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Interstitial Lung Disease in Japanese Patients with Lung Cancer

A Cohort and Nested Case-Control Study

¹ 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

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Acute interstitial lung disease (ILD) occurs in Japanese patients with non–small cell lung cancer (NSCLC) receiving gefitinib. There is, however, limited knowledge about risk factors for ILD and the incidence of ILD in patients with NSCLC receiving other treatments. What This Study Adds to the Field Acute ILD was common in Japanese patients with NSCLC receiving chemotherapy or gefitinib, with higher risk for gefitinib. Age, performance status, smoking, and preexisting chronic ILD were also important risk factors, aiding clinicians in treatment selection.

 

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