Evaluation of the Lung Cancer Risks at Which to Screen Ever- and Never-Smokers: Screening Rules Applied to the PLCO and NLST Cohorts

<div><p>Background</p><p>Lung cancer risks at which individuals should be screened with computed tomography (CT) for lung cancer are undecided. This study's objectives are to identify a risk threshold for selecting individuals for screening, to compare its efficiency with the U.S. Preventive Services Task Force (USPSTF) criteria for identifying screenees, and to determine whether never-smokers should be screened. Lung cancer risks are compared between smokers aged 55–64 and ≥65–80 y.</p><p>Methods and Findings</p><p>Applying the PLCO_m2012 model, a model based on 6-y lung cancer incidence, we identified the risk threshold above which National Lung Screening Trial (NLST, <i>n = </i>53,452) CT arm lung cancer mortality rates were consistently lower than rates in the chest X-ray (CXR) arm. We evaluated the USPSTF and PLCO_m2012 risk criteria in intervention arm (CXR) smokers (<i>n = </i>37,327) of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). The numbers of smokers selected for screening, and the sensitivities, specificities, and positive predictive values (PPVs) for identifying lung cancers were assessed. A modified model (PLCO_all2014) evaluated risks in never-smokers. At PLCO_m2012 risk ≥0.0151, the 65th percentile of risk, the NLST CT arm mortality rates are consistently below the CXR arm's rates. The number needed to screen to prevent one lung cancer death in the 65th to 100th percentile risk group is 255 (95% CI 143 to 1,184), and in the 30th to <65th percentile risk group is 963 (95% CI 291 to −754); the number needed to screen could not be estimated in the <30th percentile risk group because of absence of lung cancer deaths. When applied to PLCO intervention arm smokers, compared to the USPSTF criteria, the PLCO_m2012 risk ≥0.0151 threshold selected 8.8% fewer individuals for screening (<i>p<</i>0.001) but identified 12.4% more lung cancers (sensitivity 80.1% [95% CI 76.8%–83.0%] versus 71.2% [95% CI 67.6%–74.6%], <i>p<</i>0.001), had fewer false-positives (specificity 66.2% [95% CI 65.7%–66.7%] versus 62.7% [95% CI 62.2%–63.1%], <i>p<</i>0.001), and had higher PPV (4.2% [95% CI 3.9%–4.6%] versus 3.4% [95% CI 3.1%–3.7%], <i>p<</i>0.001). In total, 26% of individuals selected for screening based on USPSTF criteria had risks below the threshold PLCO_m2012 risk ≥0.0151. Of PLCO former smokers with quit time >15 y, 8.5% had PLCO_m2012 risk ≥0.0151. None of 65,711 PLCO never-smokers had PLCO_m2012 risk ≥0.0151. Risks and lung cancers were significantly greater in PLCO smokers aged ≥65–80 y than in those aged 55–64 y. This study omitted cost-effectiveness analysis.</p><p>Conclusions</p><p>The USPSTF criteria for CT screening include some low-risk individuals and exclude some high-risk individuals. Use of the PLCO_m2012 risk ≥0.0151 criterion can improve screening efficiency. Currently, never-smokers should not be screened. Smokers aged ≥65–80 y are a high-risk group who may benefit from screening.</p><p><i>Please see later in the article for the Editors' Summary</i></p></div

PLCO_m2012-estimated risks for high-risk individuals by smoking quit time in former smokers.

<p>Estimates were prepared for white former smokers who are 68 y old, are high-school graduates, have a body mass index of 27 kg/m², have no family history of lung cancer, have no personal history of cancer, started smoking at age 14 y, and smoked on average 30 cigarettes per day. As the quit time increases, smoking duration correspondingly decreases. The dotted horizontal line indicates the PLCO_m2012 ≥0.0151 risk threshold. PLCO_m2012 refers to the lung cancer risk prediction model described in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001764#pmed.1001764-Tammemgi1" target="_blank">[11]</a>.</p

Comparison of PLCO_m2012 risk and incident lung cancer in age strata of PLCO smokers dichotomized at age 65 y.

<p>PLCO_m2012 refers to the model described in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001764#pmed.1001764-Tammemgi1" target="_blank">[11]</a>, and described in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001764#pmed.1001764.s004" target="_blank">Table S1</a>.</p><p>*<i>p</i>-Value for PLCO_m2012 risk was by <i>t</i>-test with unequal variance applied to natural-log-transformed risk values. <i>p</i>-Values for comparing proportions were by chi-square test.</p>†<p>Because PLCO_m2012 risk distributions are right-skewed, geometric means are presented.</p><p>Comparison of PLCO_m2012 risk and incident lung cancer in age strata of PLCO smokers dichotomized at age 65 y.</p

Mortality rates, rate ratios, and rate differences in NLST participants by trial arm and by decile of PLCO_m2012 risk.

<p>PLCO_m2012 model risk decile boundaries were established in PLCO control smokers.</p><p>*Rate difference is incidence rate in CT arm per 10,000 minus incidence rate in CXR arm per 10,000. A negative absolute rate indicates a lower rate of lung cancer death in the CT arm compared to the CXR arm. PLCO_m2012 refers to the lung cancer risk prediction model described in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001764#pmed.1001764-Tammemgi1" target="_blank">[11]</a>.</p><p>NA, not applicable (because of zero occurring in denominator).</p><p>Mortality rates, rate ratios, and rate differences in NLST participants by trial arm and by decile of PLCO_m2012 risk.</p

Lung cancer mortality rates in NLST arms by PLCO_m2012 model risk deciles.

