Published ahead of print on March 12, 2008, doi:10.1164/rccm.200710-1501OC
© 2008 American Thoracic Society doi: 10.1164/rccm.200710-1501OC
Interstitial Lung Disease in Japanese Patients with Lung CancerA Cohort and Nested Case-Control Study1 Nippon Medical School, Tokyo, Japan; 2 Tokyo Medical University Hospital, Tokyo, Japan; 3 National Cancer Center Hospital East, Chiba, Japan; 4 Kinki University School of Medicine, Osaka, Japan; 5 Nakata Clinic, Tokyo, Japan; 6 National Kyushu Cancer Center, Fukuoka, Japan; 7 Toneyama National Hospital, Osaka, Japan; 8 Saiseikai Kumamoto Hospital, Kumamoto, Japan; 9 Japan Thoracic Radiology Group, Shiga, Japan; 10 AstraZeneca KK, Osaka, Japan; 11 AstraZeneca, Macclesfield, Cheshire, United Kingdom; 12 AstraZeneca R&D Charnwood, Loughborough, United Kingdom; 13 Sheffield University, Sheffield, United Kingdom; 14 Epidemiology, AstraZeneca R&D Mölndal, Mölndal, Sweden; and 15 Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden Correspondence and requests for reprints should be addressed to Fredrik Nyberg, M.P.H., M.D., Ph.D., Epidemiology, AstraZeneca R&D Mölndal, SE-413 83 Mölndal, Sweden. E-mail: fredrik.nyberg{at}astrazeneca.com
Rationale: Interstitial lung disease (ILD) occurs in Japanese patients with non–small cell lung cancer (NSCLC) receiving gefitinib. Objectives: To elucidate risk factors for ILD in Japanese patients with NSCLC during treatment with gefitinib or chemotherapy. Methods: In a prospective epidemiologic cohort, 3,166 Japanese patients with advanced/recurrent NSCLC were followed for 12 weeks on 250 mg gefitinib (n = 1,872 treatment periods) or chemotherapy (n = 2,551). Patients who developed acute ILD (n = 122) and randomly selected control subjects (n = 574) entered a case-control study. Adjusted incidence rate ratios were estimated from case-control data by odds ratios (ORs) with 95% confidence intervals (CIs) using logistic regression. Crude (observed) incidence rates and risks were calculated from cohort data. Measurements and Main Results: The observed (unadjusted) incidence rate over 12 weeks was 2.8 (95% CI, 2.3–3.3) per 1,000 person-weeks, 4.5 (3.5–5.4) for gefitinib versus 1.7 (1.2–2.2) for chemotherapy; the corresponding observed naive cumulative incidence rates at the end of 12-week follow-up were 4.0% (3.0–5.1%) and 2.1% (1.5–2.9%), respectively. Adjusted for imbalances in risk factors between treatments, the overall OR for gefitinib versus chemotherapy was 3.2 (1.9–5.4), elevated chiefly during the first 4 weeks (3.8 [1.9–7.7]). Other ILD risk factors in both groups included the following: older age, poor World Health Organization performance status, smoking, recent NSCLC diagnosis, reduced normal lung on computed tomography scan, preexisting chronic ILD, concurrent cardiac disease. ILD-related deaths in patients with ILD were 31.6% (gefitinib) versus 27.9% (chemotherapy); adjusted OR, 1.05 (95% CI, 0.3–3.2). Conclusions: ILD was relatively common in these Japanese patients with NSCLC during therapy with gefitinib or chemotherapy, being higher in the older, smoking patient with preexisting ILD or poor performance status. The risk of developing ILD was higher with gefitinib than chemotherapy, mainly in the first 4 weeks.
