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Peri -Operative Chemotherapy Is the Best Approach Wells Messersmith, MD, FACP Professor

Peri -Operative Chemotherapy Is the Best Approach Wells Messersmith, MD, FACP Professor Director , Gastrointestinal Medical Oncology Program Program co-Leader, Developmental Therapeutics University of Colorado Cancer Center. Conflict of Interest:

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Peri -Operative Chemotherapy Is the Best Approach Wells Messersmith, MD, FACP Professor

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  1. Peri-Operative Chemotherapy Is the Best Approach Wells Messersmith, MD, FACP Professor Director, Gastrointestinal Medical Oncology Program Program co-Leader, Developmental Therapeutics University of Colorado Cancer Center

  2. Conflict of Interest: • No employment, speaker’s bureaus, stock ownership, royalties, patents, etc • Data Safety Monitoring Board for OncoMed • 3. PI or Local PI of clinical trials by Genentech/Roche, GSK, Pfizer, Millenium, Bayer, Onconova, and NIH/CTEP.

  3. Rationale for Neoadjuvant Therapy • Convertunresectable patients to resectable • Assess biology/chemo-responsiveness of disease • Treat micro-metastatic disease (which chemotherapy can cure) as soon as possible • Potentially decrease surgical complications by making surgery more feasible • Potential downsides: hepatotoxicity; complications; complete response can hide metastatic sites; fear of “lost opportunity” if progression; etc

  4. What we know • Liver resection can cure patients (although no randomized trials) • Response rates to modern combination regimens are very high (40-80%) • Chemo is feasible and safe in 1st line setting What we don’t know • Optimal chemo regimens (e.g., biologics?) • Optimal sequencing and # cycles • Optimal patient selection (predictive markers)

  5. Peri-Operative FOLFOX for Hepatic Metastases (for patients with initially resectabledisease) n=182 (171 eligible) EORTC 40983 FOLFOX4 6 cycles (3m) Surgery FOLFOX4 6 cycles (3m) n = 364, resectable liver metastases Primary endpoint: disease-free survival (DFS) n=182 (171 eligible) Surgery No chemotherapy Important toxicity data: only small increase in peri-operative complications with chemo, although only 63% in chemo group received it post-operatively Nordlinger, ASCO 2005; Nordlinger, Lancet Oncology 2013;14:1208-15

  6. EORTC 40983: Peri-Op FOLFOX for Liver Mets Overall Survival HR=0.88 (p=0.34) mOS, 61m vs 54m Absolute difference: 3.4% No survival advantage to peri-operative chemo! Progression-Free Survival HR=0.81 (p=0.068) (p=0.035 for eligible pts) mPFS, 20m vs 12.5m Absolute difference: 8.2% Nordlinger, Lancet Oncology 2013;14:1208-15

  7. Key Points for EORTC 40983 (1) • No overall survival benefit to adding chemotherapy to surgery for resectable liver metastases • OS was not primary endpoint; study underpowered • HR for PFS (~0.8), and absolute benefit of ~4% in eligible patients, is similar to stage III trials (MOSAIC, C-07) • Note: a 360-patient study in stage III disease would show the same thing! • Most adjuvant trials enroll > 2000 patients.

  8. Key Points for EORTC 40983 (2) • Difficult to accrue these studies; survival studies with 1000’s patients (as in stage III) are unlikely • Peri-operative chemotherapy generally safe and well-tolerated • Only ~4-7% of patients developed extrahepatic disease while receiving chemotherapy (too much hype as a “good patient selector”?) • Fewer patients receive chemotherapy after surgery (thus, similar to rectal cancer; we treat up front so patients can tolerate better)

  9. Chemotherapy Liver Toxicity: Selected Reports Report drugs toxicity % Rubbia-Brandt 5-FU/ sinusoidal 51% total Ann Oncol 2004, n=153 Ox congestion 78% oxali Fernandez 5-FU/ steato- 64% I + O J AM C Surg 2005 , n=37 Ox / I hepatitis 10% 5-FU Karoui 5-FU/ sinusoidal 49% chemo Ann Surg 2006, n=67 Ox / I dilation 14% no chemo Aloia 5-FU vascular 52% chemo JCO 2006, n=75 Ox changes 18% no chemo Ox = oxaliplatin; I = Irinotecan

