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Journal of Clinical Oncology, Vol 24, No 16 (June 1), 2006: pp. 2549-2556 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.9866 Predictive Factors for Interstitial Lung Disease, Antitumor Response, and Survival in Non–Small-Cell Lung Cancer Patients Treated With Gefitinib
From the Department of Preventive Services, Kyoto University School of Public Health, Kyoto; Department of Medical Oncology, Kinki University School of Medicine; Department of Clinical Oncology, Osaka City General Hospital, Osaka; Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka; Department of Medical Oncology, Kinki University School of Medicine Nara Hospital, Nara; Division of Medical Oncology, Tokai University School of Medicine, Isehara; and Aichi Cancer Center Aichi Hospital, Aichi, Japan Address reprint requests to Masahiko Ando, MD, Health Service, Kyoto University, Yoshida-Honmachi, Sakyo-ku, Kyoto 606-8501, Japan; e-mail: mando{at}kuhp.kyoto-u.ac.jp
PURPOSE: Interstitial lung disease (ILD) is a serious adverse effect of gefitinib, but its prevalence and risk factors remain largely unknown. We examined the prevalence of and risk factors for gefitinib-induced ILD associated with practical use of the drug in Japanese with non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Clinical information was retrospectively assembled for NSCLC patients who started gefitinib treatment at affiliated institutions of the West Japan Thoracic Oncology Group between August 31 and December 31, 2002. Medical records of patients who developed pulmonary infiltrates were reviewed by a central committee of extramural experts for identification of patients with gefitinib-induced ILD. Multivariate logistic or Cox regression analysis was performed to identify independent predictive factors for ILD, antitumor response, and survival. RESULTS: Seventy cases of and 31 deaths from gefitinib-induced ILD were identified among 1,976 consecutively treated patients at 84 institutions, corresponding to a prevalence of 3.5% and mortality of 1.6%. Gefitinib-induced ILD was significantly associated with male sex, a history of smoking, and coincidence of interstitial pneumonia (odds ratios = 3.10, 4.79, and 2.89, respectively). Predictive factors for response were female sex, no history of smoking, adenocarcinoma histology, metastatic disease, and good performance status (PS), whereas predictive factors for survival were female sex, no history of smoking, adenocarcinoma histology, nonmetastatic disease, good PS, and previous chest surgery. CONCLUSION: ILD is a serious adverse effect of gefitinib in the clinical setting that cannot be ignored. However, patient selection based on sex and smoking history can minimize ILD risk and maximize the clinical benefit of gefitinib.
The discovery that signaling by the epidermal growth factor receptor (EGFR) plays an important role in tumorigenesis prompted efforts to target this receptor in anticancer therapy, leading to the development of inhibitors of its tyrosine kinase activity.1-3 Gefitinib, an orally active inhibitor of the EGFR tyrosine kinase, is a leading agent in the field of EGFR-targeted therapy.4,5 Two large phase II trials involving previously treated patients with advanced non–small-cell lung cancer (NSCLC) revealed that gefitinib monotherapy was well tolerated and manifested clinically meaningful antitumor activity.6,7 Objective responses that were both rapid and persistent were apparent at a dose of 250 mg/d in 12% to 18% of patients; the median survival time was 7 to 8 months, with a 1-year survival rate of 27% to 35%, and the most common adverse effects were rash and diarrhea, which were generally mild. Similar response and survival rates were apparent at a dose of 500 mg/d but were accompanied by a higher frequency of adverse events. Higher response rates were apparent in women, Japanese patients, patients with no history of smoking, and patients with adenocarcinoma.6-8 Gefitinib was licensed in Japan for the treatment of inoperable or recurrent NSCLC in July 2002. Soon after its introduction, however, life-threatening interstitial lung disease (ILD) attributed to the drug became apparent, despite the absence of severe cases of ILD in the preceding phase I and II trials, which included a total of 132 Japanese patients.6,9-11 The publicity associated with this unexpected severe adverse event led to concern among patients and physicians about the risks of taking gefitinib. Although the prevalence of gefitinib-associated ILD in Japan was estimated at approximately 2%, this estimate was based only on case series studies, with no systematic survey allowing direct determination of the prevalence and identification of risk factors for gefitinib-induced ILD having been performed.12 In the present study, the West Japan Thoracic Oncology Group (WJTOG) conducted a retrospective survey of 1,976 individuals with NSCLC, representing all the patients who started gefitinib treatment at 84 WJTOG-affiliated institutions between August 31 and December 31, 2002. We examined the prevalence of and risk factors for gefitinib-induced ILD in this Japanese patient population. The therapeutic efficacy of gefitinib was also evaluated to assess risk and benefit in real-life use of gefitinib.