Key Words: non–small cell lung cancer • interstitial lung disease • Japanese patients • gefitinib, chemotherapy
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are a well-established therapy for the treatment of non–small cell lung cancer (NSCLC) in many countries. They are generally well tolerated and not typically associated with the cytotoxic side effects commonly seen with chemotherapy. The EGFR tyrosine kinase inhibitor gefitinib (IRESSA; AstraZeneca, London, U.K.) was first approved for the treatment of advanced NSCLC in Japan in July 2002. In clinical trials and in preapproval compassionate clinical use, some reports of interstitial lung disease (ILD)–type events had been observed. As the drug was made more widely available in Japan after approval, however, an increasing number of spontaneous reports for ILD appeared. ILD is a disease that affects the parenchyma or alveolar region of the lungs (1). When associated with drug use, it can present precipitously with acute diffuse alveolar damage, which is fatal in some patients (2). Chest imaging shows ground-glass density and patients present with severe breathlessness. There is no specific treatment, but supportive therapy including oxygen, corticosteroids, or assisted ventilation is indicated. Acute exacerbations of ILD have previously been considered relatively rare in many settings, with Japan as a notable exception (3), but recent studies of patients with idiopathic pulmonary fibrosis (IPF) have challenged this and underlined this important risk (4). ILD, especially IPF, is a known comorbidity in patients with NSCLC and has also been associated with many other lung cancer therapies (5). Rates of acute ILD events up to and exceeding 10% have been reported in patients receiving chemotherapy and radiotherapy (6–11). It is recognized that ILD is more common in Japan than elsewhere (5, 6, 12, 13). When safety reports of acute ILD-type events in gefitinib-treated patients appeared in Japan, there was limited knowledge about ILD in patients with NSCLC. There was a need to better understand baseline incidence on different treatments, risk factors for developing ILD, and whether gefitinib might be associated with increased risk of ILD, or if patient selection or other aspects were involved. A pharmacoepidemiologic study was designed and conducted by an independent academic team together with scientists from AstraZeneca to define the risk and increase understanding of ILD in Japanese patients with NSCLC. Some of the results of this study have been previously reported in the form of conference abstracts (14, 15).
See also the online supplement for further details on methods.
Overall Study Design Patients who developed acute ILD events during the follow-up were registered to the case-control study nested within the cohort as clinically diagnosed potential cases. For each potential case, four patients who had not yet developed ILD were randomly selected as appropriate control subjects from patients registered to the cohort at that time, and extensive clinical and demographic risk factor data were collected on cases and control subjects (see Figure E1 in the online supplement). The study followed Good Clinical Practice procedures. An independent external epidemiology advisory board provided advice on design, conduct, and analysis of the study.
Diagnosis of ILD
Evaluation of Preexisting Lung Conditions
Detailed Data Collection
Statistical Analysis Control subjects for the nested case-control study were sampled using incidence density sampling, and consequently the odds ratio (OR) obtained from the case-control analysis estimates the study incidence rate ratio (and approximately estimates the risk ratio) (16). For the case-control statistical analysis, it was initially verified that the convenience matching for calendar time implicit in the risk set control sampling could be disregarded. In tabular analyses, we then identified potential confounders and risk factors, using as selection criteria a 10% change in the OR estimate for gefitinib versus chemotherapy treatment when stratifying for each factor separately, and a risk factor crude OR of less than 0.5 or more than 2.0, respectively. We also identified potential interactions between treatment and other risk factors, or between two potential risk factors. Modeling using logistic regression then proceeded in the corresponding four steps. Few previous data were available on risk factors for ILD in patients with NSCLC and so a hypothesis-free stepwise process with loose P value criteria (P < 0.20) for selection was used throughout to avoid bias. Two sensitivity analyses were performed. First, to investigate the potential influence of the modeling approach used, a propensity score analysis was performed (17). This analysis provides an alternative way of adjusting for potential confounding bias by stratifying for a compound score based on predictors of treatment (see online supplement for details). Second, we estimated the possible bias due to misclassification of disease under reasonable assumptions of diagnostic error. ILD-related mortality among the patients who developed acute ILD on gefitinib or chemotherapy treatment was obtained. Modeling of risk factors for ILD-related mortality followed a similar process to the ILD risk factor modeling. For gefitinib-treated patients, two additional data items were available: total all-cause mortality, which was analyzed by the Kaplan-Meier method, and SAEs, for which frequencies and possible consequences in terms of treatment discontinuation and death were calculated.
Cohort Subjects and Treatments Cohort participation rates were high. In 10 sampled study centers, 89.6% of eligible patients were enrolled to the cohort. The number of treatment periods and subjects are summarized in Table 1. In total, 4,423 treatment periods in 3,159 subjects were available for analysis. In the cohort, 70.8% of patients had only one treatment period, 21.5% had two periods, and the remaining 7.8% of patients had three or more treatment periods registered (Table 1). Chemotherapy included a wide range of treatments, the most common being taxane monotherapy, followed by taxane+platinum and gemcitabine+vinorelbine combinations.
