Lung cancer is the largest single cause of deaths from cancer in the world1-3 and is expected to account for more than 160,000 deaths in the United States during 2013.4 Most patients with lung cancer have smoked cigarettes.5 Of 94 million U.S. smokers, half are former smokers whose risk remains elevated decades after cessation.6
In the National Lung Screening Trial (NLST) of screening for lung cancer in older persons who were heavy smokers,7 mortality from lung cancer was lower with the use of 3 years of annual screening with low-dose helical computed tomography (CT) than with the use of chest radiography.8 In addition, the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO)9 showed that among approximately 30,000 participants with baseline characteristics that were similar to those of the NLST participants, mortality from lung cancer did not differ significantly between participants undergoing screening by means of chest radiography and those receiving usual care,10 confirming the results of previous randomized trials of screening with the use of chest radiography.11-13
The NLST, a joint effort of the Lung Screening Study (LSS) and the American College of Radiology Imaging Network (ACRIN), both funded by the National Cancer Institute (NCI), began randomly assigning participants in August 2002 to annual screening for 3 years with the use of either low-dose CT or chest radiography. Details of the study design7 and the rationale for choosing chest radiography as the control procedure14 have been published previously. A better understanding of the screening process, including the frequency and management of positive screening results, can inform the implementation of lung-cancer screening programs as well as efforts to improve them. Here, we describe the screening, diagnosis, and limited treatment results from the initial round of screening in the NLST.
Methods
Study Participants and Study Conduct
At 33 screening centers, we recruited asymptomatic men and women, 55 to 74 years of age, who had a history of at least 30 pack-years of cigarette smoking and who were either current smokers or had been smokers within the previous 15 years. Participants were randomly assigned to undergo annual screening for 3 years with the use of either low-dose CT or chest radiography. The study was approved by the institutional review board at each study center, and all participants provided written informed consent before undergoing randomization. Details of recruitment and randomization methods have been published previously.7
Screening Equipment and Procedures
Low-dose CT was performed on multidetector helical CT scanners of four or more channels. Single-view posteroanterior chest radiographs were obtained with the use of conventional film or digital radiographic systems. Technical standards and acquisition variables for both low-dose CT and chest radiographic screening have been published previously.7,15-17
Image Interpretation
Results were recorded on forms developed for the study. The screening image was classified as diagnostic, limited but diagnostic, or nondiagnostic, with the reasons documented.
For low-dose CT, all noncalcified nodules with long-axis diameters of 4 mm or greater in the axial plane were considered to be positive for potential lung cancer. For all positive nodules, the anatomical location (lobe), longest axial, perpendicular diameters, margin characteristics, attenuation, and representative slice number were recorded.
For chest radiography, the results were read on original film or digital image. All noncalcified nodules and masses were considered to be potentially positive for lung cancer, and for all positive nodules, the anatomical location, longest perpendicular diameters, and margin characteristics were recorded.
The interpreting radiologist judged whether the screening results were positive on the basis of findings such as noncalcified hilar or mediastinal adenopathy, atelectasis, and pleural disease. Available historical images were reviewed, and all results and recommendations were recorded. Screening results were classified as positive, negative with clinically significant abnormalities, negative with minor abnormalities, or negative with no abnormality. Participants without diagnostic results were considered to be unscreened. Although the NLST had guidelines for the follow-up of positive screening results, radiologists could make diagnostic recommendations as they saw fit. Screening results were reported to the participant and the participant's designated health care provider, by mail, within 4 weeks.
Follow-up of Study Participants
All participants were mailed annual questionnaires (for the LSS participants) or semiannual questionnaires (for the ACRIN participants) ascertaining vital status and interim cancer diagnoses. Among participants with positive screening results or with a diagnosis of lung cancer, all related diagnostic procedures, complications (not reported here), and results were abstracted by certified medical-record abstractors.
For cases of diagnosed lung cancer, the histologic type and grade, tumor stage,18 and initial treatment were documented. To augment the ascertainment of deaths from questionnaires, the National Death Index was also searched through December 31, 2007. Determination of the cause of death led to the discovery of some previously unreported cases of lung cancer, which were also abstracted.
Here, we describe the results of the first round of screening and diagnostic evaluations that were initiated on the basis of positive findings at the screening visit, as well as all cancers diagnosed and treatments initiated at any time after randomization until the second screening, if applicable, or until 1 year after the first screening. A diagnostic evaluation consisted of a series of diagnostic procedures with no more than 12 months between consecutive procedures, including the first screening.
