© 2008 American Thoracic Society doi: 10.1164/rccm.200808-1257ED
Minimizing Unintended Consequences of Detecting Lung Nodules by Computed Tomography
Denver Veterans Affairs Medical Center Screening for lung cancer is not recommended by major medical societies (1). However, lung cancer is the leading cause of cancer death and will cause over 160,000 cancer deaths in the United States this year, more than the total caused by those malignancies (breast, prostate, colon, and cervical) for which screening is recommended (2). Chest radiographs and sputum cytology were evaluated in trials designed in the mid-1970s, which were negative but have remained a topic of analysis and debate since that time (3). Chest computed tomography (CT) scans are significantly more sensitive than chest radiographs for detecting early lung cancer but also detect many benign nodules (4, 5). For example, single-arm CT screening trials show lung cancer detection in 1–3% and benign nodules in 20–50% of high-risk subjects on initial screening. Although the results of single arm trials are encouraging, trials without a control arm cannot determine whether mortality, the gold standard of efficacy for a screening test, will be reduced (6). Two randomized controlled trials, the National Lung Screening Trial (NLST) and the Nederlands-Leuvens Longkanker Screenings Onderzoek (NELSON), are underway. The lung cancer community is eager to deploy any new and effective tools for decreasing the burden of this disease. In this issue of the Journal (pp. 956–961), Wilson and colleagues present outcome results from the Pittsburgh Lung Screening Study, a large, single-center single arm study of CT screening for lung cancer (7). The study contains carefully collected data on outcomes, the most interesting of which relate to secondary diagnostic testing and procedures. To summarize, 3,642 subjects participated and 1,477 (40.6%) had noncalcified nodules on initial screening. Of course, these findings resulted in further testing; 821 of 1,477 obtained CT, positron emission tomography (PET), or both, and 36 (1%) underwent a thoracic surgical procedure (9 thoracotomy, 21 video-assisted thoracoscopic surgery, 2 median sternotomy, and 4 mediastinoscopy) for benign disease. There were 69 subjects ultimately found to have non–small cell lung cancer; 58% were stage I and potentially highly curable. Of 82 subjects who underwent video-assisted thoracoscopic surgery or thoracotomy, 28 (34%) had a noncancer diagnosis. Such a high rate of major surgical procedures for benign diagnoses (1% of the study population, 34% of those undergoing surgery) seems excessive, but is in line with some, but not all, previous single-arm screening trials as well as with published results of surgery for noncalcified pulmonary nodules, which range from 50% benign disease in the mid-1990s to 20% more recently (8). Regardless of the outcome of the NLST and NELSON, CT scans are increasingly detecting asymptomatic lung nodules suspicious for lung cancer either incidentally or in screening programs, resulting in concern and diagnostic testing. Physicians must evaluate lung nodules in a manner that is medically sound and cost-effective. Guidelines for the management of noncalcified pulmonary nodules have been suggested by several groups, with "watchful waiting" the preferred option in some situations (9). Interestingly, the Pittsburgh group made laudable efforts to educate both patients and physicians regarding the recommended management of nodules discovered on screening CT, but these recommendations were not followed in some cases. Although close adherence to the guidelines would have prevented some of the surgery for benign disease, patient anxiety should not be discounted as a strong factor in moving to a definitive diagnosis outside of the guidelines. Our challenge is how to reduce major surgery and morbidity from diagnostic procedures triggered by nodule discovery on CT. The suggested guidelines should be effective if they can be adhered to. We do not know if "watchful waiting" for a period of 3 to 6 months results in a significant proportion of patients missing a chance for surgical cure, but this is often an appropriate strategy. PET scans seem an attractive option, but recent data show that for potential stage I disease, 43% of PET-negative patients will have cancer; if patients with a high likelihood of bronchioloalveolar carcinoma are excluded, this falls to 27%, still not highly reassuring (10). False-positive disease by PET occurs with inflammation and is highly dependent on the patient population to which PET is applied. The American Cancer Society recommends that any testing for early lung cancer detection be done in settings with multidisciplinary expertise in diagnostic workup and treatment, which may serve to allay patient anxiety and promote adherence to guidelines for workup (1). Locally available skill with relatively noninvasive biopsies (transthoracic needle aspiration, standard or advanced bronchoscopic techniques) varies significantly; positive biopsies can be acted on quickly, but a negative biopsy does not lay the issue to rest. Much effort has been expended on developing biomarkers that could be used to screen high-risk populations for lung cancer. These include sputum cytology, exhaled breath analysis, gene promoter methylation in sputum or blood, chromosomal aneusomy in sputum or bronchial epithelium, gene expression patterns in bronchial brushings, proteomic analysis of blood (or potentially, bronchoalveolar lavage), and antibodies to tumor antigens (11–16). Tests based on sputum are promising but appear to be more useful for central airway cancers than peripheral nodules (11, 12). Whether the performance of these tests can be improved by enrichment for epithelial cells or the use of techniques to obtain more distal pulmonary secretions is unknown. The necessary test characteristics for screening asymptomatic high-risk populations are highly stringent, but in the setting of an indeterminate lung nodule, lower degrees of sensitivity and specificity may be clinically useful either in reassuring patients and physicians that "watchful waiting" is appropriate or in accelerating the pace of the diagnostic workup. It is likely that biomarker-based tests will initially be applied to the management of lung nodules, rather than mass screening. CT screening trials, such as the Pittsburgh Lung Screening Study and the NLST, have incorporated blood and sputum collection, which should be invaluable in evaluating the performance of biomarker based tests in the setting of indeterminate pulmonary nodules in high-risk subjects. FOOTNOTES Conflict of Interest Statement: Y.E.M. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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