2. Management of Urinary Bladder Cancer : State of the Art Hussein M. Khaled Prof. Medical Oncology Vice President for Post graduate Studies and Research Cairo University By:

4. Ranking of ASIR of Bladder Cancer worldwide rates (Males) 0 10 20 30 40 50 60 70 80 90 100 The Gambia 1.3 Belgium 42.5 Louisiana 16.6 Egypt 26.3 Western Europe Percentiles

5. Most Common Cancers within EMR

9. TNM Staging

10. CLINICAL SETTINGS OF BLADDER CARCINOMA Organ confined: Superficial 75% M. Invasive 25% Metastatic: 5 %

11. HISTOPATHOLOGIC TYPES OF BLADDER CARCINOMA 1. Transitional cell carcinoma 90 % 2. Squamous cell carcinoma 5 % 3. Adenocarcinoma 2 % 4. Undifferentiated carcinoma 2 %

12. GROWTH PATTERN OF TRANSITINAL CELL CARCINOMA Papillary (Exophytic) Non-papillary (Endophytic)

13. Urothelial Tumours Overview of Treatment Options Surgery: Radical cystectomy, urinary diversion, lymphadenectomy Radiotherapy Intravesical instillations: immunotherapy or chemotherapy Transurethral resection (TUR) Chemotherapy Chemotherapy (neo-adjuvant or adjuvant) Non-muscle invasive: 70% Muscle invasive: 25% Metastatic: 5% ± palliative RT Treatment options

14. Contents Muscle invasive urothelial carcinoma Metastatic urothelial carcinoma Non-muscle invasive urothelial carcinoma

15. Non-muscle invasive TCCU Prognostic Factors * PUNLMP: Papillary Urothelial Neoplasm of Low Malignant Potential Low risk tumours Single Ta Low grade or PUNLMP* diameter < 3cm, non-recurrent Intermediate risk tumours Low-grade Ta, or PUNLMP multifocal and/or recurrent low-grade T1 High risk tumours High grade Ta (Gr3), T1 Gr3 , recurrent T1, Cis

18. Non-muscle invasive TCCU Summary of Therapeutic Sequence & Monitoring Close follow-up is required Non-muscle invasive urothelial tumour Stage Treatment Monitoring Low-risk tumour Complete TUR Cystoscopy 3m, 9m, then annually for 15y (if normal) Intermediate-risk tumour CompleteTUR + local CT or BCG Cystoscopy and cytology 3m, 6m, 12m, then annually for at least 15y High-risk tumour Complete TUR + BCG with maintenance treatment Cystoscopy and cytology Every 3 months (2y) Every 4-6 months (3y), Then annually for 15 years

19. Contents Non-invasive urothelial carcinoma Invasive urothelial carcinoma Metastatic urothelial carcinoma

20. Prognostic Factors for Advanced Cases

22. Supervised analysis 55 genes differentially expressed with expression values significantly correlated to survival Columns: Patients Listed according to survival Rows: Genes Listed according to protein function

23. Cisplatin resistance

24. Cell-cycle regulation

25. Angiogenesis

27. Chemotherapy in metastatic bladder cancer “ Old” single agents Agent ORR Cisplatin 28 % (2 6 -3 2 ) Carboplatin 15 % (11-19) Methotrexate 29 % (23-35) Ifosfamide 28 % (19-37) Doxorubicin 17 % (1 3 -2 2 ) 5-Fluorouracil 1 7 % (1 1 - 25 ) Vinblastine 16 % (4-28) Mitomycin C 13 % (3-23)

29. Chemotherapy in metastatic bladder cancer Mead GM et al. Br J Cancer. 1998 C MV vs. MV N 214 patients Median survival 7 months vs. 4.5 months 1-year survival 29% vs. 16% Hazard ratio 0.68

