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).
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 point-mutation 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<0.001).
All of the above observations indicated that EGFR-TKIs, in particular, gefitinib and erlotinib, may be one of the key drug classes for the treatment of NSCLC among Asians, as these patients show EGFR mutations at a high frequency and are more likely to show favorable responses to gefitinib therapy.
However, even in patients with EGFR mutations who show remarkable response to gefitinib therapy, re-growth has been increasingly reported among patients with NSCLC due to resistance to gefitinib. In addition, these patients often show rapid growth of the tumors following discontinuation of gefitinib therapy. On the other hand, some patients have demonstrated the suppression of tumor progression by the continuation of gefitinib therapy even after evaluation showing progressive disease (PD) according to the response evaluation criteria in solid tumors (RECIST) despite previously showing a positive response. Therefore, physicians in charge may encounter difficulty in relation to decision-making regarding the timing of withdrawal of gefitinib therapy and the selection of subsequent treatment. New therapeutic modalities are needed for patients whose tumors have become resistant to gefitinib.
Paclitaxel is one of the drugs used for the treatment of NSCLC, and paclitaxel and gefitinib have been demonstrated to show synergistic actions against NSCLC cell lines in vitro (10). Kasahara et al. conducted a phase II trial in 20 patients with gefitinib-refractory or -resistant cancer, in whom gefitinib was administered orally at the daily dose of 250 mg everyday and paclitaxel at the dose of 60 mg/m2 on days 1, 8 and 15, the cycle repeated every 4 weeks. The investigators reported that the response rate was 30% and the frequencies of neutropenia, leukopenia, anemia and interstitial pneumonitis as grade 3 or 4 adverse events were 10%, 10%, 20% and 20%, respectively (11). These data suggested that combined gefitinib/paclitaxel therapy might be a promising therapeutic regimen for NSCLC, but the report by Kasahara et al. included not only patients who showed response to gefitinib, but also those who showed no response to gefitinib. Therefore, the efficacy of the combined therapy in the those individual patient groups is unknown. Under these circumstances, the present study was conducted to evaluate the efficacy and safety of combined gefitinib/paclitaxel therapy as a therapeutic strategy for patients with tumors that had become resistant to gefitinib after showing initial response to gefitinib monotherapy.
Patients and Methods
Patient selection. Sixteen NSCLC patients treated between April 2005 and March 2008 at the Shizuoka Cancer Center were enrolled in this retrospective cohort study. The study participants were consecutively registered according to the following inclusion criteria: histologically confirmed advanced NSCLC; previous history of treatment with gefitinib and evaluated as partial response (PR) or complete response (CR) according to RECIST during gefitinib therapy; presence of measurable disease target lesions on chest X-ray, computed tomographic (CT) images of the chest and abdomen, or other procedures as specified, including magnetic resonance imaging (MRI) of the head, positron emission tomography (PET), or combined PET/CT; age less than 80 years; Eastern Cooperative Oncology Group Performance Scale (ECOG PS) of 2 or less; adequate bone marrow, hepatic and renal functions; no other serious underlying disease and willingness to provide written informed consent.
Treatment methods. Paclitaxel was administered at a dose of 60 mg/m2 on days 1, 8 and 15 every 4 weeks, and each 4-week treatment schedule was designated as 1 cycle. Gefitinib was administered orally at a dose of 250 mg/day from the first day of administration of paclitaxel. Before the start of the treatment cycle, the patients were required to have an absolute neutrophil count (ANC) of 1,500/mm3 or more, a platelet count of 100,000/mm3 or more, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) values less than 3 times the upper limit of the normal range and serum total bilirubin and creatinine levels less than 1.5 times the upper limit of the normal range. Dose reduction, omission and discontinuation of the anticancer drugs were based on the judgment of the respective physicians in charge. However, as a rule, when grade 3 or more severe non-hematotoxicity, ANC of 1,000/mm3 or less, platelet count of 50,000/mm3 or less appeared, paclitaxel was omitted. The administration of gefitinib was modified to every other day on the basis of the hematological and non-hematological toxicities at the discretion of the physician in charge. The therapy was continued until disease progression, appearance of intolerable toxicity or withdrawal of consent. Complete blood count (CBC) and biochemistry examinations were repeated at least once a week after the initial evaluation.
Evaluation of response and toxicity. Tumor response was classified in accordance with the RECIST. The patients were evaluated to determine the stage of their disease before the start of treatment and at the time of determination of disease progression or relapse, by complete medical history and physical examination, chest X-ray, CT of the chest and abdomen and other staging procedures, such as MRI of the head and PET. Adverse events were evaluated until 4 weeks after the last administration of chemotherapy or the patient's death, according to the common terminology criteria for adverse events (CTCAE) Ver. 3.0.
Statistical methods. For analyzing the end-points, including overall survival and PFS, survival curves obtained by the method of Kaplan-Meier were used and survival rates were estimated by the Greenwood formula. Overall survival was measured from the first day of treatment to the day of death or last follow-up. PFS was defined as the interval from the initiation of treatment to failure (i.e. death or disease progression) or the date of the last follow-up. All the analyses were performed using StatView Ver. 5.0 (SAS Institute Inc., Cary, NC, USA).
