Gefitinib is a small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase. We conducted a phase III trial to evaluate whether gefitinib improves survival as sequential therapy after platinum-doublet chemotherapy in patients with advanced non–small-cell lung cancer (NSCLC).

Chemotherapy-naïve patients with advanced stage (IIIB/IV) NSCLC, Eastern Cooperative Oncology Group performance status of 0 to 1, and adequate organ function were randomly assigned to either platinum-doublet chemotherapy up to six cycles (arm A) or platinum-doublet chemotherapy for three cycles followed by gefitinib 250 mg orally once daily, until disease progression (arm B). Patients were stratified by disease stage, sex, histology, and chemotherapy regimens. The primary end point was overall survival; secondary end points included progression-free survival, tumor response, safety, and quality of life.

Between March 2003 and May 2005, 604 patients were randomly assigned. There was a statistically significant improvement in progression-free survival in arm B (hazard ratio [HR], 0.68; 95% CI, 0.57 to 0.80; P < .001); however, overall survival results did not reach statistical significance (HR, 0.86; 95% CI, 0.72 to 1.03; P = .11). In an exploratory subset analysis of overall survival by histologic group, patients in arm B with adenocarcinoma did significantly better than patients in arm A with adenocarcinoma (n = 467; HR, 0.79; 95% CI, 0.65 to 0.98; P = .03).

This trial failed to meet the primary end point of OS in patients with NSCLC. The exploratory subset analyses demonstrate a possible survival prolongation for sequential therapy of gefitinib, especially for patients with adenocarcinoma.

Lung cancer is the most common cancer worldwide, with an estimated 1.2 million new cases globally (12.3% of all cancers) and 1.1 million deaths (17.8% of all cancer deaths) in 2000.1 The estimated global incidence of non–small-cell lung cancer (NSCLC) in 2000 was approximately 1 million, which accounted for approximately 80% of all cases of lung cancer.1 Treatment of advanced NSCLC is palliative; the aim is to prolong survival without leading to deterioration in quality of life.2 The recommended first-line treatment of advanced NSCLC currently involves up to six cycles of platinum-based combination chemotherapy, with no single combination recommended over another.3,4 Recently, combination chemotherapy of pemetrexed plus cisplatin was significantly superior to gemcitabine plus cisplatin in nonsquamous NSCLC.5

Gefitinib is an orally active epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that blocks the signal transduction pathways implicated in the proliferation and survival of cancer cells.6 In two phase II trials in patients with pretreated advanced NSCLC (Iressa Dose Evaluation in Advanced Lung Cancer [IDEAL] 1 and 2), gefitinib 250 mg/d showed response rates of 12% and 18% and a median survival time (MST) of 7.0 and 7.6 months in IDEAL1 and 2, respectively; in addition, the toxicity profile was not severe.7,8 This favorable tolerability profile, coupled with a mechanism of action that is distinct from that of cytotoxic agents, provides a strong rationale for use of gefitinib in combination with standard cytotoxic regimens. Platinum-doublet chemotherapy added to gefitinib in untreated patients with NSCLC was evaluated in two large-scale, placebo-controlled, randomized trials (INTACT-1 and -2).9,10 Gefitinib showed no survival benefit over placebo when combined with standard platinum-doublet chemotherapy in both trials. Furthermore, gefitinib did not improve time to progression or objective tumor response over chemotherapy alone. These results were disappointing and surprising because of the significant antitumor activity of gefitinib when given alone to pretreated patients with NSCLC.

First, it is possible that each of the agents is working against a susceptible subpopulation of tumor cells so that the effect is redundant rather than additive, or that one agent results in the loss of an intermediary molecule that is essential to the function of the other agent, resulting in an antagonistic effect. Second, patients included in these studies were not selected on the basis of a specific biomarker, such as target EGFR expression, gene amplification, or mutations. Clinical profiles of females, never smokers, adenocarcinoma histology, and Asian ethnicity have all been recognized as favorable subgroups that respond to gefitinib.1114

Because no additive effect was observed by administering gefitinib continuously in combination with chemotherapy, possible alternatives could be the administration of gefitinib in the interval between chemotherapy cycles or as sequential treatment after chemotherapy. This could also potentially prevent the problem of drug interference or antagonism. We conducted a randomized phase III trial to evaluate whether gefitinib improves survival as sequential therapy after platinum-doublet chemotherapy in chemotherapy-naive patents with NSCLC.

