Interstitial lung disease in gefitinib-treated Japanese patients with non-small cell lung cancer – a retrospective analysis: JMTO LC03-02
- Masatsugu Nakagawa†1, 2, 5Email author,
- Tsutomu Nishimura†1, 5,
- Satoshi Teramukai1, 5,
- Harue Tada1, 5,
- Fumihiro Tanaka3, 5,
- Kazuhiro Yanagihara4, 5,
- Kiyoyuki Furuse5,
- Hiromi Wada2, 5 and
- Masanori Fukushima1, 5, 6
© Nakagawa et al; licensee BioMed Central Ltd. 2009
Received: 10 February 2009
Accepted: 5 August 2009
Published: 5 August 2009
In Japan, high incidences of interstitial lung disease (ILD) and ILD-related deaths have been reported among gefitinib-treated patients with non-small cell lung cancer (NSCLC). We investigated the efficacy of gefitinib, the incidence of ILD and risk factors for ILD in these patients.
We obtained patient data retrospectively using questionnaires sent to 22 institutions. We asked for demographic and clinical data on NSCLC patients for whom gefitinib treatment had begun between July 2002 and February 2003. Data from a total of 526 patients were analyzed. The patient characteristics were as follows: 64% male, 69% with adenocarcinoma, 61% with a performance score of 0–1, and 5% with concurrent interstitial pneumonitis. The objective response proportion was 80/439 (18.2%; 95% CI: 14.7–22.0). ILD developed in 17 patients (3.2%; 95% CI 1.9–5.1%), of whom 7 died. According to multivariate analysis, female sex, history of prior chemotherapy, low absolute neutrophil count before gefitinib treatment, and adenocarcinoma histology were associated with response to gefitinib treatment. None of the factors we evaluated were associated with the development of ILD.
The results of this study are consistent with previously published values for treatment response proportions and incidence of ILD during gefitinib treatment in Japanese patients. Future studies should be aimed at identifying factors indicating that a patient has a high probability of receiving benefit from gefitinib and a low risk of developing ILD.
In most industrialized countries, non-small cell lung cancer (NSCLC) is the leading cause of death from cancer . At the time of diagnosis, the majority of NSCLC patients have advanced disease that is not amenable to curative approaches, so NSCLC is associated with a poor prognosis. Platinum-based chemotherapy provides a survival benefit of limited duration , and combinations of newer active agents (such as gemcitabine and paclitaxel) with platinum have produced further improvement in survival [3, 4]. Docetaxel has been approved as a second-line chemotherapy agent on the basis of randomized trials involving patients in whom first-line chemotherapy was unsuccessful, but the objective response proportions to docetaxel are only 5–10%, and treatment is associated with only a modest survival benefit [5, 6].
Gefitinib is an orally active selective inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase and has been found to have antitumor activity in patients with advanced NSCLC who have undergone prior treatment. According to several multicenter phase I trials [7–9], diarrhea, skin rashes, and nausea are common adverse events associated with gefitinib treatment, but most of these adverse events are mild. Based on the results of two large-scale multicenter phase II studies (IDEAL 1 and 2; Iressa Dose Evaluation in Advanced Lung Cancer) [10, 11], in July 2002 gefitinib was approved in Japan for the treatment of inoperable or recurrent NSCLC. However, since approval, a number of deaths due to gefitinib-induced interstitial lung disease (ILD) have been reported [12, 13], and the high incidences of ILD and associated mortality have become a matter of great concern in Japan. Risk-benefit assessments have become critical in the use of gefitinib. We report here the results of a retrospective study conducted by the Japan Multinational Trial Organization (JMTO: http://www.jmto.org/) to investigate the response proportion, factors predicting response, and the incidence of and risk factors for ILD in gefitinib-treated NSCLC patients.
