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Objective <p>To comprehensively evaluate the efficacy and safety of neoadjuvant therapy combined with immunotherapy in patients with MMR-proficient/microsatellite stable (pMMR/MSS) non-metastatic rectal cancer.</p> Methods <p>Major databases, including PubMed, Web of Science, Cochrane Library, Embase, ASCO, and ESMO, were systematically searched for studies on neoadjuvant therapy combined with immunotherapy in pMMR/MSS non-metastatic rectal cancer, up to April 2025. Statistical analysis utilized Stata 18 software, calculating outcomes with pathological complete response (pCR), major pathological response (MPR), clinical complete response (cCR), R0 resection, anal preservation rate, and the incidence of adverse events. Heterogeneity and publication bias were evaluated using I² and funnel plots.</p> Results <p>A total of 21 trial cohorts from 18 studies were included in the meta-analysis. The overall pooled pCR, MPR, and cCR rates were 35% (95% CI: 30–40%, I<sup>2</sup> = 48.8%, <i>p</i> &lt; 0.001), 58% (95% CI: 51–64%, I<sup>2</sup>&#xa0;= 69.0%, <i>p</i> &lt; 0.001), and 19% (95% CI: 11–26%, I<sup>2</sup> = 86.2%, <i>p</i> &lt; 0.001), respectively. An R0 resection rate of 99% (95% CI: 99–100%, I<sup>2</sup>&#xa0;= 51.8%) and an anal preservation rate of 84% (95% CI: 79–90%, I<sup>2</sup> = 75.1%) were also achieved. Regarding safety, grade ≥ 3 immune-related adverse events (irAEs) and surgery-related adverse events (srAEs) occurred at rates of 1% and 6%, respectively. Notably, subgroup analyses demonstrated that short-course chemoradiotherapy (SCRT) yielded significantly higher pCR (46% vs. 31%, <i>p</i> &lt; 0.001) and MPR (66% vs. 53%, <i>p</i> = 0.02) rates compared to Long-course chemoradiotherapy (LCRT), with a trend toward superior cCR (25% vs. 15%, <i>p</i> = 0.08). Comparison among neoadjuvant therapy (NAT) protocols revealed comparable pCR rates across consolidation (36%), induction (34%), and concurrent (35%) strategies (<i>p</i> = 0.97), although the MPR rate differed significantly (<i>p</i> &lt; 0.05). Additionally, subgroup analysis based on immune checkpoint inhibitor type demonstrated similar efficacy between monotherapy (pCR: 36%) and dual therapy with PD-1 plus CTLA-4 inhibitors (pCR: 29%), with no statistically significant differences observed across endpoints.</p> Conclusion <p>Neoadjuvant therapy combined with immunotherapy in pMMR/MSS non-metastatic rectal cancer demonstrates promising efficacy—with high response rates, excellent R0 resection, and favorable anal preservation outcomes—and an acceptable safety profile. The improved outcomes observed with short-course radiotherapy underscore its potential role in optimizing treatment. However, the heterogeneous nature of current evidence and study designs highlight the need for further high-quality randomized trials.</p>

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Efficacy and safety of neoadjuvant therapy combined with immunotherapy in MMR‑proficient/microsatellite stable non‑metastatic rectal cancer: a systematic review and meta‑analysis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月15日

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  • Yuegang Li,
  • Chengcheng Han,
  • Jianqiang Tang

摘要

Objective

To comprehensively evaluate the efficacy and safety of neoadjuvant therapy combined with immunotherapy in patients with MMR-proficient/microsatellite stable (pMMR/MSS) non-metastatic rectal cancer.

Methods

Major databases, including PubMed, Web of Science, Cochrane Library, Embase, ASCO, and ESMO, were systematically searched for studies on neoadjuvant therapy combined with immunotherapy in pMMR/MSS non-metastatic rectal cancer, up to April 2025. Statistical analysis utilized Stata 18 software, calculating outcomes with pathological complete response (pCR), major pathological response (MPR), clinical complete response (cCR), R0 resection, anal preservation rate, and the incidence of adverse events. Heterogeneity and publication bias were evaluated using I² and funnel plots.

Results

A total of 21 trial cohorts from 18 studies were included in the meta-analysis. The overall pooled pCR, MPR, and cCR rates were 35% (95% CI: 30–40%, I2 = 48.8%, p < 0.001), 58% (95% CI: 51–64%, I2 = 69.0%, p < 0.001), and 19% (95% CI: 11–26%, I2 = 86.2%, p < 0.001), respectively. An R0 resection rate of 99% (95% CI: 99–100%, I2 = 51.8%) and an anal preservation rate of 84% (95% CI: 79–90%, I2 = 75.1%) were also achieved. Regarding safety, grade ≥ 3 immune-related adverse events (irAEs) and surgery-related adverse events (srAEs) occurred at rates of 1% and 6%, respectively. Notably, subgroup analyses demonstrated that short-course chemoradiotherapy (SCRT) yielded significantly higher pCR (46% vs. 31%, p < 0.001) and MPR (66% vs. 53%, p = 0.02) rates compared to Long-course chemoradiotherapy (LCRT), with a trend toward superior cCR (25% vs. 15%, p = 0.08). Comparison among neoadjuvant therapy (NAT) protocols revealed comparable pCR rates across consolidation (36%), induction (34%), and concurrent (35%) strategies (p = 0.97), although the MPR rate differed significantly (p < 0.05). Additionally, subgroup analysis based on immune checkpoint inhibitor type demonstrated similar efficacy between monotherapy (pCR: 36%) and dual therapy with PD-1 plus CTLA-4 inhibitors (pCR: 29%), with no statistically significant differences observed across endpoints.

Conclusion

Neoadjuvant therapy combined with immunotherapy in pMMR/MSS non-metastatic rectal cancer demonstrates promising efficacy—with high response rates, excellent R0 resection, and favorable anal preservation outcomes—and an acceptable safety profile. The improved outcomes observed with short-course radiotherapy underscore its potential role in optimizing treatment. However, the heterogeneous nature of current evidence and study designs highlight the need for further high-quality randomized trials.