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The Sidney Kimmel Comprehensive Cancer Center
Mark Yarchoan, MD, has disclosed that he has received consulting fees from AstraZeneca, Eisai, Exelixis, and Genentech.
Most patients with hepatocellular carcinoma (HCC) also have liver cirrhosis and thus have dual competing causes of mortality. Whenever I meet with a patient with HCC, I first assess the severity of the underlying cirrhosis before providing a treatment recommendation.
A challenge in managing patients with advanced HCC is that most of the clinical trials supporting the use of approved systemic therapies were conducted in populations of patients with good liver function. In this commentary, I explore how I currently make systemic therapy decisions for patients with advanced HCC and more severe cirrhosis.
Child-Pugh Scoring and Clinical Trials of Systemic Therapy in Advanced HCC
The Child-Pugh scoring system uses 5 parameters—ascites, bilirubin, albumin, prothrombin time, and encephalopathy—to classify severity of liver cirrhosis. Patients with the lowest scores (and, as such, the least severe liver disease) are classified as having Child-Pugh A disease; those with more severe cirrhosis are classified as having Child-Pugh B or C liver function. As may be expected, patients with Child-Pugh B liver function have significantly decreased OS compared with patients with Child-Pugh A liver function. Because of this, patients with Child-Pugh B liver function are often excluded from clinical trials of novel therapies for HCC due to their poor prognosis. As a result, most approved systemic therapies for HCC have only been prospectively studied in Child-Pugh A populations, with little information to guide treatment in patients with more severe levels of liver impairment.
Selecting Systemic Therapy for Patients With Advanced HCC and Child-Pugh B Cirrhosis
As of November 2020, approved treatments for advanced HCC include the tyrosine kinase inhibitors sorafenib, lenvatinib, cabozantinib, and regorafenib; the VEGFR2 inhibitor ramucirumab; the immune checkpoint inhibitors nivolumab (with or without ipilimumab) and pembrolizumab; and the recently approved PD-L1 inhibitor/VEGF inhibitor combination of atezolizumab plus bevacizumab. Atezolizumab plus bevacizumab is now the default first-line systemic treatment for most patients with advanced HCC and Child-Pugh A liver function, replacing sorafenib and lenvatinib as the preferred standard of care in this setting.
Before I make a treatment recommendation for a patient with advanced HCC and Child-Pugh B liver function, I try to assess liver reserve beyond Child-Pugh score. There is a subset of patients with Child-Pugh B liver function that is driven by cancer-related hyperbilirubinemia and hypoalbuminemia rather than decompensated cirrhosis; these patients generally had near-normal liver function and platelets prior to their HCC. Such patients can often tolerate systemic therapy better than patients with Child-Pugh B liver function driven by cirrhosis, and I treat them similarly to patients with Child-Pugh A liver function. In some cases, their liver function may actually improve if their tumor responds to systemic therapy.
For the majority of patients with Child-Pugh B liver function, however, I am uncomfortable using atezolizumab plus bevacizumab in the frontline setting. Although this combination was shown in the phase III IMbrave150 study to significantly prolong OS vs sorafenib in patients with Child-Pugh A liver function, the safety of this combination has not been established in patients with Child-Pugh B disease. A major concern with this combination in the Child-Pugh B population is hemorrhagic complications related to bevacizumab. In historical phase II trials of bevacizumab that included patients with HCC and Child-Pugh B liver function, hemorrhagic complications were observed in up to 19% of patients.
I am comfortable using sorafenib in patients with Child-Pugh B cirrhosis and consider this agent to be a reasonable frontline treatment option for these patients. This agent has been studied both retrospectively and prospectively in patients with Child-Pugh B disease, and has generally been found to be safe, tolerable, and effective in this population. Although the sorafenib label does not provide a dose recommendation for these patients, I dose reduce this agent to 200 mg twice daily in this population.
I am slightly less comfortable using lenvatinib in the frontline setting for patients with Child-Pugh B cirrhosis because safety is not as well established in this population. Furthermore, in the phase III REFLECT study comparing lenvatinib with sorafenib in patients with Child-Pugh A liver function, patients receiving lenvatinib had higher rates of liver function–related adverse events, including hepatic encephalopathy.
There are limited retrospective data with cabozantinib to support use of this agent in patients Child-Pugh B liver function. What data there are come from the phase III CELESTIAL trial, for which patients were required to have Child-Pugh A liver function to enroll. Data in the Child-Pugh B setting therefore come from those patients whose liver function deteriorated during the trial; this population may not be reflective of most patients with Child-Pugh B cirrhosis. Per the package insert, cabozantinib should be dosed at 40 mg in patients with Child-Pugh B disease.
Anti–PD-1 immunotherapy with nivolumab has also been studied in patients with HCC and Child-Pugh class B7 or B8 liver function without ascites or encephalopathy in a prospective cohort of the CheckMate-040 study, as well as in a broader Child-Pugh B retrospective cohort study from the University of California at San Francisco. These studies indicate that nivolumab has encouraging efficacy and tolerability in patients with HCC and Child-Pugh B liver function. As nivolumab is generally better tolerated than sorafenib, based on the limited data available I think nivolumab monotherapy is a compelling choice in the frontline setting for patients with HCC and Child-Pugh B liver function.
Given the poor prognosis of patients with HCC and Child-Pugh C liver function and the high risk of treatment-related liver toxicity, I generally recommend supportive care as the best option for these patients.
How do you manage patients with advanced HCC and Child-Pugh B liver function in your clinic? Please share your experience in the comment box below.