|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 24, No 19 (July 1), 2006: pp. 3214-3215 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.06.5128
In ReplyDivision of Hematology and Oncology, University of California Davis Cancer Center, Sacramento, CA
Department of Medical Oncology, Tom Baker Cancer Centre, Calgary, Alberta, Canada
Department of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada The strategy of Seki et al of intermittent gefitinib dosing to decrease the risk of recurrent hepatic toxicity appears to have worked well in their case with both successful control of tumor and reduction in toxicity. This approach deserves additional exploration and documentation. The current dosing scheme for gefitinib was based on the data from the Iressa (AstraZeneca, London, United Kingdom) Dose Evaluation in Advanced Lung Cancer (IDEAL) 1 and 2 trials; similar efficacy but higher toxicity was observed with the 500 mg dose, consequently 250 mg was selected as the recommended dose.1,2 Preclinical work with gefitinib determined an IC50 of 0.054 µM (24 ng/mL) with the oral squamous cell carcinoma cell line, KB.3 Pharmocokinetic evaluation of gefitinib demonstrated an elimination t1/2 of 48 hours with a large volume of distribution (1,400 L). Plasma levels for clinically relevant doses, 150 mg to 600 mg, ranged from a steady-state trough concentration of 122 ng/mL to 774 ng/mL.4,5 Comparison of drug levels in the plasma and tumor indicated that the gefitinib level was 12-fold higher in mouse xenograft tumors and 42-fold higher within the tumor in breast cancer patients.6 While multiple daily dosing resulted in a maximum plasma concentration 2- to 2.5-fold higher than a single dose, plasma levels greater than the IC50 were achieved with a single administration.7 Thus, intermittent dosing is a potentially feasible approach to therapy. As Seki et al point out, two groups have employed this strategy; Negoro et al performed a phase I study with gefitinib treatment daily for 14 days every 28 days with a maximum tolerated dose of 700 mg and response rates comparable with IDEAL 1 and 2.8 The second group performed a phase I/II study of high-dose erlotinib weekly with phase II efficacy results anticipated.9 It may be that the molecular characteristics of the patient's tumor may also influence the effect of an intermittent dosing approach. The patient of Seki et al was Asian with an epidermal growth factor receptor (EGFR) exon 19 deletion mutation. Retrospective series have suggested that patients harboring EGFR activating mutations are exquisitely sensitive to EGFR tyrosine kinase inhibitors.10 Therefore, one might anticipate that limited drug exposure may be sufficient to impair the EGFR signaling pathways and associated tumor growth in those select patients. The same could be expected in tumors harboring EGFR gene amplification. Gefitinib however, is cytostatic in many patients, resulting in stable disease, which may or may not be maintained with intermittent administration of the drug. Significant liver toxicity with gefitinib is uncommon; grade 3 or 4 ALT and AST elevations were observed in 1.9% at 250 mg per day and 5.6% at 500 mg per day in IDEAL 1 and 1% overall in IDEAL 2. However, in our patient, there was biopsy-confirmed inflammation and necrosis associated with treatment.11 While the EGFR mutation and amplification status of our patient was unknown, she clearly had sensitivity to gefitinib and may have been a candidate for intermittent therapy, particularly as our approach with steroid immunosuppression proved ineffective. Determining the appropriate dose and scheduling of biologic agents is difficult. Unlike chemotherapy where hematological adverse effects and toxicity dictate the maximum tolerated dose and frequency, well-tolerated, molecularly targeted therapies are not limited by such parameters. While the goal is to treat according to the biologically active dose, we still do not have the tools to delineate what this dose is for our patients. Situations like that of our patient11 and that of Seki et al have demonstrated the need for additional exploration of alternate schedules of EGFR tyrosine kinase inhibitors that may be relevant to the treatment of other patient populations. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Fukuoka M, Yano S, Giaccone G, et al: Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 21:2237-2246, 2003 2. Kris MG, Natale RB, Herbst RS, et al: Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: A randomized trial. JAMA 290:2149-2158, 2003 3. Wakeling AE, Guy SP, Woodburn JR, et al: ZD1839 (Iressa): An orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Cancer Res 62:5749-5754, 2002 4. Baselga J, Rischin D, Ranson M, et al: Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J Clin Oncol 20:4292-4302, 2002 5. Herbst RS, Maddox AM, Rothenberg ML, et al: Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: Results of a phase I trial. J Clin Oncol 20:3815-3825, 2002 6. McKillop D, Partridge EA, Kemp JV, et al: Tumor penetration of gefitinib (Iressa), an epidermal growth factor receptor tyrosine kinase inhibitor. Mol Cancer Ther 4:641-649, 2005 7. Ranson M, Hammond LA, Ferry D, et al: ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: Results of a phase I trial. J Clin Oncol 20:2240-2250, 2002 8. Nakagawa K, Tamura T, Negoro S, et al: Phase I pharmacokinetic trial of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839) in Japanese patients with solid malignant tumors. Ann Oncol 14:922-930, 2003 9. Milton DT, Miller VA, Azzoli CG, et al: Weekly high-dose erlotinib in patients with non-small cell lung cancer (NSCLC): A phase I/II study. J Clin Oncol 22:637s, 2004 (abstr 7085) 10. Bell DW, Lynch TJ, Haserlat SM, et al: Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: Molecular analysis of the IDEAL/INTACT gefitinib trials. J Clin Oncol 23:8081-8092, 2005 11. 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
Related Correspondence
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
