14-10-16 Poor-prognostic advanced Germ Cell Tumors Karim Fizazi, MD, PhD Institut Gustave Roussy, France Metastatic GCT: Prognosis (IGCCC) Good prognosis Intermediate prognosis Poor prognosis J Clin Oncol 1997, 15: 594-603 1
Poor prognosis metastatic NSGCT Definition: any of: Primary tumor site: Mediastinal Extra-pulmonary visceral mets: Yes Tumor marker before chemo: hcg: > 50 000 AFP > 10 000 LDH 15% of metastatic NSGCT Cure rate: 50% > 10 x norm J Clin Oncol 1997, 15: 594-603 Poor-risk GCT: A standard established in 1987 4 BEP > 4 PVB: DFS (p<0.05) and OS (p<0.05) Better tolerance (neurotoxicity) 4 BEP= standard Presented by: Karim Fizazi 2
4 BEP are not 5, 6, or 7 Giving additional cycles of BEP: Did not demonstrate any improvement in outcome Increases the risk of: severe paresthesia, auditive toxicity, neutropenic fever, and fertility troubles Giving > 4 BEP makes your patient at a 2% risk of meeting this: 2% risk of secondary acute leukemia if etoposide > 2 g/m 2 80% mortality a rate similar to that after a cobra bite. Kollmansberger, J Clin Oncol 1998, 16: 3386-91 3
Phases III of HD chemotherapy + transplant in first-line poor-prognosis NSGCT T87 French trial (n=115) (Droz 2007) 4 PVeBV vs 4 PVeBV + HD CisEC Intergroup US trial: (n=219) (Motzer 2007) 4 BEP vs BEP + 2 HD-CEC EORTC 30974 trial: (n=137) (Daugaard 2011) 4 BEP vs VIP + HD-VIP The only trial to include poor-risk pts only Poor-risk NSGCT: T87 phase III trial Poor-risk NSGCT (n= 115) PVeBV: 4 cycles: Cisplatin 40 mg/m 2 x 5 Etoposide 100 mg/m 2 x 5 Bleomycin 30 U/w Vinblastine 0.2 mg/kg d1 1 cycle/ 3 weeks PVeBV: 4 cycles + high dose CT (PEC): etoposide 350 mg/m 2 x 5 cisplatin 40 mg/m 2 x 5 cyclophosphamide 1600 mg/m 2 x 5 Bone marrow transplant 4
T87 phase III trial HD= Double dose cisplatin + etoposide + cyclop + autograft Median follow-up: 9.7 years Probability 0.00 0.25 0.50 0.75 1.00 Treatment PVeBV Figure 1 Overall Survival PVBV+PEC p=0.167 0 2 4 6 8 10 Years HD Chemotherapy arm Droz et al., Eur Urol 2007, 51: 739-46 Phase III intergroup US trial Intermediate/poor risk pts n= 219 R 4 BEP 2 BEP + 2 HDCT (CBDCA, VP16, CPM) Time to treatment failure Overall survival Motzer, J Clin Oncol 2007; 25: 247-256 5
Poor prognosis NSGCT: US Phase III trial 4 BEP vs 2 BEP + 2 HDCT n= 219 pts (intermediate or poor-risk) HDCT= CBDCA, VP16, CPM Time to treatment failure Overall survival Motzer, J Clin Oncol 2007; 25: 247-256 Phase III EORTC 4 BEP vs sequential HD VIP in IGCCCG poor-risk NSGCT n= 137 (222 planned) FFS p=0.057 R 4 BEP HD VIP + stem cell OS p=0.36 Daugaard G et al. Ann Oncol 2011;22:1054-1061 6
Poor prognosis NSGCT: Randomized trials Chemotherapy BEP x 4 v BEP 200 x 4 BEP x 4 v BEP/PVB x 4 BEP x 4/EP x 2 v BOP/VIP-B BEP x 4 v VIP x 4 P 200 VBE x ¾ v P 200 VBE x 2 + P 200 EC Number of patients 78 81 125 125 190 190 148 151 58 57 Favorable response rates (%) 73 68 76 72 57 54 60 63 75 67 Conclusion Double dose cisplatin not superior and more toxic Alternating regimen not superior and more toxic Dose dense alternating regimen not superior and more toxic Substitution of ifosfamide for bleomycin not superior and more toxic High dose chemotherapy not superior and more toxic Reference Nichols 1991 de Wit 1995 Kaye 1998 Nichols 1998 Droz 2007 BEP x 4 v BEP x 3 + CaEC BEP x 4 v CISCA/VB 111 108 96 94 55 56 61 54 High dose chemotherapy not superior and more toxic Alternating regimen not superior and more toxic Motzer 2007 Culine 2008 Courtesy of S. Culine Poor-risk GCT: 25 years of negative phase 3 trials VIP: Nichols, J Clin Oncol 1998, 16: 1287-93 CISCA/VB: Culine, J Clin Oncol 2007, 26: 421-7 HD: Motzer, J Clin Oncol 2007; 25: 247-256 HD: Daugaard, Ann Oncol 2011; 22: 1054-61 7
