ESMO Preceptorship Colorectal Cancer Colorectal ESMO Cancer Preceptorship Valencia May Program 20-21st 2016 Prague May 22-23rd 2014 Development of Conventional Chemotherapy in mcrc BSC vs. Chemo, Biochemical modulation, Oral fluoropyrimidines, Developmentof combination chemotherapy J.Y. DOUILLARD MD PhD Chief Medical Officer ESMO Emeritus Professor of Medical Oncology University of Nantes France
Disclosure JY Douillard Compensated participations in: Advisory Boards and Symposia: Amgen Bayer Boehringer Ingelheim Merckserono Roche/Genentech Sanofi Takeda Research Funding Merckserono
Chemotherapy vs. "Best supportive care" # Pat Response TTP Survival BSC 12 0% 2.3 mo 5 mo BSC + CTx 24 33% 6.0 mo 11 mo p<0.001 p=0.006 LQ -FLIC BSC CTx Months 0 2 4 6 8 10 12 14 16 18 Scheithauer et al. BMJ 306, 1993
Immediate vs. delayed CTx in metastatic CRC Treatment NPat Time without Survival Symptoms Progression (median) Immediate 92 10 mo 8 mo 14 mo Delayed 90 2 mo 3 mo 9 mo p-value <.001 <.001 <.002 Glimelius et al. JCO 1992
Points to be discussed Biochemical modulation, infusional 5-FU Oral fluoropyrimidines Combination treatment (irinotecan, oxaliplatin)
Fluoropyrimidine Metabolic Pathway Catabolism 85% Anabolism RNA FUH 2 DPD FU FUrd FUMP FUDP FUTP FUPA FUdR FBAL dump 5, 10 CH 3 THF FdUMP FdUDP FdUTP TS dtmp DHF DNA
modified according to Hyrniuk and Wils 5-FU dose intensity and response 40 Bolus Infusional 30 20 10 0 0 600 1200 1800 2400 5-FU dose intensity mg / m 2 / week
Results from Meta-Analyses Treatment Trials N Pat FU FU/FA 9 1381 FU FU/MTX 8 1178 FU Bolus FU CI 6 1219 FU+/-FA FU+/FA+IFN 12 1866 FU/FA FU/IFN 7 1488 ORR (CR/PR) p-value 11% 23% <0.001 10% 19% <0.001 14% 22% <0.001 25% 24% n.s. 23% 18% 0.04 med OS (Months) p-value 11,0 11,5 0,57 9,1 10,7 0.024 11,3 12,1 0.04 11,4 11,5 n.s. 11,7 11,3 n.s.
5-FU Prodrugs S1: Tegafur [1] CDHP [0.4] Oxo [1] 5 deoxy-5-fluorouridine Capecitabine 5 deoxy-5-fluorocytidinpentoxycarbomyl 5 deoxy-5-fluorocytidine Cytidindeaminase Carboxylesterase UFT: Tegafur [1] Uracil [4] C-5 Oxidation C-2 Hydrolysis Cytochrom P450 Pyrimidin Phosphorylase FUra FdUMP OXO FUMP CDHP: EU: Oxo: 5-chloro-2,4-dihydoxypyridine Ethynyluracil Oxonic acid DPD EU CDHP FUH 2
Oral Fluorpyrimidines vs. Mayo-Clinic regimen (mo) N Pat CR/PR PFS (mo) Survival Cape 301 19% 5.2 13.2 Mayo 301 15% 4.7 12.1 Cape 302 25% 4.3 12.5 Mayo 303 16% 4.7 13.3 UFT/LV 190 11% 3.4 12.2 Mayo 190 9% 3.3 11.9 UFT/LV 409 12% 3.5 12.4 Mayo 407 15% 3.8 13.4 Van Cutsem JCO 2001, Hoff JCO 2001; Douillard JCO 2002 2001, Carmichael JCO 2002
TAS 102 The latest drug added for mcrc TAS-102 is an orally administered combination of a thymidine-based nucleic acid analogue, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil hydrochloride Trifluridine is the active cytotoxic component of TAS-102; Tipiracil hydrochloride is a potent inhibitor of thymidine phosphorylase
Randomised trials have shown: Contribution of Oxaliplatin and Irinotecan
Irinotecan+5FU/LV Survival (Study V303) Probability 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 14.1 mo* CPT-11/5-FU/LV (N=198) 5-FU/LV (N=187) 17.4 mo* p<0.032 0 6 12 18 24 30 Months JY Douillard The Lancet 2000 * Medians Log-rank test
40986 40986: Overall Survival 5-FU 24h /LV (AIO) +/- Irinotecan (Secondary Endpoint) 100 90 80 Median 95% CI AIO + IRI 20.1 [18.0 21.9] AIO 16.9 [15.3 19.0] 70 60 50 40 30 p=0.2779 log-rank p=0.0509 Wilcoxon 20% of pts 20 10 0 (months) 0 6 12 18 24 30 36 42 O N Number of patients at risk : 146 216 186 136 88 43 16 4 142 214 196 153 104 52 18 4 HDFU/FA HDFU/FA/CPT11
