Peri-Operative Chemotherapy Is the Best Approach Wells Messersmith, MD, FACP Professor Director,...
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Transcript of Peri-Operative Chemotherapy Is the Best Approach Wells Messersmith, MD, FACP Professor Director,...
Peri-Operative Chemotherapy Is the Best Approach
Wells Messersmith, MD, FACPProfessor
Director, Gastrointestinal Medical Oncology ProgramProgram co-Leader, Developmental Therapeutics
University of Colorado Cancer Center
Conflict of Interest:
1. No employment, speaker’s bureaus, stock ownership, royalties, patents, etc
2. 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.
Rationale for Neoadjuvant Therapy• Convert unresectable 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
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)
Peri-Operative FOLFOX for Hepatic Metastases(for patients with initially resectable disease)
Nordlinger, ASCO 2005; Nordlinger, Lancet Oncology 2013;14:1208-15
n = 364, resectable liver metastasesPrimary endpoint: disease-free survival (DFS)
FOLFOX46 cycles (3m)
SurgeryNo chemotherapy
Surgery FOLFOX46 cycles (3m)
EORTC 40983
Important toxicity data: only small increase in peri-operative complications with chemo, although only 63% in chemo group received it post-operatively
n=182 (171 eligible)
n=182 (171 eligible)
EORTC 40983: Peri-Op FOLFOX for Liver Mets
Nordlinger, Lancet Oncology 2013;14:1208-15
Overall SurvivalHR=0.88 (p=0.34)mOS, 61m vs 54mAbsolute difference: 3.4%
Progression-Free SurvivalHR=0.81 (p=0.068)(p=0.035 for eligible pts)mPFS, 20m vs 12.5mAbsolute difference: 8.2%
No survival advantage to peri-operative chemo!
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.
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)
Report drugs toxicity % Rubbia-Brandt 5-FU/ sinusoidal 51% totalAnn Oncol 2004, n=153 Ox congestion 78% oxali
Fernandez 5-FU/ steato- 64% I + OJ AM C Surg 2005 , n=37 Ox / I hepatitis 10% 5-FU
Karoui 5-FU/ sinusoidal 49% chemoAnn Surg 2006, n=67 Ox / I dilation 14% no chemo
Aloia 5-FU vascular 52% chemoJCO 2006, n=75 Ox changes 18% no chemo
Chemotherapy Liver Toxicity: Selected Reports
Ox = oxaliplatin; I = Irinotecan
Chemotherapy Liver Toxicity:Selected Reports
Karoui, Ann Surg 2006
Influence of Number of Cycles of Pre-Op Chemo on Morbidity
More is not better!
But some is OK!
METHEP Trial: randomized phase II trial of regimens for initially unresectable* mCRC
Ychou, ASCO 2008; Ychou, Ann Surg Oncol 2013;20: 4289-4297
n = 122Primary endpoint:Response rate after 4 cycles
“standard” chemo
*Definitions: Not optimally resectable (but potentially resectable) was defined as complex hepatectomy, “risky”, close contact with major vascular structures
n=92
n=30
“Intensified” chemo
High dose FOLFIRI
FOLFOX7
FOLFIRINOX
FOLFOX4
FOLFIRI
15
15
32
30
30
n=
METHEP Trial
Ychou, Ann Surg Oncol 2013;20: 4289-4297
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)
Randomized phase II trial of chemo +/- cetuximab for initially unresectable* mCRC
Ye, J Clin Oncol 2013 Jun 1;31(16):1931-8
n = 138, KRAS WTPrimary endpoint:Rate of conversion to resectability
FOLFOX orFOLFIRI
*Definitions: “declared unresectable by a multi-disciplinary team including 3 liver surgeons and a radiologist”
n=70
n=68
FOLFOX or FOLFIRI& cetuximab
Improved survival with Cetx in phase II trial: initially unresectable liver-confined mCRC
Ye, J Clin Oncol 2013 Jun 1;31(16):1931-8
Note difference between the (negative) “New EPOC” study, which was perioperative adjuvant Ctx trial, and this one.
Biologics as adjuvant therapy: 0 for 4!
- NSABP C-08 mFOLFOX6 +/- bevacizumab (12 mos)
- N0147 FOLFOX +/- cetuximab (US Intergroup)
- AVANT FOLFOX4 vsFOLFOX + bevacizumab vsXELOX + bevacizumab
- New EPOCFOLFOX +/- Cetuximab (Liver Mets)(HR=1.49; Primose, J Clin Oncol 31, 2013 (suppl; #3504)
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
Trials for Resectable Liver Mets• Université Catholique 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
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