Highlight
This review synthesizes evidence from over 4,000 advanced hepatocellular carcinoma (HCC) patients worldwide, emphasizing that systemic therapy sequencing has evolved beyond linear second-line algorithms. Key highlights include: 1) The sustained efficacy of tyrosine kinase inhibitors (TKIs) following first-line immune-based combinations, demonstrating median overall survival around 10-11 months; 2) The critical role of preserved liver function in guiding treatment eligibility and influencing survival post-progression; 3) The introduction of the BCLC-UR classification, which enhances staging by considering treatment response and conversion; 4) The novel CUSE framework (Complexity, Uncertainty, Subjectivity, and Emotion), which underpins adaptive, patient-centered sequencing integrating clinical efficacy with toxicity, feasibility, and patient values.
Study Background
Hepatocellular carcinoma is a significant global health burden, ranking as one of the leading causes of cancer-related mortality worldwide. Historically, systemic treatment paradigms in advanced HCC followed a rigid, stepwise approach, typically progressing from first-line agents to predefined second-line therapies. However, the advent of immune checkpoint inhibitors and combination regimens has transformed treatment landscapes, necessitating more flexible sequencing approaches. Preservation of hepatic function and an individualized evaluation of therapeutic options have emerged as central components influencing treatment decisions. Despite advances, determining optimal therapeutic sequencing to maximize survival and quality of life remains an unmet clinical challenge.
Study Design
This integrative review included data from multiple phase II and III randomized controlled trials alongside real-world observational studies encompassing more than 4,000 patients with advanced HCC across diverse geographic regions. Interventions examined span first-line immune-based combination therapies—such as immune checkpoint inhibitors combined with anti-angiogenic agents—and subsequent second-line and beyond sequences predominantly involving tyrosine kinase inhibitors (TKIs). Key endpoints analyzed include overall survival, progression-free survival, liver function status changes, as well as treatment feasibility and toxicity profiles. The review further examines staging refinements and novel conceptual frameworks for sequencing to support clinical decision-making.
Key Findings
The review highlights that TKIs retain meaningful efficacy after progression on first-line immune-based therapies, producing median overall survival (OS) in the range of 10 to 11 months. Importantly, preservation of liver function consistently emerges as a critical determinant of treatment eligibility and post-progression survival outcomes. Liver function deterioration limits the feasibility of subsequent therapies, underscoring the necessity of vigilant hepatic assessment and management.
The Barcelona Clinic Liver Cancer (BCLC) “upon response” (BCLC-UR) concept refines disease classification by incorporating treatment responses such as major tumor shrinkage or conversion to resectability. This staging refinement better aligns clinical decision-making with contemporary therapeutic dynamics than traditional static models.
The introduction of the CUSE framework represents a paradigm shift, reframing treatment sequencing as a multidimensional and adaptive process that integrates four key domains: Complexity, Uncertainty, Subjectivity, and Emotion. This patient-centered approach balances efficacy outcomes with toxicity management, logistical feasibility, and patients’ individual values and preferences. CUSE facilitates multidisciplinary discussion and personalized sequencing strategies, moving beyond rigid protocols toward more nuanced clinical application.
Emerging strategies such as conversion therapy—using systemic treatments to convert initially unresectable tumors to resectable status—and “drug-off” approaches after complete or major responses exemplify how sequencing now surpasses the traditional second-line boundary. These evolving frontiers highlight the potential to optimize long-term outcomes, including potential curative opportunities in carefully selected patients.
Expert Commentary
Experts emphasize that the integration of immune-based combination therapies has substantially expanded the therapeutic arsenal for advanced HCC. However, heterogeneity in patient liver function and tumor biology requires flexible, individualized sequencing rather than a “one-size-fits-all” approach. The use of the BCLC-UR classification enhances prognostic precision and treatment tailoring by recognizing evolving tumor response states, which may signify opportunities for conversion or intensified intervention.
The CUSE framework addresses the complexity inherent in managing advanced HCC, where clinical decisions often involve navigating uncertain evidence, subjective patient preferences, and emotional considerations related to prognosis and quality of life. This conceptual model supports multidisciplinary teams in harmonizing these factors with clinical evidence to optimize care pathways.
Nonetheless, challenges remain. Many pivotal trials have heterogenous patient populations, and real-world applicability can be influenced by regional access to therapies and supportive care. Further prospective studies are needed to validate sequencing algorithms incorporating dynamic staging and patient-centered frameworks like CUSE.
Conclusion
Systemic treatment of advanced HCC has evolved into a multidimensional sequence that transcends simple linear algorithms. Tyrosine kinase inhibitors remain active post-immunotherapy, with preserved liver function as a cornerstone for sustained treatment eligibility and survival. The refinement of staging through concepts like BCLC-UR and the adoption of the CUSE framework enable a holistic, patient-centered approach to sequencing systemic therapies.
Emerging strategies such as conversion therapy and drug discontinuation after major responses underscore that sequencing in advanced HCC now extends well beyond the second line. Optimizing outcomes requires integrating clinical efficacy, toxicity tolerance, logistical feasibility, and patient values into a polyhedral, data-informed decision-making process. This adaptive framework fosters multidisciplinary reasoning and aligns contemporary treatment practice with evolving evidence and patient needs, ultimately improving care across the continuum of advanced HCC treatment.
Funding and Clinical Trials
The referenced review did not specify funding sources or clinical trial registrations; however, ongoing global trials continue to investigate optimal sequencing and combination strategies in advanced HCC management.
References
- Fortuny M, Chan LL, da Fonseca LG, Abou-Alfa GK, Chan SL, Reig M. Beyond second-line therapy: Strategic sequencing of systemic treatments in advanced hepatocellular carcinoma. Hepatology (Baltimore, Md.). 2026 Jun 8. PMID: 42289095.
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- Reig M, et al. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. J Hepatol. 2022 Mar;76(3):681-693.
- Kudo M. Immuno-Oncology Therapy of Hepatocellular Carcinoma: Recent Progress and New Perspectives. Cancers (Basel). 2020 Dec 23;13(1):155.