Patients with histologically or cytologically confirmed NSCLC of any clinical or pathological stage, who began taking gefitinib between July 2002 and February 2003, were eligible for inclusion in the study. We obtained patient data using questionnaires sent to 22 institutions, and retrospectively analyzed the information provided in the returned questionnaires, including laboratory findings. The study protocol (JMTO LC03-02) was approved by the ethics committees of JMTO and the participating institutions.
Baseline assessments included age, sex, histological type of NSCLC, clinical or pathological stage of cancer at diagnosis (using the current TNM classification system ), Eastern Cooperative Oncology Group (ECOG) performance status (PS), history of smoking before starting gefitinib treatment, medical history (including prior anticancer therapy), concurrent pulmonary disease (e.g. interstitial pneumonitis or pulmonary emphysema), and laboratory findings (complete blood cell count, blood biochemistry, arterial blood gas analysis data). Diagnoses of concurrent pulmonary disease were made by each institution on a clinical basis.
The endpoints of this study were response to gefitinib treatment or occurrence of a serious adverse event during gefitinib treatment or death due to the serious adverse event. Adverse events were evaluated using the National Cancer Institute Common Toxicity Criteria (NCI-CTC), version 2.0, and a serious adverse event was defined as being an NCI-CTC grade 4 adverse event, or any experience that resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, or caused a congenital anomaly/birth defect, according to the definition published by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use . In this study, ILD was assumed to be interstitial pneumonitis as diagnosed by each institution on a clinical basis.
If patients had measurable disease, tumor response was assessed on the basis of medical records, and if not mentioned in the medical records, the Response Evaluation Criteria in Solid Tumors (RECIST)  or the World Health Organization (WHO) criteria  were used for assessment. The objective response was calculated as the proportion of patients with a complete or partial response.
Associations between serious adverse events or objective response and patient characteristics were assessed using a logistic regression model. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using univariate analysis, and a backward elimination procedure was used to identify significant predictors in the multivariate analysis. Because of the comparability of the ORs, the units used to measure absolute neutrophil count and lactate dehydrogenase (LDH) level were Log transformed. Predictive response probabilities were estimated based on a final multivariate logistic regression model for evaluating associations between response and ILD occurrence. All statistical analyses were carried out using SAS version 8.02 (SAS Institute, Cary NC, USA).
Patient characteristics (n = 526).
Mean (± SD)
Squamous cell carcinoma
History of smoking
ECOG performance status
Concurrent interstitial pneumonitis
Concurrent pulmonary emphysema
History of pulmonary tuberculosis
Prior surgery for lung cancer
Prior chemotherapy for lung cancer
Prior thoracic radiotherapy for primary lung cancer
Concurrent chemotherapy with agent other than gefitinib
Thoracic radiotherapy concurrent with or after gefitinib treatment
Absolute neutrophil count (/μL)
4786 (± 3331)
Eosinophil count (/μL)
163 (± 181)
Creatinine level (mg/dL)
0.77 (± 0.44)
Platelet count (×104/μL)
25.8 (± 10.3)
Albumin level (g/dL)
3.67 (± 0.58)
Aspartate aminotransferase level (IU/L)
25 (± 20)
Alanine aminotransferase level (IU/L)
23 (± 25)
Lactate dehydrogenase level (IU/L)
279 (± 318)
The mean patient age was 66.2 years (range 27–91 years). A total of 336 patients (64%) were male, 360 patients (69%) had adenocarcinoma, and 319 patients (61%) were current or former smokers. In 26 patients (4.9%), NSCLC was accompanied by concurrent interstitial pneumonitis. Gefitinib was given as a first-line chemotherapeutic agent in 115 patients.
With respect to the laboratory findings before gefitinib treatment, absolute neutrophil count, aspartate aminotransferase (AST) level, alanine aminotransferase (ALT) level, and LDH level were reported for 485, 487, 515, and 495 patients, respectively (Table 1).
Response to treatment
For 439 patients (83%), tumor response was reported and evaluable. Complete and partial responses were observed for 7 and 73 patients, respectively. The objective response proportion was 80/439 (18.2%; 95% CI: 14.7–22.0), and the disease control proportion, which was the objective response plus the proportion of patients with stable disease, was 237/439 (54.0%).
