Lung cancer screening: Examining the issues

Screening is the testing of an individual who is at risk for a disease, but who does not exhibit signs or symptoms of the disease. The goal of screening is to detect disease at a stage when cure or control is possible, and an effective screening program should reduce the number of disease-specific deaths in the screened population. Screening should focus on diseases that are associated with potentially serious consequences and that are detectable in the preclinical phase, yet it should avoid identifying “pseudodisease” (ie, positive test findings that would not be expected to affect the patient’s health) or causing morbidity due to the test procedure itself.¹ Finally, screening is only worthwhile when treatment of the disease is more effective when administered early.

Since lung cancer screening began in the 1950s,^2,3 many studies have attempted to define the medical benefits and economic impact of widespread screening. Many important unresolved issues remain, including the effectiveness of lung cancer screening for reducing disease-specific mortality, the potential harms of screening, its cost-effectiveness, and the potential impact of new research methods on the early identification of lung cancer.

DOES LUNG CANCER SCREENING REDUCE DISEASE-SPECIFIC MORTALITY?

Early studies examined the usefulness of large-scale chest radiograph programs, either with or without sputum cytology, for lung cancer screening. Although several studies reported that radiographic screening identified patients with early lung cancer and reported higher survival rates, reviews and meta-analyses of these reports concluded that screening did not significantly reduce disease-specific mortality.^4,5

The utility of chest radiography for the detection of early lung cancer is limited by several factors, including poor sensitivity for the detection of small or subtle nodules and a relatively high false-positive rate.^6–8 More recently, several cohort studies and randomized, controlled trials have shown that computed tomography (CT) screening is effective for the identification of early lung cancer in high-risk patients (eg, individuals with chronic, heavy tobacco use or asbestos exposure).^9–11 A recent meta-analysis concluded that CT-based screening significantly increases the number of early lung cancers identified, but also increases the number of false-positive findings (nodules) and unnecessary thoracotomies for benign lesions.¹²

Lung cancer screening should increase the number of patients identified at early disease stages. Treatment of early-stage lung cancer should decrease the number of patients identified with late-stage cancer, resulting in a stage shift toward earlier disease for the population as a whole. Although lung cancer screening cohort studies and randomized, controlled trials have demonstrated that screening increases the number of early-stage lung cancer cases identified, these studies have generally not demonstrated decreased rates of late-stage lung cancers or stage shifting in the populations studied. In the 1970s, the National Cancer Institute began three large-scale screening trials at Mayo Clinic, Memorial Sloan-Kettering Cancer Institute, and The Johns Hopkins University, each enrolling approximately 10,000 patients. In the Mayo trial, the incidence of advanced-stage tumors was nearly identical for the screened versus unscreened patients, with 303 cancer cases detected in the screened group versus 304 cases in the control group.¹³ CT-based cohort studies have also reported increased rates of early recognition of lung cancer and accompanying large increases in the number of diagnostic procedures performed. However, early controlled trials of CT screening showed no differences between screened and unscreened groups in the numbers of patients with late-stage tumors or deaths due to lung cancer.¹⁴

Results such as these have led some researchers to argue that survival benefits of screening largely reflect observational biases. For example:

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  Reprinted with permission from The New England Journal of Medicine (Patz EF, et al. Screening for lung cancer. N Engl J Med 2000; 343:1627–1633). Copyright © 2000 Massachusetts Medical Society. All rights reserved.

  Lead-time bias occurs when screening results in earlier recognition of disease, but does not change the patient’s eventual lifespan, creating the appearance that the patient’s survival time with the disease is longer (Figure 1).¹⁵ Longer lead times should be observed in a successful screening program even if eventual mortality remains exactly the same, and lead time bias is therefore an expected outcome of screening.

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  Reprinted with permission from The New England Journal of Medicine (Patz EF, et al. Screening for lung cancer. N Engl J Med 2000; 343:1627–1633). Copyright © 2000 Massachusetts Medical Society. All rights reserved.

  Length-time bias arises from the observation that any screening test that is applied intermittently is more likely to detect indolent tumors than aggressive, fast-growing tumors that would result in clinical symptoms (Figure 2).¹⁵ Indolent tumors move more gradually from the detectable state to the onset of clinical symptoms, and are therefore especially likely to be identified by screening.
• Overdiagnosis bias occurs when a screening test identifies disease that never would have affected the patient’s life in the absence of screening. This type of bias might occur if screening identifies a lesion that is so indolent that it would never cause clinical disease, or if the population is otherwise in such poor health that successfully screened patients would die from other causes.

There is no question that these biases affect reports of survival in lung cancer screening, although it is unclear whether they explain the reported benefit of screening observed in cohort studies. Screening advocates have argued that the failure to screen high-risk patients for lung cancer has the potential for significant harm. In contrast, opponents of screening have argued that there was a lack of data showing a reduction in the number of patients diagnosed with late-stage cancers or in cancer-related mortality.