How Do We Treat Patients With Advanced Hepatocellular Carcinoma?

Hepatocellular Carcinoma: Hepatocellular CarcinomaThe treatment for hepatocellular carcinoma (HCC) has been evolving in the past 2 decades. The introduction of novel systemic therapies, including targeted therapies and immunotherapies, has transformed the treatment landscape, especially for patients with advanced disease. These advancements have resulted in unprecedented improvements in overall survival (OS) and outcomes. Despite this, HCC remains a challenging disease due to its complex biology, frequent association with liver dysfunction, limited therapy options in an advanced setting, and complexities in management of locally advanced disease. We review herein the current state of HCC management in the advanced setting, highlighting the progress in treatment options and discussing the ongoing challenges that persist. While recent breakthroughs in treatment have significantly improved patient outcomes, a thorough understanding of the underlying causes of HCC is essential for both prevention and optimizing therapeutic approaches. The most common risk factors include viral hepatitis B and C infections, alcoholic cirrhosis, and metabolic dysfunction-associated steatohepatitis (MASH), previously known as nonalcoholic steatohepatitis, which is associated with obesity with/without associated type 2 diabetes mellitus.1 Other uncommon factors include hemochromatosis and autoimmune diseases. Environmental factors that might contribute to HCC include aflatoxin-contaminated food and tobacco.2,3 Hepatitis B remains the leading cause of HCC worldwide.4 Nonetheless, changes in the annual incidence of HCC in association with etiology have been recognized globally with an increase in MASH-associated HCC cases.5 This highlights the importance of early diagnosis through surveillance of high-risk populations. Early detection significantly improves outcomes, especially with earlier diagnosis, and increases the chances for curative treatment options. A unique aspect of HCC is that we view it as two diseases rather than one: liver cancer and liver function.6 The decision on how we treat HCC in the advanced setting depends on the disease itself, as well as the extent of liver dysfunction. Liver function grading systems, such as the Child-Pugh and ALBI scores, are used to assess the severity of liver disease, stratify patients in terms of prognosis, and guide treatment decisions. Some effective therapies might not be feasible in patients with severe liver dysfunction. For these patients, systemic therapies may be risky due to the liver's compromised ability to tolerate therapy. This increases the likelihood of complications such as liver failure, making it crucial to carefully balance treatment efficacy with the potential for exacerbating underlying liver disease.7 Liver function can be assessed using several scoring systems. The Child-Pugh scoring system is mostly used and has long been a cornerstone in assessing liver function and stratifying patients with cirrhosis, including those with HCC. It evaluates five clinical parameters: bilirubin, albumin, international normalized ratio, presence of ascites, and presence of hepatic encephalopathy, categorizing patients into Child-Pugh classes A, B, or C to estimate liver disease severity and prognosis. This system is practical and easily applicable in the clinical setting, which has contributed to its widespread use. However, there are limitations to the Child-Pugh score, including the subjectivity of assessing ascites and encephalopathy and the relatively broad categories that may not fully capture subtle variations in liver function. Other scoring systems such as the albumin-bilirubin (ALBI) grade may offer a more objective assessment by focusing solely on laboratory markers. Despite this, the Child-Pugh score remains the most used due to its erroneous but now historical validation in clinical trials, which has enforced its role as a standard reference for liver function assessment in treatment decision-making. The widespread implementation of screening programs for HCC, particularly in high-risk populations, has significantly increased the reliance on imaging for early detection and diagnosis.8 Ultrasound, CT, and MRI have become essential tools in identifying liver lesions at an early stage. As imaging techniques evolved, the need for standardized and reliable tools to characterize liver lesions became apparent, leading to the development of the Liver Imaging Reporting and Data System (LI-RADS). This system provides a structured