Patients

Eligible patients were 20 to 75 years of age, with histologically or cytologically confirmed stage IIIB (with malignant pleural effusion or contralateral hilar lymph node metastases) or stage IV NSCLC who had not previously received any chemotherapy. Patients who had recurrence after complete surgical resection were permitted. Patients treated with either adjuvant or neoadjuvant chemotherapy were excluded in this trial. Additional criteria included a Eastern Cooperative Oncology Group performance status of 0 to 1, and adequate organ function as indicated by WBC count ≥ 4,000/μL, absolute neutrophil count ≥ 2,000/μL, hemoglobin ≥ 9.5 g/dL, platelets ≥ 100,000/μL, AST/ALT ≤ 2.5 times the upper limit of normal, total bilirubin ≤ 1.5 mg/dL, serum creatinine ≤ 1.2 mg/dL, and PaO2 in arterial blood ≥ 70 mmHg. Asymptomatic brain metastases were allowed provided that they had been irradiated and were clinically and radiologically stable. Patients were excluded from the study if they had radiologically and clinically apparent interstitial pneumonitis or pulmonary fibrosis. All patients provided written informed consent, and the study protocol was approved by the West Japan Thoracic Oncology Group Protocol Review Committee and the institutional review board of each participating institution.

Treatment Plan

Eligible patients were centrally registered at West Japan Thoracic Oncology Group Data Center and were randomly assigned to receive either platinum-doublet chemotherapy up to six cycles (arm A) or three cycles of platinum doublet followed by gefitinib 250 mg/d orally, until disease progression (arm B). Patients who achieved disease control (response or stable disease) treated with three cycles of platinum-doublet went for gefitinib treatment phase in arm B. Each physician selected his/her chemotherapy options before randomization. Platinum-doublet chemotherapy options included any of the following: (1) carboplatin area under the curve 6, day 1, and paclitaxel 200 mg/m2, day 1, every 3 weeks; (2) cisplatin 80 mg/m2, day 1, and irinotecan 60 mg/m2, days 1, 8, 15, every 4 weeks; (3) cisplatin 80 mg/m2, day 1, and vinorelbine 25 mg/m2, days 1, 8, every 3 weeks; (4) cisplatin 80 mg/m2, day 1, and gemcitabine 1,000 mg/m2 days 1, 8, every 3 weeks; or (5) cisplatin 80 mg/m2, day 1, and docetaxel 60 mg/m2 day 1, every 3 weeks. The dose of carboplatin was calculated using Calvert's formula, and the glomerular filtration rate was estimated by the Cockcroft-Gaut formula. These treatment schedules and doses are used as standard platinum-doublet regimens for advanced NSCLC in Japan.15,16

Randomization was stratified according to the institution, type of histology (adenocarcinoma v nonadenocarcinoma), clinical stage (IIIB v IV), and selected platinum-doublet regimens with the use of a minimization procedure. Patients receiving platinum-doublet chemotherapy received standard supportive treatments, including hydration and antiemetics, according to each institutional standard guideline. After withdrawing from the trial as a result of disease progression or intolerable toxicity, any systemic treatment, including with EGFR-TKI, was permitted in both arms.

Baseline and Follow-Up Assessments

Pretreatment evaluation included a complete medical history and physical examination, a CBC with differential and platelet count, standard biochemical profile, ECG, chest radiographs, computed tomography (CT) scans of the chest, abdomen, and brain, magnetic resonance imaging, and a whole-body bone scan. During treatment, a CBC and biochemical tests were performed at least every 2 weeks. A detailed medical history was taken and a complete physical examination with clinical assessment was performed every 2 weeks to assess disease symptoms and treatment toxicity, and chest radiographs were done every treatment cycle. Toxicity was evaluated according to the National Cancer Institute Cancer Common Toxicity Criteria (NCI-CTC) version2.17

All patients were assessed for response by CT scans monthly during treatment. Response Evaluation Criteria in Solid Tumors (RECIST) were used for the evaluation of response.18

Disease-related symptoms were assessed using the Lung Cancer Subscale (LCS) of the Functional Assessment of Cancer Therapy-Lung quality of life instrument (version 4.0).19 Patients were asked to complete the instrument at the time of enrollment and at 12 weeks and 18 weeks after initiation of treatment. The maximum attainable score on the LCS was 28, where the patient was considered asymptomatic.