Study Patients To collect all data of the potential patients with gefitinib-induced ILD, we initially asked 112 affiliated institutions of WJTOG to report the number of NSCLC patients who started gefitinib treatment between August 31 and December 31, 2002 and subsequently developed pulmonary infiltrates. We also asked them to report the total number of patients who started gefitinib treatment during the same period. After confirming the number of potential cases and total patients, we sent case report forms to the respective institutions and asked them to provide demographic and clinical data for the patients. We finally updated the information of all the patients concerning pulmonary infiltrates, antitumor response, and survival status on December 31, 2003, providing an observation period of at least 12 months. This study was approved by the Review Board of the WJTOG.
Confirmation of Gefitinib-Induced ILD
Demographic and Clinical Variables
Statistical Analysis
Prevalence and Mortality of Gefitinib-Induced ILD A total of 1,976 patients with NSCLC from 84 (75%) of 112 institutions surveyed were reported as having started gefitinib treatment between August 31 and December 31, 2002 (Fig 1). Among these patients, 102 individuals developed pulmonary infiltrates after treatment initiation and were reported as potential cases of gefitinib-induced ILD. The central review committee evaluated the clinical data of these 102 patients and determined that 70 cases of ILD and 31 deaths were attributable to gefitinib, corresponding to a prevalence of 3.5% (95% CI, 2.8% to 4.5%) and a mortality of 1.6% (95% CI, 1.1% to 2.2%) for gefitinib-induced ILD. All ILD patients had been treated with gefitinib monotherapy, with the exception of one patient who received gefitinib concurrently with cisplatin. None of the ILD patients received radiotherapy simultaneously with gefitinib treatment. The median time from the start of gefitinib treatment to the development of ILD was 31 days (interquartile range, 18 to 50 days), and the median duration of gefitinib treatment before ILD development was 29 days (interquartile range, 18 to 49 days). Among the 70 patients with gefitinib-induced ILD, nine patients (13%) underwent bronchoscopic examination, including six lung biopsies and four bronchoalveolar lavages; all the lung biopsy specimens showed interstitial inflammation and fibrosis, and bronchoalveolar lavage revealed no signs (such as neutrophilia) of infection. Cultures of blood or other specimens were performed for 49 patients with ILD (70%), with no infection detected. After the development of gefitinib-induced ILD, 66 patients (94%) received corticosteroids, and additional antibiotic treatment in 17 of these patients did not increase the proportion of individuals whose ILD improved (18% and 61% with and without antibiotics, respectively).
Risk Factors for Gefitinib-Induced ILD Of the 1,874 patients who did not develop pulmonary infiltrates, 245 individuals (13.1%) were excluded from further analysis because of insufficient clinical information (Fig 1). We also excluded the 11 unassessable patients with pulmonary infiltrates as well as one confirmed patient with gefitinib-induced ILD whose lung tumor proved to be metastatic colon cancer. Therefore, a total of 1,719 patients (69 patients with gefitinib-induced ILD and 1,650 patients without ILD) were subjected to subsequent analyses to identify predictive factors for the development of ILD, antitumor response, and survival. Among these 1,719 patients, 1,599 individuals (93%) received gefitinib as a monotherapy, whereas 71 and 49 individuals received gefitinib simultaneously with chemotherapy or palliative radiation, respectively. Univariate analysis identified male sex, a history of smoking, and the coincidence of interstitial pneumonia as being associated with the development of ILD (Table 1). Multivariate logistic regression analysis revealed sex, smoking status, and coincidence of interstitial pneumonia as independent risk factors for gefitinib-induced ILD; BSA was also selected in a forward stepwise procedure and included in the multivariate analysis to adjust for its potential confounding effect, although it was not significant in the final model (Table 2). A potential interaction between sex and smoking status was not significant (P = .399). The adjusted odds ratio for development of ILD was 20.5 (95% CI, 4.9 to 85.7) for males with a history of smoking compared with females with no history of smoking. Among 1,671 patients with known smoking status, the prevalence of ILD ranged from 0.4% in women with no history of smoking to 6.6% in men with a history of smoking (Table 3).
