title: Regorafenib induced severe toxic hepatitis: characterization and discussion.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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: Service d'Oncologie médicale, Cliniques Universitaires Saint-Luc, Université catholique de Louvain (UCL), Brussels, Belgium.
authors: Anne
authors: A
authors: Sacré
authors: Service d'Hépato-gastroentérologie, Cliniques Universitaires Saint-Luc, UCL, Brussels, Belgium.
authors: Nicolas
authors: N
authors: Lanthier
authors: Service d'anatomie pathologique, Cliniques Universitaires Saint-Luc, UCL, Brussels, Belgium.
authors: Hélène
authors: H
authors: Dano
authors: Service d'anatomie pathologique, Cliniques Universitaires Saint-Luc, UCL, Brussels, Belgium.
authors: Selda
authors: S
authors: Aydin
authors: Institute of Surgical Pathology, University Zurich, Zurich, Switzerland.
authors: Daniela
authors: D
authors: Leggenhager
authors: Institute of Surgical Pathology, University Zurich, Zurich, Switzerland.
authors: Achim
authors: A
authors: Weber
authors: Centre de Technologies Moléculaires Appliquées, Cliniques Universitaires Saint-Luc, UCL, Brussels, Belgium.
authors: Anne-France
authors: AF
authors: Dekairelle
authors: Service d'Oncologie médicale, Cliniques Universitaires Saint-Luc, Université catholique de Louvain (UCL), Brussels, Belgium.
authors: Astrid
authors: A
authors: De Cuyper
authors: Centre de Technologies Moléculaires Appliquées, Cliniques Universitaires Saint-Luc, UCL, Brussels, Belgium.
authors: Jean-Luc
authors: JL
authors: Gala
authors: Service d'Oncologie médicale, Cliniques Universitaires Saint-Luc, Université catholique de Louvain (UCL), Brussels, Belgium.
authors: Yves
authors: Y
authors: Humblet
authors: Institut Universitaire de Pathologie-IUP, Lausanne, Switzerland.
authors: Christine
authors: C
authors: Sempoux
authors: Service d'Oncologie médicale, Cliniques Universitaires Saint-Luc, Université catholique de Louvain (UCL), Brussels, Belgium. marc.vandeneynde@uclouvain.be.|Service d'Hépato-gastroentérologie, Cliniques Universitaires Saint-Luc, UCL, Brussels, Belgium. marc.vandeneynde@uclouvain.be.
authors: Marc
authors: M
authors: Van den Eynde
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001530:Belgium; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D008099:Liver / Q000473:pathology; D008297:Male; D009362:Neoplasm Metastasis / Q000188:drug therapy; D010671:Phenylurea Compounds / Q000009:adverse effects*; D011401:Promoter Regions, Genetic; D011725:Pyridines / Q000009:adverse effects*; D012189:Retrospective Studies; D000090264:UDP-Glucuronosyltransferase 1A9
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D011725:Pyridines; C000715591:UGT1A9 protein, human; C559147:regorafenib; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D014453:Glucuronosyltransferase; D000090264:UDP-Glucuronosyltransferase 1A9
keywords: hepatotoxicity; liver histology; metastatic colorectal cancer; regorafenib