Cases and Control Subjects In the overall cohort data of all treatment periods, clinicians reported 155 suspected cases of acute ILD during the follow-up, of which 122 were confirmed by the CRB after blinded review of CT and clinical data—79 of 103 gefitinib-treated (76.7%) and 43 of 52 chemotherapy-treated (82.7%) subjects. A total of 574 eligible control subjects were sampled from the person-time of the cohort. Almost all ILD cases and selected control subjects consented to participate in the nested case-control study, with final participation rates of 98.1 and 92.0%, respectively. Valid data from the CRB review of CT scans were available for 115 cases and 520 control subjects.
Descriptive Data
Cohort Analysis of ILD Occurrence The observed incidence rate of acute ILD over the entire 12-week follow-up in the overall cohort was 2.8 per 1,000 person-weeks—4.5 in the gefitinib-treated and 1.7 in the chemotherapy subcohort (Table 4). The observed incidence in the gefitinib-treated subcohort was highest in the first 4 weeks after starting treatment, greater than in the chemotherapy-treated subcohort. In the following two 4-week periods, the incidence was lower with no clear difference (Table 4, Figure 1A). The naive cumulative incidence of ILD at 84 days (i.e., observed frequency or proportion of the original cohort that developed ILD in the study) for patients in their first study treatment period was 4.0 and 2.1% for gefitinib- and chemotherapy-treated patients, respectively (Table 4), whereas the estimated theoretical 12-week risk of ILD (i.e., taking competing causes of death and loss to follow-up into consideration; Kaplan-Meier method) was 4.5 and 2.4%, respectively (Table 4, Figure 1B). Thus, the observed cohort rates and risks suggested an association of increased ILD occurrence with gefitinib treatment mainly in the first 4 weeks after treatment initiation. All cohort estimates are unadjusted for imbalances between treatments in other risk factors. Detailed comparisons between the treatments therefore used the adjusted case-control OR (as an estimate of the adjusted incidence rate ratio) to achieve comparability.
Case-Control Analysis of ILD Occurrence and Risk Factors Major results. The OR of developing acute ILD with gefitinib treatment versus chemotherapy, adjusted for the full predictor model of major confounders together with additional identified important risk factors and interactions, was 3.2 (95% confidence interval [CI], 1.9–5.4) (Table 5). Several risk factors aside from treatment also had strong effects, including WHO PS, as well as smoking status and preexisting ILD together with the extent of normal lung on CT scan, which interacted in a complex way in the model (Table 5, Figure 2). Preexisting ILD was confirmed as a strong risk factor, with OR point estimates ranging from 4.8 to 25.3 depending on the extent of remaining normal lung on CT scan, in comparison with patients without preexisting ILD and high extent of normal lung on CT scan (Table 5). The full set of ILD risk factors in both groups from the final model thus included older age (  55 yr), WHO PS (2), smoking, short duration since NSCLC diagnosis (<6 mo), reduced extent of normal lung on CT scan (<50%), preexisting ILD, and concurrent cardiac disease. Although some potential significant interactions were seen in the initial tabular analyses (Table E1), no significant interactions with treatment (i.e., treatment-specific risk factors, or variation in treatment-related effect in subgroups defined by another risk factor) were identified in the modeling after adjustment for the relevant risk factors.
When the case-control analyses focused on the first 4 weeks after treatment initiation (because the unadjusted cohort analyses above indicated that the bulk of the association with gefitinib appeared to be for this time interval) the estimated OR adjusted for a full predictor model developed on this period's data was 3.8 (95% CI, 1.9–7.7). The same model produced an OR for Weeks 5–8 of 1.6 (95% CI, 0.5–4.8), whereas the final 4-week period had too few cases for an adequate estimate. The estimate for Weeks 5–12 combined, using this same model, was 2.5 (95% CI, 1.1–5.8). The important covariates and predictors were the same in this model as in the model for the full 12-week data, with the exception of age, preexisting cardiac disease, and preexisting pulmonary emphysema, which were not included. Due to sparse data beyond 4 weeks, independent models for Weeks 5–8, 9–12, and 5–12 could not be developed.
