Abstract
BACKGROUND: The integration of immunotherapy with neoadjuvant therapy for proficient mismatch repair (pMMR) locally advanced rectal cancer (LARC) is a promising strategy. However, the optimal treatment platform, a short-course radiotherapy (SCRT)-based regimen or a long-course chemoradiotherapy (LCRT)-based regimen, remains uncertain due to the absence of direct comparative trials. This network meta-analysis (NMA) aimed to compare the efficacy and safety of these two platforms, each with or without immune checkpoint inhibitors (ICIs). METHODS: We systematically searched PubMed/MEDLINE, Embase, and Cochrane Library from inception to September 20, 2025, for randomized controlled trials (RCTs) comparing neoadjuvant SCRT-based or LCRT-based regimens combined with ICIs versus the corresponding regimens without ICIs in LARC. A frequentist NMA was performed using random-effects models. The co-primary outcomes were the curative-intent response rate [a composite of pathological complete response (pCR) or clinical complete response followed by a Watch-and-Wait strategy (WW)] and the incidence of grade ≥ 3 treatment-related adverse events (TRAEs). The pCR rate was a key secondary endpoint. Treatments were ranked using surface under the cumulative ranking curve (SUCRA) probabilities. RESULTS: Seven RCTs (1132 patients) evaluating four strategies (SCRT-based regimen alone, SCRT-based regimen with ICIs, LCRT-based regimen alone, and LCRT-based regimen with ICIs) were included. For the primary endpoint of curative-intent response, SCRT + ICIs had the highest probability of being the most effective treatment (SUCRA, 98.5%). SCRT + ICIs significantly outperformed SCRT alone (RR, 1.82; 95% CI, 1.27-2.60) and LCRT alone (RR, 2.23; 95% CI, 1.33-3.76). It also showed a numerical, but non-significant, advantage over LCRT + ICIs (RR, 1.63; 95% CI, 0.88-3.02). The addition of ICIs to LCRT resulted in a numerical increase in response (RR, 1.37; 95% CI, 0.98-1.90) compared to LCRT alone. Results for the pCR rate were consistent in treatment ranking. Regarding safety, the addition of ICIs to either platform was not associated with a significant increase in grade ≥ 3 TRAEs, and no significant difference was observed between the two combination strategies (SCRT + ICIs vs. LCRT + ICIs: RR, 0.87; 95% CI, 0.38-2.04). CONCLUSIONS: This NMA suggests that the SCRT-based platform may be the preferred option to combine with immunotherapy in pMMR LARC. The results support direct comparison of these platforms in future phase III trials focused on long-term survival and organ preservation.