1. Advanced testicular cancer has a variable prognosis depending on factors like tumor markers and site of metastases. First-line chemotherapy typically consists of bleomycin, etoposide, and cisplatin (BEP). 2. For good prognosis metastatic seminoma or non-seminoma, 3 cycles of BEP is usually sufficient. For poor prognosis, 4 cycles of BEP is standard despite trials finding no benefit to more treatment. 3. For relapsed or refractory disease, salvage regimens including ifosfamide and cisplatin offer around 25% chance of cure, with prognostic factors predicting outcome. Intensive approaches show no clear benefit.

1. Systemic treatment of advanced testicular cancer Karim Fizazi, MD, PhD Institut Gustave Roussy, France

2. Metastatic GCT: Prognosis (IGCCC) Good prognosis Intermediate prognosis Poor prognosis J Clin Oncol 1997, 15: 594-603

7. Séminomes métastatiques Bon pronostic Pronostic intermédiaire Pas de M+ visc extra-P LDH < 2N si supra-diaph M+ viscérales extra-P ou LDH > 2N si supra-diaph 4 EP 4 VIP + G-CSF IGCCCG MRC

9. Survival according to prognosis Progression-free survival (3-year): Good prognosis group: 93% (85-97) Intermediate prognosis group: 83% (63-93) Overall survival (3-year): Good prognosis group: 99% (92-100) Intermediate prognosis group: 87% (67-95) Fizazi K et al., ASCO 2009

13. Proposition étude française Séminome stade II (A-C?) 2 cycles d’EP Pet-scan Si - 1 cycle carbo Si + 2 cycles EP

14. Treatment for metastatic non-seminomatous germ-cell tumors (NSGCT)

19. Logrank p=0.06 n= 251 Good-risk NSGCT Event-Free Survival GETUG T93 trial: 3 BEP vs 4 EP Culine et al., Ann Oncol 2007 0,5 0,6 0,7 0,8 0,9 1,0 0 2 4 6 8 YEARS PROBABILITY 4EP; 84% at 4 years 3BEP; 90% at 4 years

20. GETUG T93 trial: 3 BEP vs 4 EP Logrank p=0.14 BEP: 5 deaths EP: 12 deaths Median follow-up = 51 months Culine et al., Ann Oncol 2007 Overall Survival

25. Time to treatment failure Overall survival Phase III intergroup US trial Intermediate/poor risk pts n= 219 2 BEP + 2 HDCT (CBDCA, VP16, CPM) Motzer, J Clin Oncol 2007; 25: 247-256 4 BEP R

26. Poor prognosis NSGCT: Randomized trials Courtesy of S. Culine Chemotherapy Number of patients Favorable response rates (%) Conclusion Reference BEP x 4 v BEP 200 x 4 78 81 73 68 Double dose cisplatin not superior and more toxic Nichols 1991 BEP x 4 v BEP/PVB x 4 125 125 76 72 Alternating regimen not superior and more toxic de Wit 1995 BEP x 4/EP x 2 v BOP/VIP-B 190 190 57 54 Dose dense alternating regimen not superior and more toxic Kaye 1998 BEP x 4 v VIP x 4 148 151 60 63 Substitution of ifosfamide for bleomycin not superior and more toxic Nichols 1998 P 200 VBE x ¾ v P 200 VBE x 2 + P 200 EC 58 57 75 67 High dose chemotherapy not superior and more toxic Droz 2007 BEP x 4 v BEP x 3 + CaEC 111 108 55 56 High dose chemotherapy not superior and more toxic Motzer 2007 BEP x 4 v CISCA/VB 96 94 61 54 Alternating regimen not superior and more toxic Culine 2008

29. Overall survival according to tumor marker decline at day 21 or day 42 TM assessed at Day 21 Fizazi, J Clin Oncol 2004, 22: 3868-76 Motzer, J Clin Oncol 2007; 25: 247-256 TM assessed at Day 42

31. GETUG 13: dose-dense regimen BEP x 1 Taxol-BEP + Oxaliplatin (d10) + G-CSF / 3 weeks x 2 cycles Cisplatin, Ifosfamide, bleomycine + G-CSF / 3 weeks x 2 cycles

33. Kaplan-Meier estimate of failure-free survival according to total accrual of patients by the treating institution in trial 30895/TE13. Collette L et al. JNCI J Natl Cancer Inst 1999;91:839-846 Oxford University Press Failure-Free Survival

34. Kaplan-Meier estimate of overall survival according to the total accrual of patients by the treating institution in trial 30895/TE13. Collette L et al. JNCI J Natl Cancer Inst 1999;91:839-846 Oxford University Press Overall survival

38. HD chemotherapy for 2 nd line: IT94 phase III trial n= 280 1994-2001

39. IT94: Overall survival Pico et al., Ann Oncol 2005, 16: 1152-1159 Conclusion: No demonstrated benefit for single HD chemotherapy

40. Single vs Sequential HD chemotherapy for salvage Lorch A et al., J Clin Oncol 2007, 25: 2778-84 n= 230 pts 1 VIP + 3 HD CE 3 VIP + 1 HD CEC R Accrual stopped for tox (B) No difference in outcome Sequential CT better tolerated OS PFS EFS