35. From MVAC to other cisplatin-containing regimens

36. Paclitaxel + Cisplatin in metastatic bladder cancer Dreicer R et al. J Clin Oncol. 2000 Burch PA et al. J Urol. 2000 Murphy BA et al. J Clin Oncol. 1996 Studies (n) Patients (n) OR rate ( % ) CR rate (%) Median survival (m onths ) 3 104 60% 19% 10.6 - 13.0

37. Docetaxel + Cisplatin in metastatic bladder cancer Dimopoulos MA et al. Ann Oncol. 1999 Garcia del Muro X et al. Br J Cancer. 2002 Sengelov L et al. J Clin Oncol. 1998 Studies (n) Patients (n) OR rate ( % ) CR rate (%) Median survival (m onths ) 3 129 55% 17% 8.0 - 13.6

38. Docetaxel + Cisplatin vs. MVAC in metastatic bladder cancer N=220 Bamias A et al. J Clin Oncol. 2004 Drug regimen Overall response Median survival D + C MVAC 37% 54% 9.3 months 14.2 months

39. Paclitaxel + Carboplatin in metastatic bladder cancer Studies (n) Patients (n) OR rate ( % ) CR rate (%) Median survival (m onths ) 6 165 43% 13% 8.5 - 9.5

40. Paclitaxel + Carboplatin vs. MVAC in metastatic bladder cancer N=85 Dreicer R et al. Cancer. 2004 Drug regimen Overall response Median survival PAC + Carbo MVAC 28% 36% 13.8 months 15.4 months

41. Gemcitabine + Cisplatin in metastatic bladder cancer Study Prior CT Patients (n) CR/PR (n) OR% (CR%) Survival (months) von der Maase 1999 N 38 7/9 42% (18%) 12.5 Kaufman 2000 N 46 10/9 41% (22%) 14.3 Moore 1999 N 28 6/10 57% (21%) 13.2 Lorusso 2000 N 54 8/18 48% (15%) 12.5 Wilson 2002 N 20 2/8 50% (10%) NR

42. Randomized phase III study in metastatic bladder cancer T4B N2, N3 M1 GC (203 patients) MVAC (202 patients) Study initiated Nov. 1996 - recruitment completed Sept. 1998

43. GC vs. MVAC Response Response GC (n=164) MVAC (n=151) CR 12% 12% PR 37% 34% Response Rate 49% 46%

44. GC versus MVAC Time to progressive disease GC: 7.4m (6.6-8.1m) MVAC: 7.4m (6.7-9.1m) HR: 1.05 (0.85-1.30) LR: p=0.659 W: p=0.995 GC 7.4 months (6.6-8.1) MVAC 7.4 months (6.7-9.1) HR: 1.05 (0.85-1.30)

45. GC versus MVAC Overall survival GC: 13.8 m (12.3-15.8 m) MVAC: 14.8 m (13.2-16.8 m) HR: 1.04 (0.82-1.32) LR: p=0.746 W: p=0.908 GC 13.8 months (12.3-15.8 ) MVAC 14.8 months (13.2-16.8 ) HR: 1.04 (0.82-1.32 )

46. GC versus MVAC Toxicity GC MVAC Infections (grade 3-4) 3% 15% Mucositis (grade 3-4) 1% 22% Diarrhea (grade 3-4) 3% 8% Alopecia (grade 3) 11% 55% Anemia (grade 3-4) 27% 18% Thrombocytopenia (grade 4) 29% 13% Neutropenia (grade 4) 30% 65% Neutropenic fever 2% 14% Neutropenic sepsis 1% 12% Toxic deaths 1% 3%

47. Platinum-containing triplets in metastatic bladder cancer Author Drugs N OR rate CR rate MST Bajorin 2000 Ifos + Pac + Cis 44 68% 23% 20 mo Hussain 2001 Gem + Car + Pac 47 68% 32% 15 mo Bellmunt 2000 / 2002 Pac + Cis + Gem 58 78% 28% 16 mo Pectasides 2002 Gem + Cis + Doc 35 66% 29% 16 mo von der Maase 2003 Gem + Cis + Pac 45 60% 18% 15 mo

