Gefitinib: an adverse effects profile

Cersosimo, Robert J.

doi:10.1517/14740338.5.3.469

Cited by 46 publications

(24 citation statements)

References 59 publications

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“…Despite milder changes in cardiac contractility, wet lung weights were significantly increased with EKB-569 exposure. It is important to note that interstitial lung disease has been reported in a subset of patients receiving gefinitib in nonsmall cell lung cancer clinical trials (Cersosimo, 2006;Yoneda et al, 2006;Yamamoto et al, 2007). Although we did not observe increased pulmonary fibrosis, indirect evidence of pulmonary damage was supported by increased pulmonary proteinosis and thrombi with proteinaceous material in the RV of EGFR inhibitor treated mice.…”

Section: Discussioncontrasting

confidence: 43%

Chronic pharmacologic inhibition of EGFR leads to cardiac dysfunction in C57BL/6J mice

Barrick

Chao

et al. 2008

Toxicology and Applied Pharmacology

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Molecule-targeted therapies like those against the epidermal growth factor receptor (EGFR) are becoming widely used in the oncology clinic. With improvements in treatment efficacy, many cancers are being treated as chronic diseases, with patients having prolonged exposure to several therapies that were previously only given acutely. The consequence of chronic suppression of EGFR activity may lead to unexpected toxicities like altered cardiac physiology, a common organ site for adverse drug effects. To explore this possibility, we treated C57BL/6J (B6) mice with two EGFR small molecule tyrosine kinase inhibitors (TKIs), irreversible EKB-569 and reversible AG-1478, orally for three months. In B6 female mice, chronic exposure to both TKIs depressed body weight gain and caused significant changes in left ventricular (LV) wall thickness and cardiac function. No significant differences were observed in heart weight or cardiomyocyte size but histological analysis revealed an increase in fibrosis and in the numbers of TUNEL-positive cells in the hearts from treated female mice. Consistent with histological results, LV apoptotic gene expression was altered, with significant downregulation of the anti-apoptotic gene Bcl2l1. Although there were no significant differences in any of these endpoints in treated male mice, suggesting sex may influence susceptibility to TKI mediated toxicity, the LVs of treated male mice had significant upregulation of Egf, Erbb2 and Nppb over controls. Taken together, these data suggest that chronic dietary exposure to TKIs may result in pathological and physiological changes in the heart.

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Section: Discussioncontrasting

confidence: 43%

Chronic pharmacologic inhibition of EGFR leads to cardiac dysfunction in C57BL/6J mice

Barrick

Chao

et al. 2008

Toxicology and Applied Pharmacology

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“…Although the presence of somatic mutations in the EGFR gene is considered to be the best predictor of response to these TKIs (9,10,25,26), its efficacy as biomarker is not satisfactory due to technical problems on biopsy, secondary mutation acquiring the resistance to the EGFR TKIs, and recent data showing response of patients with wild-type EGFR to erlotinib (27). Thus, an alternative approach optimizing clinical outcome of EGFR TKI therapy is necessary to accurately select patients who will benefit from the therapy and to avoid critical adverse effects such as interstitial lung disease (28).…”

Section: Discussionmentioning

confidence: 99%

“…Onset of symptoms may begin only after 2 days of gefitinib therapy. Median onset was 24 days in Japan and 42 days in United States, and about 1 of 3 of the cases were fatal (28). It has been suggested that [ 18 F]FDG-PET may help to evaluate interstitial lung disease.…”

Section: Discussionmentioning

confidence: 99%

Early [18F]Fluorodeoxyglucose Positron Emission Tomography at Two Days of Gefitinib Treatment Predicts Clinical Outcome in Patients with Adenocarcinoma of the Lung

Takahashi

Hirata

Tachibana

et al. 2012

Clinical Cancer Research

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were measured, and post-gefitinib percentage changes in SUV were calculated. Early metabolic response (SUV decline < À25%) was compared with morphologic response evaluated by CT scan and with progression-free survival (PFS).Results: At 2 days of gefitinib treatment, 10 patients (50%) showed metabolic response, 8 had metabolic stable disease, and 2 had progressive metabolic disease. Percentage changes of SUV at 2 days were correlated with those of tumor size in CT at 1 month (R 2 ¼ 0.496; P ¼ 0.0008). EGFR gene was assessable in 15 patients, and of 12 patients with EGFR mutations, 8 showed metabolic response at 2 days and 6 showed morphologic response at 1 month. None of 3 patients with wild-type EGFR showed metabolic or morphologic response. Metabolic response at 2 days was not statistically associated with PFS (P ¼ 0.095), but when a cutoff value of À20% in SUV decline was used, metabolic responders had longer PFS (P < 0.0001).Conclusion: Early assessment of [ 18 F]FDG tumor uptake with PET at 2 days of gefitinib treatment could be useful to predict clinical outcome earlier than conventional CT evaluation in patients with lung adenocarcinoma.

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“…The most common adverse effects of gefitinib treatment are rashes, diarrhea, acne, dry skin, nausea and vomiting. Although gefitinib-related interstitial lung disease is a well-known serious side effect that may result in death (11), most adverse effects of this drug are mild-to-moderate in nature and do not require the discontinuation of therapy (12). To date, adverse renal effects have been reported in only a few cases (2, 13, 14).…”

Section: Discussionmentioning

confidence: 99%

Minimal Change Nephrotic Syndrome Associated with Gefitinib and a Successful Switch to Erlotinib

et al. 2015

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Minimal change nephrotic syndrome (MCNS) is a common form of nephrotic syndrome (NS). We herein present the case of a 57-year-old woman with advanced lung adenocarcinoma treated with the tyrosine kinase inhibitor (TKI) gefitinib who developed NS. A renal biopsy revealed minor glomerular abnormalities, and the patient's symptoms improved exclusively with the discontinuation of gefitinib. Therefore, we diagnosed her with MCNS associated with gefitinib treatment. A few months later, however, she developed recurrent lung tumors. Following the challenging initiation of the TKI erlotinib, she achieved remission without proteinuria. We thus conclude that erlotinib is a potential treatment option in patients with NS associated with gefitinib therapy.

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Gefitinib: an adverse effects profile

Cited by 46 publications

References 59 publications

Chronic pharmacologic inhibition of EGFR leads to cardiac dysfunction in C57BL/6J mice

Chronic pharmacologic inhibition of EGFR leads to cardiac dysfunction in C57BL/6J mice

Early [18F]Fluorodeoxyglucose Positron Emission Tomography at Two Days of Gefitinib Treatment Predicts Clinical Outcome in Patients with Adenocarcinoma of the Lung

Minimal Change Nephrotic Syndrome Associated with Gefitinib and a Successful Switch to Erlotinib

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