Cardiopulmonar y Imaging • Original Research Pinsky et al. Lung Cancer Risk Associated With New Nodules
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Cardiopulmonary Imaging Original Research
Lung Cancer Risk Associated With New Solid Nodules in the National Lung Screening Trial Paul F. Pinsky 1 David S. Gierada2 P. Hrudaya Nath 3 Reginald Munden 4 Pinsky PF, Gierada DS, Nath PH, Munden R
Keywords: low-dose CT, lung cancer, new nodules, screening DOI:10.2214/AJR.17.18252 Received March 17, 2017; accepted after revision May 2, 2017. The opinions and assertions contained herein are the private views of the authors are not to be construed as official or as representing the views of the National Cancer Institute or the National Institutes of Health. The National Lung Screening Trial was supported by grants and contracts from the National Cancer Institute. No additional funding was obtained for this analysis. 1 Division of Cancer Prevention, National Cancer Institute, 9609 Medical Center Dr, Bethesda, MD 20892. Address correspondence to P. F. Pinsky ([email protected]). 2 Department of Radiology, Washington University School of Medicine, St. Louis, MO. 3 Department of Radiology, University of Alabama at Birmingham School of Medicine, Birmingham, AL. 4 Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC.
AJR 2017; 209:1–6 0361–803X/17/2095–1 © American Roentgen Ray Society
OBJECTIVE. As low-dose CT (LDCT) lung cancer screening moves into routine clinical practice, evaluation of nodules identified as new becomes critical. We examine the frequency and clinical outcomes of new lung nodules reported at the two postbaseline annual screening examinations (hereafter referred to as postbaseline time 1 [T1] and time 2 [T2]), compared with those detected at baseline in the National Lung Screening Trial (NLST). MATERIALS AND METHODS. Radiologists classified nodules detected at T1 and T2 as new or preexisting on the basis of comparison with findings from prior LDCT screening examinations. Subjects were tracked for lung cancer incidence and mortality. We examined the incidence of new nodules and their associated lung cancer risk by nodule size (i.e., mean diameter). RESULTS. A total of 25,002 subjects underwent the baseline LDCT screening examination and either a T1 or T2 LDCT screen. At both T1 and T2, 2.6% of subjects had new solid nodules. Of the new solid nodules, 53.0% were < 6 mm, 29.5% were 6 to < 10 mm, and 17.1% were ≥ 10 mm. Lung cancer risk (defined as diagnosis within 2 years of baseline) increased from 1.1% for nodules < 4 mm to 24.0% for those ≥ 20 mm. Compared with solid nodules detected at baseline, the cancer risk was higher for new solid nodules that were 4 to < 6 mm (p < 0.001) and 6 to < 8 mm (p < 0.001) but lower for new nodules ≥ 20 mm (p = 0.03). Cancers associated with new nodules had significantly poorer survival than did those associated with baseline nodules and were significantly less likely to be adenocarcinoma. CONCLUSION. The incidence of new nodules was 2–3% annually, with the cancer risk increasing by nodule size. New nodules may convey differential lung cancer risks by size, compared with baseline nodules. he National Lung Screening Trial (NLST) showed that screening for lung cancer with lowdose CT (LDCT) reduces death from lung cancer in high-risk current and former smokers [1]. As screening moves from the initial research phase, when the emphasis was disproportionately on baseline screening, to population-based screening, which is recommended annually for up to 25 years, the preponderance of screens in clinical practice going forward likely will be postbaseline screens. Such screens would be expected to have a prior image available for comparison; in a large study of mammography, more than 90% of postbaseline screens had a comparison image available [2]. Comparison images may not be available for baseline screens, and therefore the recent growth history of nodules detected on baseline screens can be unknown. Nodules found to be new on postbaseline screens after com-
T
parison with an earlier image must have grown in the prior year, and thus they may represent a higher risk for lung cancer. Recently, the Dutch-Belgian Randomized Lung Cancer Screening Trial (Dutch acronym: NELSON) reported new solid nodules discovered at two postbaseline screens of approximately 8000 subjects [3]. Several other studies have also reported on the presence of and risk associated with new nodules, including the Mayo Clinic study and the International Early Lung Cancer Action Program [4, 5]. These studies reported rates of 5–13% for the detection of new nodules per annual postbaseline screen [3–5]. Overall lung cancer risks for new nodules were generally approximately 5%. When analyzed by new nodule size, as in the NELSON trial, the cancer risk increased substantially with nodule size [3]. The NLST enrolled more than 25,000 subjects in the LDCT arm; subjects underwent three screening rounds (one at baseline and
AJR:209, November 2017 1
Pinsky et al. 26,309 Subjects
Downloaded from www.ajronline.org by Columbia University on 09/16/17 from IP address 128.59.222.107. Copyright ARRS. For personal use only; all rights reserved
Baseline Screen
25,002 had T1 screen, T2 screen, or both screens
Baseline nodules 5990 Subjects 8811 Nodules
New nodules T1 Screen
24,604 Subjects
T2 Screen
23,972 Subjects
644 Subjects 832 Nodules
New nodules 628 Subjects 822 Nodules
238 Linked Cancers
48 Linked Cancers
46 Linked Cancers
Fig. 1—Flowchart analysis of nodules detected at baseline low-dose CT screening examination and new nodules detected at two annual postbaseline screening examinations performed at time 1 (T1) and time 2 (T2).
