Dr. Tareq Salah Ahmed,MD,ESMO. Lecturer of clinical oncology, Assiut faculty of medicine ESMO accreditation certificate

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2 Dr. Tareq Salah Ahmed,MD,ESMO Lecturer of clinical oncology, Assiut faculty of medicine ESMO accreditation certificate 1 st Assiut Urology department conference,marsa Alam 3 rd February 2015

3 Bladder cancer Epidemiology

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6 Incidence rates in Females Incidence rates in males

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9 Gharbia Population based registry, report

10 Proportion (%) of the most common cancers in Males: Population-based data, Egypt Bladder Liver Non hodgkin Lung Leukemia Colorectum Prostate Skin (non melanoma) Brain & CNC Connective & soft tissue

11 Proportion (%) of the most common cancers in Females: Population-based data, Egypt Breast Non hodgkin Ovary Leukemia Colorectum Bladder Liver Brain & CNC Lung Connective & soft tissue

12 Proportion (%) of the most common cancers in both sexes Population-based data: Egypt Breast 17.6 NHL Bladder Liver Lung Leukemias Colorectum Brain & CNC Skin (non melanoma) Connective & soft tissue

13 The National Cancer Institute Cairo University

14 Most Common Sites in Males Bladder Liver Lymphoma Leukemia Lung Colorectal Soft tissue Skin Pancreas Larynx Percent of cases

15 SCC era TCC era

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18 PERIOD REL FREQ AGE M:F BILHARZIAL OVA Squamous Cell Ca TRANSITIONAL CELL CA LATE STAGE III -IV RADICAL CYSTECTOCTOMY % % 58% 31% 86% 80% % % 27% 66% 40% 36%

19 Relative Frequency of Bladder Cancer, NCI * * 30 * Percent * * * * * * * * * * * * 10 * * Year

20 Prevalence Schistosomiasis Control in Egypt % * * Percent 30 * 20 * * * 25 * * * * 20 * * 10 * * 15 * 10 0 * * S.haematobium S.mansoni Year

21 TNM STAGING OF UROTHELIAL CARCINOMA OF URINARY BLADDER

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24 TNM Staging of urothelial carcinoma of bladder

25 BEFORE PLANNING THINK IN.. Patient Disease Treatment

26 Disease

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30 overall survival rates : 30 % - 45 %

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32 Muscle-invasive TCC bladder Cystectomy and reconstruction Bladder conservation Goals: Cure patient and optimize survival Prevention of pelvic failure and distant metastasis functional urinary reservoir and high QOL

33 Know your patients, the disease & your capabilities Patient related factors Symptoms, age, co-morbidity, erectile function, life expectancy, expectations Tumour related factors Stage, biopsy profile.. Treatment related factors XRT methods (XRT, BT, CFRT, IMRT), dose-fractionation Resource factors: expertise, infra-structure, equipment

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36 What are the most important questions? 1- Overall survival. 2- Time to local recurrence. 3- Time to metastasis.( Distant failure).

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39 Five-year survival after Radical Cystectomy Zaghloul. Cancer Gen Cytogen 2008; 80:

40 5-year survival of radical cystectomy CIS T1 T2 T3 T4

41 Five-year survival after Radical Cystectomy Zaghloul. Cancer Gen Cytogen 2008; 80:

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43 5-year actuarial local recurrence rates in different radical cystectomy series Greven 92 Zaghloul 92 Visser 05 No % No % No % P0,is P P2a Hassan 06 No % P2b P P All NM

44 When is the Peak incidence of local recurrence to develop?

45 Local Recurrence is not rare in locally advanced Stages (Visser et al, 2005)

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48 Distant Metastasis in different series Pollack et al,95 Zaghloul, 96 Madersbacher,03 No % No % No % Pa,1 NM P2a NM P2b NM P3 NM P4 NM N- NM NM N+ NM NM All

49 Distant Metastasis From Bladder Cancer The rate of distant metastasis in TCC ranged from from 12-35% (Miller, 1977 & Werf-Messing, 1982). In a retrospective study Zaghloul (1996) reported upon distant metastasis in 357 patients treated either with cystectomy, preoperative or postoperative radiotherapy (i.e. No chemotherapy received) the 5-year cumulative incidence of distant metastasis was 23±2%.

50 Results of Radical Cystectomy 5-year disease- free survival rates of radical cystectomy ranged from 25-48% depending upon the stage, grade & nodal status. Local recurrence represented 50-60% of the causes of failure after radical cystectomy in advanced stages. Most of the local recurrences were clinically detected within the first year after cystectomy. This suggests that it originate from a large residual tumour cell burden. Most of the local recurrences were inside the true pelvis that can be encompassed within the field of radiation.

51 Bladder Preservation Protocols

52 Organ Preservation is not exclusive for UB carcinoma Anal carcinoma. Breast carcinoma. Esophageal carcinoma. Laryngeal carcinoma. Limb sarcomas. Prostate carcinoma.

53 WHY? Preserve Bladder function. Preserve sexual function. Maintain quality of life and body image. Avoid major surgery. Many patients are elderly. Co-morbidities that make patient inoperable.

