Projected Outcomes Using Different Nodule Sizes to Define a Positive CT Lung Cancer Screening Examination

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1 DOI: /jnci/dju284 First published online October 20, 2014 The Author Published by Oxford University Press. All rights reserved. For Permissions, please Article Projected Outcomes Using Different Nodule Sizes to Define a Positive CT Lung Cancer Screening Examination David S. Gierada, Paul Pinsky, Hrudaya Nath, Caroline Chiles, Fenghai Duan, Denise R. Aberle Manuscript received February 11, 2014; revised April 7, 2014; accepted July 24, Correspondence to: David S. Gierada, MD, Washington University School of Medicine, Mallinckrodt Institute of Radiology, 510 S. Kingshighway Blvd, Campus Box 8131, Saint Louis, MO ( gieradad@wustl.edu). Background Methods Results Conclusion Computed tomography (CT) screening for lung cancer has been associated with a high frequency of false positive results because of the high prevalence of indeterminate but usually benign small pulmonary nodules. The acceptability of reducing false-positive rates and diagnostic evaluations by increasing the nodule size threshold for a positive screen depends on the projected balance between benefits and risks. We examined data from the National Lung Screening Trial (NLST) to estimate screening CT performance and outcomes for scans with nodules above the 4 mm NLST threshold used to classify a CT screen as positive. Outcomes assessed included screening results, subsequent diagnostic tests performed, lung cancer histology and stage distribution, and lung cancer mortality. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated for the different nodule size thresholds. All statistical tests were two-sided. In 64% of positive screens (11 598/18 141), the largest nodule was 7 mm or less in greatest transverse diameter. By increasing the threshold, the percentages of lung cancer diagnoses that would have been missed or delayed and false positives that would have been avoided progressively increased, for example from 1.0% and 15.8% at a 5 mm threshold to 10.5% and 65.8% at an 8 mm threshold, respectively. The projected reductions in postscreening follow-up CT scans and invasive procedures also increased as the threshold was raised. Differences across nodules sizes for lung cancer histology and stage distribution were small but statistically significant. There were no differences across nodule sizes in survival or mortality. Raising the nodule size threshold for a positive screen would substantially reduce false-positive CT screenings and medical resource utilization with a variable impact on screening outcomes. JNCI J Natl Cancer Inst (2014) 106(11): dju284 doi: /jnci/dju284 In the National Lung Screening Trial (NLST), a positive lung cancer screening computed tomography (CT) examination was defined by the presence of a noncalcified pulmonary nodule at least 4 mm in greatest transverse dimension or other nonspecific findings suspicious for lung cancer (1). Using these criteria to initiate further diagnostic evaluation, lung cancer mortality was lower in the group screened with chest CT compared with the group screened with chest radiography (2). More than 24% of the three annual chest CT screens were classified as positive, but more than 96% of positive CT screens did not result in a diagnosis of lung cancer and thus were false positives. Substantial false-positive rates also have been reported in other CT screening trials (3,4). False-positive CT screens lead to additional testing, usually consisting of noninvasive follow-up CT and sometimes tissue biopsy. This increases medical resource use and the overall cost of screening for no benefit, at the potential risks of additional radiation exposure, complications arising from invasive procedures, and patient anxiety. Since the smallest pulmonary nodules are rarely malignant (5), it may be possible to reduce false-positive screening and follow-up testing rates by increasing the size threshold for a positive screen, and maintain adequate sensitivity and specificity for lung cancer detection. The acceptability of using a higher nodule size threshold for defining screen positivity depends on the balance between projected benefits and risks. We performed this retrospective analysis of NLST data to estimate the effects of increasing the nodule size threshold on lung cancer detection and false-positive rates, test sensitivity and specificity, diagnostic follow-up testing, and lung cancer stage and mortality. Methods Details regarding the NLST protocol have been reported previously (1). Relevant details are summarized below. Subjects The NLST compared lung cancer mortality rates among participants randomized to receive three annual (T0, T1, and T2) screening exams using low-dose CT scans or posteroanterior chest 1 of 7 Article JNCI Vol. 106, Issue 11 dju284 November 12, 2014

