Rapid Progression of Liver Fibrosis Induced by Acute Liver Injury Due to Immune-related Adverse Events of Atezolizumab

Honma, Yuichi; Shibata, Michihiko; Gohda, Tomonori; Matsumiya, Hiroki; Kumamoto, Keiichiro; Miyama, Aya; Morino, Kahori; Koya, Yudai; Taira, Akihiro; Shinohara, Shinji; Hayashi, Tsuguru; Kusanaga, Masashi; Oe, Shinji; Miyagawa, Koichiro; Abe, Shintaro; Tanaka, Fumihiro; Harada, Masaru

doi:10.2169/internalmedicine.6535-20

Cited by 16 publications

(13 citation statements)

References 23 publications

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“…A pathological examination showed mild lobular inflammation with inflammatory infiltrate consisting of lymphocytes. These findings were compatible with previously reported ICIrelated hepatic injury [18]. Large regenerative nodules are detected in the background liver.…”

Section: Complete Response With Atezolizumab Andsupporting

confidence: 93%

Pathologic Complete Response after Chemotherapy with Atezolizumab plus Bevacizumab for Hepatocellular Carcinoma with Tumor Thrombus in the Main Portal Trunk

et al. 2023

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We report a case of pathologic complete response after successful treatment for advanced hepatocellular carcinoma (HCC) complicated with portal venous tumor thrombus by atezolizumab and bevacizumab followed by radical resection. The patient was a male in his 60s. During follow-up for chronic hepatitis B, abdominal ultrasonography revealed a huge tumor located in the right lobe of the liver with the portal vein thrombosed by the tumor. The tumor thrombus extended to the proximal side of the left branch of the portal vein. The patient’s tumor marker levels were elevated (AFP, 14,696 ng/ml; PIVKA-II, 2,141 mAU/ml). Liver biopsy revealed poorly differentiated hepatocellular carcinoma. The lesion was categorized as advanced stage according to the BCLC staging system. As systemic therapy, atezolizumab plus bevacizumab was administered. Imaging showed marked shrinkage of the tumor and portal venous thrombus with a remarkable decrease of tumor marker levels after 2 courses of chemotherapy. After 3 additional courses of chemotherapy, radical resection was considered possible. The patient underwent right hemihepatectomy and portal venous thrombectomy. A pathological examination revealed a complete response. In conclusion, for advanced HCC, atezolizumab plus bevacizumab was considered effective and was safely administered without influencing the perioperative course. This may be an appropriate neoadjuvant therapy regimen for advanced-stage HCC.

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Section: Complete Response With Atezolizumab Andsupporting

confidence: 93%

Pathologic Complete Response after Chemotherapy with Atezolizumab plus Bevacizumab for Hepatocellular Carcinoma with Tumor Thrombus in the Main Portal Trunk

et al. 2023

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“…Hepatic sinusoidal obstruction syndrome leading to PHT was already noticed after nivolumab treatment, as well as a rapid progression to liver fibrosis after atezolizumab. One can hypothesize that it was probably the case for our patient even if we did not perform liver biopsy to study the underlying liver parenchyma 19,20 . Moreover, the appreciation of the size of the EV is left to the appreciation of the operator and it can be difficult to accurately distinguish EV of grades 1 and 2.…”

Section: Discussionmentioning

confidence: 95%

“…One can hypothesize that it was probably the case for our patient even if we did not perform liver biopsy to study the underlying liver parenchyma. 19,20 Moreover, the appreciation of the size of the EV is left to the appreciation of the operator and it can be difficult to accurately distinguish EV of grades 1 and 2.…”

Section: Discussionmentioning

confidence: 99%

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

Larrey

Campion

Evain

et al. 2022

Liver International

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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.

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“…Inhibition of VEGF may impact preserved liver sinusoids in the non‐tumoral liver leading to sinusoidal alterations, impairment of oxygen and nutrient supply to hepatocytes causing cell death and the recruitment of inflammatory cells, consequently worsening the underlying liver disease and PHT. In addition, the use of Atezolizumab, which promotes cytotoxic lymphocytes, may also contribute to increase production of proinflammatory cytokines that might activate innate immune cells, as well as HSCs and LSECs, and consequently drive liver fibrosis, chronic inflammation and PHT, 89 especially in NASH and alcoholic liver disease where chronic inflammation plays a major role in the progression of the liver disease. Immunotherapy agents have also been linked to the occurrence of colitis 90 .…”

Section: Portal Hypertension and The New Combination Bevacizumab And Atezolizumabmentioning

confidence: 99%

“…In addition, the use of Atezolizumab, which promotes cytotoxic lymphocytes, may also contribute to increase production of proinflammatory cytokines that might activate innate immune cells, as well as HSCs and LSECs, and consequently drive liver fibrosis, chronic inflammation and PHT, 89 especially in NASH and alcoholic liver disease where chronic inflammation plays a major role in the progression of the liver disease. Immunotherapy agents have also been linked to the occurrence of colitis.…”

Section: P Ortal Hyperten S I On and The Ne W Comb Inati On B E Vacizumab And Ate Zolizumabmentioning

confidence: 99%

Portal hypertension and hepatocellular carcinoma: Des liaisons dangereuses…

Allaire

Rudler

Thabut

2021

Liver International

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Background and Aims Portal hypertension (PHT) and hepatocellular carcinoma (HCC) are major complication of cirrhosis which significantly contribute to morbidity and mortality. In this review, we aim to describe the consequences of both angiogenesis and inflammation in the pathogenesis of PHT and HCC, but also the difficulty to propose adapted treatment when PHT and HCC coexist in the same patients. Methods Studies for review in this article were retrieved from the PubMed database using literature published in English until March 2021. Results Portal hypertension occurs secondary to an increase of intrahepatic vascular resistances, the opening of portosystemic collateral vessels and the formation of neovessels, related to vascular endothelial growth factor (VEGF). Recently, bacterial translocation‐mediated inflammation was also identified as a major contributor to PHT. Interestingly, VEGF and chronic inflammation also contribute to HCC occurrence. As PHT and HCC often coexist in the same patient, management of PHT and its related complications as well as HCC treatment appear more complex. Indeed, PHT‐related complications such as significant ascites may hamper the access to HCC treatment and the presence of HCC is also independently associated with poor prognosis in patients with acute variceal bleeding related to PHT. Due to their respective mechanism of action, the combination of Atezolizumab and Bevacizumab for advanced HCC may impact the level of PHT and its related complications and to date, no real‐life data are available. Conslusions Appropriate evaluation and treatment of PHT remains a major issue in order to improve the outcome of HCC patients.

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Rapid Progression of Liver Fibrosis Induced by Acute Liver Injury Due to Immune-related Adverse Events of Atezolizumab

Cited by 16 publications

References 23 publications

Pathologic Complete Response after Chemotherapy with Atezolizumab plus Bevacizumab for Hepatocellular Carcinoma with Tumor Thrombus in the Main Portal Trunk

Pathologic Complete Response after Chemotherapy with Atezolizumab plus Bevacizumab for Hepatocellular Carcinoma with Tumor Thrombus in the Main Portal Trunk

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

Portal hypertension and hepatocellular carcinoma: Des liaisons dangereuses…

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