Confounding and sensitivity analysis. The propensity score analysis approach identified the following variables as the most important predictors of selecting gefitinib treatment in this study: female sex; nonsmoking status; non–squamous tumor histology; poor PS; preexisting lymphangitis carcinomatosis; no previous gefitinib treatment; and no preexisting ILD, emphysema, or radiation pneumonitis. The estimated OR of developing ILD for gefitinib treatment when stratifying by the propensity score was 3.3 (95% CI, 1.9–5.5), very similar to the primary result, suggesting that the primary regression modeling approach well captured the confounding in the data. If some misclassification of ILD diagnosis remains despite the design features aimed to minimize it, the adjusted OR point estimate of 3.2 may apart from random variation be subject to systematic bias. A sensitivity analysis to evaluate the possible magnitude of such bias due to misclassification of ILD diagnosis suggested that the true study point estimate for the adjusted OR would be expected to lie between 2.6 and 4.8, assuming diagnostic sensitivity of more than 80% for both gefitinib- and chemotherapy-treated patients, and specificity of more than 99.0% for gefitinib and more than 99.5% for chemotherapy. Lower values for sensitivity/specificity were considered very unlikely for this serious condition in a cancer patient population, in this study setting.
Analysis of ILD Mortality
Overall mortality among gefitinib-treated patients.
SAEs among Gefitinib-treated Patients SAEs were only collected for gefitinib-treated patients in the cohort, and a total of 198 patient registrations reported SAEs (10.5%), of which 38 (2.0%) reported SAEs resulting in a fatal outcome. Within this group, there were 142 patient registrations with drug-related (as reported by the physicians) SAEs (7.5%), of which 30 (1.6%) resulted in a fatal outcome. The majority of these (25 out of 30) were due to ILD-type events. There were 122 patient registrations where study treatment was discontinued due to the reported SAEs (6.5%). SAEs seen in the gefitinib-treated patients were generally consistent with the known safety profile of gefitinib and/or the patient's underlying disease and comorbidities.
This study provides important information on ILD in an advanced/recurrent NSCLC setting in Japanese patients in Japan, and it is the largest prospective study of this condition to date. For the first time, the risk of acute ILD events for a large and relatively unselected chemotherapy-treated NSCLC patient cohort in Japan was determined in clinical practice. The study also quantified the greater risk of developing acute ILD associated with gefitinib treatment than with conventional chemotherapy, mainly in the first 4 weeks after treatment initiation. The study confirmed and further defined risk factors for developing ILD with gefitinib or chemotherapy. The factors included older age, poor WHO PS, smoking, short duration since diagnosis of NSCLC, reduced normal lung on CT scan, preexisting ILD, and concurrent cardiac disease. Several of these factors, or related factors, had been reported previously in bivariate or multivariate analyses from other studies (8, 18, 19). These risk factors were the same for patients treated with gefitinib or chemotherapy in the study, and no treatment-specific risk factors were identified. In particular, patients with CT evidence of preexisting ILD (chronic) were at considerably elevated risk of developing acute ILD during treatment, but there were relatively few subjects with preexisting ILD and the data did not indicate a statistically significant difference in treatment-related risk depending on the preexisting ILD status. Of clinical relevance, some of these risk factors were just as strong as, or stronger than, gefitinib treatment, for example having a poor WHO PS ( 2) rather than a good PS (OR, 4.0; 95% CI, 1.85–8.75), implying that they can be used to identify patients at particular risk of ILD in clinical practice. The relationship between ILD and pharmacokinetic characteristics of gefitinib, as well as genetic polymorphisms and proteomics determined in study subjects, were also investigated as secondary and exploratory objectives in this study. These analyses are ongoing and results will be submitted for publication in due course. Over the whole study follow-up, the average incidence rate for acute ILD events in patients treated with gefitinib was 3.2-fold higher relative to that seen with other chemotherapy treatments, adjusted for imbalances in other risk factors between treatments. The increased risk of ILD associated with gefitinib treatment was seen most clearly in the first 4 weeks after treatment initiation. Thus, increased physician awareness of risk factors and careful surveillance of Japanese patients during this period are indicated to manage risk. Such an approach is in line with current recommendations in Japan (20, 21). Beyond 4 weeks after treatment initiation, the risk of ILD associated with gefitinib treatment appears to fall. ILD risk factors were found to be the same for both types of NSCLC therapy. Gefitinib is, however, a molecularly targeted agent. There is a significant body of evidence to indicate that gefitinib is a valid treatment option for some patients with NSCLC. In the IRESSA Survival Evaluation in Lung cancer (ISEL) study, a large phase III, placebo-controlled trial (n = 1,692), gefitinib was associated with some improvement in overall survival versus placebo, although this failed to reach statistical significance in the primary analysis of the overall population (22). Preplanned subgroup analyses from the study showed statistically significant differences in survival in favor of gefitinib in patients of Asian origin and those who had never smoked. Furthermore, tumor biomarker data suggest that patients with a high EGFR gene copy number, or an EGFR mutation, may be more likely to benefit (23, 24). Therefore, the consideration of those patients more likely to benefit from the drug balanced with the better identification of these risk factors associated with ILD enables the physician to make careful judgment of the most appropriate therapy for the individual patient. Patients with several risk factors will generally be at more risk, and patients with risk factors may be at higher risk if gefitinib is used. This approach is facilitated by the fact that evidence to date suggests that subgroups less at risk of ILD tend to be those that respond well to gefitinib treatment (8).
