Management of patients with advanced hepatocellular carcinoma receiving atezolizumab/bevacizumab: Take care of cirrhosis!
Authors: Jean-Charles Nault, Massimo Iavarone
Journal: Hepatology (2024)

The treatment of advanced HCC has seen significant advances with the introduction of combination therapies, including immune checkpoint inhibitors such as atezolizumab/bevacizumab and durvalumab/tremelimumab.1,2 While these therapies have improved overall survival, they have also raised questions about the impact of cirrhosis management and treatment of underlying chronic liver disease on patient outcomes. A multicenter international study by Celsa et al3 analyzed 571 patients treated with atezolizumab/bevacizumab for advanced HCC. The study found that hepatic decompensation was a predictor of death independent of the radiological progression of HCC. In addition, ALBI grade 2/3 and nonviral etiology were associated with an increased risk of decompensation. The increased risk of hepatic decompensation associated with nonviral etiology was likely due to the lack of effective etiological treatments for these patients, particularly for those with metabolic dysfunction–associated steatotic liver disease, where no effective drugs are still available. Importantly, around half of the patients who experienced hepatic decompensation did not have evidence of HCC progression. The study also showed that treating the underlying causes of liver disease could reduce the risk of decompensation. This effect was particularly evident in patients receiving antiviral treatment for chronic viral hepatitis B or C. The findings underscore that while the options for systemic treatment of HCC have increased, it is still crucial not to neglect the management of the underlying liver disease. This approach is consistent with the data available in early-stage disease, where hepatic decompensation is an important prognostic factor and treatment of the underlying chronic liver disease improves survival.4 Moreover, the FDA approval of new drugs such as remestirom for the treatment of metabolic steatotic liver disease raises new questions about the targeted use of these drugs in patients with cirrhosis and HCC in the future.5 Therefore, management of cirrhosis and underlying liver disease, in addition to anticancer therapies, is a key component of the treatment of patients with advanced HCC. The study by Celsa and colleagues also suggests that the occurrence of hepatic decompensation should be systematically recorded in clinical trials, as it is an important prognostic factor together with the pattern of progression.6 Furthermore, it is important to investigate whether some cases of decompensation in patients without HCC progression could be attributed to treatment toxicity. It is well known that some previous randomized clinical trials in advanced HCC have tested drugs (such as sunitinib) that showed radiological antitumor efficacy but did not translate into improved overall survival due to drug-related adverse events.7 Furthermore, it would be interesting to assess whether a history of hepatic decompensation is associated with subsequent episodes of decompensation to better understand the natural history of cirrhosis in patients with advanced HCC.8 In terms of the type of decompensation, most patients experienced ascites, while only 13 patients (2%) experienced variceal bleeding, highlighting the low rate of variceal bleeding in patients with cirrhosis with HCC treated with atezolizumab/bevacizumab in clinical practice. One of the limitations of these results is the retrospective design: in the absence of a prospective design, radiological assessment of treatment response at unspecified times does not allow the complete exclusion of radiological progression occurring before clinical evidence of decompensation of cirrhosis, and retrospective studies are often unable to accurately assess the effect of treatment in alcoholic liver disease and metabolic dysfunction–associated steatotic liver disease. The management of cirrhosis is an important part of the treatment of patients with advanced HCC, as highlighted by the need to screen for and treat esophageal varices, particularly in patients treated with atezolizumab/bevacizumab.9,10 The role of beta-blockers in reducing the risk of decompensation in patients with clinically significant portal hypertension, as described in the PREDESCI trial, is also undetermined in patients with advanced HCC, as patients with HCC were excluded from this trial.11 It is also important to highlight the difficulty in accurately assessing the presence of clinically significant portal hypertension, as HVPG measurements could be biased by the presence of portal vein invasion or liver infiltration by the tumors, while the reliability of transient elastography as a surrogate marker of clinically significant portal hypertension in this population is unknown.12 The study by Celsa and colleagues also raises new questions, such as the optimal timing of treatment of the underlying liver disease in relation to the initiation of systemic treatment. In the current study, the authors suggested that the etiological treatment would be successful if it occurred before the start of atezolizumab/bevacizumab. It is unclear whether antiviral treatment started during atezolizumab/bevacizumab therapy achieves the same results and whether treatment should wait until the first radiological assessment to start only in patients who show a response or stability on atezolizumab/bevacizumab. In conclusion, the study by Celsa and colleagues reaffirms the importance of timely management of cirrhosis and of treating the underlying liver disease in patients with advanced HCC. This is to ensure the maximum effectiveness of systemic treatments, with prompt re-evaluation, whether in the first or second line.