Claudia I. Henschke, PhD, MD; Rowena Yip, MPH; David F. Yankelevitz, MD; James P. Smith, MD; for the International Early Lung Cancer Action Program Investigators*
* For a list of members of the International Early Lung Cancer Action Program, see the Appendix.
Grant Support: In part by the Flight Attendant Medical Research Institute, the American Legacy Foundation, Department of Energy (DE-FG02-96SF21260), Israel Cancer Association, The Rogers Family Fund, Yad-Hanadiv Foundation, Jacob and Malka Goldfarb Charitable Foundation, Auen/Berger Foundation, Princess Margaret Foundation, Berger Foundation, Mills Peninsula Hospital Foundation, Columbia University Medical Center, Mount Sinai Medical Center, Weill Medical College of Cornell University, Cornell University, New York Presbyterian Hospital, Swedish Hospital, Christiana Care Helen F. Graham Cancer Center, Holy Cross Hospital, Eisenhower Hospital, Jackson Memorial Hospital Health System, and Evanston Northwestern Healthcare.
Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-2154.
Reproducible Research Statement: Study protocol: Available at www.ielcap.org/professionals/docs/ielcap.pdf. Statistical code and data set: Not available.
Requests for Single Reprints: Claudia I. Henschke, PhD, MD, Department of Radiology, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, NY 10029; e-mail, Claudia.Henschke@mountsinai.org.
Current Author Addresses: Drs. Henschke and Yankelevitz: Department of Radiology, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, NY 10029.
Ms. Yip: Early Lung and Cardiac Action Program, Department of Radiology, Mount Sinai Medical Center, 1 Gustave L. Levy Place, Box 1234, New York, NY 10029.
Dr. Smith: Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065.
Author Contributions: Conception and design: C.I. Henschke, J.P. Smith, D. Yankelevitz.
Analysis and interpretation of the data: C.I. Henschke, R. Yip, D.F. Yankelevitz, J.P. Smith.
Drafting of the article: C.I. Henschke, J.P. Smith, D.F. Yankelevitz.
Critical revision of the article for important intellectual content: C.I. Henschke, R. Yip, J.P. Smith, D.F. Yankelevitz.
Final approval of the article: C.I. Henschke, R. Yip, J.P. Smith, D. F. Yankelevitz.
Provision of study materials or patients: C.I. Henschke.
Statistical expertise: C.I. Henschke, R. Yip.
Obtaining of funding: C.I. Henschke, D.F. Yankelevitz.
Administrative, technical, or logistic support: C.I. Henschke.
Collection and assembly of data: C.I. Henschke, R. Yip.
Henschke C., Yip R., Yankelevitz D., Smith J., ; Definition of a Positive Test Result in Computed Tomography Screening for Lung Cancer: A Cohort Study. Ann Intern Med. 2013;158:246-252. doi: 10.7326/0003-4819-158-4-201302190-00004
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Published: Ann Intern Med. 2013;158(4):246-252.
Low-dose computed tomography screening for lung cancer can reduce mortality among high-risk persons, but “false-positive” findings may result in unnecessary evaluations with attendant risks. The effect of alternative thresholds for defining a positive result on the rates of positive results and cancer diagnoses is unknown.
To assess the frequency of positive results and potential delays in diagnosis in the baseline round of screening by using more restrictive thresholds.
Prospective cohort study.
Multi-institutional International Early Lung Cancer Action Program.
21 136 participants with baseline computed tomography performed between 2006 and 2010.
The frequency of solid and part-solid pulmonary nodules and the rate of lung cancer diagnosis by using current (5 mm) and more restrictive thresholds of nodule diameter.
The frequency of positive results in the baseline round by using the current definition of positive result (any parenchymal, solid or part-solid, noncalcified nodule ≥5.0 mm) was 16% (3396/21 136). When alternative threshold values of 6.0, 7.0, 8.0 and 9.0 mm were used, the frequencies of positive results were 10.2% (95% CI, 9.8% to 10.6%), 7.1% (CI, 6.7% to 7.4%), 5.1% (CI, 4.8% to 5.4%), and 4.0% (CI, 3.7% to 4.2%), respectively. Use of these alternative definitions would have reduced the work-up by 36%, 56%, 68%, and 75%, respectively. Concomitantly, lung cancer diagnostics would have been delayed by at most 9 months for 0%, 5.0% (CI, 1.1% to 9.0%), 5.9% (CI, 1.7 to 10.1%), and 6.7% (CI, 2.2% to 11.2%) of the cases of cancer, respectively.
