A history of variceal bleeding is associated with further bleeding under atezolizumab–bevacizumab in patients with HCC

Abstract

Background Atezolizumab–bevacizumab is the new standard for advanced hepatocellular carcinoma (HCC) but its impact on portal hypertension (PHT) is unknown. We aimed to identify predictive factors of acute variceal bleeding (AVB) and to monitor PHT parameters under treatment. Methods We conducted a prospective study including all cirrhotic patients treated with atezolizumab–bevacizumab since 2020. We performed monitoring of PHT using upper endoscopy at inclusion and at 6 months and hepatic venous pressure gradient (HVPG) at inclusion, 3 and 6 months after the beginning of treatment. We also included a retrospective series of patients treated with sorafenib. Time‐to‐events data were estimated by Kaplan–Meier with the log‐rank test, along with Cox models. Results Forty‐three patients treated with atezolizumab–bevacizumab were included (male 79.1%, Child‐Pugh A 86%). At baseline, 48.8% were treated with curative anticoagulation, 16.3% already experienced AVB and 25.6% had large oesophageal varices (EV). Sorafenib group characteristics were similar. Vascular invasion was present in 60.5% and median was HVPG 8.5 mm Hg. No significant modification in HVPG and EV size was observed at 6 months in the whole cohort but also when considering vascular invasion and radiological response. 14% presented AVB within a median time of occurrence of 3 months, without bleeding‐related death. In multivariate analysis, history of AVB (HR = 10.58, p = .03) was associated with AVB. AVB incidence was higher in atezolizumab–bevacizumab compared to sorafenib group (21% vs. 5% at 1 year, p = .02). Conclusions Atezolizumab–bevacizumab treatment was associated with a higher risk of AVB compared to sorafenib. A history of AVB was associated with AVB during follow‐up, which questions the use of bevacizumab in this setting.

Portal hypertension and variceal bleeding in patients with liver cancer: Evidence gaps for prevention and management

“…Some practitioners might be reluctant to start atezolizumab-bevacizumab in the setting of large EVs, in the case of red marks on EVs, in patients with vascular invasion or in the setting of curative anticoagulation. However, recent studies, including ours, did not show a higher risk of AVB in such situations but did in the case of previous AVB regardless of the delay 55,104 . Consequently, we believe that only a history of AVB is associated with a higher risk of AVB in the setting of atezolizumab-bevacizumab treatment but not large EV size, vascular invasion, or curative anticoagulation.…”

“…[103] Notably, patients with an AVB history in the last 6 months or without efficient prophylaxis for AVB were excluded from the study, and recently published real-life data showed that 14% of the patients presented with an AVB during follow-up under this new treatment. [55,104] Some practitioners might be reluctant to start atezolizumab-bevacizumab in the setting of large EVs, in the case of red marks on EVs, in patients with vascular invasion or in the setting of curative anticoagulation. However, recent studies, including ours, did not show a higher risk of AVB in such situations but did in the case of previous AVB regardless of the delay.…”

“…In contrast, the congestion index was worsened in 28 Child-Pugh A patients who received lenvatinib, potentially due to its effect on FGF receptor 54 . In a series of 43 patientswho underwent atezolizumab-bevacizumab treatment, we did not assess significant modification in HVPG or EV size at 6 months in the whole cohort or when considering vascular invasion and radiologic response 55 . However, rapid progression in the size of EVs associated with AVB was noted under atezolizumab-bevacizumab treatment for some patients with stable HCC 44,45 .…”

“…In the Imbrave 150 study, bleeding events were more frequently observed with the combination of bevacizumab and atezolizumab than with sorafenib (25.2% vs. 17.3%), including 2.4% and 0.6% of AVB cases 103 . Notably, patients with an AVB history in the last 6 months or without efficient prophylaxis for AVB were excluded from the study, and recently published real-life data showed that 14% of the patients presented with an AVB during follow-up under this new treatment 55,104 . Some practitioners might be reluctant to start atezolizumab-bevacizumab in the setting of large EVs, in the case of red marks on EVs, in patients with vascular invasion or in the setting of curative anticoagulation.…”

“…[54] In a series of 43 patients who underwent atezolizumab-bevacizumab treatment, we did not assess significant modification in HVPG or EV size at 6 months in the whole cohort or when considering vascular invasion and radiologic response. [55] However, rapid progression in the size of EVs associated with AVB was noted under atezolizumab-bevacizumab treatment for some patients with stable HCC. [44,45] In addition, HCC progression, especially in the setting of an infiltrative form and vascular invasion, could also lead to the worsening of PHT.…”