Elsevier

Lung Cancer

Volume 45, Issue 1, July 2004, Pages 93-104
Lung Cancer

Risk factors for interstitial lung disease and predictive factors for tumor response in patients with advanced non-small cell lung cancer treated with gefitinib

https://doi.org/10.1016/j.lungcan.2004.01.010Get rights and content

Abstract

A high incidence of interstitial lung disease (ILD) has been reported in patients with non-small cell lung cancer (NSCLC) treated with gefitinib in Japan. We retrospectively analyzed 112 patients with advanced NSCLC who received gefitinib monotherapy. Univariate and multivariate analyses were used to identify risk factors for gefitinib-related ILD and predictive factors for tumor response to gefitinib. The incidence of ILD was 5.4%, and it was higher in the patients with pre-existing pulmonary fibrosis (33% versus 2%; P<0.001). The results of a multivariate analysis showed that pulmonary fibrosis was a significant risk factor for ILD (odds ratio: 177, 95% confidence interval: 4.53–6927, P=0.006). The response rate was 33% in the 98 evaluable patients and higher in women (53% versus 23%; P=0.003), patients with adenocarcinoma (38% versus 6%; P=0.010), never-smokers (63% versus 18%; P<0.001), and the patients with no history of thoracic radiotherapy (39% versus 13%; P=0.015). The results of a multivariate analysis showed that the predictors of tumor response were “no history of smoking” and “no history of thoracic radiotherapy”. Never-smokers had a significantly longer survival time than smokers (P=0.007). Although gefitinib therapy confers a clinical benefit on patients with advanced NSCLC, especially on women, patients with adenocarcinoma, never-smokers, and patients with no history of thoracic radiotherapy, it also poses a high risk of ILD, especially to patients with pulmonary fibrosis. The risk-benefit ratio must be carefully considered.

Introduction

Gefitinib (Iressa®; AstraZeneca, Osaka, Japan) is an orally available, selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that displays antitumor activity in patients with previously treated advanced non-small cell lung cancer (NSCLC). The safety and tolerability of gefitinib was established in four open-labeled, multicenter, phase I dose-escalation studies [1], [2], [3], [4]. Although diarrhea, skin rash/acne, and nausea were common adverse effects, most of them were mild. Two large-scale, multicenter, randomized phase II studies (IDEAL 1 and 2; Iressa® Dose Evaluation in Advanced Lung Cancer) have demonstrated clinically significant antitumor activity of gefitinib monotherapy in patients with advanced NSCLC who had previously received platinum-based chemotherapy [5], [6]. The response rate for gefitinib 250 mg per day in the IDEAL 1 and 2 trials was 18.4 and 11.8%, respectively. These studies also showed that gefitinib monotherapy significantly improved disease-related symptoms and quality of life.

Based on the results of the IDEAL trials, gefitinib was approved in Japan for the treatment of inoperable or recurrent NSCLC on 5 July 2002, and an estimated 28,300 patients had been treated with gefitinib as of April 2003. During the first few months after its approval, many patients demanded to be treated with gefitinib as a “magic bullet” cure; however, when the incidence of interstitial lung disease (ILD) came to light in October 2002, the media reported it in a sensational manner, and as a result patients have become confused by excessive expectations and fear of ILD. The Ministry of Health, Labour and Welfare of Japan reported that the number of gefitinib-related cases of ILD had reached 616 as of 22 April 2003 and that 246 of the patients had died of it. The incidence of ILD and mortality rate from it has been calculated at 2.2 and 0.87%, respectively. Some case reports also suggested a high incidence of gefitinib-related ILD in Japan [7]. In view of this situation, an evidence-based assessment of the risk-benefit of gefitinib for the treatment of NSCLC was urgently needed. However, many questions regarding gefitinib administration remained unanswered, particularly in regard to the risk factors associated with ILD complications. We therefore analyzed a series of cases treated with gefitinib at the National Cancer Center Hospital (NCCH) in Tokyo.

Section snippets

Patients and methods

Between July and December 2002, 115 NSCLC patients at the NCCH began taking gefitinib and the 112 of these patients who were followed at the NCCH were retrospectively analyzed in this study. The other three patients were excluded from the analysis because they were followed-up at other hospitals after the first prescription of gefitinib. All the 112 patients had histologically or cytologically confirmed NSCLC. Their disease was locally advanced, recurrent, and/or metastatic. They all received

Patient characteristics

The patient characteristics are listed in Table 1. All patients were Japanese. Twenty-eight patients (25%) received gefitinib as a first-line treatment; 19 were considered unfit for platinum-based chemotherapy because of poor PS (10 patients) or advanced age (9 patients), and 9 refused platinum-based chemotherapy. The diagnosis of pre-existing PF was almost the same between two radiologists. Although discordance occurred in three cases, 12 patients were finally diagnosed as PF by consensus. All

Discussion

Gefitinib is a promising agent for the treatment of advanced NSCLC, but risk assessment is of critical importance to using it properly. Gefitinib was thought to be a relatively safe agent at first, and physicians in Japan tended to prescribe it without careful consideration of risks. In the first 4 months after its approval, 17,000 patients began taking gefitinib, the most rapid adoption of any antitumor agent in Japan. The Ministry of Health, Labour and Welfare has estimated that the incidence

Conclusion

When gefitinib is used to treat advanced NSCLC, it confers a higher risk of ILD on patients with PF and a greater clinical benefit on never-smokers, women, patients with adenocarcinoma, and patients with no history of thoracic radiotherapy. Gefitinib therapy is an important treatment option for patients with advanced NSCLC, but the proper use of it based on individual risk-benefit assessments is crucial.

Acknowledgements

This study had no specific funding source.

References (23)

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