This was a retrospective analysis and thus whether delays in diagnosis would have altered outcomes cannot be determined.
These findings suggest that using a threshold of 7 or 8 mm to define positive results in the baseline round of computed tomography screening for lung cancer should be prospectively evaluated to determine whether the benefits of decreasing further work-up outweigh the consequent delay in diagnosis in some patients.
The Flight Attendant Medical Research Institute and the American Legacy Foundation.
Peter B. Bach, MD, MAPP; Michael K. Gould, MD, MS; Gerard A. Silvestri, MD, MS
Memorial Sloan-Kettering Cancer Center (Bach), Kaiser Permanente Southern California (Gould), Medical University of South Carolina (Silvestri)
March 7, 2013
Avoid False Positives in Low Risk Individuals by Not Screening Them
To the editor:
We believe that the participants in the study from Henschke et al. are not representative of people who should be considered for screening, and thus the quantitative estimates for the impact of changing nodule size cutoffs are not generalizable. The median pack-years of smoking in the study was 26, meaning that fewer than half of participants would be eligible for screening based on most major guidelines or on the entry criteria for the benchmark National Lung Screening Trial (NLST).(1-3) The participants in this study are also much younger and have a lower degree of smoking exposure than did participants who enrolled during earlier periods of the ELCAP study (Figure). This likely explains the lower rates of false positives seen more recently in ELCAP, more so than changes in their protocol. Alongside the decline in risk profile, ELCAP has seen a substantial reduction over time in the frequency with which they are detecting lung cancer on the initial scan (the ‘prevalence’).
In their earliest studies nearly one in 35 patients who were screened were found to have lung cancer, but now they are finding it in only about one in 180. This 80 percent decline in lung cancer detection mirrors the decline in median pack years of study participants from 42 to 26 and median age from 67 to 58 between the two time periods.(4-7) The fluctuation in the median age and pack years of smoking seen in two intervening ELCAP studies parallel the rise and fall in lung cancer detection as well. Screening can only benefit individuals in whom lung cancer is found, so the decline in lung cancer case detection in ELCAP emphasizes the importance of focusing screening on individuals who are at a substantially elevated risk of lung cancer.(8)
Up until now ELCAP has allowed member institutions to apply their own criteria for subject eligibility, and numerous free standing facilities are equally lax. For instance, this most recent study lists 11 pack years as the 25th percentile, and there likely were non-smokers in the study too (www.ielcap.org\ielcap\famri020107.htm). We agree with the authors’ stated goal of limiting false positives. However, the most effective way to achieve this goal in individuals at low risk would be to not screen them.
1. Aberle DR, Adams AM, Berg CD, Clapp JD, Clingan KL, Gareen IF, et al. Baseline characteristics of participants in the randomized national lung screening trial. J Natl Cancer Inst. 2010;102(23):1771-9.
2. Bach PB, Mirkin JN, Oliver TK, Azzoli CG, Berry DA, Brawley OW, et al. Benefits and harms of CT screening for lung cancer: a systematic review. JAMA. 2012;307(22):2418-29.
3. Wender R, Fontham ET, Barrera E, Jr., Colditz GA, Church TR, Ettinger DS, et al. American Cancer Society lung cancer screening guidelines. CA Cancer J Clin. 2013.
4. Henschke CI, McCauley DI, Yankelevitz DF, Naidich DP, McGuinness G, Miettinen OS, et al. Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet. 1999;354(9173):99-105.
5. Henschke CI, Yankelevitz DF, Libby DM, Pasmantier MW, Smith JP, Miettinen OS. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med. 2006;355(17):1763-71.
6. 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):246-52.
7. CT Screening for lung cancer: diagnoses resulting from the New York Early Lung Cancer Action Project. Radiology. 2007;243(1):239-49.
8. Bach PB, Gould MK. When the average applies to no one: personalized decision making about potential benefits of lung cancer screening. Ann Intern Med. 2012;157(8):571-3.
