Gefitinib-induced Hepatotoxicity Research Articles

Research on the Protective Effects of Different Chinese Medicine Compounds on Gefitinib-Induced Hepatotoxicity

Abstract Objective Our objective was to screen drugs with good protective effects on gefitinib-induced hepatotoxicity. Methods Fifty-four specific pathogen-free-grade male mice of the Institute of Cancer Research were randomly divided into a normal group, gefitinib group, glutathione group, ligustrazine group, silymarin group, glycyrrhizic acid group, baicalin group, paeoniflorin group, and matrine group, with six mice in each group. Except for the normal group, the remaining groups of mice were intragastrically administered 400 mg·kg−1 of gefitinib for 16 days to induce liver injury. Mice in each treatment group were intragastrically administered 100 mg·kg−1 of the corresponding drug 30 minutes after gefitinib administration each day. The normal group and model group mice were intragastrically administered with an equal volume of 0.5% carboxymethylcellulose sodium (CMC-Na), and the administration volume was 10 mg·kg−1. Then, 30 minutes after the last administration, blood was collected from the retro-orbital venous plexus, and the mice were killed by cervical dislocation to obtain liver weight and calculate the liver index. Liver pathological changes were observed by hematoxylin–eosin (HE) staining; the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum were detected using biochemical kits. AML12 cells were cultured in a medium containing drugs for 30 minutes. Except for the normal group, the remaining groups were induced cell damage with 20 μmoL·L−1 gefitinib for 24 hours. Cell viability was detected using a cell counting kit-8, and the levels of ALT, AST, and lactate dehydrogenase (LDH) in the cell culture supernatant were measured using biochemical kits. Results Animal experiments showed that compared with the gefitinib group, glycyrrhizic acid and baicalin significantly increased the body weight of mice (p < 0.01) and decreased the liver index and levels of ALT and AST (p < 0.05); ligustrazine and silymarin significantly increased the body weight of mice (p < 0.01) and decreased the level of AST (p < 0.05); paeoniflorin and matrine significantly decreased the levels of ALT and AST (p < 0.01). HE staining showed that the liver tissue of mice in the gefitinib group presented a large number of inflammatory cell infiltrations and disordered arrangement of hepatic cords; glutathione, glycyrrhizic acid, baicalin, paeoniflorin, and matrine significantly alleviated pathological damage to mouse liver tissue. Cell experiments showed that all drugs could alleviate gefitinib-induced damage to AML12 cells to varying degrees, among which glycyrrhizic acid, baicalin, and paeoniflorin had better protective effects, with cell survival rates increased to 96.4, 81.1, and 78.2%, respectively. Compared with the gefitinib group, glycyrrhizic acid significantly reduced the levels of ALT, AST, and LDH (p < 0.05); silymarin, baicalin, and paeoniflorin significantly reduced the levels of ALT and LDH (p < 0.05). Conclusion Glycyrrhizic acid, baicalin, and paeoniflorin all have good protective effects against gefitinib-induced hepatotoxicity, among which glycyrrhizic acid has the best effect.

Naringin alleviates gefitinib-induced hepatotoxicity through anti-oxidation, inhibition of apoptosis, and autophagy.

Gefitinib (GEF) is a targeted medicine used to treat locally advanced or metastatic non-small cell lung cancer (NSCLC). However, GEF's hepatotoxicity limits its clinical use. This study aims to investigate the protective effect of naringin (NG) against GEF-induced hepatotoxicity. Fifty female ICR mice were randomly divided into 5 groups: Control, GEF (200 mg/kg), NG (50 mg/kg) + GEF (200 mg/kg), NG (100 mg/kg) +GEF (200 mg/kg), NG (200 mg/kg) +GEF (200 mg/kg). After 4 weeks of continuous administration, the mice were euthanized. The blood and liver tissue samples were collected. The results indicated that the GEF group showed increased liver index, liver enzyme activities, and decreased glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) activities. Some hepatocytes showed hydropic degeneration and focal necrosis. Cell apoptosis, Cleaved-caspase3, and Poly (ADP-ribose) polymerase 1 (PARP1) increased. Transmission electron microscopy revealed the presence of numerous autophagic lysosomes or autophagosomes around the cell nucleus. Compared to the GEF group, NG can reverse these changes. In summary, NG alleviates GEF-induced hepatotoxicity by anti-oxidation, inhibiting cell apoptosis, and autophagy. Therefore, this study suggests the use of NG to mitigate GEF's toxicity to the liver.

