Total neoadjuvant therapy versus standard neoadjuvant chemoradiotherapy for locally advanced rectal cancer: A systematic review and meta-analysis of long-term outcomes

초록

Background: Total neoadjuvant therapy (TNT) is increasingly used for locally advanced rectal cancer (LARC), but most evidence is based on short- or intermediate-term follow-up. We evaluated whether TNT improves long-term disease-free survival (DFS), overall survival (OS), pathological complete response (pCR), locoregional recurrence (LR), and distant metastasis (DM) compared with standard neoadjuvant chemoradiotherapy (nCRT). Patients and methods: PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched from inception to March 2026 (PROSPERO CRD420261350004). Phase II/III randomized trials comparing TNT with nCRT in adults with MRI-confirmed LARC (cT3-4 and/or cN+, M0) and a minimum median follow-up of 5 years were included. Outcomes were pooled using DerSimonian-Laird random-effects models. Results: Five trials including 2104 patients were analyzed (1063 TNT, 1041 nCRT; median follow-up 67-87 months). TNT improved DFS (HR 0.85, 95% CI 0.74-0.98; P = 0.025; I-2 = 0%) and pCR (OR 1.99, 95% CI 1.45-2.73; P < 0.001; I-2 = 30.6%), but did not improve OS (HR 0.89, 95% CI 0.76-1.05) or significantly reduce DM (OR 0.81, 95% CI 0.64-1.03). LR was not significantly different in the primary analysis (OR 1.24, 95% CI 0.95-1.62; P = 0.111). In a harmonized sensitivity analysis restricted to true pelvic recurrences after complete resection, LR showed a non-significant numerical increase with TNT (OR 1.38, 95% CI 0.98-1.95; P = 0.062). Conclusions: TNT nearly doubled pCR and modestly improved long-term DFS, but did not improve OS or significantly reduce DM. Although not statistically significant, a possible increase in true LR could not be excluded; this hypothesis-generating signal, together with the absence of an OS benefit, suggests that the long-term benefit of TNT may be more limited than short-term outcomes imply.

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