Statistical Analysis
We compared the two screening groups with respect to adherence of the participants to the testing protocol, image quality, types of diagnostic procedures, and results (positive or negative screening result, ultimate diagnosis, and initial treatment information). The results were stratified according to group and, in some cases, age, sex, race, educational level, and smoking history. All tabulations were performed with the use of SAS/STAT software, version 9.1 of the SAS System for Unix or version 9.2 for PC (SAS Institute).
Each screening result was judged to be positive or negative, and a strict algorithm was used to ascertain whether lung cancer was present at the time of screening (see details in the Supplementary Appendix, available with the full text of this article at NEJM.org). Confidence intervals were calculated by means of bootstrapping.19
Results
Recruitment and Randomization
From August 2002 through April 2004, a total of 53,454 participants were enrolled at 33 sites across the United States; 26,722 were randomly assigned to low-dose CT and 26,732 to chest radiography. Figure 1Figure 1Enrollment and Follow-up of the Study Participants after the Initial Screening. shows the follow-up of participants during the trial.20 A total of 8 participants had lung cancer and 7 died before the first scheduled screening. Of the remaining 53,439 participants, 26,715 were in the low-dose CT group and 26,724 were in the radiography group.
Screening
The first scheduled screening examination was performed in 98.0% of the participants (52,344 of 53,439) — specifically, in 98.5% of the participants in the low-dose CT group (26,309 of 26,715) and in 97.4% of those in the chest radiography group (26,035 of 26,724) (Table 1Table 1Baseline Characteristics of the Study Participants, According to Study Group.). Compliance did not differ significantly according to sex, age, race or ethnic group, smoking status, or educational level (Table 1, and Table 1 in the Supplementary Appendix). Four participants undergoing low-dose CT and 13 participants undergoing chest radiography had nondiagnostic results, none of whom received a diagnosis of lung cancer during the follow-up period. The proportion of participants with positive screening results was higher in the low-dose CT group (7191 of 26,309 participants [27.3%]) than in the radiography group (2387 of 26,035 [9.2%]). Rates of positivity increased slightly with older age and a larger number of pack-years of smoking in both screening groups.
The proportion of all screened participants who had negative screening results but potentially clinically significant, noncancerous abnormalities was higher in the low-dose CT group (2695 of 26,309 [10.2%]) than in the radiography group (785 of 26,035 [3.0%]).
Screening Accuracy
During the baseline follow-up period, lung cancer was diagnosed in 292 of the 26,309 participants (1.1%) who underwent low-dose CT screening versus 190 of the 26,035 participants (0.7%) who underwent radiographic screening (Figure 1); 2 cases of lung cancer in each group were first reported in the National Death Index. In the low-dose CT group, 270 (92.5%) of the participants with lung cancer had a positive screening result (a true positive result), 18 (6.2%) had a negative screening result (a false negative result), and 4 (1.4%) missed the screening visit. In the radiography group, 136 (71.6%) of the participants with lung cancer had a positive screening result (a true positive result), 49 (25.8%) had a negative screening result (a false negative result), and 5 (2.6%) missed the screening visit. The sensitivity and specificity were 93.8% (270 of 288; 95% confidence interval [CI], 90.6 to 96.3) and 73.4% (19,043 of 25,954; 95% CI, 72.8 to 73.9), respectively, for low-dose CT and 73.5% (136 of 185; 95% CI, 67.2 to 79.
and 91.3% (23,547 of 25,790; 95% CI, 91.0 to 91.6), respectively, for chest radiography.
In the low-dose CT group, the positive predictive value for any positive finding that led to a biopsy procedure was 52.9% (265 of 501; 95% CI, 48.4 to 57.4), but the positive predictive value for positive screening results overall was only 3.8% (270 of 7181; 95% CI, 3.3 to 4.2) (Table 2Table 2Frequency and Positive Predictive Value of Positive Screening Results, According to Study Group.). The positive predictive value for pulmonary nodules 4 mm or more in the longest diameter was 3.8% (267 of 7010; 95% CI, 3.4 to 4.3); the value increased from 0.5% to 41.3% as the diameter of the nodule increased from 4 to 6 mm to more than 30 mm. The positive predictive value for noncalcified hilar or mediastinal adenopathy was 18.5% (51 of 276; 95% CI, 14.1 to 23.4). Overall, with low-dose CT, the negative predictive value was 99.9% (19,043 of 19,061; 95% CI, 99.86 to 99.94).