48. Platinum-containing triplets in metastatic bladder cancer Author Drugs N OR rate CR rate MST Bajorin 2000 Ifos + Pac + Cis 44 68% 23% 20 mo Hussain 2001 Gem + Car + Pac 47 68% 32% 15 mo Bellmunt 2000 / 2002 Pac + Cis + Gem 58 78% 28% 16 mo Pectasides 2002 Gem + Cis + Doc 35 66% 29% 16 mo von der Maase 2003 Gem + Cis + Pac 45 60% 18% 15 mo

49. PCG versus GC Response Bellmunt J et al. ASCO 2007 Response PCG (n=312) GC (n=315) CR 15% 10% PR 42% 36% Response Rate 57% 46%

50. Progression-Free Survival Gem/Cis median 7.7 mo 1 Pac/Cis/Gem median 8.8 mo 0.87 (0.74-1.03) Bellmunt J et al. ASCO 2007 Progression-free survival

51. Overall Survival Gem / Cis median 12.8 mo 1 Pac / Cis / Gem median 15.7 mo 0.86 (0.72-1.03) Bellmunt J et al. ASCO 2007 Overall duration of survival

55. Trials on 2 nd line treatment of TCCU Vinflunine monotherapy in TCCU after failure of a prior platinum-containing regimen Two phase II trials Culine S et al. Br J Cancer. 2006 Vaughn DJ et al. Cancer. 2009 * PS 0 = 320 mg/m²/q3w ** PS 0 with pelvic irradiation and PS 1 = 280 mg/m²/q3w

56. Efficacy results * PS 0 = 320 mg/m²/q3w ** PS 0 with pelvic irradiation and PS 1 = 280 mg/m²/q3w Culine S et al. Br J Cancer. 2006 Vaughn DJ et al. Cancer. 2009 Culine et al. Vaughn et al. Number of treated patients n (%) 51 151 Initial dose (mg/m², q3w) 320 320*/280** Objective Response Rate n (%) 95% CI 9 (17.6) [8.4 - 30.9] 22 (14.6) [9.4 – 21.2] Disease control rate n (%) IRP 95% CI 34 (66.7) [52.1 - 79. 3 ] 86 (56.9) [48,7 - 65] Median Duration of response months IRP 95% CI 9.1 [4.2 - 15.0] 6.0 [5.4 – 9.5] Median PFS months 95% CI 3.0 [2.4-3.8] 2.8 [2.6 - 3.8] Median OS months 95% CI 6.6 [4.8 - 7.6] 8.2 [6.8 – 9.6]

58. > 3.5 -year follow-up Eur Urol Suppl. 2010;9(2):38 Updated survival analysis - ITT population VFL + BSC arm BSC arm 2.3 months Overall Survival [months]

59. Bladder Guidelines Recommend Vinflunine Use as Second Line Therapy † Based on one good quality RCT ‡ Based on clinical studies of good quality and consistency addressing the specific recommendations and including at least one randomized trial Post failure of a platinum based combination Level 1b recommendation † Recommended as second line therapy after platinum failure

61. Era of &quot;molecularly targeted therapy&quot; Sorafenib 2006 Sunitinib 2006 Bevacizumab + IFN 2007 Temsirolimus 2007 Everolimus 2008 Sunitinib 2006 Imatinib 2002 Sorafenib 2008 Cetuximab + radiotherapy 2006 Bevacizumab + chemotherapy 2006 Cetuximab + chemotherapy 2008 Erlotinib 2005 Trastuzumab + chemotherapy 2001 Lapatinib + capecitabine 2006 Cetuximab 2007 Panitumumab 2007 Bevacizumab + chemotherapy 2004 Bevacizumab + paclitaxel 2007 HCC GIST RCC NSCLC CRC Breast cancer MM = malignant melanoma - HCC = hepatocellular carcinoma - GIST = gastrointestinal stromal tumour - RCC = renal cell carcinoma - NSCLC = non-small cell lung cancer - CRC = colorectal cancer - IFN = interferon Cetuximab + chemotherapy 2008 Ipilimumab 2010 MM Pazopanib 2009 Head and neck cancer … ERA OF MOLECULAR TARGETED THERAPY