Association of genetic polymorphisms of CYP3A4 and CYP2D6 with gefitinib-induced toxicities.

Dermatological, gastrointestinal and hepatic toxicities are the most common adverse events associated with gefitinib use. Gefitinib is metabolized by cytochrome P450. Inconsistent associations of single nucleotide genetic polymorphisms of CYP450 and gefitinib-induced adverse effects were reported. We aim to investigate the association between CYP450 genetic polymorphism and the development of gefitinib-associated adverse events. A retrospective cohort study of Chinese patients with metastatic nonsmall cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations who received first-line gefitinib treatment was conducted. Single nucleotide polymorphisms (SNPs) of CYP2D6, CYP3A4 and CYP3A5 were assayed using a multiplex SNP microarray. Risks of development of gefitinib-induced toxicities associated with different SNPs were determined. Among the 152 patients treated with gefitinib, 52 (34.2%) had gefitinib-induced hepatotoxicity, 113 (74.3%) had cutaneous reactions and 53 (34.9%) had gastrointestinal adverse effects. CYP2D6*41 CT, CYP2D6*10 AA and CYP3A4*1/*1G TT genotypes were significantly associated with hepatic, cutaneous and gastrointestinal adverse effects [odds ratio (OR) 3.773; (95% confidence interval {CI},1.046-13.610; P = 0.043), 3.368 (95% CI, 1.000-11.345; P = 0.050) and 20.000 (95% CI, 2.381-167.965; P = 0.006), respectively]. CYP2D6*41 CT, CYP2D6*10 AA and CYP3A4*1/*1G TT genotypes may be associated with increased risks of gefitinib-induced toxicities in the liver, skin and gastrointestinal tract.

FOXO3 mutation predicting gefitinib-induced hepatotoxicity in NSCLC patients through regulation of autophagy

Hepatotoxicity is a common side effect for patients treated with gefitinib, but the related pathogenesis is unclear and lacks effective predictor and management strategies. A multi-omics approach integrating pharmacometabolomics, pharmacokinetics and pharmacogenomics was employed in non-small cell lung cancer patients to identify the effective predictor for gefitinib-induced hepatotoxicity and explore optional therapy substitution. Here, we found that patients with rs4946935 AA, located in Forkhead Box O3 (FOXO3) which is a well-known autophagic regulator, had a higher risk of hepatotoxicity than those with the GA or GG variant (OR = 18.020, 95%CI = 2.473 to 459.1784, P = 0.018) in a gefitinib-concentration dependent pattern. Furthermore, functional experiments identified that rs4946935_A impaired the expression of FOXO3 by inhibiting the promotor activity, increasing the threshold of autophagy initiation and inhibiting the autophagic activity which contributed to gefitinib-induced liver injury. In contrast, erlotinib-induced liver injury was independent on the variant and expression levels of FOXO3. This study reveals that FOXO3 mutation, leading to autophagic imbalance, plays important role in gefitinib-induced hepatotoxicity, especially for patients with high concentration of gefitinib. In conclusion, FOXO3 mutation is an effective predictor and erlotinib might be an appropriately and well-tolerated treatment option for patients carrying rs4946935 AA.

PLK1 (polo like kinase 1)-dependent autophagy facilitates gefitinib-induced hepatotoxicity by degrading COX6A1 (cytochrome c oxidase subunit 6A1)

