Background
Phase III RCT (ACCORD 12/0405 Prodige 2). 598 patients with T3-T4 resectable rectal cancer. All received 50 Gy preoperative RT. Randomized 1:1 to capecitabine alone vs capecitabine + oxaliplatin (CAPOX) as the concurrent radiosensitizer.
Interventions and follow up
Arm A: Preoperative RT 50 Gy + capecitabine 800 mg/m² twice daily 5 days/week (Cap50)
Arm B: Preoperative RT 50 Gy + capecitabine 800 mg/m² twice daily + oxaliplatin 50 mg/m² weekly (CAPOX50)
Primary endpoint: CR rate
mFollow up: 3 year
Arm B: Preoperative RT 50 Gy + capecitabine 800 mg/m² twice daily + oxaliplatin 50 mg/m² weekly (CAPOX50)
Primary endpoint: CR rate
mFollow up: 3 year
Results
pCR: 19.2% (CAPOX50) vs 13.9% (Cap50), P=.09 — not significant
Ypт0-1: 28.9% vs 18.8%, P=.004
3-yr DFS: 67.9% vs 72.7%, P=.31 — no difference
Ypт0-1: 28.9% vs 18.8%, P=.004
3-yr DFS: 67.9% vs 72.7%, P=.31 — no difference
Adverse events
Main adverse events: Grade ≥3 toxicity: 25% (CAPOX50) vs 11% (Cap50), P<.001. Grade ≥3 diarrhea: 8% vs 4%. Grade ≥3 hematologic: 7% vs 1%. No difference in postoperative complications or sphincter preservation.
Conclusions
Adding oxaliplatin to capecitabine-based preoperative CRT did not significantly improve pCR (19.2% vs 13.9%, P=.09) and substantially increased toxicity. Neither the primary endpoint nor survival outcomes favored oxaliplatin addition, making capecitabine-based CRT the standard preoperative approach.
Key Limitations
Key Limitations: The study used a relatively low oxaliplatin dose (50 mg/m²/wk) — potentially inadequate to show benefit. The PETACC-6 trial similarly showed no DFS benefit from adding oxaliplatin to 5-FU-based preoperative CRT. Together, these trials established that oxaliplatin does not improve pCR or DFS as a concurrent radiosensitizer in preoperative rectal cancer CRT, though it does increase toxicity.
Clinical Context
ACCORD 12 and PETACC-6 definitively showed that adding oxaliplatin to preoperative CRT does not improve outcomes. Standard preoperative CRT remains 45–50.4 Gy with concurrent fluoropyrimidine (capecitabine or continuous infusion 5-FU). The benefit of oxaliplatin has been moved to the systemic (neoadjuvant/adjuvant) component in total neoadjuvant therapy (TNT) strategies.
References