66. VEGF Trap Treatment Plan Patients receive a dose of VEGF Trap 4 mg/kg IV administered over 1 hour on D1 of each 14 day cycle

68. Contents Non-invasive urothelial carcinoma Metastatic urothelial carcinoma Invasive urothelial carcinoma

84. EGYPT Gharbia Population–based registry, 1999 – 2001 report

85. 5 Most Common sites of cancer Egypt, 1999-2001, Males *ASIR: / 100,000 ASIR* R.F % Site 26.3 21.3 15.0 14.0 5.6 15.4 13.0 10.9 8.2 3.9 1. Bladder 2. Liver 3. NHL 4. Lung 5. Colon Rectum

86. Cancer Profile in Aswan, Egypt Methodology and Results Chart book 2008

87. Age-standardized Incidence rates / 100,000 By Governorate, all sites Males

88. Age-standardized Incidence rates / 100,000 By Governorate, all sites, Females

89. Age-standardized Incidence rates / 100,000 selected sites, Males Minia 2009 Damietta 2009 Aswan 2009 Aswan 2008 CI5C-IX 1999-2002 179.0 163.2 133.8 140.7 156.1 All sites ASR 116.2 126.6 97.5 96.2 93.0 All sites Crude rate 28.0 18.0 19.1 18.2 27.9 Bladder 38.8 71.5 17.4 17.4 21.9 Liver 11.7 8.8 11.8 11.2 14.0 Lung 5.5 6.8 6.9 9.2 8.5 Prostate 5.8 4.8 6.5 5.0 6.3 Colo-rectal 1.8 6.4 4.0 2.2 16.9 NHL

90. Age-standardized Incidence rates / 100,000, selected sites, Females Minia 2009 Damietta 2009 Aswan 2009 Aswan 2008 CI5C-IX 1999-2002 136.3 136.4 131.2 164.0 119.3 All sites ASR 99.6 120.1 97.5 115.2 91.8 All sites Crude rate 37.4 41.4 41.3 63.9 42.5 Breast 5.3 5.1 3.9 6.6 5.4 Bladder 5.0 5.2 7.4 9.1 5.2 Ovary 13.8 24.6 8.8 8.7 4.5 Liver 4.7 3.1 5.5 4.8 4.3 Colo-rectal 0.9 3.3 1.6 1.6 9.9 NHL

91. The National Cancer Institute Cairo University www.nci.edu.eg Cairo University National Cancer Institute

92. Most Common Sites in Males

93. What happened to bilharziasis and to Bladder Cancer in Egypt in the past three decades?

94. Oral Antibilh. AbdelWahab, 7% El-Khoby, 0.5% Miller, 30% MPH, 45% Scott, 60% THE DECLINE OF PREVALENCE OF S. HEMATOBIUM IN THE NILE DELTA IN 70 YEARS (POPULATION SURVEYS BY URINE ANALYSIS) High dam Anti-Bilh.

95. TIME TREND ANALYSIS OF BLADDER CANCER IN 37 YEARS (NCI, 9843 Pts.) 1970- 1974 1985- 1989 2003- 2007 A B C 3212 3988 2643 Gouda, Mokhtar, Belal & El-Bolkainy, J. Egypt. NCI, 2007 .