A fatal outcome is the major concern with ILD as an SAE of drug treatment. In other large studies, fatality rates due to ILD in gefitinib-treated subjects of approximately 30% have been seen (8, 25), and a similar mortality was observed in this study in both gefitinib-treated and chemotherapy-treated ILD cases. The main predictors of a fatal outcome were older age ( Some methodologic issues may have influenced the study results and deserve comment. This kind of observational pharmacoepidemiologic study is generally considered sensitive to confounding by indication. Most often, it is assumed that more "sick" or "susceptible" patients will receive a new treatment, leading to possibly more adverse effects in this group, even in the absence of a true relationship to treatment. Attempts to adjust for confounding using collected data would then push the adjusted estimate of effect closer to the null, but if sufficiently precise information on strong confounders cannot be collected, it may be impossible to remove all of the confounding. In conducting this study, the suspected adverse effect of ILD was recognized, and in the clinical setting, recommendations were in place to proceed with caution when treating some patients with suspected elevated baseline risk of ILD. This kind of selection would tend to produce the type of data pattern that was in fact observed in this study, a pattern of negative confounding that produces a more elevated OR when adjustment for confounders is performed. Thus, the results are well in line with what might be expected. Misdiagnosis of ILD (outcome misclassification) is another concern, but it is expected that the stringent design features have minimized this problem in the present study (see online supplement for details). The diagnostic CRB review is a key feature, but it was still CT based, and biopsies—generally considered the gold standard for ILD diagnosis—were in most cases not taken. Overall, a sensitivity analysis suggested that, under reasonable assumptions about possible misclassification of ILD, the main result would remain similar and the conclusions from the study would not be greatly changed. Random error is another consideration. However, although random error may be responsible for some bias in the point estimate, the confidence interval is reasonably narrow. The results are also consistent with other recent data. For example, as of January 2006, the estimated reporting rate of ILD-type events in Japan from the AstraZeneca Global Drug Safety Database of patients receiving gefitinib treatment was approximately 3.1% (26); from a retrospective study by the West Japan Thoracic Oncology Group (WJTOG), which studied 1,719 patients receiving gefitinib of whom 69 developed ILD, the frequency was 3.5% (95% CI, 2.8–4.5%) (8); from a postmarketing surveillance (PMS) study conducted by AstraZeneca KK Japan, which included 3,322 gefitinib-treated patients, it was 5.8% (25); whereas from the present study, the cumulative incidence at 12 weeks was 4.0% (95% CI, 3.0–5.1%). These estimates are quite similar, even recognizing that the populations and selection of patients differ between these samples, and duration of follow-up, although similar, varies. In the present study, for the first time, an estimate of cumulative incidence of ILD after 12 weeks of treatment was obtained also from a chemotherapy-treated patient group; this frequency was 2.1% (95% CI, 1.5–2.9%), providing an estimate of this problem unrelated to gefitinib in patients with NSCLC in Japan. The prognosis for gefitinib-treated patients who were diagnosed with ILD was also quite consistent with other studies. In the PMS study, ILD-related death among patients diagnosed with ILD was 38.6% (25); in the WJTOG study it was 44.3% (8); in the AstraZeneca Global Drug Safety Database as of January 2006, the proportion of ILD-type events with a fatal outcome in patients receiving treatment with gefitinib in Japan was 37.3% (AstraZeneca, data on file); and in the present study it was 31.6%. This proportion was quite similar to the chemotherapy-treated group, 27.9% (adjusted OR, 1.05; 95% CI, 0.4–3.2). The factors associated with risk of acute ILD observed in this Japanese NSCLC population are largely different or even complementary to factors that predict better response to gefitinib. This would seem to support a hypothesis that the mechanism by which ILD occurs is distinct from the successful cancer response mechanism, offering a potential path toward selecting patients with optimal risk–benefit