  10. Chemotherapy Liver Toxicity: Selected Reports More is not better! Karoui, Ann Surg 2006 But some is OK! Influence of Number of Cycles of Pre-Op Chemo on Morbidity

  11. METHEP Trial: randomized phase II trial of regimens for initially unresectable* mCRC n= n=92 High dose FOLFIRI 32 “Intensified” chemo 30 FOLFOX7 n = 122 Primary endpoint: Response rate after 4 cycles 30 FOLFIRINOX n=30 15 FOLFOX4 “standard” chemo FOLFIRI 15 *Definitions: Not optimally resectable (but potentially resectable) was defined as complex hepatectomy, “risky”, close contact with major vascular structures Ychou, ASCO 2008; Ychou, Ann SurgOncol2013;20: 4289-4297

  12. METHEP Trial Lesson #1: FOLFIRINOX appears more active than other regimens (mOS>48m; all others <30m; RR=57%) Lesson #2: Patients who undergo R0/R1 resections do much better than non-operated, or R2 (visible disease left behind) Ychou, Ann SurgOncol2013;20: 4289-4297

  13. Randomized phase II trial of chemo +/- cetuximab for initially unresectable* mCRC n=70 FOLFOX or FOLFIRI & cetuximab n = 138, KRAS WT Primary endpoint: Rate of conversion to resectability n=68 FOLFOX or FOLFIRI *Definitions: “declared unresectable by a multi-disciplinary team including 3 liver surgeons and a radiologist” Ye, J ClinOncol2013 Jun 1;31(16):1931-8

  14. Improved survival with Cetx in phase II trial: initially unresectable liver-confined mCRC Note difference between the (negative) “New EPOC” study, which was perioperative adjuvantCtx trial, and this one. Ye, J ClinOncol2013 Jun 1;31(16):1931-8

  15. Biologics as adjuvant therapy: 0 for 4! - NSABP C-08 mFOLFOX6 +/-bevacizumab (12 mos) - N0147 FOLFOX +/- cetuximab (US Intergroup) - AVANT FOLFOX4 vs FOLFOX + bevacizumabvs XELOX + bevacizumab - New EPOC FOLFOX +/- Cetuximab (Liver Mets) (HR=1.49; Primose, J ClinOncol 31, 2013 (suppl; #3504)

  16. Trials for Unresectable Liver Mets • METHEP2 (PRODIGE 14, NCT01442935) • Cetuximab (KRAS WT) or Bevacizumab (MT) with FOLFIRINOX vs FOLFOX/FOLFIRI • CELIM2(Dresden; NCT01802645) • Cetx/FOLFOXIRI vs cetx/FOLFIRI (KRAS WT) • FOLFOXIRI +/- Bev • FOLFOX/Cetux(Korea/Samsung; NCT00743678) • mFOLFOX7/Cetux (NSABP FC-6; NCT00803647) • Many others

  17. Trials for Resectable Liver Mets • UniversitéCatholique de Louvain(NCT01858662) • Cetuximab (KRAS WT) with either FOLFOX or FOLFIRI; pCR is primary endpoint • BOS-2 (EORTC-40091; NCT01508000) • FOLFOX alone, or with Panitumumab(KRAS WT) or Bevacizumab (KRAS MT) • PANTER (CTC-A10-005; NCT01266187) • FOLFOX/Ctx x 12w-> Surgery -> FOLFOX/Ctx x 12w vs. • Surgery -> FOLFOX/Ctx x 24w

  18. Conclusions • Liver resection of colorectal metastases appears highly effective in selected patients • “Conversion” therapy (converting unresectable to resectable) is increasingly feasible given high response rates of modern regimens • Unclear whether we should be using regimens for metastatic disease (e.g. biologics) versus adjuvant regiments (no biologics) • Overtreatment can increase complications and costs • A multi-disciplinary approach involving surgical oncologists at diagnosis in potentially curative cases is important

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