two after baseline) [1]. Although the findings from these two postbaseline screening rounds have been previously published, the analyses did not distinguish between preexisting and new nodules [6]. In this study, we analyze findings from the NLST with respect to new solid nodules. Specifically, we examine the frequency and size distribution of new solid nodules and the cancer risk associated with them, as stratified by nodule size. Among cancers linked to new nodules, we examine the relationship between nodule size and stage, histologic findings, and survival. In addition, we compare new nodules with nodules detected at baseline, with respect to nodule size and cancer risk. Materials and Methods National Lung Screening Trial Design
The NLST randomized subjects to undergo either LDCT or chest radiography as a screening examination. Eligibility criteria included a history of smoking (≥ 30 pack-years) and current smoking status or having quit smoking in the past 15 years [5]. Subjects aged 55–74 years were recruited at 33 U.S. centers during 2002–2004 and underwent either LDCT or chest radiography screens at baseline and annually for two more years after baseline (denoted as time 1 [T1] and time 2 [T2]). The NLST was approved by the institutional review board at each participating screening center, and all subjects provided informed consent. No institutional review board approval was required for this secondary analysis. The study protocol defined a noncalcified nodule with a longest diameter of ≥ 4 mm as a positive screening examination result. For each such non-
2
calcified nodule, radiologists used standardized forms to report location (i.e., lung lobe), greatest transverse and perpendicular diameter, margins, and attenuation characteristics. At T1 and T2, they also reported, on the basis of examination of prior images, whether the nodule was preexisting or new. Other abnormalities, including adenopathy or effusion, could also trigger positive screening results. Radiologists also recorded recommendations for diagnostic follow-up, which included LDCT performed at various time intervals (at 3, 3–6, 6, 12, and 24 months), diagnostic CT, CT densitometry, PET, and biopsy. Positive screening results were tracked for resultant diagnostic procedures and lung cancer diagnoses. In addition, subjects were followed by means of annual surveys to ascertain incident cancers and all-cause mortality. All reported cancers were verified with medical records, with stage and histologic findings recorded. Follow-up continued until December 31, 2009.
Quantitative Methods
The analysis included all subjects in the LDCT arm of the trial who underwent screening LDCT at baseline and at least one subsequent screening LDCT examination. The rate of new solid nodules noted at each postbaseline screen was computed as the proportion of all subjects undergoing the screen that had one or more new solid nodules reported. To assess the lung cancer risk associated with new (solid) nodules, the lobe location of the nodule and cancer was analyzed. Specifically, any lung cancer diagnosed within 2 years of the screen at which a new (solid) nodule was first identified and found in the same lung lobe as that new nodule was ascribed (i.e., linked) to that nodule. Note that the NLST did not attempt to link cancers back to specific nodules
as part of the trial findings. Cancer risk was analyzed by new nodule size category as measured by mean diameter (the mean of the longest diameter and longest perpendicular values in the transverse plane), which is more relevant to current screening practice than the longest diameter criterion used to define a positive screen result in the NLST. For multiple new nodules in the same lobe, any cancer in the lobe was ascribed to the largest new nodule in that lobe. To isolate the effects of a given new nodule on cancer risk, we performed an analysis restricted to new nodules with no other new or preexisting (solid) nodules in the same lobe (referred to as “solitary in-lobe nodules”). In addition to nodule size, we also examined nodule margins with respect to cancer risk. Because margins were correlated with nodule size, we stratified nodules into small (
Downloaded from www.ajronline.org by Columbia University on 09/16/17 from IP address 128.59.222.107. Copyright ARRS. For personal use only; all rights reserved
Cardiopulmonary Imaging Original Research
Lung Cancer Risk Associated With New Solid Nodules in the National Lung Screening Trial Paul F. Pinsky 1 David S. Gierada2 P. Hrudaya Nath 3 Reginald Munden 4 Pinsky PF, Gierada DS, Nath PH, Munden R
Keywords: low-dose CT, lung cancer, new nodules, screening DOI:10.2214/AJR.17.18252 Received March 17, 2017; accepted after revision May 2, 2017. The opinions and assertions contained herein are the private views of the authors are not to be construed as official or as representing the views of the National Cancer Institute or the National Institutes of Health. The National Lung Screening Trial was supported by grants and contracts from the National Cancer Institute. No additional funding was obtained for this analysis. 1 Division of Cancer Prevention, National Cancer Institute, 9609 Medical Center Dr, Bethesda, MD 20892. Address correspondence to P. F. Pinsky ([email protected]). 2 Department of Radiology, Washington University School of Medicine, St. Louis, MO. 3 Department of Radiology, University of Alabama at Birmingham School of Medicine, Birmingham, AL. 4 Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC.