Poor prognosis NSGCT: where did we stand until 2013? No progress demonstrated by randomized trials in the last 25 years However, general improvement observed (from 45% to 60% survival): Patient education (lower tumor burden)? Referral to well-trained centers (Collette JNCI 1999)? Improvement in the management of chemotherapy side effects? Improvement in surgery? Others? Management of pts at high risk of ARDS: «Very high risk NSGCT» 1980-19 97 ARDS 13/15 (87%) Death from ARDS Longterm survivor Extensive lung mets Dyspnea or po2<80 1997-20 06 3/10 (30%) Total 16/25 10/15 2/10 12/25 4/15 (27%) 4/10 (40%) 8/25 Massard C, Ann Oncol 2010 8
Is the number of treated cases important for outcome? n= 380 patients from the EORTC/MRC phase III trial testing BEP vs BOP-VIP 65% had a poor-prognosis according to IGCCCG 49 European institutions: 26 treated <5 patients Cox analysis for PFS and OS Collette L et al. J Natl Cancer Inst 1999;91:839-846 Kaplan-Meier estimate of failure-free survival according to total accrual of patients by the treating institution in trial 30895/TE13. Failure-Free Survival Collette L et al. JNCI J Natl Cancer Inst 1999;91:839-846 Oxford University Press 9
OS Does experience matter? (EORTC Phase III trial) 20% Collette L et al. JNCI J Natl Cancer Inst 1999;91:839-846 Survival according to tumor marker decline in Poor-prognosis GCT Tumor markers assessed at Day 21 Tumor markers assessed at Day 42 Probability 0.00 0.25 0.50 0.75 1.00 IGCCCG - POOR RISK Overall Survival Time to Normalization FAVORABLE UNFAVORABLE p=0.009 0 2 4 6 8 10 Years Fizazi, J Clin Oncol 2004, 22: 3868-76 Motzer, J Clin Oncol 2007; 25: 247-256 Presented by: Karim Fizazi 10
Calculation of tumor marker decline www.igr.fr/calculation-tumor/nsgct.xls Decline rates are calculated using a logarithmic formula : M0=initial marker value; M1=marker value at 3 w; MN=Normal value Tumor marker decline = 3 A / B A = log(m0)-log(mn) B = log(m0)-log(m1) Patients can then be classified into 4 categories as follows : AM Normal at cycle 1 and at cycle 2 BM Abnormal at cycle 1 and Normalization at cycle 2 CM Abnormal cycle 1 and TNM < TM DM Abnormal cycle 1 and TNM TM or abnormal and increasing marker at cycle 2 Cut-off points (TM) vary for each marker: TAFP = 9 w, ThCG = 6 w A favorable pattern of decline is defined by hcg and AFP being both A, B, or C. Fizazi, J Clin Oncol 2004, 22: 3868-76 GETUG 13 Phase III design Median follow-up: 4.1 years (0.3 ; 8.8 years) n=263 n=254 Poor-risk GCT (IGCCCG) Registration 1st BEP Favorable decline Day 21: Tumor marker n=51 Unfavorable decline n=203 R 4 BEP (total) Dose-dense regimen n=105 4 BEP (total) n=98 Presented by: Karim Fizazi 11
GETUG 13: Dose-dense regimen BEP 1 Cisplatin 20 mg/m 2 /d d1-5 Etoposide 100 mg/m 2 /d d1-5 Bleomycin 30 u/w Paclitaxel-BEP + Oxaliplatin + G-CSF / 3 weeks 2 cycles Paclitaxel 175 mg/m 2 d1 BEP as above Oxaliplatin 130 mg/m 2 d10 G-CSF 263 µg/d (excepted chemo days) Cisplatin, Ifosfamide, Bleomycin + G-CSF / 3 weeks 2 cycles Cisplatin 100 mg/m 2 d1 Ifosfamide 2g/m 2 d10,12,14 Mesnum Bleomycin 25 U/d d10-14 (continuous IV) G-CSF as above Presented by: Karim Fizazi Primary endpoint: PFS in randomized patients with an unfavorable decline At risk 100% 80% 60% 40% 20% 0% 98 105 46 60 HR: 0.66 [0.44-1.00] p=0.05 0 1 2 3 4 5 6 7 8 Years 37 47 31 41 30 34 20 22 9 12 2 7 1 4 3-year PFS: 59% vs 48% Unfav-Dose-dense Unfav-BEP Unfav-BEP Unfav-DoseDense cned: 63 vs 46 pts Fizazi K, Lancet Oncol 2014 (in press) 12
