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, etc2. Data Safety Monitoring Board for OncoMed3. 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