In the radiography group, the positive predictive value was 70.2% (132 of 188; 95% CI, 64.0 to 76.
for a positive screening result that led to a biopsy procedure but only 5.7% (136 of 2379; 95% CI, 4.8 to 6.6) for positive screening results overall (Table 2). The positive predictive value for pulmonary nodules was 5.8% (123 of 2105; 95% CI, 4.9 to 6.9); the value increased from 1.0% to 39.3% as the diameter of the nodule increased from 4 to 6 mm to more than 30 mm. The positive predictive value for noncalcified hilar or mediastinal adenopathy was 9.3% (8 of 86; 95% CI, 3.8 to 15.
. Overall the negative predictive value was 99.8% (23,547 of 23,596; 95% CI, 99.7 to 99.
.
The positive predictive values for atelectasis and consolidation could not be reliably estimated because, unlike pulmonary nodules 4 mm or greater in the longest diameter, these findings were not always considered to be positive and, even when reported on a positive screening result, they often coexisted with pulmonary nodules and so may not have determined a positive screening test.
Diagnostic Follow-up Procedures
Of the 9578 participants with positive screening results, 9397 (98.1%) had completely documented diagnostic follow-up. At least one diagnostic procedure was performed in 6369 of 7049 participants (90.4%) in the low-dose CT group and in 2176 of 2438 participants (92.7%) in the radiography group (Table 3Table 3Diagnostic Follow-up of Positive Screening Results among the 9397 Patients with Data, According to Study Group and Lung-Cancer Status.). A total of 5717 participants (81.1%) and 2010 (85.6%) participants in the two groups, respectively, underwent at least one follow-up imaging procedure, with chest CT performed in 5153 (73.1%) and 1546 (65.8%) and 18F-fluorodeoxyglucose–positron-emission tomography (FDG-PET) performed in 728 (10.3%) and 179 (7.6%); 155 (2.2%) and 83 (3.5%) underwent at least one percutaneous cytologic or biopsy procedure; 306 (4.3%) and 107 (4.6%) underwent at least one bronchoscopy (with or without transbronchial biopsy); and 297 (4.2%) and 121 (5.2%) underwent at least one diagnostic surgical procedure. In the low-dose CT group, thoracoscopy was performed in 44 participants with true positive results and in 38 participants with false positive results. In the radiography group, thoracoscopy was performed in 14 participants and 8 participants with true positive results and false positive results, respectively.
Because some of the imaging procedures were performed more than once in the same participant, a comparison of the total numbers of procedures in the two groups may best reflect the diagnostic burden. In the low-dose CT group, a total of 10,313 imaging procedures were performed, including 7288 chest CT examinations, as compared with 3657 imaging procedures in the radiography group, including 2158 chest CT examinations.
Procedure records were collected routinely only for participants with a positive screening result. However, participants with a negative screening result may also have undergone diagnostic procedures prompted by the screening result; thus, the data shown in Table 3 underrepresent the total number of procedures prompted by the screening examination.
Stage, Histologic Features, and Treatment of Lung Cancer
There were 292 cases of diagnosed lung cancer in the low-dose CT group and 190 in the radiography group, with the difference nearly completely accounted for by the higher incidence of stage IA cancer in the low-dose CT group (132 cases, vs. 46 in the radiography group). Table 4Table 4Stage and Histologic Features of Lung Cancers, According to Study Group and Screening Result. shows the characteristics of the diagnosed lung cancers. There was no significant difference in the total number of lung cancers in stages IIB through IV between the low-dose CT group and the radiography group (120 vs. 112). There were many more bronchioloalveolar carcinomas and adenocarcinomas in the low-dose CT group than in the radiography group (38 vs. 8 and 123 vs. 71, respectively), but the frequencies of other histologic features were similar in the two groups. More patients with lung cancer were treated with some combination of surgery, chemotherapy, and radiotherapy in the low-dose CT group than in the radiography group (277 vs. 181), but stage IA cancers that were treated only with surgery accounted for most of the difference (117 such cancers in the low-dose CT group vs. 40 in the radiography group) (Table 2 in the Supplementary Appendix). Only 10 patients in the low-dose CT group and 6 patients in the radiography group received no treatment at all. However, for each cancer stage, the relative frequencies of treatment types did not differ significantly between the two screening groups (Table 1 in the Supplementary Appendix).
Θέμα: Αξονική χαμηλής δόσης ή ακτινογραφία στο screening για καρκίνο του πνεύμονα; (Αναγνώστηκε 72823 φορές)
31 Αυγούστου 2009, 22:30:29