Abstract
We report two cases of rapid progression of esophageal varices after atezolizumab–bevacizumab treatment for hepatocellular carcinoma (HCC). Case 1: a man in his 60s with hepatitis C-related liver cirrhosis after viral eradication by direct acting antiviral. He was diagnosed with HCC 8 years previously. He had undergone surgical resection 4 times, radio-frequency ablation (RFA) several times, and transcatheter arterial chemoembolization (TACE). However, HCC progressed and could not be controlled by locoregional treatment. Systemic chemotherapy was, therefore, selected. Atezolizumab–bevacizumab was administered after lenvatinib and sorafenib failure. Before starting treatment, his liver function was preserved (Child–Pugh score 5 and class A). His alpha fetoprotein and des-gamma-carboxyprothrombin levels were 3.6 ng/mL and 443 mAU/mL, respectively. Esophagogastroduodenoscopy showed no remarkable esophageal varices before atezolizumab–bevacizumab treatment. Nine months after the initiation of atezolizumab–bevacizumab, the patient was admitted for hematemesis from esophageal varices. The disease control of HCC was classified as stable disease (SD) for the liver and lung metastases, and partial response for the lymph node metastases. Neither AST nor ALT was markedly elevated in the clinical course. Endoscopic variceal ligation (EVL) for the spurting point of large esophageal varices with red wale signs was able to successfully achieve hemostasis. Atezolizumab–bevacizumab was stopped and additional EVL eradicated the esophageal varices. However, the post-banding ulcer was prolonged in comparison to usual cases. Case 2: a man in his 60s with hepatitis C-related liver cirrhosis after viral eradication by direct acting antiviral therapy. He was diagnosed with HCC 6 years previously. He had received RFA 2 times and TACE 7 times. Atezolizumab–bevacizumab was administered after lenvatinib failure. The disease control of HCC was classified as SD; however, the esophageal varices ruptured after 15 courses of atezolizumab–bevacizumab. Neither AST nor ALT were markedly elevated in the clinical course. The esophageal varices of these patients did not require treatment before atezolizumab–bevacizumab; however, they rapidly worsened and ruptured during atezolizumab–bevacizumab treatment. Although rare, similar cases with rapid progression of portal hypertension after atezolizumab–bevacizumab have been reported. We should pay attention to the worsening of esophageal varices during atezolizumab–bevacizumab treatment and poor wound healing after EVL.
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References
Fujiwara N, Friedman SL, Goossens N, et al. Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine. J Hepatol. 2018;68:526–49.
Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391:1301–14.
European Association for the study of the liver. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;69:182–236.
Kudo M, Matsui O, Izumi N, et al. Transarterial chemoembolization failure/refractoriness: JSH-LCSGJ criteria 2014 update. Oncology. 2014;87:22–31.
Hatanaka T, Naganuma A, Kakizaki S. Lenvatinib for hepatocellular carcinoma: a literature review. Pharmaceuticals. 2021;14:36.
Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.
Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382:1894–905.
Kudo M, Kawamura Y, Hasegawa K, et al. Management of hepatocellular carcinoma in Japan: JSH consensus statements and recommendations 2021 update. Liver Cancer. 2021;10:181–223.
Honma Y, Shibata M, Gohda T, et al. Rapid progression of liver fibrosis induced by acute liver injury due to immune-related adverse events of atezolizumab. Intern Med. 2021;60:1847–53.
Riveiro-Barciela M, Gonzalez-Sans D, Marmolejo D, et al. Hepatic sinusoidal obstruction syndrome associated with nivolumab: an uncommon adverse event related to immune checkpoint inhibitors. J Gastrointest Liver Dis. 2021;30:171–2.
Vilstrup H, Amodio P, Bajaj J, et al. Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014;60:715–35.
Campion B, Larrey E, Wagner M, et al. Portal hypertension, advanced hepatocellular carcinoma and therapy by atezolizumab-bevacizumab: a “menage à trois.” Clin Res Hepatol Gastroenterol. 2021;46:101785.
West H, McCleod M, Hussein M, et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic nonsquamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20:924–37.
Schmid P, Rugo HS, Adams S, et al. Atezolizumab plus nabpaclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2020;21:44–59.
Imoto K, Kohjima M, Hioki T, et al. Clinical features of liver injury induced by immune checkpoint inhibitors in Japanese patients. Can J Gastroenterol Hepatol. 2019;2019:6391712.
De Martin E, Michot JM, Papouin B, et al. Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors. J Hepatol. 2018;68:1181–90.
Fang P, Hu J, Cheng Z, et al. Efficacy and safety of bevacizumab for the treatment of advanced hepatocellular carcinoma: a systematic review of phase II trials. PLoS ONE. 2012;7:e49717.
Agarwal V, Sgouros J, Smithson J, et al. Sinusoidal obstruction syndrome (veno-occlusive disease) in a patient receiving bevacizumab for metastatic colorectal cancer: a case report. J Med Case Rep. 2008;2:227.
Riveiro-Barciela M, González-Sans D, Marmolejo D, et al. Hepatic sinusoidal obstruction syndrome associated with nivolumab: an uncommon adverse event related to immune checkpoint inhibitors. J Gastrointest Liver Dis. 2021;30:171–2.
Sugiyama T, Mizuno M, Aoki Y, et al. A single-arm study evaluating bevacizumab, cisplatin, and paclitaxel followed by single-agent bevacizumab in Japanese patients with advanced cervical cancer. Jpn J Clin Oncol. 2017;47:39–46.
Avastin prescribing information. http://www.gene.com/gene/products/information/pdf/avastin-prescribing.pdf. Accessed 10 Jan 2022.
Allaire M, Rudler M, Thabut D. Portal hypertension and hepatocellular carcinoma: Des liaisons dangereuses…. Liver Int. 2021;41:1734–43.
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Furusawa, A., Naganuma, A., Suzuki, Y. et al. Two cases of rapid progression of esophageal varices after atezolizumab–bevacizumab treatment for hepatocellular carcinoma. Clin J Gastroenterol 15, 451–459 (2022). https://doi.org/10.1007/s12328-022-01605-9
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DOI: https://doi.org/10.1007/s12328-022-01605-9