Regorafenib induced severe toxic hepatitis: characterization and discussion
Anne Sacré1, Nicolas Lanthier2, Hélène Dano3
1Service d'Oncologie médicale, Cliniques Universitaires Saint-Luc, Université catholique de Louvain (UCL), Brussels, Belgium.
Summary
Regorafenib can cause severe liver toxicity in metastatic colorectal cancer patients. Genetic analysis revealed UGT1A9 polymorphisms in patients with acute hepatitis, highlighting the need for close liver monitoring during treatment.
Area of Science:
- Oncology
- Hepatology
- Pharmacogenomics
Background:
- Regorafenib is a multikinase inhibitor demonstrating survival benefits in pretreated metastatic colorectal cancer (mCRC).
- Hepatotoxicity is a recognized frequent side effect associated with regorafenib therapy.
- Understanding the mechanisms of regorafenib-induced liver injury is crucial for patient safety.
Purpose of the Study:
- To investigate severe treatment-related liver toxicity in patients with refractory mCRC treated with regorafenib.
- To analyze clinical history, liver histology, and genetic factors (CYP3A4, UGT1A9) in patients experiencing severe hepatotoxicity.
- To correlate genetic polymorphisms with the occurrence and presentation of regorafenib-induced liver injury.
Main Methods:
- Retrospective review of 93 patients with refractory mCRC treated with regorafenib.
- Detailed analysis of clinical data, liver histology, and genetic sequencing of CYP3A4 and UGT1A9 genes.
- Correlation of histopathological findings with the timing of hepatotoxicity (acute vs. subacute).
Main Results:
- Three out of 93 patients developed severe, icteric toxic hepatitis, with one fatality.
- Distinct histopathological patterns were observed: acute toxicity showed acinar zone 3 necrosis, while subacute toxicity presented with portal inflammation and bridging fibrosis.
- No CYP3A4 gene mutations were identified. UGT1A9 promoter polymorphisms (UGT1A9 variant -118T>10 [rs3832043]) were found in patients with acute hepatitis.
- Patients with acute hepatitis had a history of significant toxicity with prior irinotecan-based chemotherapy.
Conclusions:
- This study provides the first report on severe regorafenib-induced hepatotoxicity with detailed liver histology and genetic analysis.
- UGT1A9 polymorphisms may be associated with acute severe hepatotoxicity in patients treated with regorafenib.
- Close monitoring of liver function tests is essential during regorafenib treatment for mCRC patients.
More Related Videos
09:38Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib
Published on: June 26, 2019
8.5K
06:38An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
9.6K
Related Concept Videos
01:16Drug toxicity: Idiosyncratic Reactions
114
Idiosyncratic drug reactions represent abnormal chemical responses that vary significantly among individuals, ranging from extreme sensitivity to low doses to insensitivity to high doses. These reactions often occur due to the drug's covalent binding with serum proteins, forming a foreign hapten that triggers an immunotoxicological response. The variability in drug reactions has a strong pharmacogenetic foundation, with genetic differences crucial in how individuals metabolize drugs. For...
114
01:22Effect of Hepatic Disease on Pharmacokinetics: Pathophysiologic Assessment and Liver Function Test
248
In clinical practice, the direct measurement of hepatic blood flow to evaluate liver function presents significant challenges due to the intricate and specialized nature of the necessary techniques. Consequently, healthcare professionals often rely on empirical estimates derived from thorough patient examinations and liver function tests to gauge liver health. Among the tools at their disposal, the Child–Pugh and MELD scoring systems stand out for their ability to categorize and assess...
248
01:00Drug Toxicity: Overview
131
Drug toxicity quantifies the harm a compound causes to an organism, varying by dose and potentially impacting whole systems or specific organs like the liver. Toxic reactions may arise from venomous insect or spider bites, with effects ranging from mild symptoms to severe outcomes such as brain damage or death. Common forms of acute poisoning include ethanol intoxication and overdose of pain or fever medications, with substances like GHB and heroin being particularly lethal at doses close to...
131
01:24Drug Toxicity: Risk factors
95
Adverse Drug Reactions (ADRs) are potential complications that arise during pharmacotherapy, influenced by multiple risk factors. Age plays a significant role; both neonates and the elderly are at heightened risk due to their respective immature and diminished metabolic and elimination processes. Gender also impacts ADRs, with females experiencing a 1.5 to 1.7-fold greater risk than males, which may be linked to pharmacokinetic, pharmacodynamic, and hormonal differences. Notably, neonates, the...
95
01:08Effect of Hepatic Disease on Pharmacokinetics: Dose Adjustments Due to Hepatic Impairment
325
Hepatic impairment, characterized by decreased liver function, does not uniformly mandate adjustments in drug dosage. Whether dosage modifications are necessary depends on various factors related to the drug's metabolism and elimination pathways. If a drug is primarily excreted via the kidneys and bypasses significant hepatic processing, if it undergoes minimal metabolic transformation in the liver, or if it is volatile and primarily expelled through the lungs, dose adjustments may not be...
325
01:27Pharmacogenetics of Phase II Enzymes: N-acetyltransferase, Thiopurine S-methyltransferase, UDP-glucuronosyltransferase
57
Phase II biotransformation reactions are essential for detoxifying and eliminating xenobiotics, including many pharmaceutical compounds. These reactions typically involve conjugation, the covalent attachment of polar endogenous groups such as glucuronic acid, sulfate, methyl, or acetyl moieties to functional groups introduced during Phase I metabolism. The resulting conjugates are more water-soluble, enabling efficient renal or biliary excretion.The major classes of Phase II enzymes include...
57