96. Bladder cancer Eggs positive 82% 55% 28% 12% THE DECLINE OF BLADDER CANCER & BILHARZIAL ASSOCIATION IN 37 YEARS (NCI – 9843 PATIENTS)

97. Squamous Transitiona l Others 76% 28% 16% 66% 8% 6% THE CHANGE OF HISTOLOGIC PROFILE OF BLADDER CARCINOMA IN 37 YEARS (NCI – 9843 PATIENTS)

98. THE CHANGE OF DEMOGRAPHIC FEATURES OF BLADDER CANCER IN 37 YEARS No. of cases 3212 2643 NCI, Pathology Registry Years 1970-1974 2003-2007 Mean Age 47.4 60.5 M/F ratio 5.4 3.3

101. Grade LN Stage

105. Results of therapy Drug No. of patients Evalu- CR PR (CR+PR) Imp. SD PD able Bleomycin 21 0 0 (0 %) 2 6 13 Doxorubicin 27 0 0 (0 %) 2 4 21 Tenoposide 26 0 1 (4 %) 2 6 17 5-fluorouracil 32 0 2 (6 %) 3 17 10 Methotrexate 14 0 1 (7 %) 0 2 11 Cisplatin 18 1 2 (16 %) 0 3 12 Dibromodulcitol 22 1 3 (13 %) 0 6 12 Cyclophosphamide 21 1 3 (19 %) 2 9 6 Pentamethylmelamine 25 1 7 (32 %) 2 9 6 Etoposide` 19 0 7 (36 %) 3 5 4 Hexamethylmelamine 26 0 10 (38 %) 12 0 4 Ifosfamide 20 0 8 (40 %) 2 2 8 Vincristine 25 2 9 (44 %) 0 8 6 Vindesine 18 3 10 (41 %) 0 9 10 Epidoxorubicin 18 0 9 (50 %) 0 7 2 18 0 11 (60 %) 0 7 0

109. GEMZAR + Cisplatin in Bilharzial Bladder Cancer NCI - Cairo Treatment Schedule Gemcitabine 1000 mg/m 2 I.V. days 1,8 & 15 Cisplatin 70 mg/m 2 I.V. day 2 Every 28 days

111. Gemcitabine plus Cisplatin is an active combination for Bilharzial related bladder cancer ( Response rate 54 %), with a moderate toxicity profile European J. Cancer (2000) , 36: s34-s37

112. Treatment Schedule Gemcitabine 250 mg/m 2 over 6 hours infusion days 1,and 8 Cisplatin 70 mg/m 2 day 2 Every 21 days

114. CAIRO: BLADDER CANCER, ST III/IV Khaled , et al. Urologic Oncology (2008)

120. Egyptian Bladder Cancer Cooperative gp T2b,3,4a N0-2 Bladder Cancer Cystectomy 3 Courses Gem+Cis SD PR CR 3 courses Gem+Cis Cystectomy 3 courses Gem+Cis Cystectomy Radical Radiotherapy

123. Adjuvant Chemoradiotherapy High Risk Patients (P3b,4a,G3+/-LN+) Radical Cystectomy PORT 4500cGy/3wks/30 F 2 Courses (Gem Cis ) 1000 mg/m2 D1&D8 70 mg /m2 D1 PORT 4500cGy/3wks/30F 2 Courses (Gem Cis ) Same regimen

124. Bilharzial Bladder Cancer Drug Therapy Invasive Tumors Superficial Tumors Advanced, metastatic, and recurrent Invasive operable Single agent phase II trials 1975 now Neoadjuvant Pilot study Phase III trial Combination Chemotherapy phase II trials Epi VCR - Ifo VP16 Gemz – DDP (2) Phase III trial (combination vs single agent) Adjuvant Classic surgery Modified surgery Little experience CT-RT

126. Differentially Expressed Genes Differentially Expressed EST

127. Bilharzias VS Non MALE VS FEMALE FARMER VS NON

128. Upper Vs lower Egypt Low Vs high grade

129. Chemotherapy in bladder cancer We are approaching a new era!

130. Thank you 200 years ago