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Originally published as JCO Early Release 10.1200/JCO.2003.10.038 on May 14 2003 © 2003 American Society for Clinical Oncology Multi-Institutional Randomized Phase II Trial of Gefitinib for Previously Treated Patients With Advanced Non–Small-Cell Lung Cancer
From the Kinki University School of Medicine, Osaka City University School of Medicine, and AstraZeneca, Osaka, Tokushima University School of Medicine, Tokushima, National Cancer Center, Central Hospital, and Japanese Foundation for Cancer Research, Tokyo, National Cancer Center, East Hospital, Chiba, Kanagawa Cancer Center, Yokohama, and National Shikoku Cancer Center, Matsuyama, Japan; C.R.L.C.C. Rene Gauducheau, Saint-Herblain, France; University Hospital Gasthuisberg, Leuven, Belgium; Centre for Developmental Cancer Therapeutics, Melbourne, Australia; Mary Potter Oncology Centre, Pretoria, South Africa; Academic Hospital Free University, Amsterdam, the Netherlands; AstraZeneca, Wilmington, DE; AstraZeneca, Alderley Park, United Kingdom; and Vall d’Hebron University Hospital, Barcelona, Spain. Address reprint requests to Masahiro Fukuoka, MD, Fourth Department of Internal Medicine, Kinki University School of Medicine, 377-2 Ohnohigashi Osakasayama, Osaka 589, Japan; email: mfukuoka{at}med.kindai.ac.jp.
Purpose: To evaluate the efficacy and tolerability of two doses of gefitinib (Iressa [ZD1839]; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with pretreated advanced non–small-cell lung cancer (NSCLC). Patients and Methods: This was a randomized, double-blind, parallel-group, multicenter phase II trial. Two hundred ten patients with advanced NSCLC who were previously treated with one or two chemotherapy regimens (at least one containing platinum) were randomized to receive either 250-mg or 500-mg oral doses of gefitinib once daily. Results: Efficacy was similar for the 250- and 500-mg/d groups. Objective tumor response rates were 18.4% (95% confidence interval [CI], 11.5 to 27.3) and 19.0% (95% CI, 12.1 to 27.9); among evaluable patients, symptom improvement rates were 40.3% (95% CI, 28.5 to 53.0) and 37.0% (95% CI, 26.0 to 49.1); median progression-free survival times were 2.7 and 2.8 months; and median overall survival times were 7.6 and 8.0 months, respectively. Symptom improvements were recorded for 69.2% (250 mg/d) and 85.7% (500 mg/d) of patients with a tumor response. Adverse events (AEs) at both dose levels were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent in the higher-dose group. Withdrawal due to drug-related AEs was 1.9% and 9.4% for patients receiving gefitinib 250 and 500 mg/d, respectively. Conclusion: Gefitinib showed clinically meaningful antitumor activity and provided symptom relief as second- and third-line treatment in these patients. At 250 mg/d, gefitinib had a favorable AE profile. Gefitinib 250 mg/d is an important, novel treatment option for patients with pretreated advanced NSCLC.
LUNG CANCER is the most common cause of cancer deaths in both men and women worldwide.1 Despite advances in treatment, such as combination chemotherapy and chemoradiation, survival has improved very little over the past few decades.2 A meta-analysis demonstrated that the median survival time for patients with advanced disease receiving cisplatin-based chemotherapy is around 6 months.3 The 5-year survival rate for all stages is less than 15%.4 Prognosis is particularly poor for patients who have progressive disease following chemotherapy; for non–small-cell lung cancer (NSCLC) patients receiving best supportive care (BSC) after 1 or more prior chemotherapy regimen, median survival time is just 16 weeks, with a 1-year survival rate of 16%.5 Recently, it has become generally accepted that systemic chemotherapy is beneficial in terms of improved survival and quality of life (QoL) in those with advanced NSCLC.3,6 As more patients receive first-line chemotherapy, the need for effective second-line therapy is increasing. Currently, docetaxel, having demonstrated survival benefits over BSC, is the only approved treatment in the United States and the European Union for patients who have been failed by previous platinum-based chemotherapy.7 Patients with late-stage NSCLC are often symptomatic, with specific pulmonary problems (eg, cough, breathlessness, hemotypsis) and general symptoms (eg, fatigue, weight loss) that can cause extreme distress to the patient. Therefore, improvements in disease-related symptoms and QoL are the key desired outcomes of medical management.8 Effective, palliative, low-toxicity treatments for patients with advanced NSCLC are needed. The epidermal growth factor receptor (EGFR) is a promising target for anticancer therapy because it is expressed or highly expressed in a variety of tumors, including NSCLC.9,10 Furthermore, high levels of EGFR expression have been associated with a poor prognosis in lung cancer patients in several studies.11–13 EGFR-targeted cancer therapies are currently being