2 radiographs at 33 US medical centers. The study was approved by the institutional review boards of all screening centers, and written informed consent was obtained from all participants. We analyzed data from the participants randomly assigned to the CT screening arm. Participants were current and former smokers aged 55 to 74 years with a smoking history of at least 30 pack years and no more than 15 years since quitting. Participant demographic data have been reported previously (6). CT Screening Low-dose, noncontrast CT was performed on scanners with four or more detector rows. Screening CT examinations were interpreted on electronic monitors by board-certified radiologists who measured lung nodules using electronic calipers. Examinations containing one or more noncalcified lung nodules 4 mm or larger in greatest transverse diameter, or other findings suspicious for lung cancer (such as enlarged hilar or mediastinal lymph nodes, consolidation, more than subsegmental atelectasis, or pleural effusion) were classified as positive screens, and the nodules were designated as having soft tissue, ground glass, or mixed attenuation. Screens at T2 with nodules stable since T0 could be classified as negative at the discretion of the interpreting radiologist. The interpretations included follow-up recommendations for positive screening examinations, such as repeat thin-section, low-dose CT at a specified time interval before the next annual screening examination, diagnostic contrast-enhanced chest CT, FDG-PET scan, or biopsy. Outcomes Assessment Certified medical records abstractors collected information on subsequent diagnostic tests performed; diagnostic test results; and lung cancer incidence, histology, and stage. Vital status was ascertained from annual or semi-annual questionnaires as well as National Death Index searches with verification by death certificates. Lung cancer deaths were confirmed by an independent endpoint verification team blinded to randomization arm and the cause of death listed on death certificates (7). The mean follow-up of CT arm participants was 6.41 years. Statistical Analysis Counts and frequencies of screens with no nodules, and scans with one or more nodule in which the largest nodule was less than 4 mm in greatest transverse diameter, 4 to 9 mm in greatest transverse diameter at 1 mm increments, and 10 mm and larger, and corresponding lung cancer diagnoses, were tabulated for the three screening time points. Measurements are those recorded by the original interpreting radiologist at the time of screening. A screen-detected cancer was defined as a cancer diagnosed after a positive screening examination, prior to the next annual screening examination or within one year of the positive screen if there was no subsequent annual screen. A false positive was defined as a positive screen with no lung cancer diagnosis before the next annual screen or within a year of the screen. These definitions differ from those used to classify screen-detected and false-positive lung cancers in previous NLST reports (2,8,9), in which the follow-up period for a screen-detected cancer may have been longer than one year for some participants depending on the timing of diagnostic procedures performed after the positive screen. The definitions used here were chosen to provide reference time points for comparing the effects of different nodule size thresholds that coincide with the actual follow-up screening interval used in practice, recognizing that a nodule may be the source of a false-positive screen in one round of screening, and a screen-detected cancer of the same or larger size in a subsequent round. A false negative was defined as a negative screen with lung cancer diagnosis within one year. In calculating the sensitivity, specificity, positive predictive value, and negative predictive value of the different nodule size thresholds, positive screens having no nodule 4 mm or larger or nodules of unknown size were counted as positive for all thresholds. The numbers and types of diagnostic procedures performed, lung cancer stage (10), and vital status of participants were tabulated according to the size of the largest nodule. Lung cancer deaths through December 31, 2009 were used to determine mortality and survival (11), which differs from the primary NLST outcome article that was based on a January 15, 2009 event cutoff date (2). The chi-squared test with continuity correction was used to compare histology, stage, and lung cancer death rates across nodule size