1. 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

2. 2004; 351:

3. Sauer et al, NEJM, 2004

4. Adjuv. vs. neoadjuv. CRT in Rectal Cancer (CAO/ARO/AIO-94)
5-FU FU FU FU FU FU
5 x 1000 mg/m2 5 x 1000 mg/m mg/m2/d
120h-infusion h-infusion i.v.-bolus OP
Arm I:
RT: Gy Boost
OXALIPLATIN
5-FU FU FU FU
500 mg/m2/d
I.v.bolus
5-FU FU
5 x 1000 mg/m x 1000 mg/m2
120h-infusion h-infusion
OXALIPLATIN OP
Arm II:
RT: 50.4 Gy
Weeks

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

6. 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

7. 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 [0.71–1.42]
Stage III [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

8. Presented by:

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

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

11. 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

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

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

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

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

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

18. All recommendations Category 2A unless otherwise stated

19. 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

21. 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

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

23. 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)