ABSTRACT Liver dysfunction is an outstanding dose-limiting toxicity of gefitinib, an EGFR (epidermal growth factor receptor)-tyrosine kinase inhibitor (TKI), in the treatment of EGFR mutation-positive non-small cell lung cancer (NSCLC). We aimed to elucidate the mechanisms underlying gefitinib-induced hepatotoxicity, and provide potentially effective intervention strategy. We discovered that gefitinib could sequentially activate macroautophagy/autophagy and apoptosis in hepatocytes. The inhibition of autophagy alleviated gefitinib-induced apoptosis, whereas the suppression of apoptosis failed to lessen gefitinib-induced autophagy. Moreover, liver-specific Atg7 +/− heterozygous mice showed less severe liver injury than vehicle, suggesting that autophagy is involved in the gefitinib-promoted hepatotoxicity. Mechanistically, gefitinib selectively degrades the important anti-apoptosis factor COX6A1 (cytochrome c oxidase subunit 6A1) in the autophagy-lysosome pathway. The gefitinib-induced COX6A1 reduction impairs mitochondrial respiratory chain complex IV (RCC IV) function, which in turn activates apoptosis, hence causing liver injury. Notably, this autophagy-promoted apoptosis is dependent on PLK1 (polo like kinase 1). Both AAV8-mediated Plk1 knockdown and PLK1 inhibitor BI-2536 could mitigate the gefitinib-induced hepatotoxicity in vivo by abrogating the autophagic degradation of the COX6A1 protein. In addition, PLK1 inhibition could not compromise the anti-cancer activity of gefitinib. In conclusion, our findings reveal the gefitinib-hepatotoxicity pathway, wherein autophagy promotes apoptosis through COX6A1 degradation, and highlight pharmacological inhibition of PLK1 as an attractive therapeutic approach toward improving the safety of gefitinib-based cancer therapy. Abbreviations: 3-MA: 3-methyladenine; AAV8: adeno-associated virus serotype 8; ATG5: autophagy related 5; ATG7: autophagy related 7; B2M: beta-2-microglobulin; CCCP: carbonyl cyanide m-chlorophenylhydrazone; CHX: cycloheximide; COX6A1: cytochrome c oxidase subunit 6A1; c-PARP: cleaved poly(ADP-ribose) polymerase; CQ: chloroquine; GOT1/AST: glutamic-oxaloacetic transaminase 1, soluble; GPT/ALT: glutamic pyruvic transaminase, soluble; HBSS: Hanks´ balanced salt solution; H&E: hematoxylin and eosin; MAP1LC3/LC3: microtubule associated proteins 1 light chain 3; PLK1: polo like kinase 1; RCC IV: respiratory chain complex IV; ROS: reactive oxygen species; TUBB8: tubulin beta 8 class VIII

FOXO3 polymorphisms were correlated with gefitinib-induced hepatotoxicity in patients with non-small cell lung cancer.

9578 Background: Drug-induced liver injury (DILI) is one of the most safety concern in drug development and clinical therapy. Severe hepatotoxicity of gefitinib often leads to acute/chronic liver injury, drug discontinuation and further treatment failure, however, the mechanism of gefitinib-induced hepatotoxicity remains unclear. AKT1/FOXO3 regulates expression of genes involved in multiple biological/pathological processes in liver cells, including apoptosis, oxidative stress, and cell-cycle transition, as well as expression of autophagy-related (Atg) genes. Therefore, we investigated the correlation between single nucleotide polymorphisms (SNP) in AKT1/ FOXO3 and gefitinib-induced hepatotoxicity in patients with advanced non-small cell lung cancer (NSCLC). Methods: A total of 172 advanced NSCLC patients with activating EGFR mutations were enrolled and administered with gefitinib 250mg daily. 22 tag SNPs in AKT1/FOXO3 were selected by Heploview 4.2 and sequenced by Agena MassARRAY System. The associations between polymorphisms of AKT1/FOXO3 and gefitinib-induced hepatotoxicity were analyzed by Chi square test. This study was approved by the ethical committee of Sun Yat-Sen University Cancer Center. Results: FOXO3 rs4946935 and FOXO3 rs75544369 were found to be associated with gefitinib-induced hepatotoxicity in NSCLC patients. FOXO3 rs4946935 AA carriers have higher risk of developing gefitinib-induced hepatotoxicity than those with FOXO3 rs4946935 AG/GG. ( P = 0.018, OR = 12.414, 95%CI (1.53-100.711)). Patients with FOXO3 rs75544369 GA have higher risk of developing hepatotoxicity with P of 0.0002 (OR = 5.241, CI%(1.85-14.851)), or developing severe hepatotoxicity with P of 0.033 (OR = 2.963, 95%CI (1.090-8.059)), than those with FOXO3 rs75544369 GG. Conclusions: FOXO3 rs4946935 and FOXO3 rs75544369 are predictive biomarkers for gefitinib-induced hepatotoxicity in NSCLC patients. The mechanism underlying the association between FOXO3 polymorphisms and gefitinib-induced hepatotoxicity are worth investigating in further studies. Clinical trial information: NCT01994057 .

