Atezolizumab and bevacizumab combination in advanced hepatocellular carcinoma patients: The imperative for safety assessment studies

Abstract

Hepatocellular carcinoma (HCC) is the most prevalent cancer of the hepatobiliary tract and the third leading cause of cancer-related mortality worldwide. Atezolizumab and bevacizumab combination is currently considered among the front-line treatment modalities for advanced unresectable HCC. Most studies examining this combination were focused on evaluating its effectiveness. Despite numerous case reports documenting some side effects, there is a limited number of large-scale studies assessing these side effects. In this article, we comment on the case report by Park et al published recently, reporting a fatal intra-tumoral hemorrhage in a patient with HCC who received systemic therapy in the form of the combination of atezolizumab and bevacizumab.

Key Words: Hepatocellular carcinoma; Atezolizumab; Bevacizumab; Hemorrhage; Side effects

Core Tip: In this article, we comment on the case report by Park et al, published in the recently reporting a fatal intra-tumoral hemorrhage in a patient with hepatocellular carcinoma following successful treatment with atezolizumab/bevacizumab. Multiple predictive factors have been reported to be associated with such condition. They can be categorized as either patient-related (age, systemic hypertension, and use of anticoagulants), liver disease-related (degree of liver decompensation and thrombocytopenia), or tumor-related (portal vein thrombosis). However, future studies are required to assess the long-term safety of this combination in patients with hepatocellular carcinoma.

TO THE EDITOR

We have read with great interest the case report of a fatal intra-tumoral hemorrhage in a patient who received a combination of atezolizumab and bevacizumab as a systemic therapy for hepatocellular carcinoma (HCC) by Park et al[1]. As known, HCC is the most prevalent cancer of the hepatobiliary tract and the third leading cause of cancer-related mortality worldwide[2]. Despite the previous fact, the management of HCC still needs a lot more work, especially for patients with advanced HCC. With the recent uprising in the field of systemic therapies for HCC, instead of having sorafenib as the sole systemic treatment of HCC, we now have several options for such cases[3].

EVALUATION OF DRUG SAFETY IN PATIENTS WITH HCC

One of the currently available systemic therapies is the atezolizumab/bevacizumab combination, which is now approved globally as a first-line standard of care for unresectable or advanced HCC, resulting in an increase in survival[3]. This combination seems tolerable in those patients[4]. In particular, real-world data are already available on this combination therapy[5]. However, the main focus of the previously published studies was to assess efficacy without focusing on the possible adverse events associated with this combination. These therapies are associated with vascular endothelial growth factor inhibition which could eventually lead to increase in the risk of bleeding tendency and thromboembolic events. This has been reported significantly in some studies, including IMbrave150[6]. Gastrointestinal (GI) bleeding is a widely discussed concern when guiding patients to treatment with atezolizumab/bevacizumab. In the IMbrave 159 trial, 6% of patients on this immunotherapy treatment had GI bleeding[4,7]. The occurrence of intra-tumoral hemorrhage seems an important issue due to its complexity as regards management, the need for early intervention, high morbidity, and mortality. Intra-tumoral hemorrhage has been recently described as a possible adverse event following lenvatinib, which is an oral systemic drug of HCC that shares the same effect as bevacizumab against vascular endothelial growth factor[8]. In a cohort of unresectable HCC patients treated with lenvatinib by Uchida-Kobayashi et al[9] out of the 87 recruited patients, five patients (7.4%) suffered from bleeding, some were of intra-tumoral source, and others from intra-abdominal. Tumoral hemorrhage has also been reported in patients receiving lenvatinib for other indications, such as thyroid cancer as reported by Staub et al[10]. Other malignancies have been reported to develop intra-tumoral hemorrhage, such as in breast cancer, as reported in a patient receiving bevacizumab[11]. Also, in colorectal cancer where bevacizumab has been associated with tumoral bleeding[12]. Some risk factors may predispose to intra-tumoral hemorrhage in patients on the atezolizumab/bevacizumab combination. In a study by Ben Khaled et al[13], the authors identified the risk factors for the incidence of bleeding, either GI or non-GI bleeding, in those treated with atezolizumab/bevacizumab therapy. Those on anticoagulation were found to have a significantly increased risk for non-GI bleeding. Moreover, using direct oral anticoagulants was related to non-GI bleeding episodes.

CONCLUSION

We recommend the evaluation of some predictive factors of intra-tumoral hemorrhage occurrence in HCC patients on atezolizumab/bevacizumab combination. They can be categorized as either patient-related (age, systemic hypertension, use of anticoagulants), liver disease-related (degree of liver decompensation, thrombocytopenia), or tumor-related (portal vein thrombosis). Of note, some of these factors may occur as side effects of atezolizumab/bevacizumab combination therapy, such as systemic hypertension (7.4%) and thrombocytopenia (16.3%)[14,15]. As a result, future prospective studies into the safety of atezolizumab/bevacizumab combination therapy and its causal relationship to intra-tumoral hemorrhage becomes imperative. This seems crucial due to the rapid increase in this combination use. We think the publication of new cases and further research on this hot topic may help guide the decision to apply strict follow-up for high-risk patients based on high or low-risk prediction models validated for HCC patients. Moreover, safety considerations related to bleeding and thromboembolic events may help guide clinical decision-making regarding treatment.