Concurrent versus sequential irinotecan in neoadjuvant therapy for locally advanced rectal cancer: a systematic review and meta-analysis

The aim of this study is to systematically evaluate the efficacy and safety of irinotecan-containing neoadjuvant regimens for locally advanced rectal cancer (LARC). A comprehensive literature search was performed in PubMed, Embase, Web of Science, Cochrane Library to identify studies on irinotecan-containing neoadjuvant regimens for LARC published between January 1, 2000, and January 31, 2026; the search was last executed after this cutoff date, and no eligible study published in 2026 was identified. Study selection was carried out based on predefined inclusion and exclusion criteria, followed by risk-of-bias assessment and data extraction. Meta-analyses were then conducted using Stata 15.0 software. A total of 29 prospective studies involving 1,760 patients were analyzed. For irinotecan administered concurrently with neoadjuvant chemoradiotherapy (nCRT) (24 studies, n = 1,357), the pooled pathological complete response (pCR) rate was 21% (95% CI 18–25%). Meta-analysis of randomized controlled trials (RCTs) showed no significant improvement in pCR (RR 1.28, 95% CI 0.90–1.82), R0 resection, sphincter preservation, or 5-year overall survival (HR 0.95, 95% CI 0.81–1.12) compared to fluoropyrimidine-alone nCRT. However, toxicity was substantially increased, with significantly higher risks of grade ≥ 3 neutropenia (RR 3.61, 95% CI 1.22–10.73). For grade ≥ 3 diarrhea, the pooled RR was 2.16 (95% CI 0.79–5.90; P = 0.134), while TSA demonstrated that the cumulative Z-curve crossed the trial sequential monitoring boundary for harm. In contrast, when irinotecan was used sequentially within a TNT model (5 studies, n = 324), the pooled pCR rate was 26% (95% CI 22–31%). However, these data derive predominantly from single-arm prospective studies, and the survival benefit is based largely on a single randomized trial (PRODIGE 23). Confirmatory trials are therefore needed. Concurrent irinotecan-containing nCRT for LARC significantly increases toxicity without demonstrated survival benefit. Sequential irinotecan within TNT appears to improve pathological response; however, this evidence derives predominantly from single-arm studies and a single randomized trial. These findings generate the hypothesis that the efficacy of irinotecan may depend on its sequencing relative to radiotherapy, which requires confirmation in randomized trials.