Factors predicting tumor response
Predictive factors for tumor response and risk factors associated with ILD (univariate analysis)
ratio (95% CI)
History of smoking
ECOG performance status
Concurrent interstitial pneumonitis
Concurrent pulmonary emphysema
0.74 (0.26 -2.12)
Prior thoracic radiotherapy
Concurrent chemotherapy with
agent other than gefitinib
Thoracic radiotherapy concurrent
with or after gefitinib treatment
Absolute neutrophil count *
Aspartate aminotransferase level **
Lactate dehydrogenase level ***
Albumin level ****
Factors predicting tumor response (multivariate analysis)
Odds ratio (95% CI)
Absolute neutrophil count
ILD and other serious adverse events
Serious adverse events occurred during gefitinib treatment in 66 of 526 patients. ILD developed in 17 patients (3.2%; 95% CI: 1.9%–5.1%), 7 (41%) of whom died during treatment. Hepatic dysfunction occurred in seven patients, one of whom died during treatment. Other serious adverse events included skin rash, diarrhea, aspiration pneumonia, perforative peritonitis, acute enteritis, convulsion, epilepsy, cancerous pain.
Analysis of factors affecting ILD
The association between ILD and various clinical factors was evaluated using logistic regression. In the univariate analysis, none of the factors we evaluated were found to be associated with the development of ILD, including sex, history of smoking, concurrent interstitial pneumonitis, history of prior chemotherapy, or poor ECOG PS.
Analysis of the relation between response and ILD
In the present study, the gefitinib response proportion was 18.2%, which is similar to values determined in other studies and clinical trials [10, 18, 19]. The response proportion among patients with a history of prior chemotherapy was 15.5%, which was somewhat higher than values observed in clinical trials of docetaxel chemotherapy for previously treated NSCLC patients (10.8% and 7.1%) [5, 6].
Risk factors for ILD associated with gefitinib use and predictive factors for tumor response in Japanese patients as determined by studies in the literature
No. cases ILD (%)
No. ILD deaths (%)
Risk factors for ILD
Response Proportion (%)
Predictive factors for tumor response
National Cancer Center, Japan (2004) 
-Pre-existing pulmonary fibrosis
-No history of smoking
-No history of thoracic radiotherapy
Okayama Lung Cancer
-Pre-existing pulmonary fibrosis
-Prior thoracic irradiation
-History of smoking
West Japan Thoracic
-History of smoking
-No history of smoking
In patients with
ILD were 31.6%
-History of smoking
-Age >55 years
-Recent NSCLC diagnosis,
-Reduced normal lung on
computed tomography scan
-Preexisting chronic ILD
-Concurrent cardiac disease
No factors found to be significant
-No previous chemotherapy
-Low absolute neutrophil count
The incidence of ILD in this study was 3.2%, which is similar to the values determined in other studies (3.5–5.8%) (Table 4). Determining the incidence of anti-EGFR therapy-related ILD in NSCLC is complicated by many factors, including the underlying neoplastic disease, adverse events caused by other chemotherapy agents, oxygen treatment, radiation therapy, and opportunistic infections. In a study conducted by the West Japan Thoracic Oncology Group (WJTOG) , the incidence of ILD in gefitinib-treated NSCLC patients was found to be 3.5%. In that study, ILD was defined as diffuse interstitial changes or ground-glass appearance, and the diagnosis was confirmed on the basis of radiological findings and clinical data by a central review committee comprising chest radiologists, chest physicians, and oncologists. In the present study, ILD was defined as a diagnosis of interstitial pneumonitis during gefitinib treatment, as diagnosed by each institution on a clinical basis. A central review committee was not involved. Despite this methodological difference, the incidence of ILD in the present study population was similar to the value found in the WJTOG study.