categories, and the log-rank test was used to compare differences in lung cancer survival. Statistical testing was two-sided and performed using SAS version 9.2. Results Of subjects randomized to the CT arm, (99%) received at least one CT screening examination. Across all three screening rounds, there were CT screening examinations, of which (24%) were positive. Over 97% ( of 18141) of positive CT screening examinations contained a noncalcified lung nodule 4 mm or larger in greatest transverse dimension (Table 1). In nearly two-thirds (64%) of positive examinations, the largest nodule was 7 mm or smaller in greatest transverse diameter. In 11% of positive screens with a noncalcified nodule 4 mm or larger, another abnormality potentially related to lung cancer was present. The lung cancer rate increased with increasing size of the largest noncalcified nodule (Table 1). Cancer rates increased rapidly at a size of 10 mm, with aggregate rates of 0.8% for all nodules smaller than 10 mm and 12% for all nodules 10 mm or larger. When only ground glass nodules were present, cancer rates were lower compared with screens in which only solid or part solid nodules were present (Supplementary Table 1, available online). Table 2 shows the number of lung cancer diagnoses made within one year that would have been delayed (or missed by screening if annual screening did not continue) if size thresholds greater than 4 mm had been used to define a positive test result, and the corresponding reductions in false-positive rates. For example, with a 5 mm threshold, diagnosis of 6 (1.0%) of 598 lung cancers would have been delayed or missed and 15.8% of false positives would have been avoided; at an 8 mm threshold, 63 (10.5%) of 598 screendetected cancers would have been delayed or missed and 65.8% of false positives would have been avoided. As the positive nodule size threshold was raised from 4 mm to 10 mm, test sensitivity decreased from 93.6% to 80.1% at T0 and from 92.8% to 72.3% at T1-2, while specificity increased from 73.4% to 94.2% at T0 and from 78.1% to 95.4% at T1-2 (Figure 1). Positive predictive value at T0 increased from 3.7% at a 4 mm threshold to 12.9% at a 10 mm threshold, and was slightly jnci.oxfordjournals.org JNCI Article 2 of 7

3 Table 1. Screens with lung cancer diagnosed within one year of the screening examination according to diameter of largest noncalcified nodule* Total screens Maximum nodule diameter No. T0 screen T1 and T2 screens All screens (n = ) (n = ) (n = ) Lung cancer, No. Lung cancer, No. Lung cancer, Negative screen No noncalcified nodule (0.10) (0.06) (0.07) <4 mm (0.09) (0.08) (0.09) Positive screen 4 mm (0.40) (0.11) (0.22) 5 mm (0.20) (0.40) (0.32) 6 mm (0.83) (0.38) (0.56) 7 mm (1.11) (1.52) (1.34) 8 mm (1.23) (2.67) (2.08) 9 mm (1.34) (2.76) (2.19) mm (6.40) (6.90) (6.70) mm (17.39) (15.21) (16.08) mm (26.61) (17.52) (21.54) 30 mm (40.32) (24.63) (32.17) not specified 21 0 (0.00) 30 2 (6.67) 51 2 (3.92) Positive screen with no nodule 4 mm (2.01) (5.47) (4.27) Any positive screen (3.66) (3.06) (3.30) * T0 = initial screening examination; T1 = first annual repeat screening examination; T2 = second annual repeat screening examination. Seven T1-2 screens with largest nodule 3 mm were classified as positive; none developed cancer in one year. Table 2. Screen-detected cancer diagnoses delayed or missed and false-positive results avoided with increasing nodule size thresholds for a positive CT screen* Threshold for positive screen Cancers (n = 263) Diagnoses delayed, T0 screen T1-T2 screens T0-T2 screens (n = 6928) avoided, Cancers (n = 335) Diagnoses delayed, (n = ) Cancers (n = 598) avoided, Diagnoses delayed, (n= ) avoided, 4 mm mm 4 (1.52) 986 (14.23) 2 (0.60) 1780 (16.77) 6 (1.00) 2766 (15.77) 6 mm 7 (2.66) 2458 (35.48) 11 (3.28) 4003 (37.71) 18 (3.01) 6461 (36.83) 7 mm 17 (6.46) 3652 (52.71) 18 (5.37) 5827 (54.89) 35 (5.85) 9479 (54.03) 8 mm 26 (9.89) 4486 (64.75) 37 (11.04) 7056 (66.47) 63 (10.54) (65.79) 9 mm 33 (12.55) 5047 (72.85) 59 (17.61) 7861 (74.06) 92 (15.38) (73.58) 10 mm 38 (14.45) 5413 (78.13) 74 (22.10) 8390 (79.04) 112 (18.73) (78.68) * True positive screens with no noncalcified nodules or nodules of unknown size are not counted as missed. Percentages are cumulative (eg, for cutoff of 7 mm, cancers missed are those with maximum noncalcified nodule size of 4, 5, and 6 mm). Screen-detected is defined as lung cancer diagnosis within one year of positive screen. False-positive screen is defined as no lung cancer diagnosis within one year of positive screen. Seven T1-2 screens with largest nodule 3 mm classified as positive counted as false positives avoided at each threshold. T0 = initial screening examination; T1 = first