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

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; I2 = 0%) and pCR (OR 1.99, 95% CI 1.45-2.73; P < 0.001; I2 = 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.