Phase 3 RCT (ARISTOTLE, n=564) comparing standard neoadjuvant chemoradiotherapy (45 Gy + capecitabine 900 mg/m² twice daily on weekdays) versus the same radiotherapy plus capecitabine 650 mg/m² and weekly irinotecan 60 mg/m² (weeks 1–4) in adults with MRI-defined, high-risk locally advanced rectal cancer at 75 UK centres; median follow-up 78 months.
Adding irinotecan did not improve disease-free survival: 36-month DFS was 68% (irinotecan) vs 67% (standard care); HR 0.91 (95% CI 0.68–1.23; p=0.54). Pathological complete response was also similar (19% vs 17%; p=0.56). Grade 3–5 adverse events were substantially higher with irinotecan (78% vs 52%), including diarrhoea (14% vs 4%), neutropenia (10% vs 1%), and lymphopenia (66% vs 35%); 3 treatment-related deaths occurred in the irinotecan group vs 2 in the control group.
- Trial may be underpowered for smaller but clinically meaningful benefit; event rates were lower than assumed at design. - Open-label design; masking of patients and clinicians was not feasible. - Ethnicity data were not collected, limiting generalisability and precluding UGT1A1-stratified subgroup analysis.
Irinotecan should **not** be added to capecitabine-based chemoradiotherapy for locally advanced rectal cancer—it increases toxicity without improving disease-free survival or pathological complete response. Clinicians seeking to intensify neoadjuvant therapy should consider validated total neoadjuvant therapy approaches (e.g., RAPIDO or PRODIGE-23 regimens) instead.
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