annual repeat screening examination; T2 = second annual repeat screening examination. higher at T0 than T1-2 (Figure 2). Negative predictive value was greater than 99.7% for 4 to 10 mm thresholds in all screening years. Approximately one follow-up CT scan was performed per positive T0 screening examination, regardless of nodule size (Table 3). Follow-up CT rates were substantially lower in the T1-2 period compared with T0, reflecting the practice of recommending follow-up with the next annual screen for nodules that were stable for one year. Invasive procedures were performed in less than 2% of positive screens when the largest nodule was less than 7 mm, and increased in frequency with increasing nodule size. The projected reductions in follow-up CT scans and invasive diagnostic procedures increased with increasing nodule size threshold (Table 4). The number of patient visits to a physician for consultation after a positive screen was greater than the number of follow-up CT scans; thus, the projected reductions in the number of such visits are greater than the projected reductions in follow-up CT shown in Table 4, by 2% to 4% at each nodule size threshold (data not shown). Though statistically different (P =.04), the histologic distributions of screen-detected lung cancers (Table 5) were fairly similar across nodule size categories, with fewer bronchioloalveolar cell carcinomas and more small cell carcinomas among cancers associated with the smallest nodules (4 to 7 mm). The stage distributions (Table 5) also were statistically different (P =.01; P =.04 excluding 3 of 7 Article JNCI Vol. 106, Issue 11 dju284 November 12, 2014

4 % % Nodule Size (mm) Nodule Size (mm) Sens T0 Spec T0 Sens T1-2 Spec T1-2 Figure 1. Sensitivity and specificity using various nodule size thresholds to define a positive screen. Positive screens having no nodule 4 mm or larger or nodules of unknown size were counted as positive for all thresholds. Sens = sensitivity; Spec = specificity. PPV T0 PPV T1-2 Figure 2. Positive predictive value using various nodule size thresholds to define a positive screen. Positive screens having no nodule 4 mm or larger or nodules of unknown size were counted as positive for all thresholds. PPV = positive predictive value. small cell), though fairly similar among nodule size categories, with a somewhat greater proportion of stage IV cancer among participants with the smallest (4 to 7 mm) nodules and of stage III cancer among those with the largest ( 15 mm) nodules. There were no statistically significant differences between size categories in mortality or five-year survival (Table 5). Of 598 CT screen-detected cancers, a noncalcified nodule 4 mm or larger was reported in 579 (97%), and a noncalcified nodule with no size given was reported in two. Of these 581 lung cancer cases, an additional abnormality possibly associated with lung cancer was present in 126 (22%) (Supplementary Table 2, available online). This percentage varied with nodule size, and was highest (32%) for cancers in which the largest nodule was 4 to 7 mm. For 557 of these 581 (96%), a specific lobe was known to be the location of the primary tumor, which did not always correspond to the location of the largest nodule recorded from CT screening (Supplementary Table 2, available online). Discussion NLST investigators chose a nodule size threshold of 4 mm in greatest transverse diameter to define a screening examination as positive with recommendation for further evaluation. Other screening programs have used no threshold (3,12,13) to 5 mm average of Table 3. Diagnostic procedures following false-positive screens by maximum size of noncalcified nodule T0 screen T1 and T2 screens All screens Invasive procedures, FU scans per positive screen Invasive procedures, FU scans* FU scans per positive screen Invasive procedures, FU scans* FU scans per positive screen FU scans* Maximum nodule diameter 3 mm mm (0.91) (0.51) (0.65) 5 mm (1.36) (0.90) (1.08) 6 mm (1.76) (1.00) (1.33) 7 mm (3.60) (1.14) (2.13) 8 mm (2.67) (2.86) (2.78) 9 mm (5.46) (4.73) (5.03) 10 mm (9.42) (8.10) (8.64) No nodule (11.64) (8.26) (9.71) Unknown (4.76) (3.57) (4.08) Total (3.75) (2.73) (3.14) * Follow-up scans refers to the number of CT scans performed to assess a positive screen prior to the next screening examination. False-positive screen is defined as a positive screen in which no lung cancer is diagnosed within one year of the screen. Percentages are calculated using the number of false positive screens as the denominator, obtained from Table 1 by subtracting the number of lung cancers from the number of screens with each maximum nodule diameter. T0 = initial screening examination; T1 = first annual repeat screening examination; T2 = second annual repeat screening examination. FU = follow-up. jnci.oxfordjournals.org JNCI Article 4 of 7

