By James L. Mulshine, MD, PhD and John K. Field, PhD, FRCPath
Administration (VHA) clinicians reported their experience in implementing lowdose computed tomography (CT) lung cancer screening at 8 VHA hospitals.1 In this experience, 2,106 subjects were screened from July 2013 to June 30, 2015, which resulted in the diagnosis of 31 lung cancers (1.5%), but incurred considerable effort by the hospitals to implement the process. In a follow-up editorial, Drs. Redberg and O’Malley noted that the rate of incidental findings exceeded lung cancer diagnoses by 40 to 1.2 Certainly these are interesting findings that merit more in-depth consideration.
The VHA experience started with an assessment of screening eligibility of 93,033 primary care patients, but smoking data were missing in 36,555 or 39.3% of the cohort. It is also notable that only 57% of the screening candidates offered participation agreed to join the study. In the VHA study, the Fleischer Society guidelines developed in 2005 to guide the work-up of symptom-detected lung cancer were used as a foundational tool to decide nodule management process. Based on that management approach, a false positive diagnosis rate of 26.6% was reported.1 However, when the VHA authors reassessed their results using the more relevant screen-detected nodule management approach developed by the American College of Radiology, the false positivity rate was reduced to 12.8%.
The questions this experience raises are important and may reflect on issues beyond those related to the challenges of CT screening implementation. For example, why was the participation rate in the study so low? Were subjects concerned about the excessively high rate of false positivity that occurred as a result of not employing best screening practice? Did the informed decision-making tool reflect current realities about low-dose CT screening and relate how newer CT scanners required notably less medical radiation than the 4 detector scanners typically used in the National Lung Screening Trial? Consensus is now emerging that low-dose CT screening does not result in cumulative medical radiation doses that are predictably associated with measurable medical harms.3
A growing number of screening studies, including ACR, I-ELCAP, NELSON, and the WellStar community program experience, have all reported markedly lower false positivity rates than the initial VHA finding.4-6 Further, both the NELSON screening studies and the United Kingdom pilot CT screening trial not only documented very low rates of false positivity in the screening workup process, but also indicated that there was no significant persistence of distress from this screening process.7,8
Another common miscommunication about lung cancer screening that may be off-putting to potential screening subjects is the inappropriate conflation of the presence of lung nodules as being synonymous with the diagnosis of lung cancer.2 Lung nodules are like colonic polyps as they are both age-related in frequency and generally benign; this observation should be conveyed as part of the informed decision-making discussion to avoid unduly distressing screening subjects.
A further misconception about screening was communicated in the already-mentioned editorial by Redberg and O’Malley.2 To designate other tobacco-related imaging findings identified in the thorax in the course of CT lung screening as “incidental findings” is an inaccurate characterization. There has been a considerable and rapidly growing literature involving thousands of screening subjects that documents both frequent and expected findings of radiologically significant but asymptomatic COPD as well as coronary calcification. 9-11 This situation is aligned with the long-established host response to the pleotrophic consequences of repeated tobacco combustion particulate exposure catalogued in the Surgeon General’s multiple reports. A recent review highlighted the critical importance of finding frequent, asymptomatic COPD in the course of conducting lung cancer screening as a major opportunity to improve COPD outcomes.12 A critical new finding in regard to COPD outcomes from a metaanalysis of 4 studies evaluating COPD mortality in a total of 88,767 participants found that cardiovascular patients on chronic statin therapy had a hazard ratio of 0.48 compared to COPD patients not on a statin.13 This suggestion of potential benefit in patients taking statins relative to their COPD opens up a promising avenue of new drug intervention research to determine if individuals undergoing lung cancer screening but found to have asymptomatic COPD may benefit from receiving statin therapy for their COPD.
In conclusion, implementing screening is challenging, but many groups are now independently reporting high-quality, efficient lung cancer screening with good subject acceptance. Embedding best screening management practices in the process is critical to minimize harm while maximizing benefit. The Lung Cancer Alliance Framework for Screening Excellence provides an array of excellent resources to facilitate responsible screening implementation.14 Lung cancer screening is also presenting new opportunities to find early asymptomatic COPD and coronary artery diseases. Research is urgently needed to validate whether and how this approach can potentially extend the public health impact of CT screening to address other major tobacco-related, thoracic co-morbidities in the target screening population. ✦
1. Kisinger LS, Anderson C, Kim J, et al. Implementation of lung cancer screening in Veterans Health Administration. JAMA Intern Med. 2017;177: 399-406.
2. Redberg RF, O’Malley PG. Important questions about lung cancer screening programs when incidental findings exceed lung cancer nodules by 40 to 1. JAMA Intern Med. 2017;177:311-312.
3. Frank L, Christodoulou E, Kazerooni EA. Radiation risk of lung cancer screening. Sem Respir Crit Care Med. 2013;34:738-747.
4. Kazerooni EA, Armstrong MR, Amorosa JK, et al. ACR CT accreditation program and the lung cancer screening program designation. J Am Coll Radiol. 2015 Jan;12(1):38-42.
5. Henschke CI, Yip R, Yankelevitz DF, Smith JP. Definition of a positive test result in computed tomography screening for lung cancer: a cohort study. Ann Intern Med. 2013;158(4):246-252.
6. Miller DL, Mayfield WR, Luu TD, et al. Communitybased multidisciplinary computed tomography screening program improves lung cancer survival. Ann Thorac Surg. 2016;101(5):1864-1869.
7. van den Bergh KAM, Essink-Bot ML, Borsboom GJJM, et al. Long-term effects of lung cancer computed tomography screening on health-related quality of life: the NELSON trial. Eur Respir J. 2011;38:154-161.
8. Brain K, Lifford KJ, Carter B, et al. Long-term psychosocial outcomes of low-dose CT screening: results of the UK Lung Cancer Screening randomised controlled trial. Thorax. 2016;71(11): 996-1005.
9. Mulshine JL, D’Amico TA. Issues with implementing a high-quality lung cancer screening program. CA Cancer J Clin. 2014 Sep-Oct;64(5):352-363.
10. Gonzalez J, Marín M, Sánchez-Salcedo P, Zulueta JJ. Lung cancer screening in patients with chronic obstructive pulmonary disease. Ann Transl Med. 2016;4(8):160.
11. Htwe Y, Cham MD, Henschke CI, et al. Coronary artery calcification on low-dose computed tomography: comparison of Agatston and Ordinal Scores. Clin Imaging. 2015;39(5):799-802.
12. Seijo LM, Zulueta JJ. Understanding the links between lung cancer, COPD and emphysema: a key to more effective treatment and screening. Oncology. 2017;31:93-100. 13. Cao C, Wu Y, Xu Z, et al. The effect of statins on chronic obstructive pulmonary disease exacerbation and mortality: a systematic review and metaanalysis of observational research. Sci Rep. 2015;5: 16461.
14. Mulshine JL, Ambrose LF. Implementing computed tomography-based lung cancer screening in the community. J Thorac Dis. 2016 Oct; 8(10):E1304-E1306.