Statistical Analysis

The primary end point was OS; secondary end points included PFS, tumor response, safety, and quality of life. Based on previous trials evaluating platinum-doublet chemotherapy, the MST was approximately a range of 8 to 11 months.3 In IDEAL-1, which was the trial of gefitinib alone in patients with previously treated NSCLC, median time to treatment failure was 98 days.7 This trial was designed to detect a 3-month difference in MST. To attain 80% power at a two-sided significance level of .05, assuming a MST in the chemotherapy alone arm of 9 months with 2 years of follow-up after 3 years of accrual, 225 patients in each treatment group were required. Both the OS and PFS were estimated with the Kaplan-Meier method. Comparisons of OS and PFS between arms were assessed by the stratified log-rank test. Two interim analyses were planned after half the patients were registered and at the end of registration.

At the first interim analysis, 14% of patients in arm B unexpectedly withdrew from sequential gefitinib treatment after the three cycles of platinum-doublet chemotherapy at their own request because of hearing the news of interstitial lung disease (ILD) as a result of the use of gefitinib in Japan. If 15% of patients treated with sequential gefitinib withdrew, 284 patients in each arm were required to attain an 80% power at a two-sided significance level of .05, assuming a MST of the chemotherapy alone arm of 9 months with 2 years of follow-up after 3 years of accrual. Consequently, a protocol amendment was performed in April 2004.

For symptom analysis, comparisons of LCS between arms were conducted using a linear mixed-effects model in which the missing data depend on the observed LCS, using the MIXED procedure in SAS version 9 (SAS Institute, Cary, NC).

Patient Characteristics

From March 2003 to May 2005, 604 patients with advanced NSCLC from 39 institutions were enrolled (Appendix, online only). Patients were randomly assigned to platinum-doublet chemotherapy up to 6 cycles (n = 302, arm A) or sequential gefitinib after three cycles of platinum-doublet chemotherapy (n = 302, arm B). One patient was double entry in arm A, and three patients in arm A and two in arm B did not receive any chemotherapy. Therefore, a total of 598 patients (298 in arm A and 300 in arm B) were included in the analysis of patients' profiles and the assessment for toxicity. In addition, three patients did not meet the entry criteria; thus, 297 patients with measurable lesions by RECIST in arm A and 298 eligible patients in arm B were assessable for OS, PFS, and response. Figure 1 shows the CONSORT diagram. Table 1 presents baseline patient characteristics and lists the platinum-doublet chemotherapy regimen selected by each physician.

Table

Table 1. Patients' Characteristics and Selected Platinum-Doublet Chemotherapy Regimens

Table 1. Patients' Characteristics and Selected Platinum-Doublet Chemotherapy Regimens

Parameter Arm A
Arm B
P
No. of Patients % No. of Patients %
Patients enrolled 298 300
Median age, years 63 62 .114
    Range 35-74 25-74
Sex
    Male 191 34.6 192 64.0 .981
    Female 107 67.8 108 36.0
ECOG PS
    0 103 30.8 90 30.0 .778
    1 195 69.2 210 70.0
Histology
    Adenocarcinoma 232 77.9 237 79.0 .733
    Nonadenocarcinoma 66 22.1 63 21.0
Clinical stage
    IIIB 54 18.1 55 18.3 .946
    IV 244 81.9 245 81.7
Smoking status
    Smoker 202 67.8 210 70.0 .559
    Nonsmoker 96 32.2 90 30.0
Selected platinum-doublet chemotherapy regimens
    CP 193 64.8 195 65.0 .987
    IP 8 2.7 10 3.3
    VP 44 14.8 45 15.0
    GP 45 15.1 42 14.0
    DP 8 2.7 8 2.7

NOTE. Differences between two arms were tested by χ2 test, excluding age (Wilcoxon test), ECOG PS.

Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; CP, carboplatin and paclitaxel; IP, irinotecan and cisplatin; VP, vinorelbine and cisplatin; GP, gemcitabine and cisplatin; DP, docetaxel and cisplatin.