<p>PLCO_m2012 model risk decile boundaries were established in PLCO control smokers. PLCO_m2012 is the lung cancer risk prediction model described in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001764#pmed.1001764-Tammemgi1" target="_blank">[11]</a>.</p

Distribution of PLCO_m2012 risks in PLCO ever-smokers who are USPSTF-criteria-positive or are NLST participants.

<p>The vertical line indicates the PLCO_m2012 risk ≥0.0151 threshold. The graph is right-truncated. PLCO_m2012 is the lung cancer risk prediction model described in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001764#pmed.1001764-Tammemgi1" target="_blank">[11]</a>.</p

Distribution of PLCO_m2012 risk and natural log-transformed risk in PLCO participants stratified by age dichotomized at 65 y.

<p>The PLCO_m2012 risk ≥0.0151 threshold is marked by the dotted vertical line. The upper graph is right-truncated. PLCO_m2012 is the lung cancer risk prediction model described in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001764#pmed.1001764-Tammemgi1" target="_blank">[11]</a>.</p

Distribution of observations and lung cancer events by USPSTF criteria and PLCO_m2012 risk ≥0.0151 criterion status in PLCO intervention arm smokers.

<p>Bold indicates informative cells in which disagreement exists between the two classification criteria. PLCO_m2012 refers to the lung cancer risk prediction model described in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001764#pmed.1001764-Tammemgi1" target="_blank">[11]</a>.</p><p>Distribution of observations and lung cancer events by USPSTF criteria and PLCO_m2012 risk ≥0.0151 criterion status in PLCO intervention arm smokers.</p

Number of lung cancer cases and deaths in PLCO and NLST by PLCO_m2012 percentiles of risk.

<p>PLCO and NLST lung cancer cases and NLST lung cancer deaths were identified in 6 y of follow-up, and PLCO lung cancer deaths were identified in 11 y of follow-up. Calculations were based on PLCO_m2012 deciles of risk, and the percentiles shown are the midpoints of each decile range. PLCO_m2012 refers to the lung cancer risk prediction model described in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001764#pmed.1001764-Tammemgi1" target="_blank">[11]</a>.</p

Performance and Cost-Effectiveness of Computed Tomography Lung Cancer Screening Scenarios in a Population-Based Setting: A Microsimulation Modeling Analysis in Ontario, Canada

<div><p>Background</p><p>The National Lung Screening Trial (NLST) results indicate that computed tomography (CT) lung cancer screening for current and former smokers with three annual screens can be cost-effective in a trial setting. However, the cost-effectiveness in a population-based setting with >3 screening rounds is uncertain. Therefore, the objective of this study was to estimate the cost-effectiveness of lung cancer screening in a population-based setting in Ontario, Canada, and evaluate the effects of screening eligibility criteria.</p><p>Methods and Findings</p><p>This study used microsimulation modeling informed by various data sources, including the Ontario Health Insurance Plan (OHIP), Ontario Cancer Registry, smoking behavior surveys, and the NLST. Persons, born between 1940 and 1969, were examined from a third-party health care payer perspective across a lifetime horizon. Starting in 2015, 576 CT screening scenarios were examined, varying by age to start and end screening, smoking eligibility criteria, and screening interval. Among the examined outcome measures were lung cancer deaths averted, life-years gained, percentage ever screened, costs (in 2015 Canadian dollars), and overdiagnosis. The results of the base-case analysis indicated that annual screening was more cost-effective than biennial screening. Scenarios with eligibility criteria that required as few as 20 pack-years were dominated by scenarios that required higher numbers of accumulated pack-years. In general, scenarios that applied stringent smoking eligibility criteria (i.e., requiring higher levels of accumulated smoking exposure) were more cost-effective than scenarios with less stringent smoking eligibility criteria, with modest differences in life-years gained. Annual screening between ages 55–75 for persons who smoked ≥40 pack-years and who currently smoke or quit ≤10 y ago yielded an incremental cost-effectiveness ratio of $41,136 Canadian dollars ($33,825 in May 1, 2015, United States dollars) per life-year gained (compared to annual screening between ages 60–75 for persons who smoked ≥40 pack-years and who currently smoke or quit ≤10 y ago), which was considered optimal at a cost-effectiveness threshold of $50,000 Canadian dollars ($41,114 May 1, 2015, US dollars). If 50% lower or higher attributable costs were assumed, the incremental cost-effectiveness ratio of this scenario was estimated to be $38,240 ($31,444 May 1, 2015, US dollars) or $48,525 ($39,901 May 1, 2015, US dollars), respectively. If 50% lower or higher costs for CT examinations were assumed, the incremental cost-effectiveness ratio of this scenario was estimated to be $28,630 ($23,542 May 1, 2015, US dollars) or $73,507 ($60,443 May 1, 2015, US dollars), respectively.</p><p>This scenario would screen 9.56% (499,261 individuals) of the total population (ever- and never-smokers) at least once, which would require 4,788,523 CT examinations, and reduce lung cancer mortality in the total population by 9.05% (preventing 13,108 lung cancer deaths), while 12.53% of screen-detected cancers would be overdiagnosed (4,282 overdiagnosed cases). Sensitivity analyses indicated that the overall results were most sensitive to variations in CT examination costs. Quality of life was not incorporated in the analyses, and assumptions for follow-up procedures were based on data from the NLST, which may not be generalizable to a population-based setting.</p><p>Conclusions</p><p>Lung cancer screening with stringent smoking eligibility criteria can be cost-effective in a population-based setting.</p></div