OS in randomized patients with an unfavorable decline At risk 100% 80% 60% 40% 20% 0% 0 1 2 3 4 5 6 7 8 Years 98 105 68 76 47 56 37 47 35 37 HR: 0.78 (0.46 ; 1.31), p=0.34 25 23 10 13 3 7 2 4 3-year OS: 73% vs 65% Unfav-Dose-dense Unfav-BEP Unfav-BEP Unfav-DoseDense Alive: 78 vs 66 pts Presented by: Karim Fizazi Fizazi K, Lancet Oncol 2014 (in press) 100% Outcome according to tumor marker decline PFS 100% OS At risk 80% 60% 40% 20% 0% 0 1 2 3 4 5 6 7 8 Years 98 105 51 46 60 37 37 47 33 31 41 28 30 20 34 22 22 19 9 12 13 2 7 7 Fav-BEP Unfav-BEP Unfav-Dose-dense Unfav-DoseDense Unfav-BEP Fav-BEP 1 4 1 At risk 80% 60% 40% 20% 0% 0 1 2 3 4 5 6 7 8 Years 98 105 51 68 76 44 47 56 39 37 47 33 35 25 37 23 25 22 Fav-BEP Unfav-BEP Unfav-Dose-dense Unfav-DoseDense Unfav-BEP Fav-BEP 10 13 15 3 7 9 2 4 2 Fav-BEP vs Unfav-BEP: 3-year PFS: 70% vs 48% HR=0.66 (0.49 ; 0.88), p=0.01 Fav-BEP vs Unfav-BEP: 3-year OS: 84% vs 65% HR=0.65 (0.45 ; 0.95), p=0.024 Fizazi K, Lancet Oncol 2014 (in press) 13
Salvage chemotherapy Survival Stage I Metastatic stages (IGCCCG) - Good pronosis - Intermediate prognosis - Poor pronosis Salvage setting post-first-line CT 99% 95% 80% 50% 25% Prognostic classification: metastatic GCT + failure to first-line cisplatin-based chemotherapy n= 1984 pts PFS Prognostic factors: - Histology: NS vs Seminoma - Tumor site: Testis/Extra/Med - Visceral metastases - Previous response - Progression-free interval (3m) - hcg (1000) - AFP (1000) Prognostic score J Clin Oncol 2010, 28: 4906-11 14
Salvage treatment for patients failing first-line chemotherapy 4 cycles of a 3-drug regimen: Containing cisplatin and ifosfamide Third drug: Vinblastine (VeIP) Etoposide (VIP) Paclitaxel (TIP) Gemcitabine (GIP) G-CSF required + surgery for residual masses Cure achieved in ~25-50% Evidence based on large phase II experiences Salvage HD chemotherapy + transplant Phase II trials: With single autograft reported in the 1990 s (carboplatin, etoposide, +/- cyclophosphamide) With sequential autografts (TICE at Memorial, HD-VIP in Germany, TAXIF) Two phase III trials: IT94: Single HD vs conventional (Pico 2005) German trial: Single HD vs Sequential HD (Lorch 2012) 15
HD chemotherapy for 2 nd line: IT94 phase III trial n= 280 1994-2001 Refractory or relapsed GCT R VeIP: 2 cycles Response No response 2 VeIP 1 VeIP + CARBOPEC IT94: Event-free survival Pico et al., Ann Oncol 2005, 16: 1152-1159 16
IT94: Overall survival Conclusion: No demonstrated benefit for single HD chemotherapy Pico et al., Ann Oncol 2005, 16: 1152-1159 Indiana experience with sequential HD n= 184 pts, salvage (135 second line), retrospective 2 cycles of Carboplatin 750 mg/m 2 x3 + Etoposide 700 mg/m 2 x3 DFS: - 94/135 (70%) second-line pts - 18/40 (45%) cisplatin-refractory pts 3 toxic deaths + 3 leukemia Einhorn L, New Engl J Med 2007, 357: 340-8 17
Sequential HD: TICE regimen (MSKCC) Taxol-Ifo x 2, then HD Carbo-VP16 x 3 Overall survival n= 37 pts Poor-Pc salvage GCT: - Non testis primary - No previous CR - 2 lines No toxic death PFS: 18/37 (49%) Motzer, J Clin Oncol 2000, 18: 1173-80 Single vs Sequential HD chemotherapy for salvage n= 230 pts OS R 1 VIP + 3 HD CE 3 VIP + 1 HD CEC Accrual stopped for toxicity: 4% vs 16% toxic death rate OS border line better for sequential Sequential CT better tolerated Lorch A et al., J Clin Oncol 2007, 25: 2778-84 Lorch A et al., J Clin Oncol 2012; 30: 800-5 18
We still need to demonstrate that sequential HD is superior to standard doses The TIGER trial: TIP vs TICE Conclusion Prognostic role of tumor marker decline clearly established Early intensification in pts with unfavorable decline after 1 BEP improves PFS (GETUG 13): new standard treatment HD chemotherapy in the salvage setting: Cures (some) patients Lack of predictive factor to identify who benefits Sequential > single HD (less toxic deaths) Sequential HD > standard-dose still to be demonstrated (Tiger) 19
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