Treatment Delivery

The median number of chemotherapy cycles was three (range, 1 to 6) in arm A, and three (range, 1 to 3) in arm B. One hundred seventy-two patients (57.3%) in arm B were treated with gefitinib after completion of three cycles of platinum-doublet. The median treatment duration of gefitinib was 69.5 days, and the maximum treatment duration was 1,324 days. As presented in Figure 2, EGFR-TKIs, which included gefitinib, erlotinib, and vandetanib, were used in 54.5% and 75.2% of patients in arm A and B, respectively, at any time during treatment of NSCLC. In arm B, gefitinib treatment did not take place because of early disease progression before the completion of three cycles of platinum-doublet chemotherapy in 93 patients (31.2%), and 33 (11.1%) in arm B rejected the use of gefitinib after platinum-doublet because of publication of a news report about gefitinib-induced ILD.

Treatment Efficacy

At the time of final analysis, 247 (83.2%) and 232 patients (78.0%) had died in arm A and arm B, respectively. The MST was 12.9 months for chemotherapy alone and 13.7 months for chemotherapy followed by gefitinib (hazard ratio [HR] according to Cox's regression model, 0.86; 95% CI, 0.72 to 1.03; P = .11 stratified log-rank test, Fig 3A). The PFS was 4.3 months in arm A and 4.6 months in arm B (HR, 0.68; 95% CI, 0.57 to 0.80; P < .001, Fig 3B).

When exploratory subset analysis were performed, sequential therapy with gefitinib after three cycles of platinum-doublet chemotherapy prolonged OS significantly in the subset of patients with adenocarcinoma (HR, 0.79; 95% CI, 0.65 to 0.98; P = .03; Fig 4A). There was no significant difference in OS due to the small subset of patients with nonadenocarcinoma (HR, 1.24; 95% CI, 0.85 to 1.79; P = .25; Fig 4B). In addition to the OS plots, the PFS plots for adenocarcinoma and nonadenocarcinoma were showed in Figure 4C and 4D, respectively. Furthermore, results of the subset analysis were summarized for forest plots in Figure 5. Another subset of smokers had a survival advantage with chemotherapy followed by gefitinib over chemotherapy alone. There was no difference between the two treatment groups in the subset of never smokers. Never smokers with NSCLC had a prolonged survival of about 23.5 months in arm A and 21.7 months in arm B.

The overall response rate was 29.3% for chemotherapy alone and 34.2% for chemotherapy followed by gefitinib. There was no significant difference between treatment arms (P = .20; Fisher's exact test). The overall disease control rate (response and stable disease) were 71.0% and 75.5% in arm A and in arm B, respectively (P = .22).

Toxicity

Toxicity was assessed according to NCI-CTC version 2 in all patients who received at least one treatment cycle of platinum-doublet chemotherapy (Table 2). Grade 3 or 4 anemia developed in 21.8% of patients in arm A and 13.3% of patients in arm B. There was a significant difference between the two arms (P = .006). Grade 3 or 4 thrombocytopenia occurred in 10.7% of patients in arm A and 6.3% of patients in arm B, but differences did not reach significance (P = .054). Conversely, grade 3 or 4 AST/ALT elevation in arm B was severer than in arm A (P = .002). Severe ILD induced by gefitinib, which many patients feared developing, was observed in two patients in this study.

Table

Table 2. Toxicity According to National Cancer Institute Common Toxicity Criteria Version 2

Table 2. Toxicity According to National Cancer Institute Common Toxicity Criteria Version 2

Toxicity Arm A (n = 298)
Arm B (n = 300)
χ2 Test P for Grade 3 + 4
Grade 3
Grade 4
Grade 3
Grade 4
No. % No. % No. % No. %
Hematologic
    Leukopenia 98 32.9 21 7.0 97 32.3 14 4.7 .461
    Neutropenia 90 30.2 136 45.6 79 26.3 133 44.3 .153
    Febrile neutropenia 33 11.1 5 1.7 38 12.8 0 0 .297
    Anemia 57 19.1 8 2.7 35 11.7 5 1.7 .006
    Thrombocytopenia 32 10.7 0 0 18 6.0 1 0.3 .054
Nonhematologic
    Anorexia 43 14.4 0 0 33 11.0 2 0.7 .316
    AST/ALT 11 3.7 1 0.3 32 10.7 0 0 .002
    Constipation 25 8.4 0 0 20 6.7 1 0.3 .631
    Creatinine 1 0.3 0 0 0 0 0 0 .315
    Diarrhea 6 2.0 0 0 5 1.7 0 0 .152
    Dyspnea 3 1.0 5 1.7 4 1.3 5 1.7 .816
    Fatigue 22 7.4 7 2.3 18 6.0 4 1.3 .294
    Hypersensitivity 1 0.3 1 0.3 2 0.7 2 0.7 .417
    Infection 36 12.1 1 0.3 26 8.7 0 0 .135
    Nausea 38 12.8 0 0 29 9.7 0 0 .232
    Neuropathy
        Motor 5 1.7 1 0.3 4 1.3 1 0.3 .991
        Sensory 12 4.0 1 0.3 7 2.3 0 0 .260
    Performance status 27 9.1 8 2.7 23 7.7 9 3.0 .676
    Pneumonitis (ILD) 2 0.7 0 0 4 1.3 0 0 .417
    Rash 2 0.7 0 0 1 0.3 0 0 .559
    Stomatitis/pharingitis 0 0 0 0 2 0.7 0 0 .482
    Vomiting 12 4.0 1 0.3 15 5.0 2 0.7 .465

