Neoadjuvant Radiotherapy vs Up-Front Surgery for Resectable Locally Advanced Rectal Cancer

Importance: Guidelines for resectable locally advanced rectal cancer (LARC) advocate for neoadjuvant radiotherapy (NRT) followed by surgery as the standard approach. However, recent trials have reported no oncological benefits of NRT-based therapy for middle or lower rectal cancer, raising the question of whether NRT followed by surgery remains the optimal treatment approach for resectable LARC overall. Objective: To compare the outcomes of NRT followed by surgery vs up-front surgery for resectable LARC. Design, Setting, and Participants: This cohort study, using a target trial emulation framework with nationwide registries in Taiwan, included patients undergoing curative resection for resectable LARC (cT1-2N1-2, cT3Nany) between January 1, 2014, and December 31, 2017, with follow-up until December 31, 2020. Data were analyzed from January 1, 2024, to February 15, 2025. Exposure: NRT. Main Outcomes and Measures: The primary outcomes were overall survival (OS) and local recurrence (LR). The secondary outcome was intraoperative diverting stoma outcomes. Results: A total of 4099 patients were analyzed, including 1436 patients undergoing NRT followed by surgery (median [IQR] age, 62.0 [53.0-71.0] years; 1036 [72.1%] male) and 2663 patients undergoing up-front surgery (median [IQR] age, 65.0 [56.0-74.0] years; 1626 [61.1%] male). NRT followed by surgery, compared with up-front surgery, was associated with higher 3-year OS rates (88.5% vs 85.2%; hazard ratio [HR], 0.74; 95% CI, 0.59-0.92) but higher permanent diverting stoma rates (20.6% vs 11.1%; relative risk [RR], 1.91; 95% CI, 1.62-2.25); LR rates were not significantly different (5.7% vs 6.6%; HR, 0.78; 95% CI, 0.55-1.11). Subgroup analysis revealed that compared with up-front surgery, NRT followed by surgery was associated with improved outcomes in middle or lower rectal cancer but not upper rectal cancer (OS: HR, 1.54; 95% CI, 0.82-2.90; LR: HR, 1.08; 95% CI, 0.23-5.00). NRT followed by surgery was associated with significantly increased risks of permanent diverting stomas across different tumor heights, particularly in upper rectal cancer (RR, 3.54; 95% CI, 1.44-8.69). Conclusions and Relevance: In this cohort study of nationwide registries in Taiwan, NRT followed by surgery was associated with improved oncological outcomes for overall resectable LARC, with excessive diverting stoma nonreversal as the trade-off. However, the benefits of NRT were not observed for upper rectal cancer. These findings raise concerns about potential harm from NRT and advise caution when performing NRT for upper rectal cancer.