Risk factors for ILD have been identified in a number of studies of Japanese gefitinib-treated NSCLC patients (Table 4). In the present study, we also attempted to identify risk factors for ILD in gefitinib-treated NSCLC patients, but unlike the previous studies, none of the factors we evaluated were found to be significant, including sex, history of smoking, concurrent interstitial pneumonitis, history of prior chemotherapy, and poor PS. We cannot explain why this might be, but other risk factors that we did not investigate may possibly be associated with ILD.
In the interests of patient welfare, we need criteria by which patients with factors predicting tumor response or survival benefit and without factors predisposing to ILD can be selected. In the WJTOG study it was concluded that patient selection on the basis of female sex and the absence of a history of smoking will increase the clinical benefit of treatment with gefitinib and reduce the risk of ILD . In the present study, we found no factors that clearly increase the benefit or decrease the risk. We did not find an association between the predictive response probability and the occurrence of ILD. The mechanism by which gefitinib might cause ILD is unclear, but that may be because the site at which gefitinib acts is different from that at which ILD manifests. Because of the considerable risk to patients, further studies investigating risk factors are warranted. The limitations of the present study were the retrospective design, the relatively small number of patients, and the conduction of the study using questionnaire, but the results of present study were similar to those of the previous reports.
The results of this study are consistent with previously published values for treatment response proportions and incidence of ILD during gefitinib treatment. In the interests of patient welfare, ILD in gefitinib-treated NSCLC patients should be investigated further in large-scale prospective studies, in which patients should be selected on the basis of factors affecting ILD and predicting tumor response.
We thank Ms. Akiko Matsuyama, Mr. Naoki Eguchi, Ms. Yuka Fujii (Translational Research Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan) for their assistance with data management.
Japan-Multinational Trial Organization (JMTO) conducted this study (JMTO LC03–04) with the cooperation of the following investigators: Fumihiro Tanaka, Tadashi Mio and Hiromi Wada, Kyoto University Hospital, Kyoto; Toshiki Hirata, Kishiwada City Hospital, Osaka; Yuki Teranishi, Haruhisa Kitano, Akihiro Aoyama, Miyuki Nagasawa and Toru Shindo, Tenri Hospital, Nara; Tetuhiro Shiota, Ako City Hosipital, Hyogo; Keisuke Tomii, Kobe JapanPost Hospital, Hyogo; Seisuke Niibayashi, Kyotominami Hospital, Kyoto; Tomoaki Matsuoka and Norihito Okumura, Kurashiki Central Hospital, Okayama; Fumitsugu Kojima, Nobuya Mino and Kazuya Matsumoto, Osaka Saiseikai Noe Hospital, Osaka; Kazumi Itoi, Hyogo Prefectural Amagasaki Hospital, Hyogo; Shiro Fujita Osaka Saiseikai Nakatsu Hospital, Osaka; Motonari Fukui, Kitano Hospital, Osaka; Yoshiro Kubo and Keijiro Kono, Osaka Red Cross Hospital, Osaka; Noritaka Isowa, Matsue Red Cross Hospital, Shimane; Mitsuhiro Ueda and Tatsuji Kato, Kokura Memorial Hospital, Fukuoka; Yasumichi Yamamoto and Hiroyasu Yokomise, 2nd Department of Surgery, Faculty of Medicine, Kagawa University, Kagawa; Hiroshi Fujii, Kobe Nishi City Hospital, Hyogo; Takashi Koba, Toshihiro Okamoto and Hiroshi Mizuno, Kansai Denryoku Hospital, Osaka; Tuyoshi Takahashi and Shinji Kosaka, Shimane Prefectural Central Hospital, Shimane; Hiromi Tomioka and Minoru Aoki, Nishi-Kobe Medical Center, Hyogo; Masaaki Kawahara, National Hospital Organization Kinki-chuo Chest Medical Center, Osaka; Yuichi Ando and Yasutsuna Sasaki, Department of Clinical Oncology, Saitama Medical School, Saitama.
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