Abbreviation: ILD, interstitial lung disease.

Disease-Related Symptoms Assessment

All 595 patients completed baseline LCS questionnaires; questionnaire completion rates were 81.0% at 12 weeks and 70.3% at 18 weeks. LCS data were missing in 111 surveys because of death or severe impairment of the patient's general condition; this accounted for 6.2% of the total number of surveys scheduled. The adjusted mean of initial summed scores of LCS were 20.3 for arm A and 20.6 for arm B, respectively. The adjusted LCS scores at 12 and 18 weeks were 21.0 and 20.9 for arm A, and 21.8 and 21.2 for arm B, respectively. Sequential gefitinib seemed to provide better symptom relief, although differences did not reach statistical significance (P = .10).

Sequential gefitinib therapy after three cycles of standard platinum-doublet chemotherapy showed no survival benefit over platinum-doublet chemotherapy up to six cycles in previously untreated patients with advanced NSCLC. However, sequential gefitinib was associated with significantly prolonged PFS. Recently, positive results with maintenance or sequential chemotherapy have been reported in clinical trials in PFS or time to progression; however, OS was not significantly lengthened.20,21 More recently, pemetrexed administered to NSCLC patients without progression after four cycles of first-line treatment with platinum-doublet provided significant improvement in PFS compared with placebo (HR, 0.60; 95% CI, 0.49 to 0.73; P < .00001).22 It was the first randomized, double-blind, placebo controlled trial to demonstrate a significant OS prolongation for maintenance treatment with pemetrexed in patients with advanced NSCLC (HR, 0.79; 95% CI, 0.65 to 0.95; P = .012).22 The results of the Sequential Erlotinib in Unresectable NSCLC (SATURN) study, which was a randomized, double-blind, placebo controlled trial with erlotinib as maintenance, were presented this year. Erlotinib maintenance treatment had improvement in PFS of 41% compared with placebo.23 Maintenance or sequential chemotherapy strategy after standard treatment has lately been receiving considerable attention. As a result, our trial was considered a consolidation therapy using other agent without progression after front-line treatment rather than maintenance.

Although the median number of chemotherapy cycles was three in both arms, 47.5% of patients received more than four cycles in Arm A. The number of treatment cycles was lower in Japanese than in whites; however, comparability was to be kept between the two arms in this randomized trial. These results were consistent with Japanese data on the median number of cycles of platinum-doublet chemotherapy.15

Toxicity results were consistent with previous Japanese studies of advanced NSCLC patients who received platinum-doublet chemotherapy.15,16 Furthermore, no significant severe adverse events were seen that were not predictable from the safety profiles of gefitinib in sequential therapy after platinum-doublet chemotherapy. Recently published data suggested that gefitinib might be associated with ILD in Japanese patients11; however, in our study, the overall incidence of ILD was less than 1%, and no imbalance was identified between the two treatment arms in terms of ILD.

It was interesting that sequential gefitinib therapy had a significant survival prolongation in patients with adenocarcinoma histology (HR, 0.79; 95% CI, 0.65 to 0.98; P = .03). There was no difference also in PFS or OS for patients with nonadenocarcinoma. It was possible that these patients just did not benefit from an ineffective therapy of sequential gefitinib. In patients with NSCLC, adenocarcinoma histology, nonsmoker, and Japanese or Asian ethnicity are favorable predictive factors for a response to gefitinib treatment.1114 When the analysis was performed in the most favorable subset population that responded to gefitinib—that is, among those with both adenocarcinoma histology and nonsmokers—the MST was 23.5 months in arm A and 25.1 months and in arm B, respectively. Indeed, more than three quarters of the patients with favorable profiles in arm A received gefitinib after the protocol treatment, because physicians recognized these patients were more likely to respond to gefitinib. Patients who were nonsmokers with adenocarcinoma in arm A resulted in subsequent gefitinib therapy as well as in arm B.

