Clinical Characteristics, Predictive Factors, and the Impact of Antithrombotic Therapy on Bleeding Events in Unresectable Hepatocellular Carcinoma Treated With Atezolizumab Plus Bevacizumab

AIM: Atezolizumab plus bevacizumab (Atez/Bev) in unresectable hepatocellular carcinoma (uHCC) is a standard first-line therapy, but bleeding-related adverse events (BL-AEs) remain clinically concerning, particularly in real-world patients with advanced tumors, portal hypertension, or undergoing antithrombotic therapy (ATT). We aimed to evaluate whether ATT increases bleeding risk, identify pretreatment factors associated with BL-AEs, and assess the impact of bleeding on progression-free survival (PFS) and overall survival (OS) in patients with uHCC treated with Atez/Bev. METHODS: This multicenter retrospective study included 981 patients with uHCC treated with Atez/Bev. BL-AEs were identified by clinical assessment, imaging, or endoscopy. Predictors of BL-AEs were analyzed using logistic regression. Survival outcomes were compared by Kaplan-Meier method, with inverse probability weighting (IPW) applied to adjust for baseline imbalances. RESULTS: BL-AEs occurred in 102 patients (10.4%) and led to treatment discontinuation in 2.7% patients. Independent predictors of BL-AEs included advanced tumor burden components, such as Vp ≥ 3 portal vein invasion and extrahepatic metastasis. Neither ATT nor portal hypertension-related factors were associated with bleeding risk. PFS did not differ between groups, whereas OS was significantly shorter in the BL group before IPW adjustment than after IPW adjustment. CONCLUSIONS: During Atez/Bev therapy, BL-AEs were primarily associated with advanced tumor burden rather than with ATT or baseline portal hypertension-related factors. Although BL-AEs were associated with poorer OS, this should be interpreted cautiously, as bleeding may reflect aggressive tumor biology rather than a direct mortality cause. Careful monitoring for bleeding complications may be required in patients with advanced tumor burden receiving Atez/Bev.

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Journal
Hepatology Research
Published
2026-04-21
DOI
https://doi.org/10.1111/hepr.70190
Primary Topic
Hepatocellular Carcinoma Treatment and Prognosis
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article
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article

Clinical Characteristics, Predictive Factors, and the Impact of Antithrombotic Therapy on Bleeding Events in Unresectable Hepatocellular Carcinoma Treated With Atezolizumab Plus Bevacizumab

Takanori Matsuura, Yoshihide Ueda, Hideko Ohama, Norio Itokawa et al.
Hepatology Research
Hepatocellular Carcinoma Treatment and Prognosis
article

Clinical Characteristics, Predictive Factors, and the Impact of Antithrombotic Therapy on Bleeding Events in Unresectable Hepatocellular Carcinoma Treated With Atezolizumab Plus Bevacizumab

Takanori Matsuura, Yoshihide Ueda, Hideko Ohama, Norio Itokawa, Joji Tani, Kazunari Tanaka, Yuki Kanayama, Hidenao Noritake, Kazuhito Kawata, Hiroki Nishikawa, Kazuya Kariyama, Hidenori Toyoda, Hirayuki Enomoto, Kazuhiro Nouso, Hideyuki Tamai, Takeshi Hatanaka, Masatoshi Kudo, Yoichi Hiasa, Kunihiko Tsuji, Atsushi Hiraoka, Takashi Kumada, Shinya Fukunishi, Takuya Nagano, Ei Itobayashi, Masaki Kaibori, Masashi Hirooka, Chikara Ogawa, Hisashi Kosaka, Kazuto Tajiri, Shohei Komatsu, Takashi Nishimura, Toshifumi Tada, Atsushi Naganuma, Akemi Tsutsui, Hidekatsu Kuroda, Toru Ishikawa, Yutaka Yata, Yuichi Koshiyama, Tomoko Aoki, Fujimasa Tada, Asahiro Morishita, Michitaka Imai, Satoru Kakizaki, Kosuke Matsui, Hironori Tanaka, Osamu Yoshida, Soo Ki Kim, Tomomitsu Matono, Taeang Arai, Hironori Ochi, Takumi Fukumoto, Jumpei Okamura, Yoshiko Nakamura, Koichi Takaguchi, Tomomi Okubo, Shinichiro Nakamura, Masanori Atsukawa
article en

Abstract

AIM: Atezolizumab plus bevacizumab (Atez/Bev) in unresectable hepatocellular carcinoma (uHCC) is a standard first-line therapy, but bleeding-related adverse events (BL-AEs) remain clinically concerning, particularly in real-world patients with advanced tumors, portal hypertension, or undergoing antithrombotic therapy (ATT). We aimed to evaluate whether ATT increases bleeding risk, identify pretreatment factors associated with BL-AEs, and assess the impact of bleeding on progression-free survival (PFS) and overall survival (OS) in patients with uHCC treated with Atez/Bev. METHODS: This multicenter retrospective study included 981 patients with uHCC treated with Atez/Bev. BL-AEs were identified by clinical assessment, imaging, or endoscopy. Predictors of BL-AEs were analyzed using logistic regression. Survival outcomes were compared by Kaplan-Meier method, with inverse probability weighting (IPW) applied to adjust for baseline imbalances. RESULTS: BL-AEs occurred in 102 patients (10.4%) and led to treatment discontinuation in 2.7% patients. Independent predictors of BL-AEs included advanced tumor burden components, such as Vp ≥ 3 portal vein invasion and extrahepatic metastasis. Neither ATT nor portal hypertension-related factors were associated with bleeding risk. PFS did not differ between groups, whereas OS was significantly shorter in the BL group before IPW adjustment than after IPW adjustment. CONCLUSIONS: During Atez/Bev therapy, BL-AEs were primarily associated with advanced tumor burden rather than with ATT or baseline portal hypertension-related factors. Although BL-AEs were associated with poorer OS, this should be interpreted cautiously, as bleeding may reflect aggressive tumor biology rather than a direct mortality cause. Careful monitoring for bleeding complications may be required in patients with advanced tumor burden receiving Atez/Bev.

Hepatology Research
Hiroshima University (JP), Kansai Medical University (JP), Iwate Medical University (JP), Kagawa University (JP), Hamamatsu University School of Medicine (JP), Wakayama Rosai Hospital (JP), Takamatsu Red Cross Hospital (JP), Saiseikai Niigata Daini Hospital (JP), National Hospital Organization Takasaki Medical Center (JP), Matsuyama Red Cross Hospital (JP), Ogaki Municipal Hospital (JP), Himeji Medical Center (JP), Hanwa Memorial Hospital (JP), Gunma Saiseikai Maebashi Hospital (JP), Himeji Red Cross Hospital (JP), Teine Keijinkai Hospital (JP), Asahi General Hospital (JP), Toyama University Hospital (JP), Ehime Prefectural Central Hospital (JP), Kobe Asahi Hospital (JP), Kagawa Prefectural Central Hospital (JP), Takarazuka City Hospital (JP), Nippon Medical School Hospital (JP), Ehime University (JP), Gifu Kyoritsu University (JP), Kobe University (JP), Nippon Medical School (JP), Hyogo University (JP), Osaka University of Pharmaceutical Sciences (JP), Kindai University (JP)
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Hepatocellular Carcinoma Treatment and Prognosis
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