Pathological complete response and major pathological response as surrogate endpoints for recurrence-free survival in perioperative immunotherapy for hepatocellular carcinoma: a systematic review and meta-analysis

Background High post-resection recurrence of hepatocellular carcinoma (HCC) limits long-term survival. Perioperative immunotherapy, including neoadjuvant therapy for resectable HCC and conversion therapy for unresectable HCC, has become a research hotspot. Whether pathological complete response (pCR) and major pathological response (MPR) can serve as surrogate endpoints for recurrence-free survival (RFS) remains unclear, with important implications for accelerating trial design. Objective To systematically evaluate the correlation between pCR/MPR and RFS following HCC perioperative immunotherapy, quantitatively synthesize hazard ratios (HRs) of pCR/MPR versus non-pCR/non-MPR for RFS (and overall survival, OS) across studies, and assess their reliability as surrogate endpoints. Methods We systematically searched PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI) and Wanfang Data databases (from inception to June 2026), supplemented by manual searching and citation tracking. The DerSimonian-Laird random-effects model was used to pool effect sizes. Heterogeneity was assessed using I 2 statistic and Q test. Sensitivity analysis was performed using leave-one-out method. Subgroup analyses were conducted by treatment stage (neoadjuvant vs. conversion), treatment regimen (ICI mono/dual vs. ICI + TKI vs. triple therapy), study design (prospective vs. retrospective), and MPR definition (≥70% vs. ≥ 90% necrosis). Publication bias was evaluated using Egger’s regression test. Results The systematic review included 21 studies for descriptive analysis. The meta-analysis included 10 studies reporting HR values: 5 pCR studies (n = 720) and 6 MPR studies (n = 785), one of which (NeoHCC, D’Alessio 2024) (D'Alessio et al., Lancet Oncol, 2024, 25(12), 1465–1475) encompassed both. The pCR vs. non-pCR → RFS/DFS: Pooled HR = 0.342 (95% CI: 0.248–0.472), p < 0.000001, heterogeneity I 2 = 0.0%. In sensitivity analysis, pooled HR remained stable at 0.244–0.354. MPR vs. non-MPR → RFS/PFS: Pooled HR = 0.291 (95% CI: 0.155–0.548), p = 0.000132, I 2 = 66.6%. Heterogeneity was primarily driven by one study containing non-immunotherapy cohorts (Zhang 2024, n = 481) (Zhang et al., Hepatobiliary Pancreat Dis Int, 2025, 24(2), 157–163); after exclusion, I 2 decreased to 0.0%, HR = 0.215. Conclusion The pCR and MPR after perioperative immunotherapy are strongly associated with improved RFS in HCC, corresponding to approximately 66% and 70% reductions in recurrence risk, respectively. These findings support pCR/MPR as promising surrogate endpoints, although prospective randomized validation remains necessary.