Activating mutations in the gene for EGFR appear in a subset of adenocarcinoma of lung cancer.24,25 A higher response to EGFR-TKIs is noted in specific subgroups that include females, never smokers, patients with adenocarcinoma histology, and East Asians.12 Higher EGFR mutation rates are also noted in these subgroups and are also related to a better response to EGFR-TKIs24,25 and longer survival.12 Patients with these mutations exhibit objective response rates in the range of 75% to 95%.1214,26,27

Patients included in this study were not selected on the basis of the target EGFR mutation status, because when this study was planned, we had not recognized the EGFR mutation as a predictive factor to respond to gefitinib. In Japanese patients with adenocarcinoma, a higher incidence of EFGR mutations, are estimated compared with white patients. It seems that more than 40% of Japanese patients with adenocarcinoma have an EGFR mutation.12 Complex results in this study can be explained by analyzing the EGFR mutation status of participating patients. It may be important to select patients who are known to receive a clinical benefit with treatment using an EGFR-TKI.

In conclusion, this trial failed to meet the primary end point of OS in patients with advanced NSCLC. The exploratory subset analyses demonstrate a possible survival prolongation for sequential therapy of gefitinib, especially for patients with adenocarcinoma. Further investigations are warranted to confirm the best sequential therapy after platinum-based chemotherapy for patients with advanced NSCLC.

© 2009 by American Society of Clinical Oncology

See accompanying editorial on page 713 and article on page 744

This study is registered with UMIN-CTR [http://www.umin.ac.jp/ctr/index.htm, identification number C000000035].

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical trial information can be found for the following: C000000035.

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Takayasu Kurata, Takeda Pharmaceutical (U) Stock Ownership: None Honoraria: Miyako Satouchi, AstraZeneca; Yukito Ichinose, AstraZeneca; Nobuyuki Yamamoto, AstraZeneca; Takayasu Kurata, AstraZeneca, Eli Lilly; Kazuhiko Nakagawa, AstraZeneca, sanofi-aventis; Masahiro Fukuoka, AstraZeneca, Chugai Pharmaceutical Research Funding: None Expert Testimony: None Other Remuneration: None

Conception and design: Koji Takeda, Toyoaki Hida, Masahiko Ando, Miyako Satouchi, Nobuyuki Yamamoto, Takayasu Kurata, Kazuhiko Nakagawa, Masahiro Fukuoka

Administrative support: Tosiya Sato, Masahiko Ando, Masahiro Fukuoka

Provision of study materials or patients: Koji Takeda, Toyoaki Hida, Takashi Seto, Miyako Satouchi, Nobuyuki Katakami, Nobuyuki Yamamoto, Shinzoh Kudoh, Jiichiro Sasaki, Kaoru Matsui, Koichi Takayama, Tatsuhiko Kashii, Yasuo Iwamoto, Toshiyuki Sawa, Takayasu Kurata, Kazuhiko Nakagawa, Masahiro Fukuoka

Collection and assembly of data: Koji Takeda, Toyoaki Hida, Takashi Seto, Miyako Satouchi, Yukito Ichinose, Nobuyuki Katakami, Nobuyuki Yamamoto, Shinzoh Kudoh, Jiichiro Sasaki, Kaoru Matsui, Koichi Takayama, Tatsuhiko Kashii, Yasuo Iwamoto, Toshiyuki Sawa, Takayasu Kurata, Kazuhiko Nakagawa

Data analysis and interpretation: Koji Takeda, Toyoaki Hida, Tosiya Sato, Masahiko Ando, Miyako Satouchi, Yukito Ichinose, Nobuyuki Yamamoto, Isamu Okamoto, Takayasu Kurata, Kazuhiko Nakagawa, Masahiro Fukuoka