AJR 2017; 209:1–6 0361–803X/17/2095–1 © American Roentgen Ray Society
OBJECTIVE. As low-dose CT (LDCT) lung cancer screening moves into routine clinical practice, evaluation of nodules identified as new becomes critical. We examine the frequency and clinical outcomes of new lung nodules reported at the two postbaseline annual screening examinations (hereafter referred to as postbaseline time 1 [T1] and time 2 [T2]), compared with those detected at baseline in the National Lung Screening Trial (NLST). MATERIALS AND METHODS. Radiologists classified nodules detected at T1 and T2 as new or preexisting on the basis of comparison with findings from prior LDCT screening examinations. Subjects were tracked for lung cancer incidence and mortality. We examined the incidence of new nodules and their associated lung cancer risk by nodule size (i.e., mean diameter). RESULTS. A total of 25,002 subjects underwent the baseline LDCT screening examination and either a T1 or T2 LDCT screen. At both T1 and T2, 2.6% of subjects had new solid nodules. Of the new solid nodules, 53.0% were < 6 mm, 29.5% were 6 to < 10 mm, and 17.1% were ≥ 10 mm. Lung cancer risk (defined as diagnosis within 2 years of baseline) increased from 1.1% for nodules < 4 mm to 24.0% for those ≥ 20 mm. Compared with solid nodules detected at baseline, the cancer risk was higher for new solid nodules that were 4 to < 6 mm (p < 0.001) and 6 to < 8 mm (p < 0.001) but lower for new nodules ≥ 20 mm (p = 0.03). Cancers associated with new nodules had significantly poorer survival than did those associated with baseline nodules and were significantly less likely to be adenocarcinoma. CONCLUSION. The incidence of new nodules was 2–3% annually, with the cancer risk increasing by nodule size. New nodules may convey differential lung cancer risks by size, compared with baseline nodules. he National Lung Screening Trial (NLST) showed that screening for lung cancer with lowdose CT (LDCT) reduces death from lung cancer in high-risk current and former smokers [1]. As screening moves from the initial research phase, when the emphasis was disproportionately on baseline screening, to population-based screening, which is recommended annually for up to 25 years, the preponderance of screens in clinical practice going forward likely will be postbaseline screens. Such screens would be expected to have a prior image available for comparison; in a large study of mammography, more than 90% of postbaseline screens had a comparison image available [2]. Comparison images may not be available for baseline screens, and therefore the recent growth history of nodules detected on baseline screens can be unknown. Nodules found to be new on postbaseline screens after com-
T
parison with an earlier image must have grown in the prior year, and thus they may represent a higher risk for lung cancer. Recently, the Dutch-Belgian Randomized Lung Cancer Screening Trial (Dutch acronym: NELSON) reported new solid nodules discovered at two postbaseline screens of approximately 8000 subjects [3]. Several other studies have also reported on the presence of and risk associated with new nodules, including the Mayo Clinic study and the International Early Lung Cancer Action Program [4, 5]. These studies reported rates of 5–13% for the detection of new nodules per annual postbaseline screen [3–5]. Overall lung cancer risks for new nodules were generally approximately 5%. When analyzed by new nodule size, as in the NELSON trial, the cancer risk increased substantially with nodule size [3]. The NLST enrolled more than 25,000 subjects in the LDCT arm; subjects underwent three screening rounds (one at baseline and
AJR:209, November 2017 1
Pinsky et al. 26,309 Subjects
Downloaded from www.ajronline.org by Columbia University on 09/16/17 from IP address 128.59.222.107. Copyright ARRS. For personal use only; all rights reserved
Baseline Screen
25,002 had T1 screen, T2 screen, or both screens
Baseline nodules 5990 Subjects 8811 Nodules
New nodules T1 Screen
24,604 Subjects
T2 Screen
23,972 Subjects
644 Subjects 832 Nodules
New nodules 628 Subjects 822 Nodules
238 Linked Cancers
48 Linked Cancers
46 Linked Cancers
Fig. 1—Flowchart analysis of nodules detected at baseline low-dose CT screening examination and new nodules detected at two annual postbaseline screening examinations performed at time 1 (T1) and time 2 (T2).
