkušnje z zdravljenjem možganskih tumorjev. Odrasli bolniki z novo diagnosticiranim glioblaslomom multi­orme Temodal se uporablja v kombinaciji z žarišcno radioterapijo (laza socasne terapije), temu pa sledi do 6 ciklov monoterapije z temozolomidom.Faza socasne tera­ije Zdravilo Temodal naj bolnik jemlje peroralno v odmerku 75 mg/m2 na dan 42 dni, socasno z žarišcno radioterapijo (60 Gy, danih v 30 delnih odmerkih). Odmerka e boste zmanjševali, vendar se boste vsak teden odlocili o morebitni odložitvi jemanja temozolomida ali njegovi ukinitvi na podlagi kriterijev hematološke in ehematološke toksicnosti. Zdravilo Temodal lahko bolnik jemlje ves cas 42-dnevnega obdobja socasne terapije do 49 dni, ce so izpolnjeni vsi od naslednjih pogojev: bsolutno število nevtrofilcev ? 1,5 x 109/1, število trombocitov ? 100 x 109/1, skupni kriteriji toksicnosti (SKT) za nehematološko toksicn_ost :S 1. stopnje (z izjemo lopecije, slabosti in bruhanja). Med zdravljenjem morate pri bolniku enkrat na teden pregledati celotno krvno sliko. Faza monolerapije Stiri tedne po zakljucku faze ocasnega zdravljenja z zdravilom Temodal in radioterapijo naj bolnik jemlje zdravilo Temodal do 6 ciklov monoterapije. V 1. ciklu (monoterapija) je odmerek zdravila 150 1g/m2 enkrat na dan 5 dni, temu pa naj sledi 23 dni brez terapije. Na zacetku 2. cikla odmerek povecajte na 200 mg/m2 , ce je SKT za nehematološko toksicnost za 1. cikel topnje :s-2 (z izjemo alopecije, slabosti in bruhanja), absolutno število nevtrofilcev (AŠN) ? 1,5 x 10'/I in število trombocitov? 100 x 109/1. ce odmerka niste pov­cali v 2. ciklusu, ga v naslednjih ciklusih ne smete povecevati. Ko pa odmerek enkrat povecate, naj ostane na ravni 200 mg/m2 na dan v prvih 5 dneh vsakega nasled­jega ciklusa, razen ce nastopi toksicnost. Med zdravljenjem morate pregledati celotno krvno sliko na 22. dan (21 dni po prvem odmerku zdravila Temodal). Ponavljajoci e ali napredujoci maligni gliom: Odrasli bolniki Posamezen ciklus zdravljenja traja 28 dni. Bolniki, ki še niso bili zdravljeni s kemoterapijo, naj jemljejo Temodal pero­lino v odmerku 200 mg/m2 enkrat na dan prvih 5 dni, temu pa naj sledi 23-dnevni premor (skupaj 28 dni). Pri bolnikih, ki so že bili zdravljeni s kemoterapijo, je acetni odmerek 150 mg/m2 enkrat na dan, v drugem ciklusu pa se poveca na 200 mg/m2 enkrat na dan 5 dni, ce ni bilo hematoloških toksicnih ucinkov. Pediatricni olniki Pri bolnikih, starih 3 leta ali starejših, posamezen ciklus zdravljenja traja 28 dni. Temodal naj jemljejo peroralno v odmerku 200 mg/m2 enkrat na dan prvih 5 dni, otem pa naj sledi 23-dnevni premor (skupaj 28 dni). Otroci, ki so že bili zdravljeni s kemoterapijo, naj prejmejo zacetni odmerek 150 mg/m2 enkrat na dan 5 dni, s ovecanjem na 200 mg/m2 enkrat na dan 5 dni v naslednjem ciklusu, ce ni bilo hematoloških toksicnih ucinkov. Bolniki z motnjami v delovanju jeter ali ledvic Pri olnikih z blagimi ali zmernimi motnjami v delovanju jeter je farmakokinetika temozolomida podobna kot pri tistih z normalnim delovanjem jeter. Podatki o uporabi dravila Temodal pri bolnikih s hudimi motnjami v delovanju jeter (razred III po Child-u) ali