Background
Phase III randomized trial. 1,236 patients with locally advanced rectal cancer (cT3–4 or cN+) eligible for sphincter-preserving surgery or requiring abdominoperineal resection. Assessed whether adding oxaliplatin to standard fluorouracil-based neoadjuvant CRT improves pCR and long-term outcomes.
Interventions and follow up
Arm A: Experimental CRT: 50.4 Gy in 28 fractions + concurrent oxaliplatin 50 mg/m² weekly (5 doses) + continuous infusion 5-FU 250 mg/m²/day → surgery at 6 weeks → adjuvant FOLFOX (8 cycles)
Arm B: Standard CRT: 50.4 Gy in 28 fractions + concurrent continuous infusion 5-FU 1,000 mg/m²/day on days 1–5 and 29–33 → surgery → adjuvant bolus 5-FU (4 cycles)
Primary endpoint: Pathological complete response (pCR, ypT0N0)
mFollow up: 50 months
Arm B: Standard CRT: 50.4 Gy in 28 fractions + concurrent continuous infusion 5-FU 1,000 mg/m²/day on days 1–5 and 29–33 → surgery → adjuvant bolus 5-FU (4 cycles)
Primary endpoint: Pathological complete response (pCR, ypT0N0)
mFollow up: 50 months
Results
pCR: 17% vs 13%, P=.038
3-yr DFS: 75.9% vs 71.2%, HR 0.79 (95% CI 0.64–0.98), P=.030
3-yr OS: 88.7% vs 85.0%, HR 0.79, P=.065
R0 resection: 97% vs 96%, P=.43
Sphincter preservation: 88% vs 88%, P=.93
3-yr DFS: 75.9% vs 71.2%, HR 0.79 (95% CI 0.64–0.98), P=.030
3-yr OS: 88.7% vs 85.0%, HR 0.79, P=.065
R0 resection: 97% vs 96%, P=.43
Sphincter preservation: 88% vs 88%, P=.93
Adverse events
Overall/GI: Grade ≥3 toxicity during CRT 20% (Arm A) vs 14% (Arm B), P=.006; diarrhea 10% vs 7%; treatment discontinuation due to toxicity 8% vs 5%
Neurologic: Peripheral neuropathy any grade 23% vs 3% with oxaliplatin addition
Neurologic: Peripheral neuropathy any grade 23% vs 3% with oxaliplatin addition
Conclusions
Adding oxaliplatin to neoadjuvant CRT for LARC significantly improved pCR (17% vs 13%, P=.038) and 3-year DFS (HR 0.79, P=.030), though at the cost of increased acute toxicity and neuropathy. The 3-year OS improvement trended but did not reach statistical significance.
Key Limitations
Key Limitations: Modest absolute pCR improvement (4%) of uncertain clinical significance. Neuropathy with oxaliplatin (23% any grade) is a meaningful long-term toxicity concern. Different adjuvant regimens between arms (FOLFOX vs 5-FU) make it difficult to isolate the contribution of neoadjuvant oxaliplatin to the DFS benefit — adjuvant FOLFOX alone could account for part of the improvement. Trial predates MRI-guided selection and organ preservation strategies. OS benefit was not demonstrated.
Clinical Context
CAO/ARO/AIO-04 influenced practice in some European centers toward oxaliplatin-containing CRT for high-risk LARC. However, the German approach has largely been superseded by full TNT paradigms (RAPIDO, PRODIGE-23) that incorporate systemic FOLFOX/FOLFIRINOX rather than simply adding oxaliplatin to CRT. ESMO guidelines list CRT ± oxaliplatin as an option for intermediate/high-risk LARC where TNT is not pursued.
References