5 Table 4. Projected reductions in diagnostic tests following false-positive screens at different size thresholds for screen positivity* Nodule threshold for positive screen FU CTs avoided, T0 T1-T2 All Invasive procedures avoided, FU CTs avoided, Invasive procedures avoided, FU CTs avoided, Invasive procedures avoided, 4 mm 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 5 mm 884 (13) 9 (3) 516 (11) 9 (3) 1400 (12) 18 (3) 6 mm 2361 (33) 29 (11) 1305 (27) 29 (10) 3666 (31) 58 (11) 7 mm 3553 (50) 50 (19) 2016 (41) 48 (17) 5569 (47) 98 (18) 8 mm 4446 (63) 80 (31) 2543 (52) 62 (21) 6989 (59) 142 (26) 9 mm 5026 (71) 95 (37) 2940 (60) 85 (29) 7966 (67) 180 (33) 10 mm 5412 (77) 115 (44) 3239 (66) 110 (38) 8651 (73) 225 (41) * Percentages are based on total follow-up CT scans performed at each time interval (bottom row in Table 3). T0 = initial screening examination; T1 = first annual repeat screening examination; T2 = second annual repeat screening examination. FU = follow-up. Table 5. Lung cancer histology, stage, and mortality according to nodule size Feature 4 7 mm (n = 63) 8 9 mm (n = 49) mm (n=149) 15 mm (n = 318) Histology (P =.04)* Bronchioloalveolar cell 4 (6) 6 (12) 21 (14) 54 (17) Adenocarcinoma 22 (35) 24 (49) 71 (48) 118 (37) Squamous cell 15 (24) 12 (24) 25 (17) 66 (21) Large cell 4 (6) 3 (6) 7 (5) 14 (4) Other non-small cell 7 (11) 3 (6) 15 (10) 41 (13) Small cell 10 (16) 1 (2) 8 (5) 20 (6) Other (2) Stage (P =.01) I 34 (54) 37 (76) 104 (70) 188 (59) II 7 (11) 4 (8) 6 (4) 23 (7) III 6 (10) 6 (12) 22 (15) 62 (20) IV 14 (22) 2 (4) 13 (9) 41 (13) Stage excluding small cell (P =.04) I/II 41 (77) 41 (85) 110 (78) 208 (71) III 3 (6) 5 (10) 20 (14) 53 (18) IV 8 (15) 2 (4) 8 (6) 33 (11) Lung cancer death Deaths (P =.12) 24 (38) 18 (37) 39 (26) 117 (37) Deaths excluding small cell (P =.10) 15 (28) 17 (35) 32 (23) 101 (34) 5-year survival (P =.13) 60.1% 62.7% 74.0% 63.8% 5-year survival excluding small cell (P =.18) 70.0% 64.0% 77.5% 67.0% Nodule in same lobe as cancer 5-year survival (matching lobe) (P =.37) 72.3% 77.4% 75.6% 65.6% P values comparing each feature for differences by nodule size category. All statistical tests were two-sided. * Large cell, other non-small cell, and other were grouped together for chi-square statistic. Chi-square test. Log-rank test. length and width (14,15). The detailed screening and clinical outcome data of the NLST now allow for an informed analysis of the effect of nodule size positivity threshold on CT screening performance and projected patient outcomes. From these NLST data, we project that each millimeter increase in the nodule size threshold for screen positivity would result in a small but steadily increasing proportion of lung cancer diagnoses being delayed or missed, and a marked decrease in false-positive rates. Specifically, the percentage of screendetected cancers that would have been delayed or missed, over all three screening years, was 1.0 % at a 5 mm threshold, 3.0% at 6 mm, 5.9% at 7 mm, and 10.5% at 8 mm. False-positive rates would have been reduced by nearly one-eighth, one-third, onehalf, and two-thirds, respectively, at these thresholds. Sensitivity was greater than specificity for thresholds below 7 mm, and specificity was greater than sensitivity above 7 mm. Positive predictive value steadily increased, and there was minimal effect on negative predictive value. Our findings also suggest that an increase in the size threshold for a positive screen would lead to a considerable reduction in the number of follow-up tests, paralleling the reductions in false-positive rates. In the NLST, diagnostic follow-up procedures were recommended, but not mandated by the trial protocol. Therefore, the follow-up evaluations performed during the NLST and estimated 5 of 7 Article JNCI Vol. 106, Issue 11 dju284 November 12, 2014

6 reductions should be a reasonable reflection of patient and physician behavior in the real-world clinical setting. Invasive procedures for lesions subsequently determined to be benign represent a major potential source of harm related to screening. Since invasive testing was performed infrequently when the largest nodule was smaller than 10 mm, an increased nodule size threshold would have had less effect on the number of invasive procedures than on the number of follow-up CT scans. Still, more than 25% of invasive procedures would have been avoided with a threshold of 8 mm. Because some of the invasive procedures may have been falsely negative (if lung cancer was subsequently diagnosed), not all of these invasive procedures may have been unnecessary. A