Manuscript writing: Koji Takeda, Toyoaki Hida, Masahiko Ando, Isamu Okamoto

Final approval of manuscript: Koji Takeda, Kazuhiko Nakagawa, Masahiro Fukuoka

1. DM Parkin: Global cancer statistics in the year 2000 Lancet Oncol 2: 533543,2001 Crossref, MedlineGoogle Scholar
2. J Dancey, FA Shepherd, RJ Gralla , etal: Quality of life assessment of second-line docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy: Results of a prospective, randomized phase III trial Lung Cancer 43: 183194,2004 Crossref, MedlineGoogle Scholar
3. MA Socinski, DE Morris, GA Masters , etal: Chemotherapeutic management of stage IV non-small cell lung cancer Chest 123: 226S243S,2003 suppl 1 Crossref, MedlineGoogle Scholar
4. DG Pfister, DH Johnson, CG Azzoli , etal: American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: Update 2003 J Clin Oncol 22: 330353,2004 LinkGoogle Scholar
5. GV Scagliotti, P Parikh, J von Pawel , etal: Phase III comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer J Clin Oncol 26: 35433553,2008 LinkGoogle Scholar
6. RN Jorissen, F Walker, N Pouliot , etal: Epidermal growth factor receptor: Mechanisms of activation and signaling Exp Cell Res 284: 3153,2003 Crossref, MedlineGoogle Scholar
7. M Fukuoka, S Yano, G Giaccone , etal: Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer J Clin Oncol 21: 22372246,2003 LinkGoogle Scholar
8. MG Kris, RB Natale, RS Herbst , etal: 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: 21492158,2003 Crossref, MedlineGoogle Scholar
9. G Giaccone, RS Herbst, C Manegold , etal: Gefitinib in combination with gemcitabine and cisplatin in advanced non-small cell lung cancer: A phase III trial – INTACT 1 J Clin Oncol 22: 777784,2004 LinkGoogle Scholar
10. RS Herbst, G Giaccone, JH Schiller , etal: Gefitinib in combination with paclitaxel and carboplatin in advanced non-small cell lung cancer: A phase III trial – INTACT 2 J Clin Oncol 22: 785794,2004 LinkGoogle Scholar
11. M Ando, I Okamoto, N Yamamoto , etal: Predictive factors for interstitial lung disease, antitumor response, and survival in non-small-cell lung cancer patients treated with gefitinib J Clin Oncol 24: 25492556,2006 LinkGoogle Scholar
12. T Mitsudomi, T Kosaka, H Endoh , etal: Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence J Clin Oncol 23: 25132520,2005 LinkGoogle Scholar
13. SF Huang, HP Liu, LH Li , etal: High frequency of epidermal growth factor receptor mutations with complex patterns in non-small cell lung cancers related to gefitinib responsiveness in Taiwan Clin Cancer Res 10: 81958203,2004 Crossref, MedlineGoogle Scholar
14. M Tokumo, S Toyooka, K Kiura , etal: The relationship between epidermal growth factor receptor mutations and clinicopathologic features in non-small cell lung cancers Clin Cancer Res 11: 11671173,2005 MedlineGoogle Scholar
15. Y Ohe, Y Ohashi, K Kubota , etal: Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: Four-arm cooperative study in Japan Ann Oncol 18: 317323,2007 Crossref, MedlineGoogle Scholar
16. K Kubota, K Watanabe, H Kunitoh , etal: Phase III randomized trial of docetaxel plus cisplatin versus vindesine plus cisplatin in patients with stage IV non-small-cell lung cancer: The Japanese Taxotere Lung Cancer Study Group J Clin Oncol 22: 254261,2004 LinkGoogle Scholar
17. National Cancer Institute Common Toxicity Criteria version 2.0 National Cancer Institute http://ctep.cancer.gov/forms/CTCv20_4-30-992.pdf Google Scholar
18. P Therasse, SG Arbuck, EA Eisenhauer , etal: New guidelines to evaluate the response to treatment in solid tumors J Natl Cancer Inst 92: 205216,2000 Crossref, MedlineGoogle Scholar
19. DF Cella, AE Bonomi, SR Lloyd , etal: Reliability and validity of the Functional Assessment of Cancer Therapy-Lung (FACT-L) quality of life instrument Lung Cancer 12: 199220,1995 Crossref, MedlineGoogle Scholar
20. T Brodowicz, M Krzakowski, M Zwitter , etal: Cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small cell lung cancer: A phase III trial Lung Cancer 52: 155163,2006 Crossref, MedlineGoogle Scholar
21. P Fidias, S Dakhil, A Lyss , etal: Phase III study of immediate versus delayed docetaxel after induction therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer: Updated report with survival J Clin Oncol 27: 591598,2009 LinkGoogle Scholar
22. CP Belani, T Brodowicz, T Ciuleanu , etal: Maintenance pemetrexed (Pem) plus best supportive care (BSC) versus placebo (Plac) plus BSC: A randomized phase III study in advanced non-small cell lung cancer (NSCLC) J Clin Oncol 27: 407s,2009 suppl abstr CRA8000 LinkGoogle Scholar
23. F Cappuzzo, T Ciuleanu, L Stelmakh , etal: SATURN: A double-blind, randomized, phase III study of maintenance erlotinib versus placebo following nonprogression with first-line platinum-based chemotherapy in patients with advanced NSCLC J Clin Oncol 27: 407s,2009 suppl abstr 8001 Google Scholar
24. JG Paez, PA Janne, JC Lee , etal: EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy Science 304: 14971500,2004 Crossref, MedlineGoogle Scholar
25. TJ Lynch, DW Bell, R Sordella , etal: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib N Engl J Med 350: 21292139,2004 Crossref, MedlineGoogle Scholar
26. CH Yang, CJ Yu, JY Shih , etal: Specific EGFR mutations predict treatment outcome of stage IIIB/IV patients with chemotherapy-naive non-small-cell lung cancer receiving first-line gefitinib monotherapy J Clin Oncol 26: 27452753,2008 LinkGoogle Scholar
27. K Tamura, I Okamoto, T Kashii , etal: Multicentre prospective phase II trial of gefitinib for advanced non-small cell lung cancer with epidermal growth factor receptor mutations: Results of the West Japan Thoracic Oncology Group trial (WJTOG0403) Br J Cancer 98: 907914,2008 Crossref, MedlineGoogle Scholar