developed; strategies include inhibition of the intracellular tyrosine kinase domain of the receptor by small molecules such as gefitinib (Iressa [ZD1839]; AstraZeneca, Wilmington, DE).14 Gefitinib is an orally active, selective EGFR tyrosine kinase inhibitor that blocks signal transduction pathways implicated in the proliferation and survival of cancer cells.15,16 Four phase I studies assessed gefitinib tolerability and pharmacokinetics in pretreated patients with solid tumors, including 100 patients with heavily pretreated advanced NSCLC.17 Evidence of major tumor regression was seen in 10 patients with NSCLC; a number of other patients had nonprogressive disease lasting for 6 months or longer; and palliation of specific symptoms was also frequently observed. In these trials, responses were seen across the dose range 150 to 800 mg/day, while the majority of dose interruptions and reductions due to toxicity were required in patients receiving more than 600 mg/d. From these data, two doses (250 and 500 mg/d) were selected for investigation in phase II and phase III trials. The 250 mg/d dose is higher than the lowest dose level at which objective tumor regression was seen, while 500 mg/d is the highest dose that was well tolerated when taken over an extended period in phase I trials. The aims of this Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL 1) trial were to further investigate the efficacy and safety of oral gefitinib in patients with advanced NSCLC who had previously received one or two chemotherapy regimens, with at least one containing platinum. The population was prospectively stratified into Japanese and non-Japanese patients to investigate whether there were any differences between the two patient populations with respect to efficacy.
Study Design This randomized, double-blind, parallel group, phase II multicenter trial recruited patients at 43 centers across Europe, Australia, South Africa, and Japan. Primary objectives were to evaluate the objective tumor response rate (RR) for gefitinib doses of 250 and 500 mg/d and to further characterize the safety profile of these doses. Secondary objectives were to estimate disease-related symptom improvement rate, disease control rate (response + stable disease), progression-free survival (PFS), and overall survival (OS); to evaluate changes in QoL; and to assess any differences between Japanese and non-Japanese patients with respect to efficacy and safety.
Patient Eligibility
Treatment One dose reduction per patient was permitted in the event of unacceptable toxicity. New blinded treatment supplies, decreasing the dose from 500 mg to 250 mg or from 250 mg to 100 mg, were dispensed. Gefitinib administration could be interrupted for a maximum of 14 days. No systemic anticancer treatment was permitted during the trial, except for palliative radiotherapy in patients with isolated symptomatic bone metastases, and as long as trial drug administration was not interrupted for longer than 14 days.
Efficacy
Disease Control
Disease-related symptom improvement was measured using the Lung Cancer Subscale (LCS), a validated subscale of the QoL instrument, the Functional Assessment of Cancer Therapy – Lung (FACT-L) questionnaire (Fig 1
QoL Assessment Patients completed the FACT-L questionnaire to assess QoL. The FACT-L assessment has been validated with respect to its psychometric properties and sensitivity to clinical changes.19 FACT-L was completed at baseline and then every 28 days after the start of treatment. The questionnaire was administered before clinical assessment and before patients heard news about their disease status. The Trial Outcome Index (TOI) of FACT-L (Fig 1  ) measures the more physical aspects of patient QoL that are shown to be sensitive to chemotherapy.19 TOI and FACT-L scores were derived in a similar manner to the LCS scores; the highest scores attainable for TOI and FACT-L were 84 and 136, respectively. TOI and FACT-L responses were prospectively defined as a 6-point (or greater) improvement (for 4 weeks or longer), a change that has been shown to be clinically meaningful.20
PFS and OS
Safety and Tolerability
Statistical Methods The target sample population of 200 patients (100 in each dose group and 100 in each ethnic group) was chosen to enable the tumor lower limit for RR to be independently evaluated in the four strata defined by dose and ethnicity. Within each stratum, the goal was to have 90% power for a two-sided 5% significance test to show that the RR was greater than 5% assuming that the actual RR was 20%, which required 45 or more evaluable patients per stratum. RRs and disease control rates were compared between strata using Fisher’s exact test. Logistic regression models were used to further explore observed differences and to identify baseline factors that may independently predict for tumor response and disease control. PFS and OS were compared between strata using the log-rank test. Further analyses were conducted on these data using Cox’s proportional hazard modeling.
