Led by Dr. Jianhong Zhong of Guangxi Medical University Cancer Hospital, the GUIDANCE003 study presents compelling evidence that hepatectomy significantly improves survival in patients with initially unresectable hepatocellular carcinoma (HCC) who achieve either complete or partial response following conversion therapy. Conducted across 20 medical centers in China, this large-scale retrospective analysis is the most comprehensive investigation to date addressing whether surgical resection provides additional benefit after successful tumor downstaging.Patient Characteristics and Methodology
Patients who underwent hepatectomy tended to be younger, have better liver function, and were more likely to exhibit a complete radiological response to conversion therapy. Baseline differences were adjusted through propensity score matching (PSM), which resulted in two well-balanced groups of 190 patients each. The primary endpoint of the study was overall survival (OS), while secondary outcomes included event-free survival (EFS), recurrence-free survival (RFS), and complete pathological response rate. All patients were followed for a median of 22.1 months from the start of treatment.
Key Findings: Overall Survival
Patients who underwent hepatectomy experienced significantly better OS than those who did not. The one-, two-, and three-year OS rates were 96.9%, 85.6%, and 79.7% in the surgical group, compared to 90.0%, 76.1%, and 58.5% in the non-surgical group (p < 0.001). After matching, hepatectomy remained independently associated with superior OS (HR: 0.51, 95% CI: 0.31–0.83, p = 0.007). These findings were confirmed across multiple Kaplan-Meier survival analyses and subgroup comparisons.
Event-Free Survival and Recurrence-Free Survival
While hepatectomy significantly improved OS, EFS did not differ meaningfully between the surgical and non-surgical groups. Median EFS was 40.6 months in the hepatectomy group and 33.4 months in the non-hepatectomy group (p = 0.403). In patients who underwent surgery, the presence of complete pathological response (pCR) was associated with a substantial RFS benefit (HR: 0.38, 95% CI: 0.25–0.59) and improved OS (HR: 0.34, 95% CI: 0.18–0.65).
Impact of Response to Conversion Therapy
The degree of radiological response to conversion therapy had a critical impact on outcomes. Among surgical patients, those with complete response had significantly better OS (HR: 0.40, 95% CI: 0.21–0.75) and EFS (HR: 0.45, 95% CI: 0.29–0.70) compared to partial responders. Among non-surgical patients, however, survival outcomes did not differ significantly between those with complete and partial responses.
Comparison with Non-Surgical Treatments
Among patients who did not undergo hepatectomy, those who received locoregional or systemic therapy showed significantly better outcomes than those under active surveillance. OS was notably higher in the treated group (HR: 0.51, 95% CI: 0.26–0.99), with similar trends seen for EFS (HR: 0.47, 95% CI: 0.25–0.90). In patients with complete response to conversion therapy, locoregional/systemic therapy also outperformed surveillance in terms of OS, though not EFS.
Predictors of Survival Outcomes
Multivariate analysis after propensity score matching revealed that non-hepatectomy, Child-Pugh B liver function, exceeding the “up-to-seven” tumor criteria, and partial response to conversion therapy were independently associated with worse OS. For EFS, additional predictors included presence of liver cirrhosis, high alpha-fetoprotein levels, and multiple tumors. These findings emphasize the importance of both baseline tumor characteristics and the degree of treatment response in shaping long-term prognosis.
Safety and Postoperative Outcomes
Hepatectomy was curative in 97.0% of cases and was generally well tolerated. Only one perioperative death (0.3%) occurred, and 48.0% of patients experienced at least one postoperative complication. Of all surgical patients, 38.7% achieved pCR. Approximately 27% of patients received adjuvant transarterial chemoembolization, while 20.7% were treated with adjuvant immune checkpoint inhibitors. The safety profile of conversion therapy was comparable between surgical and non-surgical patients.
Conclusion
The GUIDANCE003 study provides compelling evidence that hepatectomy significantly improves overall survival in patients with unresectable HCC who respond to conversion therapy. While EFS may not differ substantially, the survival benefit is especially pronounced in patients achieving a complete response. The findings highlight the importance of integrating surgery into treatment planning following successful conversion therapy, particularly for those with favorable tumor biology and preserved liver function. In carefully selected patients, hepatectomy remains a critical component of curative-intent strategies for advanced HCC.
