1. Prof. Francesco Boccardo University and National Cancer Research Institute of Genoa, Italy Prof. Francesco Boccardo University and National Cancer Research Institute of Genoa, Italy “Neoadjuvant and adjuvant chemotherapy for high risk bladder cancer” Rome, May 9-10,2008

2. Prevalence of infiltrating bladder cancer in surgical series 80-90%(Kaye & Lange, 1982) (Hopkins et al, 1983) 57%(Vaidya et al, 2001)

3. (A) Recurrence-free survival and (B) overall survival in 1,054 patients after radical cystectomy stratified by pathologic subgroups (organ confined, extravesical, and lymph node positive. Stein JP et al, 2001

4. Stein JP et al J Urol, 2003

5. Stein JP et al, J Urol., 2003

6. Nodes Examined (n) Patients (n) 5-yr Local Relapse Rate (%) 5-yr Survival Rate (%) 0-51491733 6-101528.544 11-14157773 >14179479 Table I. Outcome by number of nodes examined (quartiles) in all patients Herr HW, Urology, 2003

7. Herr H et al,JCO 2004

8. Neoadjuvant chemotherapy PROS  Early control of micrometastasis   local control (bladder sparing)  Better compliance to CT (  acute toxicity and lethality)  Chemosensitivity (postcystectomy treatment)  Prognostic significance of T response CONTRA  Delay in local control  Understaging? (postcystectomy treatment)  Overtreatment for a definite proportion of patients (patients selection)

9. Investigator/Group Type of evidence Benefit (% reduction mortality vs cystectomy alone) Remarks SWOG (NEJM, 2003) Multicentric randomized study (317 pts) HR 5yr  HR 5yr  0.67 14% 0.67 14% p=0.06 (two sided) p=0.06 (two sided) Benefit more evident in T3 or T4a pts NORDIC (Eur Urol, 2004) Metanalysis of 2 randomized trial (Nordic I and II) (620 pts) HR 5yr  HR 5yr  0.80 8% 0.80 8%(0.64-0.99) p=0.05 p=0.05 Benefit more evident in T3 or <65 yr pts ABC Collaboration (Lancet, 2003) Metanalysis of 9 randomized trials (including MRC/EORTC (2688 pts) HR 5yr  HR 5yr  0.91 3% 0.91 3% 0.87 5% 0.87 5% p=0.01 p=0.01 Benefit for combination chemotherapy only CANCER CARE ONTARIO PROGRAM (J Urol, 2004) Metanalysis of 11 randomized trials (including MRCEORTC) (2605 pts) HR 5yr  HR 5yr  0.90 0.90 p=0.02 p=0.02 0.87 6.5% 0.87 6.5% p=0.006 p=0.006 Benefit for combination chemotherapy only Evidence supporting the efficacy of neoadjuvant chemotherapy in MIBC

10. Neoadjuvant chemotherapy PROS  Early control of micrometastasis   local control (bladder sparing)  Better compliance to CT (  acute toxicity and lethality)  Chemosensitivity (postcystectomy treatment)  Prognostic significance of T response CONTRA  Delay in local control  Understaging? (postcystectomy treatment)  Overtreatment for a definite proportion of patients (patients selection)

11. T versus P staging for radical cystectomy patients T stage No. of patients* Patients for whom T < P (%) Patients for whom T > P (%) T1/Tis124 23 (19) 18 (15) T2181 71 (39) 45 (25) T3a104 37 (36) 19 (18) T3b56 32 (57) 23 (45) Total465 163 (35) 105 (23) *Combined series from Whitmore 1977, Prout 1977, Richie 1975 and Skinner 1982 Fair WR, 1993

12. Why adjuvant chemotherapy? 1.Pathologic staging most accurately predicts the risk of relapse 2.The risk for new tumor formation is reduced or eliminated after surgery 3.No delay in surgery

19. Adjuvant Chemotherapy In Muscle-invasive Bladder Cancer: A Pooled Analysis From Phase III Studies. Overall Survival

20. Adjuvant Chemotherapy In Muscle-invasive Bladder Cancer: A Pooled Analysis From Phase III Studies. Disease-Free Survival

21. IPD 1 AD 2 RR0.750.77 p0.0190.002 Heter. Test 0.810.72 Absolute Benefit 9%9.4% 1 Vale, Eur Urol 2005; 2 Ruggeri, Cancer in press Meta-Analysis of Adjuvant Chemotherapy for Bladder Cancer: Overall Survival: IPD vs AD

22. Ongoing Studies Trial Design 10% Absolute  in survival 25%  death risk 35%  26%  =0.05;  =20% 80% ; 610 patients

23. Assigned treatments Control (delayed) n=92 (%) n=92 (%) CDDP/GEM (early) n=102 (%) n=102 (%) Median age, years(range) Median age, years(range) 63.5 (36.0-75.0) 64.0 (38.0-75.0) Sex Male Male Female Female 80 (87.0) 12 (13.0) 95 (93.1) 7 ( 6.9) 7 ( 6.9) Performance status 0 1 missing missing 65 (70.7) 21 (22.8) 6 ( 6.5) 6 ( 6.5) 82 (80.4) 16 (15.7) 4 ( 3.9) 4 ( 3.9) Tumor size (depth) pT1-2 pT1-2 pT3-4 pT3-4 missing missing 20 (21.7) 66 (71.7) 6 ( 6.6) 6 ( 6.6) 32 (31.4) 66 (64.7) 4 ( 3.9) 4 ( 3.9) Nodal status pN0 pN0 pN1-2 pN1-2 missing missing 49 (53.3) 37 (40.2) 6 ( 6.5) 6 ( 6.5) 48 (47.1) 50 (49.0) 4 ( 3.9) 4 ( 3.9) Italian study: Patients demography

24. N° pts Obs p= HR (95% CI) p= CONTROL 86 37 0.7 1.0 0.7 CDDP/GEM 98 42 0.92 (0.59-1.44) CONTROL( delayed) CDDP/GEM (early) Years % Progression free survival

25. Hazard of progression Delayed favoredEarly favored 0.92 (0.59-1.44) 0.88 (0.53-1.47) 0.99 (0.40-2.47) 0.49 (0.17-1.45) 1.04 (0.63-1.71) 1.18 (0.54-2.61) HR (95% CI) 0.7 0.6 p value= 0.9 0.2 0.9 0.7 All patients PS=0 pN0 pN1-20.90 (0.52-1.56)0.7 PS=1 pT1-2 pT3-4

26. HR (95% CI) p= Treatment CONTROL CONTROL CDDP/GEM CDDP/GEM1.0 0.98 0.98(0.63-1.54)0.9 Performance status 0 11.0 1.14 1.14(0.68-1.92)0.6 Tumor size (depth) pT1-2 pT1-2 pT3-4 pT3-41.0 1.73 1.73(0.99-2.99)0.05 Nodal status pN0 pN0 pN1-2 pN1-21.0 3.47 3.47(2.15-5.62)0.000 Multivariate Analysis – Progression-free survival

27. Adjuvant chemotherapy for deep muscle-invasive transitional cell bladder carcinoma – a practice guideline Roanne Segal, MD, Eric Winquist, MD Himu Lukka, MB,ChB, Joseph L. Chin, MD, Michael Brundage, MD, MSc, BR Markman,MA The Canadian Journal of Urology, 2002