Interstitial lung disease in Japanese patients with lung cancer: a cohort and nested case-control study.

Abstract

Interstitial lung disease (ILD) occurs in Japanese patients with non-small cell lung cancer (NSCLC) receiving gefitinib.
To elucidate risk factors for ILD in Japanese patients with NSCLC during treatment with gefitinib or chemotherapy.
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.
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).
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.

Full text

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Interstitial Lung Disease in Japanese Lung Cancer Patients – A Cohort and Nested
Case-Control Study

AUTHOR LIST
Shoji Kudoh1, Harubumi Kato2, Yutaka Nishiwaki3, Masahiro Fukuoka4, Kouichiro
Nakata5, Yukito Ichinose6, Masahiro Tsuboi2, Soichiro Yokota7, Kazuhiko Nakagawa4,
Moritaka Suga8, JTRG9, Haiyi Jiang10, Yohji Itoh10, Alison Armour11, Claire Watkins11,
Tim Higenbottam12,13, and Fredrik Nyberg14,15

1Nippon Medical School, Tokyo, Japan; 2Tokyo Medical University Hospital, Tokyo,
Japan; 3National Cancer Center Hospital East, Chiba, Japan; 4Kinki University School of
Medicine, Osaka, Japan; 5Nakata Clinic, Tokyo, Japan; 6National Kyushu Cancer Center,
Fukuoka, Japan; 7Toneyama National Hospital, Osaka, Japan; 8Saiseikai Kumamoto
Hospital, Kumamoto, Japan; 9 Japan Thoracic Radiology Group, Shiga, Japan;
10AstraZeneca KK, Osaka, Japan; 11AstraZeneca, Macclesfield, Cheshire, UK;
12AstraZeneca R&D Charnwood, Loughborough, UK; 13Sheffield University, Sheffield,
UK; 14Epidemiology, AstraZeneca R&D Mölndal, Mölndal, Sweden; and 15Institute of
Environmental Medicine, Karolinska Institute, Stockholm, Sweden
Corresponding author: Fredrik Nyberg, Epidemiology, AstraZeneca R&D Mölndal, SE-
413 83 Mölndal, Sweden. Phone: +46 31 607 5203. Fax: +46 31 706 3828. E-mail:
Fredrik.Nyberg@astrazeneca.com

Sources of support: This study was funded by AstraZeneca.
Running head: ILD in Japanese NSCLC patients
Subject category: 84. Lung cancer: clinical aspects

AJRCCM Articles in Press. Published on March 12, 2008 as doi:10.1164/rccm.200710-1501OC
Copyright (C) 2008 by the American Thoracic Society.

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Statement of impact on clinical medicine and basic science and how the research adds
to our knowledge base of the disease process: This study establishes that the incidence
of acute interstitial lung disease (ILD) is high in Japanese patients during treatment of
advanced/recurrent non-small-cell lung cancer (NSCLC) with conventional chemotherapy
or gefitinib. An increased risk of ILD associated with gefitinib treatment relative to
chemotherapy treatment was seen. Age, WHO performance status, smoking and pre-
existing chronic ILD were also important risk factors, allowing clinicians to evaluate ILD
risk in Japanese NSCLC patients when selecting a treatment.

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

Word count: 4748 excluding abstract, references and online supplement


This article has an online data supplement, which is accessible from this issue’s table
of content online at www.atsjournals.org

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Abstract
Rationale: Interstitial lung disease (ILD) occurs in Japanese non-small-cell lung cancer
(NSCLC) patients receiving gefitinib.
Objective: To elucidate risk factors for ILD in Japanese NSCLC patients during treatment
with gefitinib or chemotherapy.
Methods: In a prospective epidemiological cohort, 3166 Japanese patients with
advanced/recurrent NSCLC were followed for 12 weeks on 250 mg gefitinib (n=1872
treatment periods) or chemotherapy (n=2551). Patients who developed acute ILD (n=122)
and randomly selected controls (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.
Results: The observed (unadjusted) incidence rate over 12 weeks was 2.8 (95%CI 2.3-3.3)
per 1000 person-weeks - 4.5 (3.5-5.4) for gefitinib vs. 1.7 (1.2-2.2) for chemotherapy; the
corresponding observed naïve cumulative incidence rates at end of 12 weeks 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 vs. 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: older age; poor WHO performance status; smoking; recent NSCLC
diagnosis; reduced normal lung on CT scan; pre-existing chronic ILD; concurrent cardiac
disease. ILD-related deaths in patients with ILD were 31.6% (gefitinib) vs. 27.9%
(chemotherapy); adjusted OR 1.05 (95%CI 0.3-3.2).
Conclusions: ILD was relatively common in these Japanese NSCLC patients during
therapy with gefitinib or chemotherapy, being higher in the older, smoking patient with

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pre-existing ILD or poor performance status. The risk of developing ILD was higher with
gefitinib than chemotherapy, mainly in the first 4 weeks.
Word count: 277

Keywords: NSCLC, ILD, Japanese patients, gefitinib, chemotherapy

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INTRODUCTION

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) was first approved for the
treatment of advanced NSCLC in Japan in July 2002. In clinical trials and in pre-approval
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 (DAD), 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 idiopathic interstitial
fibrosis (IPF) patients have challenged this and underlined this important risk (4).
ILD, especially IPF, is a known co-morbidity 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).