two after baseline) [1]. Although the findings from these two postbaseline screening rounds have been previously published, the analyses did not distinguish between preexisting and new nodules [6]. In this study, we analyze findings from the NLST with respect to new solid nodules. Specifically, we examine the frequency and size distribution of new solid nodules and the cancer risk associated with them, as stratified by nodule size. Among cancers linked to new nodules, we examine the relationship between nodule size and stage, histologic findings, and survival. In addition, we compare new nodules with nodules detected at baseline, with respect to nodule size and cancer risk. Materials and Methods National Lung Screening Trial Design
The NLST randomized subjects to undergo either LDCT or chest radiography as a screening examination. Eligibility criteria included a history of smoking (≥ 30 pack-years) and current smoking status or having quit smoking in the past 15 years [5]. Subjects aged 55–74 years were recruited at 33 U.S. centers during 2002–2004 and underwent either LDCT or chest radiography screens at baseline and annually for two more years after baseline (denoted as time 1 [T1] and time 2 [T2]). The NLST was approved by the institutional review board at each participating screening center, and all subjects provided informed consent. No institutional review board approval was required for this secondary analysis. The study protocol defined a noncalcified nodule with a longest diameter of ≥ 4 mm as a positive screening examination result. For each such non-
2
calcified nodule, radiologists used standardized forms to report location (i.e., lung lobe), greatest transverse and perpendicular diameter, margins, and attenuation characteristics. At T1 and T2, they also reported, on the basis of examination of prior images, whether the nodule was preexisting or new. Other abnormalities, including adenopathy or effusion, could also trigger positive screening results. Radiologists also recorded recommendations for diagnostic follow-up, which included LDCT performed at various time intervals (at 3, 3–6, 6, 12, and 24 months), diagnostic CT, CT densitometry, PET, and biopsy. Positive screening results were tracked for resultant diagnostic procedures and lung cancer diagnoses. In addition, subjects were followed by means of annual surveys to ascertain incident cancers and all-cause mortality. All reported cancers were verified with medical records, with stage and histologic findings recorded. Follow-up continued until December 31, 2009.
Quantitative Methods
The analysis included all subjects in the LDCT arm of the trial who underwent screening LDCT at baseline and at least one subsequent screening LDCT examination. The rate of new solid nodules noted at each postbaseline screen was computed as the proportion of all subjects undergoing the screen that had one or more new solid nodules reported. To assess the lung cancer risk associated with new (solid) nodules, the lobe location of the nodule and cancer was analyzed. Specifically, any lung cancer diagnosed within 2 years of the screen at which a new (solid) nodule was first identified and found in the same lung lobe as that new nodule was ascribed (i.e., linked) to that nodule. Note that the NLST did not attempt to link cancers back to specific nodules
as part of the trial findings. Cancer risk was analyzed by new nodule size category as measured by mean diameter (the mean of the longest diameter and longest perpendicular values in the transverse plane), which is more relevant to current screening practice than the longest diameter criterion used to define a positive screen result in the NLST. For multiple new nodules in the same lobe, any cancer in the lobe was ascribed to the largest new nodule in that lobe. To isolate the effects of a given new nodule on cancer risk, we performed an analysis restricted to new nodules with no other new or preexisting (solid) nodules in the same lobe (referred to as “solitary in-lobe nodules”). In addition to nodule size, we also examined nodule margins with respect to cancer risk. Because margins were correlated with nodule size, we stratified nodules into small (
