Is there a role for adjuvant oxaliplatin in rectal cancer? - YES! - Axel Grothey Professor of Oncology Mayo Clinic, Rochester

Does adjuvant chemotherapy work at all in rectal cancer?

Bosset et al., Lancet Oncol 2014 EORTC 22921 252 253 253 253

Conclusions EORTC 22921 “Adjuvant fluorouracil-based chemotherapy after preoperative radiotherapy (with or without chemotherapy) does not affect disease-free survival or overall survival.”

DFS EORTC 22921 Bosset et al., Lancet Oncol 2014

Critique EORTC 22921 1011 pts accrued from 1993-2003 2x2 design with 250 pts per arm T3/T4 tumors, pretreatment LN staging not documented yN+ between 21-37% 4 cycles of a dose-reduced, abbreviated Mayo Clinic bolus 5-FU/LV regimen Less than 43% of pts received planned dose

Stage II&III Rectal Cancer Treated with Pre-op Fluoropyrimidines + RT +/- Oxaliplatin Study # Pts ChemoRT Regimen ypCR Rate (%) ACCORD 12 (JCO 2010) 291 Cape+RT 14 293 Cape + Oxali 50mg/m2 wkly+RT 19 (p=0.09) STAR-01 (JCO 2011) 379 FU CI+RT 16 368 FU CI + Oxali 60mg/m2 wkly+RT 16 (p=NS) NSABP R-04 (JCO 2014) 636 FU/Cape+RT 18 640 FU/Cape + Oxali 20 (p=0.42) PETACC-6 (ASCO 2014) 547 12 14 (p=0.27) CAO/ARO/AIO-04 615 13 596 17 (p=0.04)* * Unplanned exploratory analysis

ADORE study schema R Adjuvant FOLFOX Adjuvant 5-FU/LV Every 2 weeks x 8 cycles n = 149 Preop FP with radiation  TME ypStage II (ypT3-4N0) ypStage III (ypTanyN1-2) R Adjuvant 5-FU/LV Days 1-5 q 4 weeks x 4 cycles n = 146 1:1 Primary Endpoint: 3-year DFS Secondary Endpoints: AEs Patterns of failure OS QOL Kim et al., ASCO 2014

Kim et al., ASCO 2014

Kim et al., ASCO 2014

Kim et al., ASCO 2014

DFS – Adjuvant Rectal Ca Trials STUDY REGIMEN # pts % LN+ 3 yr DFS HR ADORE “Mayo” 321 62 (yp N+) 63 mFOLFOX6 72 0.63 p=0.03 AIO-04 5-FU 1265 72 (clinical) 71 FOLFOX6 76 0.79 p=0.03 PETACC-6 Cap 1094 71 (clinical) 75 CAPOX 74 1.04 p=0.78 NSABP C-07 2407 FLOX 0.80 p=0.003 MOSAIC 2246 60 73 FOLFOX4 78 0.77 p=0.002 Rectal Colon Rectal cancer trials from ASCO 2014

Conclusions from the rectal cancer studies Adjuvant therapy in rectal cancer should be guided by same principles as in colon cancer Adjuvant oxaliplatin-based therapy is superior to FP alone in stage III (assessed before neo-adjuvant therapy!) Supported by similarities in biology between colon and rectal cancer in TCGA Oxaliplatin does not provide benefit as radiation sensitizer in the neoadjuvant setting ypCR rates not increased in 4/5 studies  Validates current clinical practice

TCGA Consortium, Nature 2012

TCGA Consortium, Nature 2012

NCCN 2.2015