Traitement médicamenteux des cancers colorectaux métastatiques M. OUKKAL COMAZ CHU BENI MESSOUS - ALGER
EGFR VEGF mccr les traitements systémiques Fluoropyrimidines Oral/IV Bevacizumab Raltitrexed Aflibercept Irinotécan Regorafenib Oxaliplatin Cetuximab Panitumumab
EGFR-Targeted Monoclonal Antibodies in mcrc Cetuximab IgG 1 mab Chimeric protein Panitumumab [1] IgG 2 mab Fully humanized Role of Kirsten-ras (K-ras) mutation 1. Yang XD, et al. Crit Rev Oncol Hematol. 2001;38:17-23.
Ligand EGF-R Extracellular PTEN PI3K Akt Raf Ras MEK Intracellular MAPK Cell survival Proliferation DNA Angiogenesis Cell Motility Metastasis
The Angiogenic Switch is Necessary for Tumor Growth and Metastasis Tumor is dormant Angiogenic switch Neovascularization: Allows rapid tumor growth by providing oxygen, nutrients, and waste removal Facilitates metastasis Somatic mutation Small avascular tumor Tumor secretion of angiogenic factors stimulates angiogenesis Rapid tumor growth and metastasis Carmeliet and Jain. Nature. 2000; 407:249; Bergers and Benjamin. Nat Rev Cancer. 2003; 3:401.
VEGF et Angiogenèse VEGF VEGFR binding and activation P P P P PLC PI3-K FAK Ras Endothelial cell activation PKC IP3 AKT Paxillin MAPK Survival Proliferation Migration ANGIOGENESIS
A
Adjuvant Therapy: AURC 9002 Surgery 5-FU + LV days 1-5 every 4 weeks x 6 R Surgery 171 patients Resected liver metastases 95% had 3 or fewer Goal: Improved DFS Portier, G. et al. J Clin Oncol 2006; 24:4976-4982.
Survival (%) Disease-free Survival After Liver Resection 100 90 80 70 60 50 40 30 20 10 0 Chemotherapy No chemotherapy Group Median DFS Surgery 17.6 months Chemotherapy 24.4 months (p=0.028) 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 Months Portier, G. et al. J Clin Oncol; 2006;24:4976-4982.
Original EPOC Trial: Phase III EORTC 40983 FOLFOX4 6 cycles (3 months) Surgery FOLFOX4 6 cycles (3 months) Surgery Primary endpoint: PFS N=364 patients Nordlinger et al: Lancet 2008; Lanc Onc 2013
After a median follow-up of 8.5 yrs, no difference in 5-yr OS (51% vs. 48%, p=0.34)
Les métastases résecables Métastases résecables Chirurgie d emblée CT adjuvante Folfox4 Chirurgie Folfox4
B
Liver Metastases in Colorectal Cancer: Outcomes Liver Metastases Resectable 20% to 25% Nonresectable 75% to 80% Location Size Number Downsizing Survival Benefit 30% to 40% at 5 years 15% at 10 years Resectable 10% to 20%
The first GONO phase III study Primary endpoint: response rate 60% vs 34% Falcone, et al. J Clin Oncol 2007
BRAF MT Patients Have Better Outcomes with Intensified Chemo Backbone TRIBE Previously untreated, unresectable mcrc (N = 508) *Up to 12 cycles. R Induction Bevacizumab + FOLFIRI* Bevacizumab + FOLFOXIRI* Maintenance Bevacizumab + 5-FU/LV Bevacizumab + 5-FU/LV PD PD Median OS, months n Bevacizumab + FOLFIRI Bevacizumab + FOLFOXIRI HR (95% CI) p Value RAS and BRAF WT 93 33.5 41.7 0.77 (0.46 1.27) RAS MT 236 23.9 27.3 0.88 (0.65 1.18) 0.522* BRAF MT 28 10.7 19.0 0.54 (0.24 1.20) *p value for interaction. mcrc, metastatic colorectal cancer; PD, progressive disease; WT, wild-type; MT, mutant; OS, overall survival; HR, hazard ratio; CI, confidence interval. Cremolini, et al. WCGC 2015.
Le revers de la médaille de la chimiothérapie préopératoire 1. Disparition des métastases 0,3 à 7% 1-4 Situation rare mais en augmentation Dogme : résection de tous les sites? 1 Adam et al. JCO 2008 2 Benoist et al. JCO 2006 3 Tan et al. J Gastrointest Surg 2007 4 Elias et al. Ann Surg Oncol 2007 2. Foies de chimiothérapie Stéatohépatite Syndrome d obstruction sinusoïdal Yellow liver (irinotécan) Blue liver (oxaliplatine)
Chemotherapy Liver Toxicity: Selected Reports Karoui, Ann Surg 2006 More is not better! But some is OK! Influence of Number of Cycles of Pre-Op Chemo on Morbidity
Métastases potentiellement résecables RAS sauvage RAS mute CT + Anti EGFR CT + Beva
C
Prolonger la survie Survie spontanée après diagnostic d un CCRM 5 à 8 mois Etudes randomisées : chimiothérapie vs soins de confort Protocole de chimiothérapie Survie Qualité de vie Scheithauer W. Br Med J 1993:752 AF (200 mg/m2) + 5 FU bolus (550 mg/m2) + CDDP (20 mg/m2) J1 à J4 11 vs 5 mois (p=0,006) Améliorée Hafström L. Cancer 1994:2749 5FU intraportal + occlusion artère hépatique 17 vs 8 mois (p=0,004) Allen-Mersh TG. Lancet 1994:1255 5FUdR IAH 13,5 vs 7,5 mois (p=0,04) Améliorée Cunningham D. Lancet 1998:1413 CPT11 monothérapie, 2ème ligne 9,2 vs 6,5 mois Améliorée
REGORAFENIB Regorafenib inhibits multiple cell-signaling kinases: Angiogenic VEGFR1-3, TIE2 Stromal PDGFR-ß, FGFR Oncogenic KIT, PDGFR, RET Inhibition of proliferation of certain tumor cells Inhibition of stromal signaling Inhibition of neoangiogenesis Grothey A et al. Gastrointestinal Cancers Symposium 2012;Abstract LBA385.
Métastases jamais résecables RAS Muté ou inconnu RAS WT Folfox + beva Folfiri + beva Folfox + Beva Folfiri + anti EGFR Folfiri + beva Folfox + beva Folfiri + beva Folfox + Beva Regorafenib Regorafenib Irino + anti EGFR Regorafenib Regorafenib
Overall survival
Conclusion Armes multiples Chirurgie +++ Décisions pluridisciplinaires