Critical Appraisal of Guideline Recommendations on Systemic Therapies for Advanced Hepatocellular Carcinoma: A Review

Abstract

Importance: The combination of immune checkpoint inhibitors with antiangiogenic agents has revolutionized the treatment landscape of advanced hepatocellular carcinoma (HCC). However, due to rapid publication of new studies that attained their predefined primary end points, a lack of robust cross-trial comparison of first-line therapies, and diverging clinical guidelines, no clear-cut treatment flowchart and sequence of therapies are available. This critical analysis of the recommendations for the management of advanced HCC from the main scientific societies in the US and Europe adopted an integrated approach to provide information on the clinical benefit (overall survival and progression-free survival) and safety profile of these therapies using the European Society for Medical Oncology (ESMO)-Magnitude of Clinical Benefit Scale (MCBS) score and an ad hoc network meta-analysis.

Observations: There is a major consensus among guidelines that atezolizumab plus bevacizumab has a primacy as the recommended first-line treatment of choice in advanced HCC. On progression after immunotherapy-containing regimens and for patients with contraindications for immunotherapies, most guidelines maintain the established treatment hierarchy, recommending lenvatinib or sorafenib as the preferred options, followed by either regorafenib, cabozantinib, or ramucirumab. Thus far, the first-line immune-based regimen of tremelimumab plus durvalumab has been integrated only in the American Association for the Study of Liver Diseases guidance document and the latest National Comprehensive Cancer Network guidelines and has particular utility for patients with a high risk of gastrointestinal bleeding. Overall, in the first-line setting, both atezolizumab plus bevacizumab and sintilimab plus IBI305 (a bevacizumab biosimilar) and durvalumab plus tremelimumab received the highest ESMO-MCBS score of 5, indicating a substantial magnitude of clinical benefit. In a network meta-analysis, no significant differences in overall survival were found among the various combination regimens. However, the newly reported combination of camrelizumab plus rivoceranib was associated with a significantly higher risk of treatment-related adverse events compared with atezolizumab plus bevacizumab (relative risk, 1.59; 95% CI, 1.25-2.03; P < .001).

Conclusions and relevance: This narrative review found that atezolizumab plus bevacizumab is regarded as the primary standard of care for advanced HCC in the first-line setting. These findings from integrating the recommendations from scientific societies' guidelines for managing advanced HCC along with new data from cross-trial comparisons may aid clinicians in decision-making and guide them through a rapidly evolving and complex treatment landscape.

Figure 1.. Proposed Treatment Algorithm for Advanced Hepatocellular Carcinoma (HCC)

Scientific societies shown are those that endorse the treatment regimen. AASLD indicates American Association for the Study of Liver Diseases; AGA, American Gastroenterological Association; ASCO, American Society of Clinical Oncology; BCLC, Barcelona Clinic Liver Cancer; EASL, European Association for the Study of the Liver; ECOG, Eastern Cooperative Oncology Group; ESMO, European Society for Medical Oncology; NCCN, National Comprehensive Cancer Network; PD, progressive disease. ^a For patients with serum α-fetoprotein >400 ng/mL before treatment.

Figure 2.. Network Meta-Analysis of Clinical Benefit and Safety of Combined Regimens vs Sorafenib in First-Line Treatment of Advanced Hepatocellular Carcinoma

HR indicates hazard ratio; OS, overall survival; PFS, progression-free survival; RR, relative risk; SUCRA, surface under the cumulative ranking; TRAE, treatment-related adverse event.