The NLST is a landmark trial demonstrating that implementation of low-dose CT screening lowers lung cancer–related mortality. We must put the study results and cost-effectiveness analyses in the context of the staggering statistics: up to 65% of lung cancer patients present with advanced-stage disease where treatments are often costly, toxic, and only palliative in nature.
For decades, strategies to reduce lung cancer–related deaths through screening methods have failed.[1-7] The results of the National Lung Screening Trial (NLST) have generated considerable enthusiasm, as this is the first randomized trial to demonstrate a reduction in lung cancer mortality. Despite these findings, several controversies have surfaced, leading to contentious debate about implementation and payment for computed tomography (CT)-based lung cancer screening. In his perspective, Dr. Grannis advocates for CT screening by highlighting shortcomings and misinterpretations of the NLST, which he believes have led to an “underestimation of benefits and overestimation of adverse effects.” His argument focuses on three central issues in the debate: benefit, harm, and cost. As thoracic medical oncologists, we offer our perspective on these same essential features of lung cancer screening.
The NLST demonstrated a 20% decrease in lung cancer morality and a 6% reduction in all-cause mortality. Grannis highlights the challenges of a randomized trial of this size, along with its limitation of annual screening to only 3 years and its inclusion of chest x-rays in the control arm. Despite these design limitations, the trial met its primary endpoints and suggests a clear benefit for screening. Subsequent publications, including a recent analysis by Ma et al, suggest that up to 12,000 lung cancer deaths could be averted annually if CT screening were applied to a population identified by the NLST criteria.
Furthermore, the NLST demonstrated that the number needed to screen (NNS) to prevent 1 lung cancer-related death was 320, which compares favorably with other screening modalities. While the Centers for Medicare and Medicaid Services (CMS) seemed to express reservations about the benefit of CT screening in a Medicare population, a recent subset analysis of 7,110 NLST patients over the age of 65 demonstrated a greater benefit in this population, resulting in a lower NNS (245). Based on these results, more than 40 medical societies, including the American Cancer Society and the American Society of Clinical Oncology (ASCO), as well as members of Congress, have petitioned CMS to provide national Medicare coverage of lung cancer screening.
Perhaps one of the most commonly cited critiques of the NLST is the high false-positive rate (96.4%), which led to further diagnostic tests and unnecessary invasive procedures. While some have suggested that this contributes to patient anxiety and worsening quality of life (QOL), a formal analysis demonstrated no statistically significant difference in anxiety or QOL scores between participants with false-positive results and those with normal results. Grannis highlights NSLT limitations that contributed to the high-false positive rate, including use of a nodule cutpoint of 4 mm rather than 6 mm, failure to incorporate a diagnosis/treatment algorithm into the trial protocol, and counting the same nodule twice as positive on the first two rounds of screening in each patient. We agree with Grannis that using a diagnostic algorithm and increasing the size of nodules characterized as suspicious are likely to improve the risk:benefit ratio of CT screening for lung cancer. For example, the algorithm implemented in the European NELSON trial-in which nodules were considered “positive” only if their volume was greater than 500 Î¼L and they had a volume doubling time of less than 400 days-lowered the false-positive rate to a staggeringly low 1.2%. Further lowering of this rate will most likely be achieved with the implementation of the Lung Imaging Reporting and Data System (Lung RADS) recently released by the American College of Radiology. The Lung RADS can be used for standardized reporting of lung cancer CT screening studies, and preliminary evidence demonstrates a reduction in the false-positive rate from 25% to 10%. Finally, strategies including both breath and serum tests are forthcoming and, combined with CT screening, may enrich the screening population for patients most likely to have malignant nodules. The promise of this approach has been demonstrated in a recent study that identified 23 unique volatile organic compound biomarkers in exhaled breath that could discriminate lung cancer patients from controls with 96.47% sensitivity and 97.47% specificity.
Given the fiscal challenges confronting our healthcare system, many have questioned whether national implementation of CT screening would be cost-effective. While data presented at this year’s ASCO meeting contend that CT screening would cost Medicare $9.3 billion over a 5-year period, a more recent actuarial analysis by the Milliman firm suggests that low-dose CT screening would be highly cost-effective. With economic modeling, Pyenson et al demonstrated that the cost per life-year saved would be less than $19,000, or a cost of approximately $1 per Medicare beneficiary per month, which is more cost-effective than other current screening protocols. The study echoes a prior analysis performed by the same group in 2012. The benefit of smoking cessation that has recently been associated with screening-detected abnormalities in the NLST would further lower the cost per life saved if integrated into analyses.
The NLST is a landmark trial demonstrating that implementation of low-dose CT screening lowers lung cancer–related mortality. We must put the study results and cost-effectiveness analyses in the context of the staggering statistics: up to 65% of lung cancer patients present with advanced-stage disease where treatments are often costly, toxic, and only palliative in nature. Early identification of potentially resectable disease, coupled with the investigation of novel targeted therapies in the neodjuvant/adjuvant setting (tyrosine kinase inhibitors and anti–programmed death 1 [anti–PD-1] and anti–programmed death 1 ligand [anti–PD-L1] antibodies) represents a unique opportunity to improve outcomes. We believe that measures of efficacy, harm, and cost-effectiveness support the current use of low-dose CT screening for the population studied in the NLST.
Financial Disclosure: Dr. Levy serves as an advisor and consultant to, and receives speaker honoraria from, Eli Lilly, Genentech, and Pfizer. Dr. Becker has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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