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Regorafenib induced severe toxic hepatitis: characterization and discussion.

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Sacré, Anne [UCL] Lanthier, Nicolas [UCL] Dano, Hélène [UCL] Aydin, Selda [UCL] Leggenhager, Daniela Dekairelle, Anne-France [UCL] De Cuyper, Astrid [UCL] Gala, Jean-Luc [UCL] Humblet, Yves [UCL] Sempoux, Christine [UCL] Van den Eynde, Marc [UCL]

(eng) BACKGROUND: Regorafenib is the first small-molecule multikinase inhibitor which showed survival benefits in pretreated metastatic colorectal cancer (mCRC) patients. Besides 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 P3A4 (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 of the 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 close liver tests monitoring during regorafenib treatment.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès restreint
Publication date 2016
Language Anglais
Journal information "Liver International" - Vol. 36, no. 11, p. 1590-1594 (2016)
Peer reviewed yes
Publisher Wiley-Blackwell Publishing, Inc. ((United States) Malden, MA)
issn 1478-3223
e-issn 1478-3231
Publication status Publié
Affiliations UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie
UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie
UCL - SSS/IREC/CTMA - Centre de technologies moléculaires appliquées (plate-forme technologique)
UCL - SSS/IREC/SLUC - Pôle St.-Luc
UCL - (SLuc) Service d'anatomie pathologique
UCL - (SLuc) Service d'hépato-gastro-entérologie
UCL - (SLuc) Centre de génétique médicale UCL
UCL - (SLuc) Unité d'oncologie médicale
UCL - (SLuc) Centre du cancer
Keywords Hepatotoxicity ; Liver histology ; Metastatic colorectal cancer ; Regorafenib
Links
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Bibliographic reference Sacré, Anne ; Lanthier, Nicolas ; Dano, Hélène ; Aydin, Selda ; Leggenhager, Daniela ; et. al. Regorafenib induced severe toxic hepatitis: characterization and discussion.. In: Liver International, Vol. 36, no. 11, p. 1590-1594 (2016)
Permanent URL http://hdl.handle.net/2078.1/180131