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Regorafenib induced severe toxic hepatitis: characterization and discussion


Sacré, Anne; Lanthier, Nicolas; Dano, Hélène; Aydin, Selda; Lenggenhager, Daniela; Weber, Achim; Dekairelle, Anne-France; De Cuyper, Astrid; Gala, Jean-Luc; Humblet, Yves; Sempoux, Christine; Van den Eynde, Marc (2016). Regorafenib induced severe toxic hepatitis: characterization and discussion. Liver International:15.

Abstract

BACKGROUND Regorafenib is the first small-molecule multikinase inhibitor which showed survival benefits in pretreated metastatic colorectal cancer (mCRC) patients. Beside classical adverse events of this drug class, hepatotoxicity has been described as a frequent side effect. MATERIAL AND METHODS Patients with refractory mCRC treated with regorafenib in our institution were reviewed. Severe treatment-related liver toxicity was investigated. Clinical history, liver histology and genetic assessment (sequence analysis) of cytochrome P 3A4 (CYP3A4) and uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) involved in regorafenib metabolization were here reported for patients with severe hepatotoxicity. RESULTS Among the 93 reviewed patients, 3 presented severe and icteric toxic hepatitis which was fatal for 1 patient. Histopathological liver lesions were different depending on the onset of hepatotoxicity (acute or subacute): acinar zone 3 necrosis in case of acute symptoms and portal tract inflammation with porto-central bridging and fibrosis in the delayed presentation. None patients had CYP3A4 gene mutations. Similar polymorphisms in UGT1A9 gene promoter region (UGT1A9 variant -118T9>10 (rs3832043)) were found in both patients who presented acute hepatitis. Moreover, it appears retrospectively that both of them already experienced significant toxicity under irinotecan-based chemotherapy. CONCLUSION This is the first report of severe hepatotoxicity with available liver histology and genetic assessment of enzymes involved in regorafenib metabolization. This report also reminds the importance of a close liver tests monitoring during regorafenib treatment. This article is protected by copyright. All rights reserved.

Abstract

BACKGROUND Regorafenib is the first small-molecule multikinase inhibitor which showed survival benefits in pretreated metastatic colorectal cancer (mCRC) patients. Beside classical adverse events of this drug class, hepatotoxicity has been described as a frequent side effect. MATERIAL AND METHODS Patients with refractory mCRC treated with regorafenib in our institution were reviewed. Severe treatment-related liver toxicity was investigated. Clinical history, liver histology and genetic assessment (sequence analysis) of cytochrome P 3A4 (CYP3A4) and uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) involved in regorafenib metabolization were here reported for patients with severe hepatotoxicity. RESULTS Among the 93 reviewed patients, 3 presented severe and icteric toxic hepatitis which was fatal for 1 patient. Histopathological liver lesions were different depending on the onset of hepatotoxicity (acute or subacute): acinar zone 3 necrosis in case of acute symptoms and portal tract inflammation with porto-central bridging and fibrosis in the delayed presentation. None patients had CYP3A4 gene mutations. Similar polymorphisms in UGT1A9 gene promoter region (UGT1A9 variant -118T9>10 (rs3832043)) were found in both patients who presented acute hepatitis. Moreover, it appears retrospectively that both of them already experienced significant toxicity under irinotecan-based chemotherapy. CONCLUSION This is the first report of severe hepatotoxicity with available liver histology and genetic assessment of enzymes involved in regorafenib metabolization. This report also reminds the importance of a close liver tests monitoring during regorafenib treatment. This article is protected by copyright. All rights reserved.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Pathology and Molecular Pathology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:8 August 2016
Deposited On:25 Aug 2016 08:48
Last Modified:08 Dec 2017 20:13
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:1478-3223
Additional Information:This is the peer reviewed version of the following article: Sacré, Anne; Lanthier, Nicolas; Dano, Hélène; Aydin, Selda; Leggenhager, Daniela; Weber, Achim; Dekairelle, Anne-France; De Cuyper, Astrid; Gala, Jean-Luc; Humblet, Yves; Sempoux, Christine; Van den Eynde, Marc (2016). Regorafenib induced severe toxic hepatitis: characterization and discussion. Liver International:15., which has been published in final form at DOI: 10.1111/liv.13217. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving (http://olabout.wiley.com/WileyCDA/Section/id-820227.html#terms).
Publisher DOI:https://doi.org/10.1111/liv.13217
PubMed ID:27500989

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