CT Screening for Lung Cancer
Is Smaller Better?

John E. Heffner, M.D. and Gerard Silvestri, M.P.H.

Medical University of South Carolina, Charleston, South Carolina

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Healthcare screening is intended to delay or prevent by early detection the adverse consequences of advanced disease (1). Successful screening programs 1) diagnose early disease in asymptomatic patients, 2) detect diseases that respond better to early versus late treatment, and 3) provide benefits in treating the small number of patients diagnosed with disease, outweighing the harm associated with screening a large number of healthy individuals. The biologic nature of lung cancer would appear to lend itself to fulfilling the conditions for successful screening. It is a common malignancy that presents a tremendous healthcare burden among high-risk patients who are identifiable by their smoking history. Moreover, the prognosis of lung cancer improves when patients are diagnosed and treated in the earliest stage (stage 1A) of disease.

Unfortunately, four prospective randomized studies that enrolled nearly 38,000 high-risk patients failed to demonstrate any improvement in cancer-related mortality from screening with chest radiographs and sputum cytologic analyses (1, 2). The advent of low-dose spiral computed tomography (CT) has reignited interest in lung cancer screening because it can detect smaller nodules than conventional radiography can. In the current issue (pp. 508-513) of the American Journal of Respiratory and Critical Care Medicine, Swensen and coworkers report the Mayo Clinic's experience with lung cancer screening using low-dose spiral CT and sputum cytologic analysis combined with an evaluation algorithm (3). The study provides insight into how spiral CT might perform in fulfilling the three conditions of a successful screening program.

First, can spiral CT diagnose early disease? The Swensen study demonstrates what we would expect from CT scanning - many of the prevalence and incidence nodules identified in 66% of screened persons were smaller than the detection threshold of conventional radiography. Of the 21 patients with cancer detected by CT, nine had chest radiographs of which only five had identified malignant nodules. These observations concur with findings from three other studies that spiral CT can detect small lung cancers missed by standard radiographs (4).

Unfortunately, the study does not permit a precise estimate of the diagnostic sensitivity of CT because only one radiologist interpreted each scan. Without a measure of inter-observer variability, considerable errors in interpretation could go undetected, considering that errors occur in the interpretation of 20 to 50% of conventional radiographs (5). The Lung Cancer Screening Workshop emphasizes the importance of measuring inter-observer performance because it can dominate differences between assessed technologies and screening results (6). The observation that 26% of nodules were identifiable only in retrospect on baseline studies suggests a significant rate of error in the Swensen study.

Second, does the ability of CT to detect smaller lung cancers really matter? We are not convinced that it does. No evidence exists that prognosis varies with the size of a primary lung cancer among patients with stage 1A disease. On the contrary, tumors as small as 1 to 2 mm have the capacity to metastasize even before angiogenesis occurs (4), and patients with 0.5 cm cancers have a similar clinical course (7, 8) to those with 3 cm cancers. Because of the rapid doubling times of some lung cancers, previous screening trials have succumbed to a high incidence of "interval tumors" wherein patients present with incurable disease between screening examinations.

Swensen and coworkers mention the possibility of "overdiagnosis" of cancer by CT screening, which deserves further comment. Overdiagnosis occurs when screening detects cancers that would not have affected patients' lives if they had never been diagnosed. Overdiagnosed cancersalso termed `pseudodisease'have the morphology of malignant tumors but grow so slowly that affected patients are more likely to die from other health conditions. Detection of cancer in such patients exposes them to risks of unnecessary cancer therapy and offers no potential for clinical benefit. Autopsy series support the existence of indolent lung cancer by their frequent detection of lung cancers that were undiagnosed ante mortem (9). Overdiagnosis represents the most likely reason that previous screening studies observed a paradoxical 11% relative increase in lung cancer mortality in screened as compared with unscreened patients, which may result from treatment of indolent lesions (2, 8, 10). The prevalence of lung cancer in the study by Swensen and coworkers was about five times higher than the incidence, which supports the existence of overdiagnosis bias.

Third, do the benefits of early detection outweigh the inherent risks of CT screening? Possibly not, if we consider that 7 of 29 resected nodules were benign in the Swensen study. This high rate of surgery for benign disease contrasts sharply with the Early Lung Cancer Action Project (ELCAP) study, which biopsied only one benign and 27 malignant nodules in 1,000 persons screened by CT (11). The ELCAP investigators emphasized that the success of CT screening depends as much on the algorithm used to manage indeterminate nodules as on the imaging technology itself. Unfortunately, we have no information from the Swensen study as to how many referring physicians, who made patient management decisions, used the study algorithm to evaluate indeterminate nodules. It may be that loose adherence to the algorithm by practicing physicians combined with a high rate of unnecessary resections for benign disease portends what would occur if CT screening became routine clinical practice.

The ELCAP study provided data for a cost-effectiveness analysis of CT screening, which estimates program costs would be as high as $93,000 per life saved (12). The greater number of benign lesions resected in the Swensen study would markedly diminish the cost-effectiveness of CT screening and expose more patients to risks from diagnostic and therapeutic interventions.

Where do we go from here? Although the impressive accomplishment of Swensen and coworkers in screening 1,520 patients provides an important and necessary initial step, the role of lung cancer screening must be determined in randomized clinical trials that incorporate multiple healthcare outcomes. The Lung Screening Study (LSS), sponsored by the National Cancer Institute, is now underway and will randomize high-risk patients to screening CT or conventional chest radiographs. Such trials have assumed even greater significance now that doubts have surfaced over the benefits of screening mammography (13, 14). The dialogue surrounding these emerging doubts about screening for breast cancer, which has become ingrained in clinical practice and Western culture, sounds uncomfortably similar to the initial debate over the potential benefits of CT screening for lung cancer (15, 16). Until the results of the LSS study appear, sometime after 2005, we know from the Swensen and ELCAP studies that screening CT can detect small lung cancers, but we are yet to learn if smaller is better.

	References

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