Alan P. Venook, MD University of California, SF GREAT DEBATE: ROLE FOR ADJUVANT OXALIPLATIN IN RECTAL CANCER ? Alan P. Venook, MD University of California, SF

2004; 351: 1731-1740

Sauer et al, NEJM, 2004

Adjuv. vs. neoadjuv. CRT in Rectal Cancer (CAO/ARO/AIO-94) 5-FU 5-FU 5-FU 5-FU 5-FU 5-FU 5 x 1000 mg/m2 5 x 1000 mg/m2 500 mg/m2/d 120h-infusion 120h-infusion i.v.-bolus OP Arm I: RT: 50.4 + 5.4 Gy Boost OXALIPLATIN 5-FU 5-FU 5-FU 5-FU 500 mg/m2/d I.v.bolus 5-FU 5-FU 5 x 1000 mg/m2 5 x 1000 mg/m2 120h-infusion 120h-infusion OXALIPLATIN OP Arm II: RT: 50.4 Gy 0 2 4 6 8 10 12 14 16 18 20 22 Weeks

NSABP R-04: Preoperative oxaliplatin O’Connell et al, JCO, 2014

Oxaliplatin in rectal cancer ACCORD/PRODIGE 2 Gerard, JCO, 2010 STAR -01 Aschele, JCO, 2011 NSABP R-04 O’Connell, JCO, 2014 CAO/ARO/AIO-04 Rodel, ASCO, 2014 PETACC-6 Schmoll, ASCO, 2014 Neoadjuvant oxaliplatin More toxicity No change in path CR Weiser, JCO, 2011: Rectal cancer trials: no movement

MOSAIC OS: Stage II and Stage III Overall survival (months) Probability 1.0 0.8 0.6 0.4 0.2 0.9 0.7 0.5 0.3 0.1 6 12 18 24 60 30 36 42 48 54 66 96 72 78 84 90 HR [95% CI] Stage II 1.00 [0.71–1.42] Stage III 0.80 [0.66–0.98] p=0.996 0.1% p=0.029 4.4% FOLFOX4 stage II LV5FU2 stage II FOLFOX4 stage III LV5FU2 stage III Data cut-off: January 2007

Presented by:

ADORE: FOLFOX v. FU/LV post-op DFS: 62.9 % v. 71.6 % p = 0.047 Hong et al, Lancet Oncology, 2014

ADORE: FOLFOX v. FU/LV post-op Hong et al, Lancet Oncology, 2014

EORTC 22921: Chemotherapy with preoperative radiotherapy Accrual: 1993 – 2003 Clinical stage II or III 2 X 2 factorial design Power to demonstrate 10% OS benefit Bosset et al, NEJM, 2006

EORTC 22921: local control Bosset, et al, NEJM, 2006

EORTC 22921: Disease-Free Survival Progression- Free Survival Bosset, Lancet Oncology, 2014 Bosset, NEJM, 2006

EORTC 22921 Bosset J-F, et al, Lancet Oncology, 2014

EORTC 22921: Overall survival Bosset J-F, et al, Lancet Oncology, 2014

Post-operative chemotherapy use following neoadjuvant chemoradiation NO CHEMOTHERAPY Haynes et al, Cancer, 2014

All recommendations Category 2A unless otherwise stated

NCCN: Categories of Evidence and Consensus Category 1 Based upon high-level, there is uniform NCCN consensus that the intervention is appropriate Category 2A Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate Category 2B Based upon lower level of evidence, there is NCCN consensus that the intervention is appropriate Category 3 Based upon any level of evidence, there is major NCCN disagreement that the intervention is approrprrate

N1048: Prospect “Standard Arm” 5FUCMT* TME RANDOMIZE 1:1 TME Chemo per primary MD Chemo per primary MD RANDOMIZE 1:1 Response 20% TME FOLFOX x 6 “Selective Arm” 5FUCMT* TME Chemo per primary MD Response <20% *5FUCMT = infusional or oral 5FU + radiation therapy

N1048: PROSPECT Primary Outcomes: Randomized Phase II Component R0 Resection Rate Time to local recurrence (TLR) N = 277 / 366 INTERIM ANALYSIS PASSED Phase III Component: Co-primary endpoints Disease free survival (DFS) N = 1010

Study Schema with Suggested Post-op Regimens “Standard Arm” 5FUCMT TME FOLFOX x 8* FOLFOX x 6* RANDOMIZE 1:1 Response 20% TME FOLFOX x 6 “Selective Arm” 5FUCMT TME FOLFOX x 4* Response <20% *Post-op chemo is suggested; # of cycles & regimen may be modified (modification is not a protocol violation)