motnjami v delovanju ledvic niso na voljo. Na podlagi farmakokineticnih last­osti temozolomida obstaja majhna verjetnost, da bo pri bolnikih s hudimi motnjami v delovanju jeter ali ledvic potrebno zmanjšanje odmerka zdravila. Kljub temu je otrebna previdnost pri uporabi zdravila Temodal pri teh bolnikih. Starejši bolniki Analiza farmakokinetike je pokazala, da starost ne vpliva na ocistek temozolomida. Kljub imu je potrebna posebna previdnost pri uporabi zdravila Temodal pri starejših bolnikih. Nacin uporabe Temodal mora bolnik jemati na tešce. Temodal kapsule mora olnik pogoltniti cele s kozarcem vode in jih ne sme odpirati .li žveciti. Predpisani odmerek mora vzeti v obliki najmanjšega možnega števila kapsul. Pred jemanjem dravila Temodal ali po njem lahko bolnik vzame antiemetik. Ce po zaužitju odmerka bruha, ne sme še isti dan vzeti drugega odmerka. Kontraindikacije Temodal je ontraindiciran pri bolnikih, ki imajo v anamnezi preobcutljivostne reakcije na sestavine zdravila ali na dakarbazin (DTIC). Temodal je kontraindiciran tudi pri bolnikih s hudo 1ielosupresijo. Temodal je kontraindiciran pri ženskah, ki so nosece ali dojijo. Posebna opozorila in previdnostni ukrepi Pilotno preskušanje podaljšane 42-dnevne sheme dravljenja je pokazalo, da imajo bolniki, ki so socasno prejemali zdravilo Temodal in radioterapijo, še posebej veliko tveganje za nastanek pljucnice zaradi okužbe s 'neumocystis carinii (PCP). Profilaksa proti tovrstni pljucnici je torej potr_ebna pri vseh bolnikih, ki socasno prejemajo zdravilo Temodal in radioterapijo v okviru 42-dnevne heme zdravljenja (do najvec 49 dni), ne glede na število limfocitov. Ce nastopi limfopenija, mora bolnik nadaljevati s profilakso, dokler se limfopenija ne povrne na topnjo :s-1. Antiemeticna terapija: Z jemanjem zdravila Temodal sta zelo pogosto povezana slabost in bruhanje. Laboratorijske vrednosti Pred jemanjem zdravila 1orata biti izpolnjena naslednja pogoja za laboratorijske izvide: ANC mora biti ? 1,5 x 109/1 in število trombocitov ? 100 x 109/1. Na 22. dan (21 dni po prvem odmerku) li v roku 48 ur od navedenega dne, morate pregledati celotno krvno sliko in jo nato spremljati vsak teden, dokler ni ANC nad 1,5 x 109/1 in število trombocitov nad 100 109/1. ce med katerimkoli ciklusom ANC pade na < 1,0 x 109/1 ali število trombocitov na < 50 x 109/1, morate odmerek zdravila v naslednjem ciklusu zmanjšati za eno dmerno stopnjo. Odmerne stopnje so 100 mg/m2 , 150 mg/m2 in 200 mg/m2 • Najmanjši priporoceni odmerek je 100 mg/m2 • Moški bolniki Temozolomid lahko deluje enotoksicno, zato morate moškim, ki se zdravijo z temozolomidom svetovati, da naj ne zaplodijo otroka še šest mesecev po zdravljenju. Interakcije Socasna uporaba dravila Temodal in ranitidina ni povzrocila spremembe obsega absorpcije temozolomida ali monometiltriazenoimidazol karboksamida (MTIC). Jemanje zdravila Temodal hrano je povzrocilo 33 % zmanjšanje Cmax in 9 % zmanjšanje površino pod krivuljo (AUC). Ker ne moremo izkljuciti možnosti, da bi bila sprememba Cmax lahko linicno pomembna, naj bolniki jemljejo zdravilo Temodal brez hrane. Analiza populacijske farmakokinetike v preskušanjih