Patients A total of 210 patients were randomized within 4 months (October 2, 2000 to January 30, 2001). Of these, 208 patients were evaluable for efficacy, and 209 patients were evaluable for safety (Fig 2  ). The two dose groups were well balanced for most baseline demographic factors, with the exception of sex (Table 1). As planned, approximately half of the patients randomized were Japanese. There were some demographic imbalances between the Japanese and non-Japanese populations (62.7% v 77.8% male; 20.6% v 15.7% PS of 0; 8.8% v 16.7% PS of 2; and 76.5% v 50.0% adenocarcinoma, respectively).
Efficacy The investigator assessments of the best overall tumor responses are shown in Table 2 . RR was 18.4% for the 250-mg/d group, which was not statistically different from that of the 500-mg/d group (RR, 19.0%; Table 2). The independent response evaluation committee reviewed 107 of the 110 patients whom the investigator considered to have CR, PR, PRNM or SD. These included 38 of the 39 responders. There was a high concordance in tumor response evaluation between investigators and independent reviewers (73.8%; Table 3). In addition, the response evaluation committee evaluated an additional 25 patients who were assessed by the investigators as having a best response of PD. Of these 25 patients, the response evaluation committee considered 7 patients to have had a best response of SD.
Of the patients who responded, most showed rapid tumor regression, with 68% meeting the criteria for objective response by the first postbaseline assessment. The remaining patients met the criteria in the second, third, or fourth month following randomization. Furthermore, across both doses, most responders (87.2%) still had a response at the data cutoff, with a median follow-up of 6.3 months (range, 4.0–7.9 months). For patients who responded, median duration of response was more than 3 months (ranges: 250-mg/d group, 1–5 months; 500-mg/d group, 1–5.5 months). RRs were similar irrespective of whether gefitinib was used as second-line (17.5%, 250 mg/d; 18.3%, 500 mg/d) or third-line treatment (19.6%, 250 mg/d; 20.0%, 500 mg/d). A post hoc nonrandomized analysis showed that RRs for the subgroup of patients who had previously received a platinum and a taxane were 24.0% at 250 mg/d and 28.0% at 500 mg/d. Similarly, RRs for patients previously given platinum and docetaxel were 24.0% at 250 mg/d and 26.0% at 500 mg/d. RRs for patients who had progressed on two prior chemotherapy regimens were 13.6% at 250 mg/d and 7.9% at 500 mg/d. As expected, the mean number of days under treatment was higher for responders than for nonresponders (150 v 68 days, respectively); however, the number of days under treatment, as compared with the number of days under the trial was 95% versus 96% in both groups.
Disease Control
Disease-Related Symptom Improvement
The median of the maximum change in LCS score for the patients with symptom improvement was 7.0 points (range, 3–17 points) during the first interval of improvement (time between the first visit response of improved, to the subsequent response of worsened). Importantly, median time to symptom improvement was only 8 days (the time of first postbaseline assessment) for both doses. Median duration of symptom improvement was 5.1 month (range, 1.1–5.6+ months) at 500 mg/d. At 250 mg/d, the median duration of symptom improvement was not calculable because patients were still responding at the time of data cutoff; symptom improvement lasted for at least 3 months in 75% of patients and for 6 months in 65% of patients. Median time to symptom worsening, for all patients, was longer for the 250-mg/d group (4.1 months) than for the 500-mg/d group (2.8 months). Generally, more patients showed an improvement in the pulmonary items of the LCS than in the nonpulmonary items. Improvements in shortness of breath, cough, and breathing were each seen in 78% of LCS responders, while appetite, weight loss, and clear thinking improved in 54% to 57% of LCS responders.
PFS and OS
Tumor response was associated with improved OS. For patients with either CR or PR, the median OS was 13.3 months for 250-mg/d group and 10.6 months for the 500-mg/d group (Fig 4c ).
