Measuring effectiveness of lung cancer screening: from consensus to controversy and back

Abstract

Background: While intense controversy exists regarding screening for breast, colorectal, and prostate cancer, a consensus exists regarding lung cancer screening. All organizations recommend against any efforts to detect early lung cancer because each of four randomized controlled trials (RCTs) has failed to demonstrate a significant reduction in lung cancer mortality as a result of screening.

Synthesis: Disease-specific mortality is assumed to represent the best measure of screening effectiveness in RCTs, because it is not subject to confounding by lead time, length, or overdiagnosis biases. However, the effects of these biases are predictable, so accurate assessments of the degree of confounding by these biases can be made. Moreover, the ability of mortality to accurately reflect cancer death rates depends on the ability of randomization to create experimental and control populations that have an equal risk of dying of the disease under study, except insofar as early detection may reduce that risk. Because the majority of participants in screening trials never develop the disease under investigation, small absolute differences in disease risk between groups often persist despite randomization, and such differences translate into much larger proportional differences in the size of subgroups at risk for disease-specific mortality. This effect confounds the ability of disease-specific mortality to accurately measure screening effectiveness.

Results: A total of 18 RCTs have been conducted to evaluate screening for breast, colorectal, and lung cancer. In the only two RCTs that reported a significant mortality reduction for screening mammography in breast cancer, and in the one RCT that reported a significant mortality reduction for fecal occult blood screening in colorectal cancer, population differences led mortality comparisons to overestimate the effectiveness of screening. In lung cancer, no significant mortality reductions have been reported (to my knowledge), but in the two RCTs most directly addressing the effectiveness of chest radiograph (CXR) screening, population differences led mortality comparisons to underestimate the ability of CXRs to reduce the risk of dying of lung cancer. Although mortality is believed to be the best measure of outcome, not a single example can be cited as definitive proof of efficacy for any screening strategy. Thus, screening cannot be recommended for any cancer on the basis of consistent reductions in mortality in RCTs.

Analysis: Current policy, which calls for no early detection efforts for lung cancer, implicitly accepts the validity of two contradictory assertions. Conventional wisdom maintains that lung cancer is a highly virulent disease and that metastases are present at inception; accordingly, early detection is ineffective. However, RCTs suggest that lung cancer is an indolent disease and that radiographically detected lesions are clinically unimportant; accordingly, early detection is unnecessary. Such contradictions mandate some rethinking of the fundamental assumptions underlying screening evaluation.

Conclusions: Considerable evidence suggests that annual CXR screening could result in a dramatic reduction in lung cancer mortality in our society. However, proper interpretation of the data depends completely on how screening effectiveness is measured. Given the enormous public health importance of this issue, a consensus conference is recommended to determine whether lung cancer screening can save lives.