The NLST Puzzle

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 - Paul Pinsky, PhD, MPH
Paul Pinsky, PhD, MPH

Three years ago, the National Lung Screening Trial[1] (NLST) reported a 20% reduction in lung-cancer mortality with annual low-dose CT (LDCT) screening. The NLST findings were seminal: the first demonstration that early detection could reduce mortality from the cancer that’s the world’s leading killer.

Uptake of LDCT screening has been slow, but with the recent grade B recommendation[2] of the United States Preventive Services Task Force (USPSTF) for LDCT screening, which mandates that private insurers cover it without cost sharing, the time might be right for LDCT screening to expand considerably. Therefore, it is now critical to examine how to translate the results of the NLST (and other LDCT studies) into the clinical-practice setting.

As a so-called efficacy trial, the NLST was designed to determine whether, under optimal conditions, LDCT screening could reduce lung-cancer mortality. It was not designed to answer the question of how LDCT screening should be implemented in the clinical-care setting, nor how well it would perform there. A cancer-screening trial is a large, long-term, and expensive instrument designed to answer a single critical question.

In contrast, myriad questions need to be addressed concerning the population implementation of LDCT screening. Who should be eligible for screening, in terms of age and smoking history? How frequently should screening be performed? How should a positive screening result be defined? Should a standard diagnostic follow-up algorithm be employed—and if so, which one? What training is required for radiologists, and what types of institutions should be allowed to perform LDCT screening?

The first of these questions has received some scrutiny recently. By considering it in more detail, one can get some sense of what is involved in translating trial results into clinical practice. The USPSTF recommendations deviate slightly from the NLST eligibility criteria (age 55 to 74 years; a smoking history of 30 or more pack years; and having stopped smoking, if they no longer smoke, within the past 15 years) by modestly expanding the upper age limit to 80 years.[2]

The National Comprehensive Cancer Network[3] expanded the NLST criteria by including people with 20 or more pack years of smoking history with other lung-cancer risk factors, including occupational exposures and history of chronic obstructive pulmonary disease. Other organizations’ guidelines, such as those of the American Cancer Society[4], generally follow the NLST criteria.

It is useful to conceptualize the question of extending LDCT screening beyond the NLST–eligible population by dividing it into two components. First, is the efficacy of screening, as measured by the percentage of reduction in lung-cancer mortality, likely to differ in an expanded (lower-risk) eligible population? Second, assuming equivalent efficacy, is the benefit-to-harm trade-off worthwhile in this expanded group? The harm of LDCT screening includes false positives (with the resulting diagnostic work-up and complications thereof), as well as radiation exposure.

Efficacy Drivers

The primary drivers of LDCT efficacy are the characteristics of incident lung cancers: A similar cancer profile in the expanded (versus NLST-eligible) population should result in similar LDCT efficacy. Lowering the pack-year requirement to 20 years, for example, or increasing the time since smoking cessation to 20 years would be unlikely to change the histology (or other characteristics) of the lung cancers appreciably, and many cancers would still be caused by cigarette smoking.

Therefore, similar LDCT efficacy would be a reasonable assumption for a modestly expanded eligibility group. An NLST subset analysis[5] found no evidence of differential LDCT efficacy by smoking status (current versus former), even though the groups differed by a factor of two in lung-cancer–incidence rates.

For the second component, the benefit-to-harm ratio for screening is typically measured as the number of people who must be screened to prevent one death from the relevant cancer.[6] This figure, number needed to screen (NNS), is computed as the reciprocal of the difference in lung-cancer mortality rates among the screened and unscreened populations; for the same efficacy (percentage reduction), halving the lung-cancer risk in the unscreened population doubles the NNS.

Overall, the NLST showed an NNS of 320 for LDCT.[5] There were, however, substantial differences in the NNS between trial subgroups.