A Targeted Approach to Reducing Lung Cancer Mortality

Abstract

Despite major efforts to reduce smoking rates, lung cancer continues to claim more lives than the next three major cancers combined. In the Western world, the incidence of lung cancer in men has begun to decline over the past 10 years, but it is expected that lung cancer in women will continue to rise, as the birth cohorts of women who have the highest smoking prevalence have not yet reached the age of greatest lung cancer risk. Unfortunately, lung cancer continues to increase in numbers in underdeveloped countries, particularly China, where smoking continues unabated. Indeed, many of the world’s major tobacco manufacturers are focusing their advertising campaigns in these parts of the world, where children are their prime targets. Lung cancer, particularly in women, is truly an epidemic of global proportions. In this era of targeted therapy, it is clear that we must be prepared to take a multitargeted approach to the diagnosis and treatment of lung cancer if we hope to have a major impact on the death rates from this malignancy. Tobacco use must be the first ‘‘target,’’ since the most effective way to reduce lung cancer deaths undoubtedly will, in the long run, be prevention. However, the long latency period between exposure to tobacco-related carcinogens and the development of lung cancer means that the benefits of smoking cessation programs will not be realized until decades from now, since the chromosomal damage caused by tobacco may be irreversible. Indeed, in most Western countries, up to 50% of lung cancer cases occur in never or former smokers. Since more than two thirds of lung cancer patients present at a stage for which curative therapy is not available, the second ‘‘target’’ must be early detection. Older screening studies, whether evaluating chest radiographs alone or radiographs coupled with sputum cytology, were all disappointingly negative and failed to reduce lung cancer mortality even though they concentrated on high-risk populations of male smokers. In this issue of the Journal of Clinical Oncology, James Mulshine has summarized the current status of screening for lung cancer, and provides evidence that, with state-of-the-art computed tomography scanning techniques, the ability to detect small, potentially curable lung cancer lesions is now a reality. However, all studies to date have lacked a randomly assigned unscreened control arm, and so the ability of computed tomography screening to reduce mortality awaits the results of prospectively randomized controlled trials. Functional imaging techniques, including positron emission tomography and dynamic-contrast magnetic resonance imaging, may play a role in determining the likelihood of malignancy in screen-detected cancers, although it appears that their greatest role will be in the area of more accurate staging and the early evaluation of response. The final ‘‘target’’ in the war against lung cancer must be the development of better treatment. To this end, advances in our understanding of lung cancer biology have led to the development of numerous molecularly targeted therapies, and some agents are even being evaluated to determine whether they might play a preventative role in high-risk individuals. The greatest degree of research and clinical activity in lung cancer has been in the area of epidermal growth factor receptor inhibition and inhibition of angiogenesis, where recent trials have resulted in significant improvement in survival and symptom control in patients with advanced disease. Initially, it was though that some of these targeted drugs might be cytostatic rather than tumoricidal, and that classical phase II testing looking for response might not be necessary or even applicable. This thinking resulted in the initiation of large clinical studies based only on laboratory models and phase I toxicity testing. Sadly, many initially promising treatments fell by the wayside as they failed to improve outcome when tested in large randomized VOLUME 23 d NUMBER 14 d MAY 1