Supplemental Material for: The efficacy and safety of neoadjuvant therapy for resectable hepatocellular carcinoma with high recurrence risk: A multicenter real-world study

This multicenter retrospective study included resectable HCC patients with high recurrence risks (single tumor >5 cm, multiple tumors without portal vein tumor thrombus [PVTT], or any tumor number/size with Vp1/Vp2 PVTT, but not Vp3/Vp4) who received short-course neoadjuvant therapy from five tertiary hospitals (2019-2023). Efficacy was assessed using RECIST v1.1/mRECIST, Kaplan-Meier survival analysis, and Cox regression.

Safety was evaluated by CTCAE and Clavien-Dindo classification criteria. Endpoints included overall survival (OS), recurrence-free survival (RFS), objective response rate (ORR), disease control rate (DCR), and pathological responses. Results: Of 672 patients, 272 received neoadjuvant therapy and 400 underwent direct surgery; 328 remained after 1:1 propensity score matching.

Neoadjuvant therapy (n=164) reduced mortality risk by 53% (HR=0.47, p=0.001) and recurrence risk by 40% (HR=0.60, p<0.001), with median RFS extended by 24.1 months. The exploratory subgroup analysis suggested that immunotherapy-based neoadjuvant therapy (n=116) was associated with improved outcomes compared to direct surgery (OS, HR=0.43, p=0.004; RFS, HR=0.60, p=0.007), only in male patients with HBV infection, multiple tumors, maximum tumor diameter ≤5 cm, CNLC stage IIb or BCLC stage B, and good liver function.

In the full immunotherapy-based neoadjuvant group (n=212), ORR/DCR were 46.2%/98.1% (RECIST v1.1) and 73.6%/99.5% (mRECIST). The major pathological response (mPR) and pathological complete response (pCR) rates were 18.4% and 23.6%, respectively. No statistically significant difference was observed in Clavien-Dindo grade.

Conclusion: Short-course, immunotherapy-based neoadjuvant therapy appears feasible and safe, and may be associated with improved survival in resectable HCC with high recurrence risk. However, these findings remain hypothesis-generating and require further exploration and validation in future prospective studies.</p>