SCRT-based TNT increases pathological complete response rates in patients with locally advanced rectal cancerShort-course radiation with chemotherapy improves response in rectal cancer

OBJECTIVE: Short-course radiotherapy (SCRT)-based regimens, including SCRT-alone and SCRT-based total neoadjuvant therapy (SCRT-based TNT, defined as SCRT followed by consolidation chemotherapy), have emerged as alternative neoadjuvant options to long-course chemoradiotherapy (LCCRT) for locally advanced rectal cancer (LARC). This meta-analysis stratified analyses by the type of SCRT regimen and whether LCCRT arms received preoperative consolidation chemotherapy, to systematically compare their efficacy and safety and inform personalized treatment selection. METHODS: A systematic search of PubMed, Embase, Cochrane Library, and Web of Science identified randomized controlled trials (RCTs) comparing SCRT-based regimens and LCCRT up to November 2025. Two reviewers independently performed study selection, data extraction, and risk-of-bias assessment. Pooled analyses were conducted using Review Manager 5.3, with relative risk (RR) or hazard ratio (HR) and 95% confidence intervals (CIs). RESULTS: Nine randomized trials (reported in 16 publications), involving 3,061 patients, were included. In the primary comparison of SCRT-based TNT versus standard LCCRT, the SCRT-based TNT group achieved a significantly higher pathological complete response rate (RR = 1.56, 95% CI: 1.24-1.97, P = 0.0002), whereas tumor downstaging and locoregional failure showed no significant differences from the LCCRT group. The SCRT-based TNT regimen was associated with a significantly higher incidence of grade ≥ 3 acute toxicity (RR = 1.63, 95% CI: 1.14-2.34, P = 0.008), and showed numerical trends toward improved overall survival (HR = 0.99, 95% CI: 0.76-1.28, P = 0.91) and disease-free survival (HR = 1.05, 95% CI: 0.77-1.43, P = 0.77) that did not reach statistical significance. SCRT alone was associated with lower pCR (RR = 0.13, 95% CI: 0.03-0.51, P = 0.003) and downstaging rates (RR = 0.66, 95% CI: 0.56-0.79, P < 0.00001) but a markedly lower incidence of acute toxicity (RR = 0.12, 95% CI: 0.05-0.29, P < 0.00001). An exploratory analysis based on a single small trial found no significant differences between SCRT-based TNT and LCCRT-based TNT across all major endpoints. Pooling all SCRT-based strategies obscured clinically meaningful heterogeneity and yielded no significant differences for any primary endpoint. CONCLUSIONS: SCRT-based TNT significantly improves pCR compared with standard LCCRT but does not translate into survival benefit, with a numerical increase in locoregional failure. SCRT-alone offers lower acute toxicity but substantially poorer tumor response, warranting use only in selected patients. The comparison between SCRT-based TNT and LCCRT-based TNT remains inconclusive. SCRT-based regimens represent heterogeneous treatment pathways rather than a uniform substitute for LCCRT, requiring individualized clinical decision-making.