FOCUS- trial Pts receiving all 3 drugs 2100 Pts. not suitable for neoadjuv. therapy 1. line 2. line 3. line A 5-FU/FA Irinotecan OxCape B1 5-FU/FA FOLFIRI OxCape B2 5-FU/FA FOLFOX IriCape C1 FOLFIRI OxCape C2 FOLFOX IriCape 16% 19% 33% Seymour, Lancet 2007
FOCUS- trial Seymour, Lancet 2007
Focus trial
Efficacy of Oxaliplatin Plus Capecitabine or Infusional Fluorouracil/Leucovorin in Patients With Metastatic Colorectal Cancer: A Pooled Analysis ofrandomized Trials Arkenau et al. JCO 2009
Efficacy of Oxaliplatin Plus Capecitabine or Infusional Fluorouracil/Leucovorin in Patients With Metastatic Colorectal Cancer: A Pooled Analysis of Randomized Trials Arkenau et al. JCO 2009
Efficacy of Oxaliplatin Plus Capecitabine or Infusional Fluorouracil/Leucovorin in Patients With Metastatic Colorectal Cancer: A Pooled Analysis ofrandomized Trials Arkenau et al. JCO 2009
Survival according to availability of lines of treatment Mediane Überlebenszeit (Monate) 22 IROX 21 FOLFOX type 20 FOLFIRI type IFL 19 18 17 16 P=.0008 15 14 0 10 20 Grothey et al. J Clin Oncol 2004; 22;1209-30 40 50 60 70 80 % Patienten mit FU, Oxaliplation und Irinotecan
Oxaliplatin in adjuvant pretreated patients Factor N HR p FOLFOXIRI + Bev 0.5 1 1.5 2 FOLFIRI + Bev SWJOG4407GS Subgroup analysis for PFS FOLFIRI / Bev vs. FOLFOX / Bev Category Subgroup mfolfox6 +Bev N FOLFIRI+Bev MST (m) mfolfox6 FOLFIRI+Bev HR p value +Bev Overall 198 197 10.7 12.0 0.874 0.234 ECOG PS 0 154 159 11.1 12.9 0.913 0.478 1 44 38 9.3 9.4 0.775 0.297 Adjuvant Chemotherapy yes 31 33 11.5 19.4 0.551 0.042 no 167 164 10.7 11.0 0.979 0.860 *Except for 3 patients of multiple sites 0,100 1,000 10,000 Favors FOLFIRI+Bev Favors mfolfox6+bev Falcone et al. ASCO 2013, Yamazaki et al. ASCO 2014
5-Year Survival Rate for Stage IV CRC Remains Only 6% Adapted from E Van Cutsem 2000 5-FU/LV bolus 2000 2000 2000 2004 2004 2007 2008 2011 2011 2011 2012 2013 2013 2014 2014 5-FU/LV infusion IFL LVFU2/irinotecan FOLFOX IFL + bevacizumab FOLFOX/FOLFIRI XELOX/FOLFOX + bevacizumab FOLFOX + cetuximab FOLFIRI + cetuximab FOLFOX + panitumumab FOLFIRI + bevacizumab FOLFOX + panitumumab FOLFIRI + cetuximab FOLFOXIRI + bevacizumab FOLFIRI + cetuximab FOLFOX/FOLFIRI + cetuximab or bevacizumab 22.8* Overall Survival (months) *KRAS wild type tumors; **Extended RAS wild type population. Note: Informal comparison as these are not head-to-head clinical trials. 1. Saltz. N Engl J Med. 2000; 2. Douilliard. Lancet. 2000; 3. Goldberg. J Clin Oncol. 2004; 4. Hurwitz. N Engl J Med. 2004; 5. Saltz. J Clin Oncol. 2008; 6. Falcone. J Clin Oncol. 2007; 7. Bokemeyer. Ann Oncol. 2011; 8. Van Cutsem. J Clin Oncol. 2011; 9. Douilliard. ASCO 2011. Abstract 3510; 10. Heinemann. ASCO 2013. Abstract LBA3506; 11. Stintzing and Heinemann. ESMO 2013. Abstract LBA17; 12. Falcone. ASCO 2013. Abstract 3505; 13. Douillard JY, et al. New Engl J Med. 2013;369(11):1023-1034;14. Van Cutsem et al. Ann Oncology ESMO GI 2014 A. 15. Venook P, et al. ASCO 2014. Abstract LBA3; Plenary presentation.
Survival with multidiciplinary approach 100 91% --- BSC --- 5-FU 80 60 66% 48% --- FOLFIRI/FOLFOX6 --- FOLFOX6/FOLFIRI --- resectabel --- primary non-resectabel 40 52% 30% 20 33% Long term survival with chemotherapy and resection 23% 0 1 2 3 4 5 6 7 8 9 10 Colon Cancer Collaborative Group, BMJ 2000 / Tournigand, JCO 2004 / Adam, Ann Surg 2004