framework for evaluating and reporting liver observations, ensuring consistent diagnostic criteria, reducing variability, and improving the accuracy of HCC diagnosis.9 When a liver lesion is detected on imaging and in the presence of high-risk features that include patients with liver cirrhosis, patients with chronic hepatitis B viral infection or without cirrhosis, and patients with current or prior HCC, radiologists use the LI-RADS scoring system to classify liver lesions in patients at risk for HCC based on imaging features only. However, in the absence of high-risk features and the setting of metastatic disease, this scoring system faces limitations and can lead to misclassification or underdiagnosis of metastatic disease, as this system was not validated in the setting of advanced HCC.9 Liver biopsy remains to be the gold standard method for diagnosis of HCC.10 Obtaining a biopsy offers critical benefits beyond confirming the diagnosis, especially in cases where distinguishing between HCC and mixed tumors, such as combined hepatocellular-cholangiocarcinoma, is necessary. Biopsies also provide tissue for next-generation sequencing (NGS), which plays an increasingly important role in HCC management. NGS allows for comprehensive genetic profiling of tumors, enabling the identification of actionable mutations, potential biomarkers for targeted therapies, and insights into tumor heterogeneity. This personalized approach to treatment can optimize therapeutic decisions and improve outcomes in HCC, especially as molecularly targeted agents and immunotherapy options continue to evolve. Advanced & Metastatic Disease Historically, chemotherapy had a limited role in the management of HCC, largely due to its poor efficacy and the unique biology of HCC, which often renders these agents ineffective.11-14 In contrast, the biology of HCC makes tyrosine kinase inhibitors (TKIs) more effective, as these agents inhibit signaling pathways that are crucial for tumor growth and angiogenesis. Later, immunotherapy emerged as a powerful therapeutic agent due to the immunogenic nature of HCC, which often arises in the context of chronic inflammation. Immune checkpoint inhibitors (ICI), including anti-PD-1/PD-L1 and anti-CTLA-4 agents, plus other enhancers, modulate the immune response by targeting key inhibitory pathways, thereby enhancing the immune system's ability to recognize and eliminate tumor cells. This approach presents a more biologically rational and effective treatment strategy compared to conventional chemotherapy. Most advances in HCC treatment have been in this category. The TKI sorafenib was the standard of care for advanced HCC for decades.15 Sorafenib inhibits key kinases within the RAF/MEK/ERK pathway, which is crucial for cell proliferation, as well as vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR), impacting tumor angiogenesis. Lenvatinib, another TKI, is also FDA-approved for the first-line advanced disease.16 Lenvatinib targets a broader range of tyrosine kinases, including VEGFR 1, 2, and 3; FGFR 1, 2, 3, and 4; PDGFRα; and RET, leading to a more robust inhibition of tumor angiogenesis and cell proliferation compared to sorafenib. Lenvatinib is favored over sorafenib in advanced HCC due to its comparable or superior efficacy, higher response rates, broader mechanism of action, and potentially better tolerability.17 Later, the role of immunotherapy was established. To date, the combination of atezolizumab plus bevacizumab and durvalumab plus tremelimumab are FDA-approved therapies in the first-line setting based on the IMbrave 150 and HIMALAYA trials, respectively.18,19 Results from both trials favor ICI-based therapy over sorafenib with improvement in OS, progression-free survival (PFS), and objective response rates (ORR). Based on IMbrave 150, the median OS in the atezolizumab/bevacizumab arm was 19.2 months (95% CI: 17.0-23.7) and the sorafenib arm was 13.4 months (95% CI: 11.4-16.9) (P<0.001). Based on the HIMALAYA study, the median OS in the tremelimumab plus durvalumab, now called the STRIDE regimen, was 16.43 months (95% CI: 14.16-19.58) and the sorafenib arm was 13.77 months (95% CI: 12.25-16.13) (p=0.0037). Five-year updated OS data are available from the HIMALAYA study. Results demonstrated a sustained OS benefit for the STRIDE regimen arm compared to sorafenib (OS rates 19.6% vs. 9.4% at 5 years respectively).20 More recently, the results of CheckMate-9DW, a Phase III trial assessing combination nivolumab plus ipilimumab compared to investigator choice of sorafenib or lenvatinib, favored