QoL Assessed by TOI and FACT-L QoL improvement rate measured by TOI was 20.9% (95% CI, 11.9 to 32.6) for the 250-mg/d group and 17.8% (95% CI, 9.8 to 28.5) for the 500-mg/d group. QoL improvement rate measured by FACT-L was 23.9% (95% CI, 14.3 to 35.9) and 21.9% (95% CI, 13.1 to 33.1) at 250 and 500 mg/d, respectively. The median time to improvement (measured by TOI and FACT-L) for both doses was 29 days, the time of the first postbaseline assessment.
Efficacy in Japanese and Non-Japanese Patients
The final multivariate model, including all four significant baseline prognostic factors and the factor for ethnicity, resulted in a Japanese:non-Japanese odds ratio of 1.64 (95% CI, 0.71 to 3.93; P = .25), which is not considered to be statistically significant.
Safety and Tolerability
Of all the drug-related AEs reported, CTC G3 or G4 was seen in only 1.5% of patients receiving 250 mg/d and in 4.7% of those receiving 500 mg/d; no G4 drug-related AEs were reported at 250 mg/d. The most frequent drug-related G3 or G4 AEs included diarrhea, rash, and ALT elevation (Table 5 ). The AE profile and the incidence of G3 or G4 drug-related AEs were similar for the Japanese and non-Japanese populations. Diarrhea could be controlled, if necessary, with antidiarrheal agents such as loperamide. Twenty-four percent of 250-mg/d patients and 43% of 500-mg/d patients took antipropulsives or antidiarrheal agents. Furthermore, diarrhea resolved in 84% (250 mg/d) and 83% (500 mg/d) of patients. Of these patients, resolution occurred during treatment (with or without dose reduction) or during temporary therapy interruption in 47.6% (250 mg/d) and 57.6% (500 mg/d) of patients, or following treatment cessation in 19.0% (250 mg/d) and 15.3% (500 mg/d). We did not record the exact time at which the event resolved in 33.3% of the 250-mg/d group and in 27.1% of the 500-mg/d group. Only one patient, receiving 500 mg/d, was withdrawn from the trial due to drug-related gastrointestinal disturbance (combination of G3 diarrhea, G3 nausea, and G2 vomiting).
Skin disorders, including rash, pruritus, dry skin, and acne, were generally mild (Table 5 Two patients experienced interstitial lung-disease–type events during the study (interstitial pneumonia and pneumonitis). Both patients were receiving 500 mg/d of gefitinib. One patient recovered from the event following withdrawal from treatment due to disease progression; in the other patient, the pneumonitis occurred 3 days after stopping gefitinib treatment because of severe fatigue, and was ongoing at the time of death due to disease progression 5 weeks later. A computed tomography scan for this patient showed progression of carcinomatous pleuritis. Both patients received antibiotics, steroids, and oxygen therapy. Most patients had no deterioration in hepatic function during the trial, and occurrences of elevated levels of transaminases were generally G1 and asymptomatic. Four patients (three at 500 mg/d) were withdrawn from the trial due to G3 or G4 elevations in hepatic enzymes. No clinically significant deterioration in renal function was observed during the trial, even in patients who entered the trial with mild or moderate renal impairment. The incidence of cardiovascular events was low; seven patients (one at 250 mg/d; six at 500 mg/d) had G1 or G2 cardiovascular events. Two patients in the 250-mg/d group had a G3 drug-related AE (atrial fibrillation and bundle branch block), and one patient in the 500-mg/d group had G4 deep thrombophlebitis. Ophthalmic monitoring did not reveal any significant drug-related abnormalities and no drug-related G3 or G4 events were reported. G1 or G2 drug-related ophthalmic AEs were reported in 43 patients (21%), but none of these events required withdrawal from therapy. These events included conjunctivitis, blepharitis, keratitis, eye pain, dry eyes, and corneal erosion. No clinically significant changes in hematology parameters were observed during the trial; most patients experienced no changes from baseline in CTC grade for hemoglobin, platelets, or WBC values. The only drug-related G3 or G4 hematologic AE reported was anemia, which was seen in three 500-mg/d patients (G3, one patient; G4, two patients), but no patients were withdrawn due to anemia.