Guglielmo M Trovato, MD, Marco Sperandeo, MD, Daniela Catalano, MD
University of Catania
March 11, 2013
Lung Cancer and Thoracic Ultrasound. Tools that can be of help.
Henschke et al. suggest that using a threshold of 7 or 8 mm to define positive results in the baseline round of computed tomography screening for lung cancer could produce the benefit of decreasing further work-up and delay in diagnosis in some patients(1). Although nodule size in an important variable, it is not the sole predictor of risk for cancer (2). In our experience, by Trans-Thoracic-Ultrasound (TUS) 70% of pleural surface is accessible when it comes up to pleura or is reachable via a sound window. Contrast-Enhanced Ultra Sound (CEUS) provides further information in this regard. In a comparison of 204 lung cancer vs 193 pneumonitis lung consolidation, all lung cancer presented CEUS intralesional enhancement consistent with tumor neovascularization. In some cases, there were unenhanced areas consistent with zones of necrosis and these areas were avoided during FNAB(3-5). TUS Elastography (Fibroscan) is a novel approach useful to estimate the stiffness/elasticity of tissues, allowing a reliable preliminary differentiation with non-cancer consolidation. It is followed by a focused and guided Fine Needle Aspiration Biopsy (FNAB) for diagnosing and staging lung cancer. TUS with Elastography and FNAB after chest x-ray and CT-scan were performed in 91 patients (m 67, f 24; years 62,84-7,51) with lung consolidation. The total of lung cancer patients (n=67) have a significant (P<0.0001) lower elasticity of nodules (4,19-0,55) vs pneumonitis (2,2.35-0,48); the size of consolidation is greater in pneumonitis (cm.4,03-0,82 vs 3,06-8,88;p,0.0001), and this is a further argument against the use of the size of nodules as a discriminant. Both US approaches, even not yet widely validated, as it as not the CT approach itself, could contribute to a more efficient work-up, at least in some patients. Both TUS procedures provide diagnostically useful information on peripheral lung lesions and increase the diagnostic yield of transthoracic FNAB by reducing the risk of inadequate tissue sampling.
1. Henscke, CI, Yip R, Yankelevitz DF, Smith JP; International Early Ling Cancer Action Program Investigators*. Definition of a positive test result in computed tomography screening for lung caner: a cohort study. Ann Intern Med. 2013;158;246-52.
2. Lam S, McWilliams A, Mayo J, Tammemagi M. Computed tomography screening for lung cancer: what is a positive screen? Ann Intern Med. 2013;158:289-90.
3. Sperandeo M, Sperandeo G, Varriale A, Filabozzi P, Decuzzi M, Mimitri L, el al. Contrast-enhanced ultrasound (CEUS) for the study of peripheral lung lesions: a preliminary study. Ultrasound Med Biol. 2006;32:1467-72.
4. Sperandeo M, Filabozzi P, Varriale A, Carneval V, Piattelli ML, Sperandeo G, ir al. Role of thoracic ultrasound in the assessment of pleural and pulmonary diseases. J Ultrasound. 2008;11:39-46.
5. Sperandeo M, Carnevale V, Muscarella S, Sperandeo S, Varriale A, Filabozzi P, et al. Clinical application of transthoracic ultrasonography in inpatients with pneumonia. Eur J Clin Inves. 2011;41:1-7.
Claudia I. Henschke, PhD, MD
Mount Sinai Medical Center
May 17, 2013
We appreciate Dr. Lam and colleagues’ expression of an often misunderstood event in the process of screening for lung cancer, which is the unique character of the initial (baseline) round (1). As they note, this – once only – round generates the greatest frequency of diagnostic work-up because no previous CT is available to determine if a nodule is new, growing or stable and the diagnosed cancers are relatively slower growing than those identified in subsequent repeat rounds of screening. Necessarily then, the definition of positive result should be different at baseline than for all subsequent rounds. In I-ELCAP, the nodule diameter threshold is 5.0 mm and 3.0 mm respectively, our article addressed only the baseline round. (A threshold of 4 mm in greatest length was used in the NLST)
Dr. Lam and colleagues emphasize the desirability of identifying criteria in addition to nodule size to better understand its probability of malignancy. We share the view that this is a laudable goal. However, for now and the near future, we believe that nodule size will remain the main driver that defines positive test in the baseline round. It should be emphasized that in I-ELCAP, small nodules (5 mm to 14 mm), whether solid or part-solid, only prompt a non-contrast, low-dose CT 3 months later to assess for growth. Dr. Lam and colleagues describe our results as provocative and indeed, it was our aim to stimulate interest and discussion among those interested in CT screening research.