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55 Radical cystectomy (RC) is associated with considerable morbidity. Aside from the perioperative period, RC with urinary diversion poses great potential for long-term complications and morbidity. Bladder preservation therapies for muscle-invasive bladder cancer (MIBC) have been developed to address the needs of two cohorts : Patients with severe medical co-morbidities for whom a radical surgery is too high risk. Patients with limited disease who wish to avoid radical surgery. The goal of achieving complete response to treatment while maintaining bladder form and function has led to the development of multimodal approaches to this disease.

56 In medically operable patients ( fit for surgery), there is abundant evidence to support trimodal therapy as an acceptable treatment option for highly selected patients with MIBC with favourable pathological parameters. While outcomes are worse for medically inoperable patients ( unfit for surgery), bladder preservation approaches still offer curative potential.

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58 Small tumor size (<2 cm). Early tumor stage (T2,T3 disease). Complete TURBT. No ureteral obstruction (Hydronephrosis). No evidence of pelvic lymph node metastases. Absence of carcinoma in situ (Tis).

59 Radiotherapy Chemotherapy

60 University of Paris/Harvard University University of Erlangen

61 Maximal TURBT Cover systemic disease XRT + Concomitant Chemotherapy Radiosenstization of tissues Cystoscopic response evaluation CR Consolidation Chemo-radiation (64Gy) +/- adjuvant chemo Non-CR Radical Cystectomy +/- adjuvant chemo

62 Max. TURBT 3 cycles of Gem+Cisplatin Follow up cystoscopy CR another 3 cycles + Rth Reaidual Disease Unfit Radiochemo fit Cysectomy

63 What is the importance of an aggressive TURBT for Cystectomy Avoidance? The TURBT must be done with the determination to resect all visible tumor. Nothing less will suffice NM Heney et al NATURE Rev Clin Oncol

64 Pathological exam of cystoscopic biopsy should comment on: Tumor growth pattern. Grade. Evidence of muscle invasion. Multifocality. Presence of associated carcinoma in situ.

65 What is the incidence comorbidities in patients with MIBC?

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67 Co-morbidities and bladder cancer CO-MORBID ILLNESS None 1 2 OR MORE DM Hypertension Cardiovascular Pulmonary TOTAL % TYPE OF CO-MORBID ILLNESS MEAN AGE (n=2445) in south of Netherlands Goosens-Loan et al. Int J. Cancer: 135, ;

68 I ll save the patient.. From this serial killer!! Son, Patient will lose his bladder Sooner or later! Why not to try trimodality technique sir?

69 CYSTECTOMY 11% PARTIAL CYSTECTOMY 1% NO SUBSEQUENT SURGICAL PROCEDURE AT THE HOSPITAL 57% TURBT OR DESTRUCTION 31% TOTAL CYSTECTOMY PARTIAL CYSTECTOMY TURBT NO SUBSEQUENT SURGICAL PROCEDURE AT THE HOSPITAL Hayter et al IJROBP P

70 Cochrane Central Register of Controlled Trials and MEDLINE. Considered all controlled trials providing information about the efficacy and safety of trimodality therapy for selective organ preservation in urothelial cell carcinoma of the bladder as eligible.

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73 What about side effects and toxicity?

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75 Results Median follow-up was 5.4 years (range, 2.0 to 13.2 years). 7% experienced late grade 3 + pelvic toxicity: 5.7% GU and 1.9% GI. Notably there were no late grade 4 toxicities. No treatment-related deaths. None of the clinical variables studied predicted for late grade 3 + pelvic toxicity. Conclusion Rates of significant late pelvic toxicity for patients completing combined-modality therapy for invasive bladder cancer and retaining their native bladder are low.

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88 Bloom 1982 study, preoperative radiation treatment consisted of 4000 cgy in 4 weeks to the whole pelvis followed 4 weeks later by cystectomy (method not stated). The radical radiotherapy schedule was 4000 cgy in 4 weeks plus a 2000 cgy boost in 2 weeks to the bladder and perivesical tissue. Eighteen patients had salvage cystectomy for recurrent or residual tumour. Miller 1973 study the preoperative and radical radiotherapy schedules were 5000 cgy in 25 fractions over 5 weeks and 7000 cgy in 35 fractions over 7 weeks, respectively. Radical cystectomy consisted of radical cystoprostatectomy (anterior pelvic exenteration in women) and bilateral ureto-ileostomy with no node dissection. Two patients underwent salvage cystectomy following radical radiotherapy. Sell 1991 employed radiotherapy to the whole pelvis with rectal shielding using schedules of 4000 cgy in 20 fractions over 5 weeks (pre-operative) and a total dose of 6000 cgy (radical). Cystectomy was performed according to the method of Whitmore 1977, which included cystoprostatectomy plus pelvic lymph node dissection, and diversion as an ileal conduit. A nerve-sparing procedure was carried out in 9 patients from the radical cystectomy group and 2 from the radical radiotherapy group.

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90 Rosinger et al 1992

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94 RADIOLOGY PATHOLOGY UROLOGY ONCOLOGY

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