Multicenter randomized phase 2-3 trial of chemoradiotherapy versus short-course radiotherapy for organ preservation in rectal cancer

Total mesorectal excision (TME) is the standard treatment for most early-stage and intermediate0-stage rectal cancer but can cause substantial perioperative morbidity, functional impairment, and reduced quality of life. The randomized phase 2-3 STAR-TREC trial, at 37 centers in five European countries, investigated whether long-course chemoradiotherapy (LCCRT) or short-course radiotherapy (SCRT) could increase organ preservation and reduce surgery, toxicity, and quality of life harms without compromising oncological outcomes. Eligible patients were aged 16 year or older in the UK or aged 18 years or older elsewhere, had an ECOG performance status 0-1, and rectal adenocarcinoma (≤40 mm staged as mr T1-3bN0). Overall, 503 participants were enrolled. Phase 2 (n=120) assessed feasibillity. Patients were randomized 1:1:1 to LCCRT-based organ preservation (LCCRT-OP), SCRT-based organ preservation (SCRT-OP), or primary TME. Overall, 12-month TME-free survival was 60%. After phase 3 recruitment ended, interim analysis of unmasked phase 2 data showed an early TME-free survival benefit with LCCRT versus SCRT (12-month TME-free survival not reached versus 7.6 months; HR 3.7; 95% CI 1.7-8.0). In phase 3, patients that chose organ preservation were randomized 1:1 to LCCRT-OP or SCRT-OP. The 12-month TME-free survival was 78.5% with LCCRT and 60.6% with SCRT (HR 1.90; 95% CI 1.29-2.81). The most common grade 3-4 serious adverse events were gastrointestinal disorders (2% with LCCRT versus 4% with SCRT versus 8% with TME) and procedural complications (2% versus 3% versus 6%). One participant allocated to primary TME died after an anastomotic leak. The authors conclude that these early results support a response-adapted organ-preservation approach, with LCCRT appearing more effective than SCRT at 12 months.