Background and Rationale

Hepatocellular carcinoma (HCC) is a major global health burden and a leading cause of cancer-related mortality. Curative hepatectomy is often not feasible due to advanced disease or insufficient liver function. Transarterial chemoembolization (TACE) remains the standard treatment for patients in the intermediate stage, and in some guidelines, even for advanced stages. However, the landscape has evolved with the introduction of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). While these therapies have shown clinical efficacy individually or in dual combinations, the benefit of combining all three modalities—TACE, TKIs, and ICIs—as a “triple conversion therapy” had not been validated in large, real-world cohorts until the GUIDANCE001 study.

Study Design and Patient Population

The GUIDANCE001 study is a multicenter, retrospective investigation conducted across 20 medical centers in China. The study included 802 patients with initially unresectable HCC treated between January 2019 and June 2023. Of these, 343 patients received triple therapy (TACE plus TKIs and ICIs), while 459 received TACE alone. After 1:1 propensity score matching to reduce baseline imbalance, 301 matched pairs were analyzed. The primary endpoint was overall survival (OS), with secondary endpoints including progression-free survival (PFS), tumor response, conversion to hepatectomy, pathologic response, and safety.

Overall and Progression-Free Survival

Triple conversion therapy was associated with a significantly improved OS. In the overall cohort, median OS was not reached in the triple therapy group versus 18.3 months in the TACE-alone group (hazard ratio [HR]: 0.43, 95% CI: 0.35–0.53, p < 0.001). In the matched cohort, the OS HR remained significant at 0.49 (95% CI: 0.38–0.63, p < 0.001). One-year OS was 86.2% in the triple group versus 65.9% in the TACE group; three-year OS was 56.2% versus 31.1%.

Similarly, triple therapy significantly prolonged PFS. Median PFS in the full cohort was 15.9 months compared to 8.0 months in the TACE-alone group (HR: 0.64, 95% CI: 0.53–0.77, p < 0.001). This benefit was confirmed in the matched analysis, with an HR of 0.61 (95% CI: 0.49–0.76, p < 0.001).

Subgroup Analysis by BCLC Stage

Subgroup analysis based on the Barcelona Clinic Liver Cancer (BCLC) staging system showed that the survival benefit of triple therapy was most significant in patients with stage B and stage C disease. In BCLC stage B, triple therapy reduced the risk of death by 70% (OS HR: 0.30, 95% CI: 0.20–0.46, p < 0.001) and improved PFS (HR: 0.69, 95% CI: 0.48–0.99, p = 0.043). In stage C patients, OS and PFS were also significantly improved (OS HR: 0.42, PFS HR: 0.50, both p < 0.001). For patients with early-stage disease (BCLC A), triple therapy did not show statistically significant survival benefits (OS HR: 0.51, p = 0.064; PFS HR: 0.72, p = 0.245).

Tumor Response

Triple therapy achieved superior tumor responses compared to TACE alone. According to RECIST 1.1 criteria, the objective response rate (ORR) was 28.6% in the triple therapy group versus 15.0% in the TACE group (p < 0.001). Using the modified RECIST (mRECIST) criteria, the ORR was 51.9% with triple therapy versus 28.1% with TACE alone (p < 0.001). Complete response rates based on mRECIST were also significantly higher in the triple group (23.9% vs. 10.0%, p < 0.001), and the disease control rate (complete + partial + stable disease) was 67.3% versus 56.6% (p = 0.002).

Conversion to Hepatectomy and Pathologic Response

Triple therapy led to a significantly higher rate of conversion to curative hepatectomy. Surgery was performed in 36.4% of patients in the triple therapy group versus 23.5% in the TACE-alone group (p < 0.001). Among those who underwent resection, the rate of major or complete pathologic response was higher after triple therapy. Importantly, patients who achieved complete pathologic response had significantly improved long-term outcomes, with an OS HR of 0.20 (95% CI: 0.09–0.42, p = 0.012) and recurrence-free survival HR of 0.43 (95% CI: 0.26–0.70, p = 0.008).

Prognostic Factors

Multivariate analysis identified several independent predictors of poor survival: receiving TACE alone, alpha-fetoprotein levels ≥ 400 ng/mL, maximum tumor diameter ≥ 10 cm, and the presence of extrahepatic metastasis. Conversely, undergoing hepatectomy after conversion therapy emerged as a strong predictor of improved survival. Macrovascular invasion was associated with worse PFS but not significantly with OS.

Safety Profile

Triple therapy was associated with a higher incidence of grade 3–4 adverse events compared to TACE alone. These included hypertension, rash, vomiting, hand-foot skin reaction, and hypothyroidism. Common side effects such as abdominal pain, nausea, and liver enzyme elevations occurred at similar rates in both groups. Although toxicity was higher in the triple therapy arm, most events were manageable, and the overall benefit-risk profile was favorable in intermediate and advanced-stage patients.

Conclusion

The GUIDANCE001 study, under Dr. Jianhong Zhong’s leadership, provides compelling real-world evidence that triple conversion therapy significantly improves survival, tumor response, and resectability in patients with unresectable HCC—especially those in BCLC stage B or C. For early-stage patients, benefits were limited, emphasizing the importance of careful patient selection.