This multicenter, randomized, double-blind, parallel-group trial conducted in Europe, Australia, South Africa, and Japan evaluated the efficacy and safety of daily oral doses of 250 and 500 mg of gefitinib in patients with locally advanced or metastatic NSCLC who had previously received either one, or a maximum of two, chemotherapy regimens (at least one of which had contained platinum). The major aim of the randomization was to identify the optimal dose for patients in this setting. In 103 patients treated with gefitinib at 250 mg/d, the RR was 18.4%, with a median PFS of 2.7 months and a median OS of 7.6 months, suggesting that gefitinib is an effective treatment for previously treated patients with advanced NSCLC. The RR was similar for the 500-mg dose and for patients receiving gefitinib as second- and third-line treatment. With respect to safety, drug-related AEs at both doses were generally mild (G1 or G2), consisting mainly of skin reactions and diarrhea, but the incidence of AEs, dose modifications, and withdrawals was lower for 250-mg/d group than for 500-mg/d group. Additionally, gefitinib was not associated with common conventional chemotherapy AEs such as neutropenia, thrombocytopenia, or neuropathy. Less than 1% of patients experienced interstitial lung-disease–type events during the study. The data from this trial suggest that treatment with gefitinib at 250 mg/d does not require any special clinical or laboratory monitoring beyond the usual standards of care in this patient population. Overall, 250 mg/d was as effective as, and better tolerated than, 500 mg/d, and is thus the recommended dose for patients with NSCLC who have previously received platinum-based chemotherapy. This dissociation of the efficacy and safety dose-response relationships was predicted for molecularly targeted anticancer agents such as gefitinib.22 Following inevitable first progression or recurrence after first-line chemotherapy, the current therapeutic option for patients with advanced NSCLC is additional chemotherapy. In the second-line setting, numerous phase II trials of one or more chemotherapy agents have reported widely varying RRs and little or no data concerning other efficacy end points.23 The notable exception is docetaxel, the only approved chemotherapy agent for treatment of previously treated patients and the only agent for which phase III data exists in a large number of patients with prior platinum therapy. In the first of two randomized phase III trials, median survival with docetaxel was significantly better than the supportive care arm (7.0 v 4.6 months; P = .047).7 The RR for the 55 patients who received docetaxel at 75 mg/m2 was 5.5%, and the overall disease control rate was 52.8%. In the second trial, the median survival with 75 mg/m2 of docetaxel was 5.7 months, the RR was 6.7%, and the disease control rate was 42.7%.24 These trials also demonstrated that docetaxel has a positive impact on QoL.25 A key therapeutic aim in patients with NSCLC is to palliate disease-related symptoms without compromising overall QoL. Patients with progressive NSCLC who have been failed by previous chemotherapy have an extremely poor prognosis and often exhibit severe symptoms. The patient population in this study was symptomatic, with median baseline LCS and TOI scores of 18.0 and 53.0, respectively. This is comparable with a randomized trial comparing three first-line chemotherapeutic regimens in patients with advanced NSCLC, which reported mean baseline LCS and TOI scores of 18.7 and 56.4, respectively.20 Our study provided a unique demonstration of clinically significant improvement in disease-related symptoms, which was documented both in patients with tumor regression and in those with stable disease. The rate of disease-related symptom improvement was high, with approximately 40% of the patients in the 250-mg/d group experiencing improvement for at least 1 month. The median time to symptom improvement was short, occurring within 8 days, and QoL improvements also appeared rapidly. The statistically significant difference in RR between Japanese and non-Japanese patients could not be explained on the basis of pharmacokinetic differences in the two populations. However, it was possible to identify baseline prognostic factors that accounted for these results (PS of 0–1, receipt of prior immuno/hormonal treatment, female sex, and adenocarcinoma histology). After accounting for baseline imbalances between the populations, the odds ratio for ethnicity was 1.64, which is not considered to be statistically significant (P = .25). Performance status and sex have been previously identified as prognostic factors for RR and survival following first-line chemotherapy in individuals with NSCLC.23 In this study, the better outcome in women could not be accounted for by sex differences in pharmacokinetic parameters. It is interesting that adenocarcinoma is a prognostic factor, given that EGFR is more frequently expressed in squamous cell carcinoma26; it may be that the relatively slow growth of adenocarcinoma cells renders them more sensitive to gefitinib, or there might be an unknown factor at the protein level that determines sensitivity to gefitinib rather than the level of EGFR expression. We do not yet know whether the EGFR status of tumors influences the efficacy of gefitinib. However, tissue samples have been retained to assess EGFR status by immunohistochemistry, and analysis of these samples is underway. A second phase II trial of gefitinib monotherapy for the treatment of advanced NSCLC in patients who have received at least two previous chemotherapy agents, including platinum and docetaxel, has been completed and confirms the activity of gefitinib in heavily pretreated patients.27 In conclusion, oral gefitinib at 250 or 500 mg/d provides clinically significant durable antitumor activity, accompanied by rapid, clinically meaningful symptom relief and improvements in QoL as second- and third-line treatment in patients with advanced NSCLC who have received previous platinum-based therapy. The 250-mg/d dose of gefitinib has a more favorable safety profile and better tolerability than the 500-mg/d dose and is, therefore, the recommended dose in this clinical setting. The data from this multi-institutional, randomized phase II trial suggest that oral gefitinib is an important, novel treatment option for patients with previously treated advanced NSCLC.
