Effect of prolonged interval between neoadjuvant chemoradiotherapy and surgery on pathological and oncological outcomes in locally advanced rectal cancer: a randomized controlled trial

BACKGROUND: The optimal interval between neoadjuvant chemoradiotherapy (nCRT) and total mesorectal excision (TME) in locally advanced rectal cancer (LARC) remains controversial. This randomized controlled trial evaluated whether prolonging the interval between nCRT and surgery improves pathological response and oncological outcomes. METHODS: Adult patients with histologically confirmed, MRI-staged II-III rectal adenocarcinoma located within 12 cm of the anal verge were randomized to undergo surgery at 8 weeks or 12 weeks after completion of long-course nCRT (50 Gy with concurrent 5-fluorouracil). The primary endpoint was pathological complete response (pCR; Dworak grade 4). Secondary endpoints included postoperative complications, surgical quality, disease-free survival (DFS), overall survival (OS), and patterns of recurrence. RESULTS: A total of 124 patients were analyzed (61 in the 8-week group and 63 in the 12-week group). Median time to surgery was 72 days (10.3 weeks) and 93 days (13.3 weeks), respectively. pCR was achieved in 14.8% vs 14.5% (p = 0.904). There were no significant differences in ypT stage, ypN stage, CRM positivity, or TME quality. Anastomotic leakage was numerically higher in the 12-week group (15.9% vs 4.9%). Three-year OS (76.3% vs 80.0%, p = 0.657) and DFS (62.9% vs 62.2%, p = 0.838) were comparable. Adjuvant chemotherapy was administered more frequently in the 8-week group (61.7% vs 39.7%, p = 0.015). CONCLUSION: Extending the surgical interval from 8 to 12 weeks did not improve pathological response or oncological outcomes. These results should be interpreted cautiously in the context of evolving total neoadjuvant therapy (TNT) strategies. TRIAL REGISTRATION: Clinicaltrialtrials.gov No. NCT03607370.