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

Abstract

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. To compare the outcomes of NRT followed by surgery vs up-front surgery for resectable LARC. 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. NRT. The primary outcomes were overall survival (OS) and local recurrence (LR). The secondary outcome was intraoperative diverting stoma outcomes. 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). 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.