Anne Sacré1, Nicolas Lanthier2, Hélène Dano3, Selda Aydin3, Daniela Leggenhager4, Achim Weber4, Anne-France Dekairelle5, Astrid De Cuyper1, Jean-Luc Gala5, Yves Humblet1, Christine Sempoux6, Marc Van den Eynde7,8. 1. Service d'Oncologie médicale, Cliniques Universitaires Saint-Luc, Université catholique de Louvain (UCL), Brussels, Belgium. 2. Service d'Hépato-gastroentérologie, Cliniques Universitaires Saint-Luc, UCL, Brussels, Belgium. 3. Service d'anatomie pathologique, Cliniques Universitaires Saint-Luc, UCL, Brussels, Belgium. 4. Institute of Surgical Pathology, University Zurich, Zurich, Switzerland. 5. Centre de Technologies Moléculaires Appliquées, Cliniques Universitaires Saint-Luc, UCL, Brussels, Belgium. 6. Institut Universitaire de Pathologie-IUP, Lausanne, Switzerland. 7. Service d'Oncologie médicale, Cliniques Universitaires Saint-Luc, Université catholique de Louvain (UCL), Brussels, Belgium. marc.vandeneynde@uclouvain.be. 8. Service d'Hépato-gastroentérologie, Cliniques Universitaires Saint-Luc, UCL, Brussels, Belgium. marc.vandeneynde@uclouvain.be.
Abstract
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.
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.
Authors: Tom Luedde; Jonel Trebicka; Frank Erhard Uschner; Florian Schueller; Ivelina Nikolova; Sabine Klein; Robert Schierwagen; Fernando Magdaleno; Stefanie Gröschl; Sven Loosen; Thomas Ritz; Christoph Roderburg; Michael Vucur; Glen Kristiansen; Twan Lammers Journal: Oncotarget Date: 2018-11-16
Authors: Elena De Mattia; Erika Cecchin; Michela Guardascione; Luisa Foltran; Tania Di Raimo; Francesco Angelini; Mario D'Andrea; Giuseppe Toffoli Journal: World J Gastroenterol Date: 2019-08-07 Impact factor: 5.742