surprisingly high proportion of participants with cancer and largest nodule of 4 to 7 mm had small cell histology, and an even higher proportion with largest nodule of this size had stage IV cancer. This may be in part because of the tendency for the primary tumor in small cell cancer to be small in size despite the presence of distant metastases, but the reasons for these observations aren t entirely clear. However, these observations are relevant to the expected clinical impact of raising the nodule size threshold for a positive screen. For example, a threshold of 8 mm would have resulted in 10.5% of lung cancer diagnoses being delayed or missed. However, those with 4 to 7 mm nodules and stage IV cancer would likely have obtained little benefit from a threshold under 8 mm. In addition, more than one third of cancer cases with 4 to 7 mm nodules had other suspicious findings, and many of these may have been called positive even with a higher nodule size threshold, potentially preventing a delay in diagnosis. Furthermore, some indolent small nodule lung cancers may never become clinically apparent in the absence of screening (16), and for these there would be no harm in delaying the diagnosis until growth is demonstrated on a subsequent annual screen. Thus, the proportion of cases in which raising the threshold would be detrimental is likely smaller than the proportion of cancer diagnoses that would be delayed or missed because of the higher threshold. There was no clear relationship between nodule size and survival or lung cancer mortality. To estimate the effect of increased nodule size thresholds on lung cancer mortality, we used a worst-case mortality rate of 80% (the rate observed for the 44 interval cancers diagnosed within 12 months of a negative screen) for the cancers (other than bronchioloalveolar cell carcinoma) that would have been missed with different thresholds. Using the December 31, 2009 cutoff date for counting lung cancer deaths, the risk ratio for death relative to the chest X-ray (CXR) arm with the 4 mm size threshold was 0.84 (11). At thresholds of 6 mm, 8 mm, and 10 mm, the projected number of extra CT arm lung cancer deaths and the projected risk ratios would be 7 and 0.855, 23 and 0.886, and 41 and 0.916, respectively. The number needed to screen to prevent one lung cancer death would increase from 320 to 352, 445, and 630, respectively, at these same thresholds. The relationship between nodule size threshold, delayed or missed diagnosis, and false-positive rates is generally similar to an analysis of baseline screening data from the Early Lung Cancer Action Project (ELCAP) (4). Notable differences from our study are that nodule size in ELCAP was defined by the average of length and width, and in the ELCAP study the effects of nodule size threshold on the number of invasive procedures, sensitivity and specificity, positive and negative predictive value, stage, mortality, or beyond the first round of screening were not assessed (14). To our knowledge, no other screening studies have examined the effects of different nodule size thresholds. However, the National Comprehensive Cancer Network guidelines on lung cancer screening recently raised the recommended nodule size threshold for a positive screen to 6 mm mean diameter (17). One limitation of this study is that the screening occurred predominantly in academic medical centers within a supervised clinical trial, and performance with different screen positivity thresholds in the general medical community could be different than estimated here. This may be unlikely, though, since nodule detection and measurement are basic tasks for radiologists who regularly interpret chest CT scans, and substantial variability was seen even among the NLST radiologists (18,19). Screening efficacy with higher thresholds also could be different than estimated here if screening eligibility criteria or compliance with annual screening are different than in the NLST. Because some cancers were not diagnosed until more than one year after the first positive screen, and screening outcomes here were based on annual intervals, the false-positive rates are likely overestimated. Diagnosed cancers could not be correlated to specific nodules, so the degree of false-positive overestimation is unknown. However, this should not affect the estimated increases in the annual numbers of cancers missed or diagnostic procedures avoided with increased nodule size thresholds. In conclusion, this analysis suggests that false-positive CT screenings and medical resource utilization would be substantially reduced by raising the nodule size threshold for a positive screen, with a delay in the diagnosis of lung cancer and an impact