Predictive Factors for Antitumor Response An antitumor response was observed in 348 of the total of 1,976 patients (including 256 unassessable patients), corresponding to a response rate of 17.6% (95% CI, 16.0% to 19.4%). Univariate analysis revealed that an age of less than 70 years, female sex, no history of smoking, adenocarcinoma histology, metastatic disease, good PS, a history of chest surgery, no history of chest irradiation, the absence of interstitial pneumonia, and a BSA of less than 1.5 m2 were associated with an antitumor response (Table 1). Multivariate logistic regression analysis revealed that sex, smoking status, histology, disease stage, and PS were independently associated with response rate (Table 4). No synergistic effect on antitumor response was apparent between sex and smoking status, sex and histology, or smoking status and histology (P = .514, .734, and .573, respectively). The adjusted odds ratio for an antitumor response was 9.2 (95% CI, 5.5 to 15.3) for women with adenocarcinoma and no history of smoking compared with male smokers with a nonadenocarcinoma histology.
Predictive Factors for Survival We confirmed 1,076 deaths among the study population as of December 31, 2003. Overall, the median survival time and 1-year survival rate were 312 days (interquartile range, 114 to 579 days) and 44.8% (95% CI, 42.3% to 47.2%), respectively. Univariate analysis identified female sex, no history of smoking, adenocarcinoma histology, nonmetastatic disease, good PS, previous chest surgery, no history of chest irradiation, the absence of interstitial pneumonia or diabetes, and a BSA of less than 1.5 m2 as being associated with longer survival (Table 1). Cox regression analysis showed that sex, smoking status, histology, disease stage, PS, and previous chest surgery were independent prognostic factors (Table 5). No synergistic effect on survival was observed between sex and smoking status, sex and histology, or smoking status and histology (P = .490, .785, and .531, respectively). Given that previous chemotherapy status is a clinically important factor, we re-examined the survival data separately according to chemotherapy history (Table 6). Survival curves for patients with metastatic disease and a history of chemotherapy (according to independent prognostic factors identified in the Cox regression model) are shown in Figure 2.
We have evaluated clinical data from 1,976 patients with advanced NSCLC who were treated with gefitinib since its licensure in Japan. The present study constitutes the first large-scale survey designed to assess the prevalence of and risk factors for gefitinib-induced ILD during practical use of this drug in the Japanese population. The development of ILD subsequent to treatment with conventional cytotoxic chemotherapeutic agents has been recognized for many years, with the use of standard drugs for treatment of NSCLC being associated with ILD at a prevalence of up to 5%.17,18 Drug-induced ILD in lung cancer patients is difficult to diagnose because of the high prevalence of pre-existing lung disease and respiratory tract infections as well as the progressive malignancy in such individuals. Clinical symptoms of ILD, such as escalating dyspnea, cough, and fever, may be indistinguishable from the symptoms of progressive tumor growth or infection. Computed tomographic features of ILD include pulmonary reticular changes and ground-glass opacity, which are also nonspecific and may not readily indicate a precise etiology.18 Diagnosis of drug-induced ILD thus relies on rigorous exclusion of all other differential diagnoses, especially those of infection and tumor progression. In the present study, all suspected cases of ILD were meticulously reviewed at a single study site by extramural experts, including at least three thoracic radiologists, one pulmonologist, and one oncologist, taking into account clinical history, the results of clinical examination, and comparisons of current and previous radiologic findings. Seventy patients with gefitinib-related ILD were thereby confirmed, yielding an overall prevalence of 3.5% and mortality of 1.6%. The prevalence of ILD in our study was slightly higher than the prevalence (1.1%) among gefitinib-treated patients in recent phase III trials of standard chemotherapy with or without gefitinib conducted in the United States and Europe.19,20 In addition, the worldwide prevalence of ILD among 92,750 patients treated with gefitinib was approximately 1%, being approximately 0.3% in a US AstraZeneca Expanded Access Program.21,22 The reason for the difference in the frequency of gefitinib-related ILD between Japan and Western countries remains unclear. It is possible that a greater awareness of the disease in Japan might lead to more careful and critical examination for ILD or that Japanese may have an increased genetic susceptibility to ILD.22 The mechanism of gefitinib-induced ILD has not been fully elucidated. EGFR and transforming growth factor alpha, a member of the EGF family of proteins that binds to and activates the EGFR, are both