balance for gefitinib treatment. Interestingly, the issue of ILD in patients with NSCLC, after gefitinib or other treatments, appears to be a problem largely limited to Japan. From the AstraZeneca Global Drug Safety Database, the reporting rate of ILD-type events in patients receiving treatment with gefitinib was only 0.23% in the rest of the world excluding Japan, based on more than 215,000 patients worldwide estimated to have been exposed to gefitinib (26). Even for neighboring countries, the pattern differs from Japan: the rate for East Asian countries, including Korea and Taiwan but excluding Japan, was 0.17% (26). The proportion of ILD-type events with a fatal outcome was similar, however: 37% in Japan and 31% in the rest of the world. The reasons for this difference in incidence of ILD between Japan and other countries remain unclear, but may relate to both constitutional and environmental factors specific to Japan or Japanese patients. For other drug treatments, too, a higher incidence of ILD has been noted in Japan than elsewhere (12, 13). Within the study, some exploratory analyses are still ongoing related to genetic and proteomic predictors for ILD in patients with NSCLC, to search for biomarkers for early recognition of ILD and hopefully individualized risk assessment. This may help to shed light on why ILD appears to be a particular issue for Japanese patients and the possible underlying mechanisms. The EGFR is expressed on a number of constituent cells of the lungs including epithelium, smooth muscle cells, fibroblasts, and endothelium (27). There have been a number of animal studies using bleomycin- and vanadium pentoxide–induced lung injury with EGFR–tyrosine kinase inhibitors to determine the role of EGFR in lung fibrosis. Gefitinib and AG1478 have been used in such studies of mice and, when administered in a range of therapeutic doses, show clear attenuation of both bleomycin- (28) and vanadium pentoxide–induced (29) lung fibrosis, although one study (30) has shown augmentation of bleomycin-induced fibrosis (when using a subtoxic dose of gefitinib). The similarity of study design and choice of animal strain in the bleomycin studies make it difficult to explain the discrepant results other than by the excessive dosing. This leaves uncertainty as to the underlying mechanism of lung fibrosis in patients with NSCLC receiving gefitinib. In summary, the study appears to be of adequate validity to avoid serious systematic biases, random error does not seem to be the most likely explanation for the results, and the observed increased risk of ILD with gefitinib treatment relative to chemotherapy treatment in Japanese patients is consistent with previous studies. Although preexisting ILD was confirmed as an important determinant of developing acute ILD symptoms after treatment with gefitinib or chemotherapy, the results also suggested that risk of ILD may be generally affected by a variety of other factors that decrease the amount of normally functioning lung tissue or affect the capability of tissue repair and recovery. The study thus identified several risk factors apart from treatment, which included preexisting ILD, which were not treatment specific, and which were partly similar to risk factors for idiopathic or rheumatic pulmonary lung fibrosis. These findings taken together suggest that there may be a common etiology that gives some patients a greater susceptibility both to idiopathic or rheumatic pulmonary fibrosis and to acute drug-induced lung injury after various treatments.
The authors thank the study monitors, nurses, data managers, other support staff, and the patients participating in the study; the external epidemiology advisory board (Kenneth J. Rothman, Jonathan M. Samet, Toshiro Takezaki, Kotaro Ozasa, Masahiko Ando) for their advice and scientific review of study design, conduct, and analysis; Professor Nestor Müller for his expert input into radiologic aspects of ILD diagnosis; all case review board members (including Japan Thoracic Radiology Group members [with *]) individually (Moritaka Suga, Takeshi Johkoh*, Masashi Takahashi*, Yoshiharu Ohno*, Sonoko Nagai, Yoshio Taguchi, Yoshikazu Inoue, Takashi Yana, Masahiko Kusumoto*, Hiroaki Arakawa*, Akinobu Yoshimura, Makoto Nishio, Yuichiro Ohe, Kunihiko Yoshimura, Hiroki Takahashi, Yukihiko Sugiyama, Masahito Ebina, and Fumikazu Sakai*) for their valuable work in blindly reviewing ILD diagnoses, as well as prestudy CT scans for preexisting comorbidities; and all hospitals and clinical investigators who