Evaluation of gefitinib systemic exposure in EGFR-mutated non-small cell lung cancer patients with gefitinib-induced severe hepatotoxicity.

Severe hepatotoxicity induced by the standard dose of gefitinib (250mg daily) often becomes manageable by dose reduction to 250mg every other day. Thus, we hypothesized that systemic exposure of standard-dose gefitinib in patients with experience of severe hepatotoxicity might be higher than that in patients without severe hepatotoxicity. Patients with advanced epidermal growth factor receptor-mutated non-small cell lung cancer who were receiving gefitinib either at a reduced dose (250mg every other day) because of intolerable severe toxicity or at a standard dose (250mg daily) were enrolled. A series of blood samples were collected to estimate pharmacokinetic parameters and calculate systemic exposure of standard-dose gefitinib (area under the concentration-time curve from 0 to 24h at steady state, AUC0-24,ss). Systemic exposure of unbound gefitinib (fu·AUC0-24,ss) was also assessed, because gefitinib is extensively bound to serum proteins. Of the 38 enrolled patients, 34 (23 patients without experience of severe hepatotoxicity, 11 patients with experience of severe hepatotoxicity) were evaluable. There was no significant differences in total AUC0-24,ss or unbound fu·AUC0-24,ss between patients with and without experience of severe hepatotoxicity. Analysis of the time to severe hepatotoxicity indicated no difference between patients with a high AUC0-24,ss and those with a low AUC0-24,ss of either total or unbound gefitinib. This study suggests that reversible severe hepatotoxicity is not caused by high systemic exposure of gefitinib.

Factors affecting time to reach and recover from gefitinib-induced hepatotoxicity.

Gefitinib is an oral tyrosine kinase inhibitor targeting the epidermal growth factor receptor (EGFR) for non-small-cell lung cancer with EGFR mutations. Although a few studies have analyzed the causes of gefitinib-induced hepatotoxicity, research focusing on the time intervals before and after hepatotoxicity has yet to be reported. Therefore, this study investigated two types of factors: the time to reach gefitinib-induced hepatotoxicity and the time for recovery. From January 2013 to December 2014, a retrospective study was carried out on 473 non-small-cell lung cancer patients who were treated with gefitinib. The following data were collected: sex, age, body weight, height, body surface area, underlying disease, Eastern Cooperative Oncology Group Performance Status, smoking history, gefitinib dose, EGFR mutation, and concomitant drugs. Multivariate models showed that patients with mutations in exon 19 had around two-fold higher hepatotoxicity (≥grade 2). Use of CYP3A4 inhibitors and smoking shortened time to hepatotoxicity ∼5-2-fold, respectively, whereas mutations in exon 21 prolonged time to hepatotoxicity by about 2.4-fold. Termination of gefitinib therapy showed 3.8-fold faster recovery. Our study showed that the concomitant use of CYP3A4 inhibitors, smoking, and exon 21 affected the time to reach gefitinib-induced hepatotoxicity. Among the factors examined in this study including hepatotonic use and gefitinib termination, only cessation of gefitinib therapy significantly accelerated recovery.

Effects of Concomitant Medication Use on Gefitinib-Induced Hepatotoxicity.

Gefitinib is a drug used for the treatment of non-small cell lung cancer (NSCLC) patients. Severe hepatotoxicity was observed, but only a few cases have been reported on the hepatotoxicity of gefitinib. This study aimed to investigate the association between gefitinib-induced hepatotoxicity and various factors including concomitant medications in lung cancer patients. From January 2013 to December 2014, a retrospective study was performed with NSCLC patients who were treated with gefitinib. Associations between hepatotoxicity and various factors including concomitant drugs were analyzed. Based on multivariate models, it was found that H2 antagonists, proton pump inhibitors (PPIs), and H2 antagonists or PPIs increased hepatotoxicity by about 1.5- to 1.7-fold. Patients younger than 65 years showed 1.6 times higher hepatotoxicity than those older than 65 years. Patients with EGFR mutations had around 2-fold higher hepatotoxicity, and the percentage of incidence of hepatotoxicity because of exon 19 deletion was 32.7%. Our study showed that anti-acid-secreting agents in addition to age younger than 65 years and EGFR mutation were associated with gefitinib-induced hepatotoxicity. Thus, close monitoring of liver function is recommended, especially for patients using anti-acid-secreting agents.