on outcomes in a small percentage of all lung cancer cases. A reduction in the number of false-positive screens and the ensuing work-ups could substantially affect the cost-effectiveness of low-dose CT screening for lung cancer. The specific tradeoffs demonstrated here may help to inform decisions regarding the optimal threshold to use in clinical practice, or the thresholds to evaluate in a clinical trial setting. In the future, risk models that take into account patient factors and nodule characteristics other than size (20) may help to further refine the criteria for screening CT interpretation. References 1. Aberle DR, Berg CD, Black WC, et al. The national lung screening trial: Overview and study design. Radiology. 2011;258(1): Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365(5): Swensen SJ, Jett JR, Hartman TE, et al. Lung cancer screening with ct: Mayo clinic experience. Radiology. 2003;226(3): 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): MacMahon H, Austin JH, Gamsu G, et al. Guidelines for management of small pulmonary nodules detected on ct scans: A statement from the fleischner society. Radiology. 2005;237(2): Aberle DR, Adams AM, Berg CD, et al. Baseline characteristics of participants in the randomized national lung screening trial. J Natl Cancer Inst. 2010;102(23): Marcus PM, Gareen IF, Miller AB, et al. The national lung screening trial s endpoint verification process: Determining the cause of death. 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7 9. Church TR, Black WC, Aberle DR, et al. Results of initial low-dose computed tomographic screening for lung cancer. N Engl J Med. 2013;368(21): Sobin LH, Wittekind C. Tnm classification of malignant tumors. New York, NY: Wiley-Liss; Pinsky PF, Church TR, Izmirlian G, Kramer BS. The national lung screening trial: Results stratified by demographics, smoking history, and lung cancer histology. Cancer. 2013;119(22): Diederich S, Thomas M, Semik M, et al. Screening for early lung cancer with low-dose spiral computed tomography: Results of annual follow-up examinations in asymptomatic smokers. Eur Radiol. 2004;14(4): MacRedmond R, Logan PM, Lee M, Kenny D, Foley C, Costello RW. Screening for lung cancer using low dose ct scanning. Thorax. 2004;59(3): Henschke CI, Yankelevitz DF, Naidich DP, et al. Ct screening for lung cancer: Suspiciousness of nodules according to size on baseline scans. Radiology. 2004;231(1): Wilson DO, Weissfeld JL, Fuhrman CR, et al. The pittsburgh lung screening study (pluss): Outcomes within 3 years of a first computed tomography scan. Am J Respir Crit Care Med. 2008;178(9): Patz EF Jr, Pinsky P, Gatsonis C, et al. Overdiagnosis in low-dose computed tomography screening for lung cancer. JAMA Intern Med. 2014;174(2): Lung cancer screening version NCCN clinical practice guidelines in oncology: National Comprehensive Cancer Network; Gierada DS, Pilgram TK, Ford M, et al. Lung cancer: Interobserver agreement on interpretation of pulmonary findings at low-dose ct screening. Radiology. 2008;246(1): Singh S, Pinsky P, Fineberg NS, et al. Evaluation of reader variability in the interpretation of follow-up ct scans at lung cancer screening. Radiology. 2011;259(1): McWilliams A, Tammemagi MC, Mayo JR, et al. Probability of cancer in pulmonary nodules detected on first screening ct. N Engl J Med. 2013;369(10): Funding The National Lung Screening Trial was supported by National Institutes of Health grants U01-CA and CA79778 and contracts N01-CN-25511, N01-CN-25512, N01-CN-25513, N01-CN-25514, N01-CN-25515, N01-CN-25516, N01-CN-25518, N01-CN-25522, N01-CN-25524, N01-CN-75022, N01-CN-25476, and N02-CN Notes The authors acknowledge the screening center investigators and staff of the National Lung Screening Trial and the staff from Information Management Services and Westat. Most important, we thank the study participants, whose contributions made this study possible. The National Cancer Institute of the US National Institutes of Health provided the data for this study. Dr. Pinsky is employed by the National Cancer Institute and collaborated in the design, implementation, interpretation, and writing of study results. Affiliations of authors: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO (DSG); Division of Cancer Prevention, National Cancer Institute, Bethesda, MD (PP); University of Alabama at Birmingham, Birmingham, AL (HN); Wake Forest University Health Science Center, Winston-Salem, NC (CC); Center for Statistical Sciences and Department of Biostatistics, Brown University School of Public Health, Providence, RI (FD); Radiological Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA (DRA). 7 of 7 Article JNCI Vol. 106, Issue 11 dju284 November 12, 2014