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Liver Toxicity After Treatment With Gefitinib and Anastrozole: Drug-Drug Interactions Through Cytochrome p450?

Department of Medical Oncology, Regina Elena Cancer Institute, Rome, Italy

To the Editor:

We read with great interest the clinical case reported by Ho et al¹ on hepatitis after treatment with gefitinib. We agree with the authors' conclusions, and we report on a similar case of gefitinib-related liver toxicity in a 63-year-old white female patient with metastatic breast cancer receiving gefitinib plus anastrozole.

Because of the appearance of pleural effusion and metastases in the lymph nodes of the neck, this women was enrolled onto a clinical trial using the tyrosine kinase inhibitor of epidermal growth factor receptor gefitinib (250 mg given orally once per day) plus the aromatase inhibitor anastrozole (1 mg given orally once per day) as a first-line option for metastatic breast cancer. At the immunohistochemical analysis, the pleural biopsies resulted estrogen receptor–positive (90%), progesterone receptor–negative, and human epidermal growth factor receptor 2–positive (score 2+ DAKO HercepTest; Dako, Hamburg, Germany). She had no prior history of liver disease, excess alcohol intake, or hepatitis. Baseline blood tests showed normal cell count, electrolytes, renal function, and liver function. The patient had been taking adjuvant tamoxifen for 4 years. This drug was suspended for 4 weeks before starting gefitinib plus anastrozole.

After 16 weeks of gefitinib plus anastrozole, laboratory investigations showed a significant elevation of her transaminases (AST, 56 U/L; ALT, 77 U/L; range, 0 to 35), which progressively increased after 28 weeks of gefitinib use (AST, 143 U/L; ALT, 213 U/L). Hepatitis work-up was negative. Because it was thought that her liver toxicity was related to gefitinib, she discontinued it, but kept assuming anastrozole. After 7 days, her transaminases levels remained stable (AST, 139 U/L; ALT, 211 U/L). After 2 weeks of gefitinib suspension, her transaminases gradually decreased (AST, 63 U/L; ALT, 102 U/L; Fig 1). At that time, an abdominal ultrasound and computed tomography scan of the abdomen and pelvis demonstrated normal liver and no significant abnormalities. A decision was taken to reintroduce gefitinib (she was assuming anastrozole in the meanwhile) with weekly monitoring of her transaminases. Within 1 week, her enzymes rose rapidly again (AST, 181 U/L; ALT, 283 U/L; Fig 1) and gefitinib was definitively discontinued.

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. AST and ALT levels during gefitinib treatment. Reintroduction of gefitinib resulted in rapid increases of enzyme levels.

Therefore, based on these data, we agree with Ho et al¹ that, even in this case, gefitinib was implicated in the development of hepatitis, and it is advisable to routinely monitor liver transaminases in all patients treated with this drug. Anastrozole does not seem to be involved in causing or worsening this adverse effect.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Ho C, Davis J, Anderson F, et al: Side effects related to cancer treatment: CASE 1. Hepatitis following treatment with gefitinib. J Clin Oncol 23:8531-8533, 2005[Free Full Text]

2. Buzdar AU, Robertson JF, Eiermann W, et al: An overview of the pharmacology and pharmacokinetics of the newer generation aromatase inhibitors anastrozole, letrozole, and exemestane. Cancer 95:2006-2016, 2002[CrossRef][Medline]

3. Cantarini MV, Macpherson MP, Marshall AL, et al: Phase I study to determine the effect of tamoxifen on the pharmacokinetics of a single 250 mg oral dose of gefitinib (IRESSA) in healthy male volunteers. Cancer Chemother Pharmacol 56:557-562, 2005[CrossRef][Medline]

4. Swaisland H, Smith RP, Farebrother J, et al: The effect of the induction and inhibition of CYP3A4 on the pharmacokinetics of single oral doses of ZD1839 ('Iressa'), a selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), in healthy male volunteers. Proc Am Soc Clin Oncol 21, 2002 (abstr 328)

5. Swaisland HC, Ranson M, Smith RP, et al: Pharmacokinetic drug interactions of gefitinib with rifampicin, itraconazole and metoprolol. Clin Pharmacokinet 44:1067-1081, 2005[CrossRef][Medline]

6. Polychronis A, Sinnett HD, Hadjiminas D, et al: Preoperative gefitinib versus gefitinib and anastrozole in postmenopausal patients with oestrogen-receptor positive and epidermal-growth-factor-receptor-positive primary breast cancer: A double-blind placebo-controlled phase II randomised trial. Lancet Oncol 6:383-391, 2005[CrossRef][Medline]

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Carlini, P. Articles by Ferretti, G. Search for Related Content PubMed PubMed Citation Articles by Carlini, P. Articles by Ferretti, G. Social Bookmarking                            What's this?