© 2008 American Thoracic Society doi: 10.1164/rccm.200802-339ED
From Nihilism to IndividualismThe Evolution of Lung Cancer Therapy
Winship Cancer Institute Lung cancer is the leading cause of cancer-related death worldwide. In 2008, more than 1.6 million people will develop lung cancer, with over 1.3 million deaths (1). Initially considered curable only in its earliest stages, the last two decades have seen tremendous advances in the treatment of lung cancer. The development of a multimodality approach has rendered 15–20% of patients with locally advanced disease curable, and has produced substantial progress even in the most advanced stages of disease (2). Thus, once greeted with a pervasive sense of therapeutic nihilism among physicians, lung cancer can now be treated with therapies that prolong survival for all stages of disease. One such therapy includes a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), erlotinib, which confers a survival advantage even when used as a third-line therapy of metastatic disease (3). Despite this substantial progress, the urge to treat patients aggressively has been tempered by the large number of patients whose treatment is limited by their performance status. Today, there is no clear evidence of benefit in treating patients whose performance status is significantly worse than Eastern Cooperative Oncology Group (ECOG) 2. The factors that contribute to the decline in an individual's physiologic state often dictate the appropriate therapy, and one such underrated factor has been the presence of baseline interstitial lung disease (ILD). Interest in ILD among the oncologist community peaked earlier this decade when several reports indicated that treatment with gefitinib was associated with a significant increase in ILD, especially in Japanese patients. Like erlotinib, gefitinib is a novel small-molecule TKI that blocks EGFR by competitively binding to the ATP binding site in the tyrosine kinase domain. The minimal toxicity and meaningful improvements in quality of life previously seen with this agent in phase II trials (4) led to its widespread use in patients with non–small cell lung cancer (NSCLC), including those with moderate performance status. However, the discovery that this intervention is associated with an increased risk of ILD serves as a cautionary tale (5). The first reports of ILD in the setting of gefitinib treatment raised the specter of complex pharmacogenomic interactions (5, 6). This concern was compounded by the relatively disappointing results of the phase III Iressa Survival Evaluation in Lung Cancer (ISEL) study, which, unlike the BR21 study of erlotinib (3), failed to show an overall survival advantage for gefitinib versus placebo in patients with lung cancer when used as second- and third-line therapy (7), although improved overall survival was seen in nonsmokers and women. Explanations for these findings ranged from poor selection of the study population (the ISEL study had a significantly greater number of heavy smokers than BR21) to whether the dose of gefitinib used was further from its maximal tolerated dose than that for erlotinib. Following these findings, the use of gefitinib in the United States declined precipitously, whereas erlotinib usage surged. Emerging data now show that the greatest and most durable responses to both EGFR inhibitors are seen in patients who have mutations in codons 19 and 21 of their EGFR tyrosine kinase domain (8, 9), and that patients with EGFR gene amplification have the greatest long-term benefit from both inhibitors. In this issue of the Journal (pp. 1348–1357), Kudoh and coworkers provide important information concerning risk for ILD in patients treated with EGFR inhibitors (10). In a prospective epidemiologic cohort study, 3,166 Japanese patients with advanced/recurrent NSCLC were monitored for 12 weeks on 250 mg of gefitinib or chemotherapy to identify risk factors for ILD. Those patients who developed acute ILD, defined as in the 2002 American Thoracic Society/European Respiratory Society consensus statement (11), and randomly selected control subjects were entered into a case-control study, which showed that the adjusted hazard ratio of developing ILD was 3.7 times higher in the gefitinib group than the chemotherapy group, and the vast majority of ILD manifested after 4 weeks of gefitinib therapy. Increased age, poor performance status, baseline presence of ILD, reduced normal lung on computed tomography scan, a history of smoking, and a recent NSCLC diagnosis all independently predicted a significantly higher incidence of ILD. Most impressive is the fact that these risk factors represent opposite and perhaps even complementary descriptors of those individuals who have the most dramatic responses to tyrosine kinase inhibitors, namely patients with gene mutations in the EGFR tyrosine kinase domain, including individuals who are women, nonsmokers, and of Asian descent. An unresolved question is why this disease is more common in the Japanese population than in other Asian populations, where the incidence of ILD with gefitinib is approximately 0.2%, similar to that in white populations. A more fundamental issue relates to the mechanisms involved in the development of gefitinib-associated ILD. In the Kudoh and colleagues' study, the exact nature of the newly detected cases of ILD was not defined. Limited pathologic studies reveal evidence for organizing pneumonia, patchy interstitial fibrosis, and hyperplastic type II pneumocytes suggestive of the organizing stage of diffuse alveolar damage (12). Similarities between these findings and those described for acute exacerbation of idiopathic pulmonary fibrosis are intriguing, but likely represent a manifestation of the limited pathways for repair of the injured lung (13). This area is ripe for translational studies designed to investigate biological factors that promote drug-induced ILD, and the differential expression of genes that underlie its development. Although Kudoh and colleagues' study is to be commended for more precisely defining not only the risk of gefitinib-induced ILD in patients with lung cancer patients but other clinical factors that independently predict an enhanced likelihood of developing ILD, we believe that its greatest contribution is that it provides a novel approach to risk-stratified therapy. With the emergence of state genomic data that can predict, even in the earliest stage, which patients are most likely to relapse (14), and that can suggest which patients benefit from platinum-based or other chemotherapy in the adjuvant setting and in advanced disease (15, 16), opportunities now exist to develop pharmacogenomically based, risk-stratified, individualized therapy for patients with lung cancer across all stages. Given the fragile nature of this patient population we treat and the often devastating (and even lethal) but previously unpredictable toxicities that our most active agents can cause, the development of an evidence-based, individualized approach to lung cancer treatment must be the premier goal of all physicians and investigators engaged in the study and treatment of this disease (17). FOOTNOTES Conflict of Interest Statement: F.R.K. has attended five advisory boards for Sanofi-Aventis in the past 3 years, for which he received about $15,000; he gives CME talks on the use of Taxotere in lung cancer and head and neck cancer; he has research grants from Sanofi-Aventis, Genentech, and Novartis. J.R. serves on a safety review board for Genzyme and received $70,000 from Intermune (2006, 2007) and $50,000 from Actelion in support of research conducted in clinical trials. REFERENCES
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