Acknowledgment

We thank Shinichiro Nakamura, MD, Kouichi Hosoda, and other staff members of West Japan Thoracic Oncology Group data center for data management.

Supported by Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

Presented in part at the 44th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 30-June 3, 2008, and at the 33rd European Society of Medical Oncology Congress, Stockholm, Sweden, September 12-16, 2008.

The following institutions participated in this study: Osaka City General Hospital (Osaka), Kinki University School of Medicine (Osaka-Sayama), Hyogo Cancer Center (Akashi), National Kyusyu Cancer Center (Fukuoka), Kobe City General Hospital (Kobe), Tokai University School of Medicine (Isehara), Shizuoka Cancer Center (Nagaizumi), Osaka City University Medical School (Osaka), Kumamoto University Hospital (Kumamoto), Osaka Prefectural Medical Center for Respiratory and Allergic Disease (Habikino), Kyusyu University Hospital (Fukuoka), Toyama University Hospital (Toyama), Hiroshima City Hospital (Hiroshima), Aichi Cancer Center (Nagoya), Gifu Municipal Hospital (Gifu), Aichi Cancer Center Aichi Hospital (Okazaki), Rinku General Medical Center (Izumisano), Kumamoto Regional Medical Center (Kumamoto), Iizuka Hospital (Iizuka), National Hospital Organization Nagoya Medical Center (Nagoya), Nagoya City University Hospital (Nagoya), Tottori University School of Medicine (Tottori), Kouseiren Takaoka Hospital (Takaoka), Mitoyo General Hospital (Kanonji), Osaka Prefectural General Hospital (Osaka), Nagoya Ekisaikai Hospital (Nagoya), Ogaki Municipal Hospital (Ogaki), Kinki University Sakai Hospital (Sakai), Anjo Kousei Hospital (Anjo), Osaka University Hospital (Suita), Kanazawa University Hospital (Kanazawa), Osaka Medical Collage Hospital (Takatsuki), Osaka City Sumiyoshi Hospital (Osaka), Kumamoto Chuo Hospital (Kumamoto), Kobe University Hospital (Kobe), Shinbeppu Hospital (Beppu), Toyota Memorial Hospital (Toyota), Hekinan Municipal Hospital (Hekinan), and Yamaguchi Grand Medical Center (Hofu).

COMPANION ARTICLES

No companion articles

ARTICLE CITATION

DOI: 10.1200/JCO.2009.23.3445 Journal of Clinical Oncology 28, no. 5 (February 10, 2010) 753-760.

Published online December 28, 2009.

PMID: 20038730

ASCO Career Center