contributed to the data collection in the study (see below). The authors thank Sarah Charlesworth, from Complete Medical Communications, who provided editing assistance funded by AstraZeneca. Hospitals and principal investigators contributing to the study: National Hospital Organization Hokkaido Cancer Centre (Hiroshi Isobe), Hokkaido University Hospital (Koichi Yamazaki), National Hospital Organization Dohoku National Hospital (Yuka Fujita), Tohoku University Hospital (Akira Inoue), Sendai Kousei Hospital (Shunichi Sugawara), National Cancer Centre Hospital East (Yutaka Nishiwaki), Nippon Medical School Chiba Hokusoh Hospital (Yasushi Ono), Tokyo Medical University Hospital (Masahiro Tsuboi), Nippon Medical School Hospital (Tetsuya Okano), Toho University Omori Medical Centre (Nobuyuki Hamanaka), Toranomon Hospital (Kunihiko Yoshimura), National Hospital Organization Tokyo Hospital (Atsuhisa Tamura), Juntendo University Hospital (Kazuhisa Takahashi), Kyorin University Hospital (Tomoyuki Goya), Tokai University Hospital (Kenji Eguchi), Kitasato University School of Medicine (Noriyuki Masuda), Kanagawa Cardiovascular and Respiratory Centre (Takashi Ogura), Niigata Cancer Centre Hospital (Akira Yokoyama), National Nishi-Niigata Central Hospital (Hiromi Miyao), Toyama University Hospital (Muneharu Maruyama), Kanazawa University Hospital (Kazuo Kasahara), Aichi Hospital, Aichi Cancer Centre (Hiroshi Saito), National Hospital Organization Nagoya Medical Centre (Hideo Saka), Fujita Health University Hospital (Hiroki Sakakibara), Nagoya Ekisaikai Hospital (Masashi Yamamoto), Shiga University of Medical Science Hospital (Noriaki Tezuka), Kyoto Katsura Hospital (Takeshi Hanawa), National Hospital Organization Kyoto Medical Centre (Yoshiyuki Sasaki), Rinku General Medical Centre Municipal Izumisano Hospital (Hisao Uejima), Kinki University, School of Medicine (Kazuhiko Nakagawa), National Hospital Organization Kinki-chuo Chest Medical Centre (Masaaki Kawahara), Osaka City General Hospital (Koji Takeda), Osaka City General Hospital (Hirohito Tada), Osaka City University Hospital (Shinzoh Kudoh), Osaka Prefectural Medical Centre for Respiratory and Allergic Diseases (Kaoru Matsui), Osaka Police Hospital (Kiyoshi Komuta), Toneyama National Hospital (Soichiro Yokota), Kobe City General Hospital (Keisuke Tomii), Hyogo Medical Centre for Adults (Shunichi Negoro), Kobe University Hospital (Yoshihiro Nishimura), Institute of Biomedical Research and Innovation (Nobuyuki Katakami), Tenri Hospital (Yoshio Taguchi), Okayama University Medical and Dental School Hospital (Katsuyuki Kiura), Hiroshima City Hospital (Hidetaka Sumiyoshi), Hiroshima City Hospital (Noritomo Senoo), National Hospital Organization Shikoku Cancer Centre (Tetsu Shinkai), National Hospital Organization Kyushu Cancer Centre (Yukito Ichinose), Fukuoka National Hospital (Akira Motohiro), University of Occupational and Environmental Health (Masamitsu Kido), University of Occupational and Environmental Health (Kenji Sugio), National Hospital Organization Nagasaki Medical Centre (Akitoshi Kinoshita), Kumamoto University Hospital (Mitsuhiro Matsumoto), Kumamoto-Chuo Hospital (Sunao Ushijima), Okinawa National Hospital (Mutsuo Kuba).
Supported by AstraZeneca.
* A list of Japan Thoracic Radiology Group members may be found in the ACKNOWLEDGMENT. This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org Originally Published in Press as DOI: 10.1164/rccm.200710-1501OC on March 12, 2008 Conflict of Interest Statement: S.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. H.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Y.N. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. K.N. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Y.I. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.Y. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. K.N. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. The Japan Thoracic Radiology Group does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. H.J. has been an AstraZeneca employee since 2001. Y.I. has been an AstraZeneca employee since 2000. A.A. is a full-time employee of AstraZeneca. C.W. has been a full-time employee at AstraZeneca since 2001 until present and owns shares in the company. T.H. is a full-time R&D scientist at AstraZeneca, UK, and received stock options. F.N. is a full-time employee of AstraZeneca and owns shares in the company. Received in original form October 11, 2007; accepted in final form March 12, 2008
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