druge faze je pokazala, da socasna uporaba eksametazona, proklorperazina, fenitoina, karbamazepina, ondansetrona, antagonistov receptorjev H2 ali fenobarbitala ne spremeni ocistka temozolomida. Socasno :manje z valprojsko kislino je bilo povezano z majhnim, a statisticno znacilnim zmanjšanjem ocistka temozolomida. Uporaba zdravila Temodal v kombinaciji z drugimi 1ielosupresivnimi ucinkovinami lahko poveca verjetnost mielosupresije. Nosecnost študij na nosecih ženskah ni bilo. Predklinicne študije na podganah in kuncih z dmerkom 150 mg/m2 so pokazale teratogenost in/ali toksicnost za plod. Zato naj nosece ženske naceloma ne bi jemale zdravila Temodal. ce pa je uporaba v casu osecnosti nujna, morate bolnico opozoriti na možne nevarnosti zdravila za plod. Zenskam v rodni dobi svetujte, naj med zdravljenjem z zdravilom Temodal preprecijo anositev. Oojenje Ni znano, ali se temozolomid izloca v materino mleko, zato ženske, ki dojijo, ne smejo jemati zdravila Temodal. Neželeni ucinki V klinicnih preskušanjih o bili najpogostnejši neželeni ucinki, povezani z zdravljenjem, prebavne motnje, natancneje slabost (43 %) in bruhanje (36 %). Oba ucinka sta bila ponavadi 1. ali 2. topnje (od O do 5 epizod bruhanja v 24 urah) in sta prenehala sama ali pa ju je bilo mogoce hitro obvladati s standardnim antiemeticnim zdravljenjem. lncidenca hude sla­osti in bruhanja je bila 4 %. Laboratorijski izvidi: Trombocitopenija in nevtropenija 3. in. 4. stopnje sta se pojavili pri 19 % in 17 % bolnikov, zdravljenih zaradi malignega lioma. Zaradi njiju je bila potrebna hospitalizacija in/ali prekinitev zdravljenja z zdravilom Temodal pri 8 % in. 4 % bolnikov. Mielosupresija je bila predvidljiva (ponavadi e je pojavila v prvih nekaj ciklusih in je bila najizrazitejša med 21. in 28. dnem), okrevanje pa je bilo hitro, ponavadi v 1 do 2 tednih. Opazili niso nobenih dokazov umulativne mielosupresije. Trombocitopenija lahko poveca tveganje za pojav krvavitev, nevtropenija ali levkopenija pa tveganje za okužbe.Imetnik dovoljenja za pro­iet SP Europe 73, rue de Stalle B-1180, Bruselj, Belgija. Nacin in režim izdaje Zdravilo se izdaja samo na recept, uporablja pa se pod posebnim nadzorom zdravnika pecialista ali od njega pooblašcenega zdravnika. Datum priprave informacije januar 2006 Podrobnejše informacije o zdravilu Temodal dobite na sedežu podjetja . .,, ScherinfJ-Plough resnicni napredek Pri na novo odkritem glioblastomu multiforme in malignih gliomih, ki se ponovijo ali napredujejo. nove barve kapsul Temodal, omogocajo lažje odmerjanj l[MOOAl lEMOM lEMODAL 100mg 150 m. Dunajska 22, 1000 Ljubljana tel: 01 300 10 70 lax: 01 300 1 O 80 Teanodal® cf., Schering-Plough temozol.mid KE ED Za . bioznanosti SYNGENE, INVITROGEN: DYNAL, ZYMED, MOLECULAR PROBES, CALTAG @ diagnostike MINERVA, MEDAC, BIOTEK gojenja celicnih kultur INVITROGEN-GIBCO, TPP, GREINER in SANYO merjenja absorbance, fluorescence in luminiscence BIOTEK @ pipetiranja BIOHIT in BIOTEK @ laboratorijske opreme SANYO ® ciste vode za laboratorije ELGA LABWATER @ HPLC in GC kolon, vial in filtrov PHENOMENEX in CHROMACOL/NATIONAL SCIENTIFIC SVETOVANJE, TRGOVINA, TRŽENJ Ed.o.o.• l