Observation of hepatotoxicity during long-term gefitinib administration in patients with non-small-cell lung cancer

To observe drug-induced hepatotoxicity by long-term gefitinib administration in the treatment of non-small-cell lung cancer. The data of 101 patients with locally advanced or metastatic non-small-cell lung cancer, for which gefitinib had been used orally for 3 months or longer, were retrospectively analyzed. The median duration of gefitinib administration was 14 months (3–60 months). Forty patients (39.6%) developed abnormal hepatic function, among whom 30 patients (29.7%) had grade I hepatotoxicity, six patients (5.9%) had grade II, and four patients (4.0%) had grade III, respectively. The median time from starting gefitinib oral therapy to developing liver dysfunction was 4 months (1–23 months) for the entire cohort. The incidence of hepatotoxicity in the group with a duration of more than 14 months was much higher than that in the group with a duration of less than 14 months (52.0 vs. 27.5%, P=0.012). In thirty-two patients (32/40), abnormal liver function resolved with hepatoprotective treatment, whereas eight patients (8/40) had persistent grade I hepatotoxicity until the last follow-up. Our study showed that long-term gefitinib-induced hepatotoxicity was a common adverse event, especially for the cohort with a duration of longer than 14 months. In most patients with hepatotoxicity, normal liver function was restored and discontinuation of gefitinib was not necessary.

Impact of single nucleotide polymorphisms on severe hepatotoxicity induced by EGFR tyrosine kinase inhibitors in patients with non-small cell lung cancer harboring EGFR mutations.

Many patients are forced to discontinue treatment with EGFR tyrosine kinase inhibitors (TKIs), particularly gefitinib, due to severe hepatotoxicity. Here, we investigated the association between the rate of severe hepatotoxicity and single nucleotide polymorphisms (SNPs) in metabolic enzymes. Multi-SNP analyses were performed in 60 patients with EGFR-mutated non-small cell lung cancer using blood samples obtained prior to starting treatment with gefitinib. The poor metabolizer (PM) phenotype was defined as homozygosity or double heterozygosity for variant alleles that confer reduced enzyme activities. Associated enzymes were screened using univariate logistic regression analyses adjusted for multiplicity and were further evaluated using multivariate logistic regression analyses to determine the influence of these enzymes on severe hepatotoxicity. Severe hepatotoxicity was detected in 19 (32%) of the 60 patients. Patient phenotypes consisted of CYP3A5, PM/non-PM (31/29) and CYP2D6, PM/non-PM (5/55). In multivariate logistic regression analyses, the rate of severe hepatotoxicity was significantly higher among patients with PM phenotypes than those without (CYP3A5 PM vs. non-PM: 48.4% vs. 13.8%, P=0.0069; CYP2D6 PM vs. non-PM: 80.0% vs. 27.3%, P=0.0364). Of the 9 patients switched from gefitinib to erlotinib due to severe hepatotoxicity, 8 had a PM phenotype for CYP2D6 or CYP3A5. All cases were successfully managed without exacerbation of severe hepatotoxicity. Evaluation of SNPs in CYP3A5 and CYP2D6 can effectively predict severe hepatotoxicity induced by gefitinib. Erlotinib can be used as an alternative treatment for patients who develop gefitinib-induced severe hepatotoxicity.

Correlation of polymorphisms of JAK and STAT with gefitinib-induced hepatotoxicity in patients with non-small cell lung cancer.

e19102 Background: Drug-induced liver injury (DILI) is a major safety concern in drug development and clinical drug therapy. Severe hepatotoxicity of gefitinib often leads to discontinuation or ter...