upregulated early in the response to acute lung injury,23,24 and EGF family members are implicated in the repair of pulmonary damage.25,26 In a rodent model of bleomycin-induced pulmonary fibrosis, treatment with gefitinib was shown to augment fibrosis.27 These findings suggest that inhibition of EGFR signaling by gefitinib impairs the repair of and, thereby, exacerbates pulmonary injury, especially in patients with pulmonary comorbidities. In the present study, we have sought to identify clinical features of NSCLC patients that might increase the risk for development of ILD. Multivariate analysis identified male sex, a history of smoking, and coincidence of interstitial pneumonia as significant risk factors. Thus, the prevalence of gefitinib-induced ILD differed markedly according to sex and smoking status, ranging from 0.4% in females with no history of smoking to 6.6% in male smokers. This is the first study in which predictive factors for ILD, antitumor response, and survival have been evaluated with the same data set. Multivariate analysis showed that sex, smoking status, tumor histology, disease stage, and PS were independently associated with both antitumor response and survival, mostly consistent with results of previous studies.6-8 Although not confirmed by multivariate analysis, a smaller BSA might also confer greater efficacy on gefitinib, with further investigation of possible dose dependency being warranted. Female sex and the absence of a history of smoking were both associated with a lower risk for ILD, a higher response rate, and longer survival, suggesting that patient selection on the basis of this favorable profile will not only increase the clinical benefit of treatment with gefitinib but also reduce the risk for development of this life-threatening toxicity. Activating mutations of the EGFR have been identified in a subset of NSCLC patients, and tumors with EGFR mutations are highly sensitive to gefitinib.28,29 However, these genetic factors have not been confirmed to be predictive of true clinical benefit because they have not yet been found to be associated with survival in NSCLC patients treated with gefitinib.30 These previous studies showed that EGFR mutations were more frequent in females, individuals with no history of smoking, and patients with adenocarcinoma. We have no data on the frequency of EGFR mutations in the present patient cohort, and further studies to explore the relationship of genetic alterations with ILD risk and treatment efficacy are warranted. The objective response rate in the present study was 17.6%, which is indicative of an acceptable single-agent activity of gefitinib outside clinical trial settings. Our data showed the median survival time and 1-year survival rate to be 10.0 months and 44%, respectively, in all patients who received gefitinib after the failure of prior chemotherapy. Given that the present study included many elderly and patients with a poor PS, these survival data do not differ substantially from those obtained with the Japanese cohort of a phase II study (11.8 months and 50%, respectively).6 These findings suggest that gefitinib treatment in clinical practice may lead to clinical benefit as it did in the clinical trials. Furthermore, the survival data in the present study are similar to those obtained with previously treated patients with a PS of 0 to 2 in a phase III trial of docetaxel (7.5 months and 37%, respectively), which is a standard second-line treatment for NSCLC.30 These observations emphasize the importance of further comparison of gefitinib with docetaxel as a second-line treatment for NSCLC in ongoing phase III studies. In previous phase III clinical trials, however, gefitinib failed to prolong survival in unselected patients, suggesting the necessity for patient selection on the basis of clinical or genetic factors if true clinical benefit is to be achieved from gefitinib treatment.19,20,31 Indeed, a randomized phase III trial is now planned in Asian countries to assess the effect of gefitinib on survival in patients selected on the basis of clinical profile. In conclusion, we have determined the prevalence of gefitinib-related ILD and identified risk factors for this life-threatening adverse event in a large population of Japanese patients with NSCLC treated with this drug. Our data confirmed an acceptable single-agent activity of gefitinib in routine clinical practice. We found that female sex and the absence of a history of smoking, which were known predictive factors for the efficacy of gefitinib, were also associated with a lower risk of gefitinib-induced ILD. Thus, our results indicate that patient selection on the basis of clinical factors can simultaneously minimize the risk of life-threatening ILD and maximize the clinical benefit of gefitinib treatment. They provide both important insight into individual risk-benefit assessment for gefitinib therapy in the practical setting as well as a basis for the planning of future clinical trials to accurately define the scope for gefitinib treatment in NSCLC patients.
