ANTICANCER RESEARCH 29: 2747-2752 (2009)
Gefitinib Plus Paclitaxel after Failure of Gefitinib in Non-small Cell Lung Cancer Initially Responding to Gefitinib TAKEHITO SHUKUYA1, TOSHIAKI TAKAHASHI1, AKIHIRO TAMIYA1, AKIRA ONO1, SATOSHI IGAWA1, YUKIKO NAKAMURA1, ASUKA TSUYA1, HARUYASU MURAKAMI1, TATEAKI NAITO1, KYOICHI KAIRA1, MASAHIRO ENDO2 and NOBUYUKI YAMAMOTO1
Divisions of 1Thoracic Oncology and 2Diagnostic Radiology, Shizuoka Cancer Center, 411-8777, Japan
Abstract. Background: New therapeutic modalities are needed for non-small cell lung cancer (NSCLC) patients whose tumors have become resistant to gefitinib. Patients and Methods: Between 2005 and 2008, 16 NSCLC patients, who had been previously treated with gefitinib and evaluated as partial response or complete response according to the response evaluation criteria in solid tumors (RECIST), received gefitinib plus paclitaxel. Paclitaxel was administered at 60 mg/m2 on days 1, 8 and 15 every 4 weeks, and gefitinib was administered at 250 mg/day from the first day of administration of paclitaxel. Results: The response rate and disease control rate were 13% and 75% , respectively. The median progression-free survival (PFS) and median overall survival were 4.3 months and 8.1 months, respectively. The toxicities were mild, and there were no treatment-related deaths. Conclusions: Gefitinib plus paclitaxel after failure of gefitinib exhibits activity and acceptable toxicity. Gefitinib, one of the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI), is widely used for the treatment of non-small cell lung cancer (NSCLC). In the Iressa™ survival evaluation in lung cancer (ISEL) study, conducted on advanced NSCLC patients with a previous history of chemotherapy with 1 or 2 regimens, no prolongation of the overall survival by gefitinib monotherapy was demonstrated (1). On the other hand, in the Iressa™ NSCLC trial evaluating response and survival versus taxotere (INTEREST) study conducted on patients with similar characteristics to those enrolled in the ISEL study, the non-inferiority of geftinib as compared to docetaxel was demonstrated in relation to the overall survival (2).
Correspondence to: Takehito Shukuya, MD, Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Suntou-gun, Shizuoka, 411-8777, Japan. Tel: +81 559895222, Fax: +81 559895783, e-mail:
[email protected] Key Words: Non-small cell lung cancer, gefitinib, paclitaxel, EGFRTKI, resistant.
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In April 2004, two study groups demonstrated the presence of EGFR mutations in some NSCLC patients and reported higher response rates to gefitinib therapy among these patients (3, 4). Deletion of exon 19 and pointmutation of exon 21 from T to G at codon 858 (L858R) are the most frequently encountered EGFR mutations, accounting for 90% of all the cases (5). The reported response rates to gefitinib therapy of NSCLC patients with these mutations are in the range of 66-80% (6). The frequencies of EGFR mutations in Asian and Western populations have been reported to be 25-50% and 10% , respectively (7). Furthermore, in the Iressa™ pan-Asian study (IPASS) comparing gefitinib monotherapy and carboplatin/paclitaxel therapy in Asian patients with chemonaive advanced lung adenocarcinoma who were non- or light smokers, the progression-free survival (PFS) and the response rate were statistically significantly more favorable in the group receiving gefitinib monotherapy (8). The results of those for whom the EGFR mutation status could be retrieved showed that the tendency towards these favorable end-points was particularly marked in the patients with EGFR mutations. Takano et al. reported a retrospective study comparing the overall survival of patients treated before and after the approval of gefitinib for NSCLC treatment in the Japanese national cancer center hospital (9). While there was no significant difference in the overall survival of cohorts treated before and after approval of the drug among the patients without EGFR mutations (median survival time (MST), 10.4 months vs. 13.2 months, p=0.13), the overall survival was significantly more favorable in the cohort treated after the drug approval among the patients with EGFR mutations (MST, 13.6 months vs. 27.2 months, p