ICI-based therapy with improvement in OS, PFS, and ORR, pending longer follow-up data and FDA approval for first-line therapy in advanced HCC.21 These Phase III trials included varying proportions of patients with viral hepatitis B as an etiology for HCC. For example, the HIMALAYA trial had approximately 30 percent with hepatitis B, 30 percent with hepatitis C, and 40 percent with nonviral etiology, compared to the IMbrave 150 which had 49 percent patients with hepatitis B. This difference is thought to impact the reported outcomes as patients with HCC secondary to viral hepatitis rather than non-viral etiologies tend to have favorable outcomes. Conducting trials based on etiology to distinguish its impact on treatment efficacy or studying the immune microenvironment to see what variables lead to different outcomes with immunotherapy in HCC are to be considered and underway. Moreover, exploring the efficiency and safety of regimens evaluated in clinical trials through real-world evidence studies has progressively increased in recent years. Results from the AB-Real study, a prospectively maintained database including patients treated with atezolizumab plus bevacizumab for unresectable HCC across Europe, Asia, and the U.S., reported effectiveness and safety of the combination therapy.22 Portal vein tumor thrombosis and liver function evaluated by ALBI grade were identified as independent prognostic factors for OS and associated with an increased risk of hemorrhagic events in a population characterized by well-preserved liver functional reserve. In addition, evaluation of the occurrence of immune-mediated adverse events (imAE) in association to outcomes is critical. Data from the HIMALAYA study suggests that improvement in OS was observed in patients who had imAE versus those who did not (median 23.2 months vs. 14.1 for patients with imAE and no imAE, respectively, HR 0.727).23 Hence, development of imAE, with the majority being Grade 1 or 2 and generally manageable, might be a positive signal for response to therapy. Once the disease progresses on first-line treatment, TKIs are used in the second-line setting. The efficacy of TKIs has been proven in prior randomized clinical trials. As such, clinicians can use TKIs as second- and third-line therapies in confidence with options including second-line sorafenib or lenvatinib, or regorafenib, cabozantinib, and ramucirumab after sorafenib failure.24-26 The role of more innovative therapies such as chimeric antigen receptor-T cells and vaccine therapy is being evaluated.27,28 With the advancements in management of HCC and abundance of therapeutic options, especially in the metastatic first-line setting, we always need to remember who our patients are and what is best for them as cancer treatment is moving from “one size fits all” into the era of personalized medicine. This paradigm necessitates tailoring of treatment strategies based on individual patient factors, including tumor biology, liver function, and comorbid conditions. By focusing on personalized treatment plans, clinicians can optimize therapeutic efficacy and minimize adverse effects, ultimately enhancing patient outcomes in HCC management. Summary The treatment for HCC has transformed over the past decades. Therapies for HCC are evolving rapidly. Current therapies for HCC have revolutionized patient care, particularly with the advent of targeted therapies and immune checkpoint inhibitors. Understanding the etiology and evaluating liver function and the extent of the disease are key elements to decide appropriate therapy. A multidisciplinary approach should always be considered in challenging cases. This ensures that patients receive the best and most appropriate care in an individualized and personalized manner. However, challenges remain, such as the need for better biomarkers to predict treatment response, limited efficacy in certain patient subgroups, and resistance to therapy. Looking ahead, the emphasis is on personalizing treatment strategies, exploring novel combinations of immunotherapies, and investigating new molecular targets to enhance patient outcomes and address existing limitations in HCC management. While keeping up with the most recent updates on management of HCC, we need to remember there are major gaps regarding access and availability of care for HCC worldwide. Global efforts to reduce the gaps and ensure access to care are needed. LAYAL AL MAHMASANI, MD, is a Hematologist/Oncologist and GHASSAN ABOU-ALFA, MD, is a Gastrointestinal Medical Oncologist, both at Memorial Sloan Kettering Cancer Center.