The following institutions of the West Japan Thoracic Oncology Group participated in this study: Aichi Cancer Center Hospital, Tokyo Medical University, Japanese Red Cross Society Wakayama Medical Center, Hyogo Medical Center for Adults, Osaka City General Hospital, Osaka Prefectural Medical Center for Respiratory and Allergic Disease, Osaka Medical Center for Cancer and Cardiovascular Diseases, Toneyama National Hospital, Kurashiki Central Hospital, Kurume University School of Medicine, Kinki University School of Medicine, Kanazawa University Graduate School of Medicine Science, Kyushu University Graduate School of Medical Sciences, Kumamoto Regional Medical Center, Aichi Cancer Center Aichi Hospital, Kyoto National Hospital, National Kyushu Cancer Center, Kobe City General Hospital, Shikoku Cancer Center, Osaka General Medical Center, Tenri Hospital, Tokai University School of Medicine, Gifu Municipal Hospital, Hiroshima Red Cross Hospital and Atomic Bomb Survivors Hospital, Kagawa Prefectural Central Hospital, Okinawa National Hospital, National Minami-Kyoto Hospital, Ogaki Municipal Hospital, Osaka City University Graduate School of Medicine, Otemae Hospital, Higashiosaka City General Hospital, Tochigi Cancer Center, Aso Iizuka Hospital, Toyota Memorial Hospital, Kumamoto University Graduate School of Medical Science, Anti-Tuberculosis Association Osaka Hospital, Koseiren Takaoka Hospital, Hiroshima University Graduate School of Biomedical Science, Osaka Medical College, Osaka University Graduate School of Medicine, Osaka Saiseikai Nakatu Hospital, Tokai University School of Medicine, Toyama Medical and Pharmaceutical University, Hyogo College of Medicine, Magoya City University Hospital, Nagoya Ekisaikai Hospital, Rinku General Medical Center, Asahikawa Medical College, Gifu University School of Medicine, International Medical Center of Japan, Medical Seiransou Hospital, Mie University School of Medicine, Yamaguchi Prefectural Hospital, Shiga University of Medical Science, Kobe University Graduate School of Medicine, Shizuoka Cancer Center, Nara Medical University, and Wakayama Rosai Hospital.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) > $100,000 (N/R) Not Required
We thank Kazumi Kubota for data management.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Madtes DK, Rubenfeld G, Klima LD, et al: Elevated transforming growth factor-alpha levels in bronchoalveolar lavage fluid of patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 158:424-430, 1998 25. Hardie WD, Prows DR, Leikauf GD, et al: Attenuation of acute lung injury in transgenic mice expressing human transforming growth factor-alpha. Am J Physiol 277:L1045-L1050, 1999[Medline] 26. Hardie WD, Prows DR, Piljan-Gentle A, et al: Dose-related protection from nickel-induced lung injury in transgenic mice expressing human transforming growth factor-alpha. Am J Respir Cell Mol Biol 26:430-437, 2002 27. Suzuki H, Aoshiba K, Yokohori N, et al: Epidermal growth factor receptor tyrosine kinase inhibition augments a murine model of pulmonary fibrosis. Cancer Res 63:5054-5059, 2003 28. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. 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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test or Fisher's exact test. Multivariate logistic regression analysis was performed to identify predictors of ILD development or antitumor response.