Polymorphisms of CYP2D6 Gene and Gefitinib-Induced Hepatotoxicity

IntroductionGefitinib induces severe hepatotoxicity in approximately a quarter of Japanese patients with epidermal growth factor receptor (EGFR) mutation–positive non–small-cell lung cancer (NSCLC). Gefitinib is metabolized by cytochrome P450 (CYP) enzymes—including CYP3A4/5, CYP1A1, and CYP2D6—in the liver. We hypothesized that polymorphisms of the CYP2D6 gene may account for gefitinib-induced hepatotoxicity. Patients and MethodsPolymorphisms of the CYP2D6 gene were analyzed in 55 patients with NSCLC who experienced grade ≥ 2 transaminase elevation from gefitinib. The distribution of the CYP2D6 genotype was compared with that of the healthy Japanese population. The correlations between the nonfunctional allele *5 or the reduced-function allele *10 and hepatotoxicity-related clinical factors were also examined. ResultsThe distribution of the CYP2D6 genotype in the study participants was not different from that of the general Japanese population, reported previously. Existence of allele *5 or *10 did not correlate with clinical factors such as onset of hepatotoxicity within 2 months, grade ≥ 3 serum transaminase elevation, and tolerability to dose reduction or rechallenge of gefitinib. However, in 7 patients taking CYP3A4-inhibitory drugs, rechallenge of gefitinib again caused hepatotoxicity in 4 patients with allele *5 or *10 but not in 3 patients with normal alleles (P = .029). Moreover, switching to erlotinib did not cause hepatotoxicity in any of 17 patients with allele *5 or *10 but did in 3 of 8 patients without these alleles (P = .024). ConclusionReduced function of CYP2D6 may partly account for gefitinib-induced hepatotoxicity when CYP3A4 is inhibited. Erlotinib could be safely used in patients with decreased CYP2D6 activity even after they experienced gefitinib-induced hepatotoxicity.

ゲフィチニブによる肝機能障害後のエルロチニブが安全かつ有効であった肺腺癌の3症例

ゲフィチニブによる肝機能障害後のエルロチニブが安全かつ有効であった肺腺癌の3症例

Treatment of Non-Small-Cell Lung Cancer with Erlotinib following Gefitinib-Induced Hepatotoxicity: Review of 8 Clinical Cases.

Objective. Gefitinib often induces liver damage. A few reports have described that the subsequent administration of erlotinib was associated with less hepatotoxicity, but the safety and efficacy of this treatment are still not fully investigated. Therefore, we evaluated retrospectively the patients with erlotinib following gefitinib-induced hepatotoxicity. Methods and Patients. We retrospectively reviewed the medical records between December 2007 and March 2010. The patients were evaluated including the following information: age, gender, histology of lung cancer, performance status, smoking status, epidermal growth factor receptor (EGFR) mutation status, liver metastasis, viral hepatitis, alcoholic liver injury, clinical response, and hepatotoxicity due to EGFR tyrosine kinase inhibitors. Results. We identified 8 patients with erlotinib following gefitinib-induced hepatotoxicity. All achieved disease control by gefitinib. Hepatotoxicity was grades 2 and 3 in 3 and 5 patients, respectively. The median duration of treatment with gefitinib was 112.5 days and the median time to gefitinib-induced hepatotoxicity was 51.5 days. The median duration of treatment with erlotinib was 171.5 days. Grade 1 and 2 erlotinib-induced hepatotoxicity was observed in 2 and 1 patient, respectively. Conclusions. Erlotinib administration with careful monitoring is thought to be a good alternative strategy for patients who respond well to gefitinib treatment but experience hepatotoxicity.

Safe and Successful Treatment With Erlotinib After Gefitinib-Induced Hepatotoxicity: Difference in Metabolism As a Possible Mechanism

Safe and Successful Treatment With Erlotinib After Gefitinib-Induced Hepatotoxicity: Difference in Metabolism As a Possible Mechanism

Successful treatment of two lung cancer patients with erlotinib following gefitinib-induced hepatotoxicity

Introduction Hepatotoxicity secondary to gefitinib, an oral tyrosine kinase inhibitor (TKI) against the epidermal growth factor receptor (EGFR), is under-appreciated, even though it has a reported incidence of 10–20% in phase II trials. Methods/results We present two patients with non-small cell lung cancer (NSCLC) who developed grade 2/3 hepatotoxicity starting between 4 and 6 weeks after initiation of gefitinib, with toxicity peaking between 10 and 20 weeks. Both patients were switched to treatment with erlotinib, another EGFR TKI, without further development of hepatotoxicity. One patient with measurable metastatic disease achieved a durable near complete response while on erlotinib. The other patient experienced recurrence of hepatotoxicity when gefitinib was briefly reintroduced. Conclusions Patients with NSCLC receiving gefitinib should undergo routine monitoring of liver enzymes. For those who develop gefitinib-induced hepatotoxicity but are otherwise deriving clinical benefit, consideration can be given to switching to erlotinib.