Gefitinib frequently induces liver damage in patients with lung adenocarcinoma previously treated by chemotherapy

Abstract

Background: Gefitinib is known as one of the agents for treating patients with both advanced lung cancer and an epidermal growth-factor receptor mutation. In the epidermal growth-factor receptor-mutant advanced non-small-cell lung cancer population, gefitinib therapy has been associated with increased response rate, longer progression-free survival, and better quality of life compared to other anticancer drugs. However, gefitinib has to be discontinued for patients in whom adverse events occur, even if it is still effective. Here, we retrospectively assessed the clinical course of patients receiving gefitinib therapy, with a particular focus on liver damage. Patients and methods: Of 24 Asian patients treated with 250 mg gefitinib daily at Kanagawa National Hospital, Japan, between January 2008 and June 2012, grade 3 liver damage (Common Terminology Criteria for Adverse Events, version 4.0) occurred in nine and were eligible for our assessment. The regimen was subsequently changed to alternate-day administration. The relationships between liver damage and each clinical factor were retrospectively examined using Fisher's exact test. Results: Of the nine patients with liver damage, seven had previous exposure to another anticancer drug. There was a significant relationship between the incidence of liver damage and previous chemotherapy (P = 0.009). The objective response rates of patients treated with daily gefitinib 250 mg and alternate-day gefitinib following liver damage were 66.7% and 46.7%, respectively; these were not significantly different (P = 0.597). Conclusion: Gefitinib for advanced adenocarcinoma patients who have previously undergone chemotherapy should be used cautiously and liver function monitored closely, because it frequently induces significant liver damage. The alternate-day administration of gefitinib may be a suitable option for patients in whom daily gefitinib therapy induces liver damage.

Metabolomics reveals the formation of aldehydes and iminium in gefitinib metabolism

“…In line with the clinical data, a 12-fold increase in GSH adduct formation was observed in human pulmonary microsomes from smokers over nonsmokers [23]. Recent studies suggested that GEF frequently induced liver damage in advanced adenocarcinoma patients who had previously undergone other chemotherapies [41]. The significant liver injuries induced by GEF were observed in patients pretreated with cisplatin (CPT)+docetaxel and CPT+pemetrexed sodium.…”

Bevacizumab versus Ramucirumab in EGFR-Mutated Metastatic Non-Small-Cell Lung Cancer Patients: A Real-World Observational Study

“…The incidences of hepatitis were higher in patients receiving bevacizumab than in those treated with ramucirumab, which may be explained by more patients combined with gefitinib and bevacizumab. Gefitinib frequently induces liver damage in patients with lung adenocarcinoma after chemotherapy [36]. The frequency and dose of ramucirumab in the present study were lower than those used in a clinical trial [17], which explains the lower incidences of adverse effects (such as bleeding and hepatitis) in patients who received ramucirumab than in those who received bevacizumab.…”

Exacerbation of gefitinib-induced liver injury by glutathione reduction in mice

“…GEF frequently induces liver injury in patients with NSCLC who were previously treated with chemotherapy, such as cisplatin (Sugiura et al, 2013). For the treatment of NSCLC, cisplatin or carboplatin in combination with docetaxel, gemcitabine, irinotecan, paclitaxel, or vinorelbine are used.…”