Results
Patient characteristics. Between April 2005 and March 2008, 16 patients were enrolled in this study. The characteristics of the patients are listed in Table I. In all, 9 patients had a performance status (PS) of 2 and 5 had a PS of 1. All the patients had adenocarcinoma and stage 4 disease. All the patients had received some form of chemotherapy including gefitinib and had exhibited PR during the gefitinib monotherapy. The median and mean time from the last administration of gefitinib monotherapy to the initiation of the present study treatment were 1 and 33 days respectively (range 1-216 days, 1 day in 10 patients); 8 of the patients had a previous history of treatment with a paclitaxel-containing regimen.
Patient characteristics.
Toxicity. The toxicities of the treatment are summarized in Table II, which shows the worst toxicity level in each patient. The median number of paclitaxel dosings was 11.5 (range, 1-26) and the total number was 194. The median duration of gefitinib administration was 105 days (range, 7-284 days).
Among the hematological toxicities, the principal toxicity was neutropenia. Grade 3 neutropenia and grade 3 leukopenia were observed in 2 patients (12%) and 1 patient, respectively. There were no severe toxicities in terms of anemia or thrombocytopenia. Among the non-hematological toxicities, those that were grade 3 or more severe were fatigue, anorexia and infection in 1 patient each. The frequently occurring toxicities (observed in more than 5 patients) were fatigue, anorexia and neuropathy. There were no treatment-related deaths.
Response to therapy and survival. No CR, 2 PR, 10 stable disease (SD) and 2 PD were observed among the 16 patients. The response was unevaluable (not available: NA) in 2 patients. The response rate and disease control rate were 13% and 75%, respectively. The distribution of the best tumor shrinkage is shown as a waterfall plot in Figure 1. Among the 10 patients with no time interval from the last administration of gefitinib monotherapy to the initiation of the present treatment, tumor shrinkage was observed in 6 patients. Among the 8 patients who had a history of treatment with a paclitaxel-containing regimen, tumor shrinkage was observed in 5 patients. Among 7 smokers and 9 non-smokers, tumor shrinkage was observed in 5 patients, respectively. The median PFS, MST and 1-year survival rate were 4.3 months (131 days), 8.1 months (246 days) and 25%, respectively (Figures 2 and 3).
Toxicity.
Discussion
Although, in the present study, the EGFR mutation status was not examined, the frequency of EGFR mutation would have been high, taking the initial response to gefitinib and the ethnicity into account.
Cho et al. reported a phase II study of erlotinib in 21 advanced NSCLC patients after the failure of gefitinib. The efficacy of erlotinib tended to be superior in the patients with SD in the previous gefitinib monotherapy (12). On the other hand, in the present study, all the patients showed PR to the previously administered gefitinib monotherapy and the response rate and disease control rate were 13% and 75%, respectively. The therapy was considered to be efficient even for the patients who showed PR to gefitinib therapy. The PFS was considered to be favorable as compared with the time-to-progression of 60 days in the report by Cho et al. (12). The overall survival may also be considered favorable, taking into account the fact that gefitinib/paclitaxel therapy was conducted as third- or subsequent-line chemotherapy in all the patients.
Distribution of the best tumor shrinkage in each of the 14 evaluable patients.
Overall survival.
In the present study, tumor shrinkage following combined gefitinib/paclitaxel therapy was recognized, even among the ten patients who had received gefitinib monotherapy until just before the start of the combined therapy and regardless of the presence/absence of a previous history of therapy with a paclitaxel-containing regimen. Paclitaxel has been shown to increase the phosphorylation of EGFR in NSCLC cell lines and to show synergistic action when used in combination with gefitinib against NSCLC lines in vitro (10). Paclitaxel may have some effect on intracellular signal transmission that increases the dependence of the tumor cells on EGFR signaling, allowing the mechanism by which the tumors became resistant to gefitinib to be overcome.
Progression-free survival.
In regard to toxicity, the characteristic toxicities of paclitaxel and gefitinib were observed. There were no serious toxicities and all toxicity was controllable. There were no treatment-related deaths. In this study toxicity was recorded if it was newly appearing or judged to be at least one grade more severe as compared with the baseline, the present study treatment initiation. In ten patients, therefore, the rate of toxicity characteristic of gefitinib in the present study may have been underestimated, because these patients had received gefitinib monotherapy until just before the start of the combined therapy. In addition, the severity of non-hematological toxicity, in particular, may have been underestimated in the present study, because the study was retrospective in nature. In fact, the incidences of rash and diarrhea were lower than those in ISEL study and INTEREST study (1, 2).
The present study indicated the efficacy and safety of combined gefitinib/paclitaxel therapy as subsequent treatment in patients with gefitinib-resistant tumors that had shown initial response to gefitinib monotherapy. However, the interpretation of the study results is limited by the small number of patients and the retrospective nature of the study. The development of treatments for patients with tumors that have become resistant to EGFR-TKI after showing initial response is necessary, and further assessment in a large-scale prospective study would be needed to obtain definitive evidence.
- Received March 2, 2009.
- Revision received May 5, 2009.
- Accepted May 13, 2009.
- Copyright© 2009 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