The following individuals are the principal investigators (PIs) and coinvestigators at cancer centers participating in this trial: J. Baselga (PI), E. Felip, Vall d’Hebron University Hospital, R. Rosell (PI), J.M. Sanchez, J.L. Manzano, Hospital Universitario Germans, Barcelona; and J.L.G. Larriba (PI), R. Alfonso, J.C. Camara, Hospital Clinico S. Carlos de Madrid, Madrid, Spain. M. Green (PI), J.C. Ding, S. Fan, Western Hospital, D. Rischin (PI), G. McArthur, L. Mileshkin, M. Michael, J. Zalcberg, C. Scott, L. Sullivan, M. Grossi, Peter MacCallum Cancer Institute, M. Rosenthal (PI), R. Basser, M. Green, Royal Melbourne Hospital, Melbourne; and P. Mitchell (PI), R. de Boer, Austin & Repatriation Medical Centre, Heidelberg, Australia. L. Dirix (PI), Medicine Institute St. Augustinus, Wilrijk; and J. Vansteenkiste (PI), K. Nackaerts, University Hospital Gasthuisberg, Leuven, Belgium. R. Callaghan (PI), L. Jooste, R. De Bruyne, S. Cullis, Hopelands Cancer Centre, Durban; B. Rapaport (PI), Medical Oncology Centre of Rosebank, Saxonworld; P. Ruff (PI), D. Moodley, Johannesburg Hospital, Parktown; and C. Slabber (PI), R.W. Eek, M.R. Chasen, G. Cohen, Mary Potter Oncology Centre, Pretoria, South Africa. B. Milleron (PI), C. Epaud, M.A. Massiani, J. Cadranel, Tenon University Hospital, Paris; J.Y. Douillard (PI), V. Barbarot, C.R.L.C.C. Rene Gauducheau, Saint-Herblain; D. Moro-Sibilot (PI), V. Frappat, G. Orliaguet, Michallon Hospital, Grenoble; and J.L. Pujol (PI), X. Quantin, D. Choma, Hopital Arnaud de Villeneuve, Montpellier, France. U. Gatzemeier (PI), G. Groth, Krankenhaus Grosshansdorf, Grosshansdorf; E. Kaukel (PI), G. Koschel, M. Eichler, Krankenhaus Harburg, Hamburg; and C. Manegold (PI), E. Buchholz, K. Schott, D. Wagner-Hug, Thoraxklinik, Heidelberg, Germany. G. Giaccone (PI), E. Smit, H. Smit, K. Hoekman, Academic Hospital Free University, Amsterdam, the Netherlands. S. Casinu (PI), S. Salvagni, L. Biscari, V. Franciosi, G. Vasini, University Hospital, Parma; A. Santoro (PI), R. Cavina, H. Parra, Istituto Clinico Humanitas, Rozzano-Milano; and G. Scagliotti (PI), G. Selvaggi, S. Novello, University of Turin, Orbassano, Italy. A. Yokoyama (PI), T. Shinbo, Y. Tsukada, M. Makino, K. Nanba, Niigata Cancer Center Hospital, Niigata, Japan; Dr H Saka (PI), Dr M Oki, Dr A Kumazawa, Dr C Sako, Dr H Hirose, Dr Y Kamiya, Nagoya University School of Medicine, and T. Sugiura (PI), T. Hida, K. Yoshida, K. Kato, Aichi Cancer Center Hospital, Aichi; I. Takata (PI), K. Eguchi, Y. Segawa, K. Fujiwara, Y. Tokuda, N. Seki, H. Shikata, N. Hashimoto, National Shikoku Cancer Center, Matsuyama; K. Kiura (PI), H. Ueoka, A. Hiraki, T. Kishino, Y. Emori, T. Matsuo, Okayama University Medical School, Okayama; K. Noda (PI), F. Oshita, I. Nomura, K. Yamada, M. Ikehara, K. Tsukahara, N. Kouno, K. Amano, Kanagawa Cancer Center, and K. Watanabe (PI), H. Kunikane, H. Okamoto, A. Nagatomo, H. Aono, H. Miyata, Yokohama Municipal Citizen’s Hospital, Yokohama; K. Nakagawa (PI), N. Yamamoto, H. Uejima, T. Komiya, G. Asai, A. Moriyama, J. Tsurutani, K. Akiyama, S. Tsukiyama, M. Fukuda, T. Hibino, M. Fukuoka, K. Yonesaka, T. Kurata, K. Tamura, Kinki University School of Medicine, K. Takeda (PI), S. Negoro, N. Takifuji, K. Terakawa, M. Miyazaki, M. Sumitani, Y. Ichimaru, H. Mori, S. Yu, T. Sugiura, Osaka City General Hospital, M. Takada (PI), T. Yana, T. Shimizu, F. Yamagami, H. Kaneda, T. Nishino, H. Shikata, Y. Morita, Y. Kuzumoto, T. Matsuyama, Osaka City University Medical School, K. Matsui (PI), T. Hirashima, T. Nitta, Y. Ogata, M. Kobayashi, Y. Takada, T. Sasabe, T. Kawamura, H. Bando, Osaka Prefectural Habikino Hospital, S. Kudoh (PI), H. Kamoi, T. Okamoto, N. Yoshimura, S. Shiraishi, T. Mukouhara, S. Yamauchi, K. Asai, A. Obana, M. Matsumoto, T. Kohno, T. Yasunari, Osaka City University School of Medicine, and F. Imamura (PI), K. Ueno, S. Yamamoto, I. Nagatomo, K. Karashima, S. Fujioka, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka; N. Katakami (PI), M. Okazaki, M. Hasegawa, A. Ikeda, T. Nishimura, S. Fujita, C. Nishio, K. Miyamoto, Kobe University Hospital, Hyougo; S. Yano (PI), S. Sone, Y. Nishioka, M. Azuma, A. Yamamoto, T. Kanematsu, T. Tajika, K. Shinomiya, Tokushima University School of Medicine, Tokushima; T. Horai (PI), M. Nishio, A. Karato, H. Tuji, Japanese Foundation for Cancer Research, and T. Tamura (PI), H. Kunito, I. Sekine, Y. Ohe, N. Yamamoto, A. Kaneko, K. Horie, H. Nokihara, T. Shimoyama, H. Murakami, N. Yamazaki, National Cancer Center, Central Hospital, Tokyo; T. Sawa (PI), T. Yoshida, M. Sawada, T. Ishiguro, Y. Kono, Gifu Citizens Hospital, Gifu; and Y. Nishiwaki (PI), R. Kakinuma, K. Kubota, T. Matsumoto, H. Omatsu, K. Goto, S. Niho, M. Nomura, Y. Minegishi, K. Araki, T. Mizoguchi, National Cancer Center, East Hospital, Chiba, Japan.
We would like to acknowledge the assistance of the Clinical Study Leader, Sally Sambrook; the Clinical Team Leader, Yuhiko Nogi; the Clinical Research Leader, Sue Hunter; and the Clinical Strategy Manager, Masaru Hirose.
The authors wish to disclose the following conflicts of interest statement: José Baselga has been in receipt of a research grant from AstraZeneca and honoraria to attend advisory boards and to give talks on ZD1839; Johan Vansteenkiste has received honoraria from AstraZeneca to attend advisory boards; Jean Yves Douillard has received honoraria for participating in advisory boards or symposia; Giuseppe Giaccone has received honoraria and research grants; and Danny Rischin has been in receipt of honoraria and travel grants from AstraZeneca. Steven Averbuch, Angela Macleod, Andrea Feyereislova, and Rui-Ping Dong were employed by AstraZeneca at the time of study completion, and as such, may hold stock in the company. All other authors have nothing to declare.
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ABSTRACT
INTRODUCTION
is frequent in resectable non-small cell lung cancer but does not predict tumor progression. Clin Cancer Res 3:515–522, 1997