Dr. Travato and colleagues also noted the desirability of improving the probability of diagnosing malignancy using non-surgical biopsy techniques (2). In their hands, the results of unique modifications of ultrasound technology are impressive and it is of interest to know the lower limit of nodule size that can be reliably assessed with these methods.
Drs. Bach, Gould and Silvestri take issue with the inclusion in the I-ELCAP research database of some 60,000 baseline screening CTs, of participants with risk profiles (age and tobacco exposure) that are higher, the same, and lower than those in the National Lung Screening Trial (NLST) (3). We emphasize the need for data over a broad range of risk profiles. Certainly, it was never intended that screening would be restricted to only people who meet the NLST criteria. Equally certain are we that Bach and colleagues’ assertion of laxity by the I-ELCAP Investigators was not the cause for inclusion of people over a broad range of risk of lung cancer; it was by design, after completion of our earliest studies.
Bach and colleagues make the obvious point that the number of lung cancers diagnosed under screening will decrease in people of relatively lower risk. We note that coincident with the decrease in cancer, there is a decrease in nodules so that the proportional reduction in positive results as we increase size threshold remain essentially constant over the broad range of age and smoking profiles, including those of the NLST. It should also be noted that the NLST itself encompasses a broad range of risk. The recently published ACCP (4) and Fleischner Society guidelines (5) for evaluation of nodules 8 mm or less provides no differentiation of workup based on extent of risk. Bach et al.’s critique of I-ELCAP seems to contradict this aspect of the ACCP and Fleischner guidelines. Our article focused on one powerful means of reducing the potential harms of “false positives” – increasing the nodule size threshold. The concern of these authors about screening individuals of lower risk implies that the benefit may be too meager to offset potential harms. This in turn may derive from their misinterpretation of the benefits which have been seriously underestimated. The 20% mortality reduction result of the NLST is specific to that particular trial – a stop-screen design – which could not measure the maximum achievable mortality reduction (6). More regrettable is that this 20% result has been inappropriately translated to be equivalent with the reduction in case-fatality, the clinically relevant parameter (6). In our view, one author, an NLST investigator, demonstrated how this misunderstanding can affect clinical decisions when he advised a hypothetical person who meets NLST enrollment criteria to not get a CT scan (7). The decision not to screen at all would be the ultimate means to reduce “false positives.”
Claudia I. Henschke, Rowena Yip, David F. Yankelevitz, James P. Smith
1. Lam S, McWilliams A, Tammemagi M. Computed Tomography Screening for Lung Cancer: What is a Positive Screen? Annals of Internal Medicine 2013; 158: 289-290.
2. Travato GM, Perandeo M, Catalano D. Lung Cancer and Thoracic Ultrasound. Tools that can be of help. Posted online March 11, 2013
3. Bach PB, Gould MK, Silvestri GA. Avoid False Positives in Low Risk Individuals by Not Screening Them. Posted on March 7, 2013.
4. Gould MK, Donington J, Lynch WR, Mazzone PJ, Midthun DE, Naidich DP, Wiener RS. Evaluation of Individuals With Pulmonary Nodules: When Is It Lung Cancer? Diagnosis and Management of Lung Cancer, 3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2013; 143(5_suppl) e93S.doi.1378/chest.12-2351\
5. MacMahon H, Austin JH, Gamsu G, Herold CJ, Jett JR, Naidich DP, Patz EF Jr,
Swensen SJ; Fleischner Society. Guidelines for management of small pulmonary
nodules detected on CT scans: a statement from the Fleischner Society. Radiology 2005; 237: 395-400.
6. Yankelevitz DF, Smith JP. Understanding the core result of the National Lung Screening trial. N Engl J Med. 2013; 368: 1460-1
7. Silvestri GA. Screening for Lung Cancer: It Works, but Does It Really Work? Ann Intern Med. 2011; 155: 537-539.
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