Between January 2002 and April 2005, the PLuSS used advertisements and mass mailings to recruit volunteers with the following characteristics: (1) age 50 to 79 years; (2) no personal lung cancer history; (3) nonparticipation in concurrent lung cancer screening studies; (4) no chest computed tomography (CT) within 12 months; (5) current or ex-cigarette smoker of at least one-half pack per day for at least 25 years, and, if quit, quit for no more that 10 years before study enrollment; and (6) body weight less than 400 pounds. Individuals were not excluded because of symptoms.
Baseline activities included completing a risk factor questionnaire, collecting peripheral blood samples, forced expiratory spirometry conducted and analyzed in accordance with American Thoracic Society standards (18
), low-radiation-dose CT screening, and physician referral for noncalcified lung nodules. Follow-up activities included repeat CT screening after 12 months and active surveillance for lung cancer–related endpoints. Occurring between March 2002 and September 2005 and between March 2003 and November 2006, respectively, subjects received the initial and 1-year repeat CT at study expense.
Of 9,386 persons assessed by telephone for study eligibility, we excluded 4,352 (46.4%) for reasons related to age (n = 84), lung cancer history (n = 60), participation in other lung cancer screening studies (n = 1,043), recent chest CT (n = 120), cigarette smoking history (duration or dose; n = 1,439), duration quit (n = 1,600), and body weight (n = 6) (exclusions applied in sequential fashion). Of 5,034 eligible persons, 1,279 (25.4%) did not accept an enrollment visit and 113 (2.2%) enrolled, but did not return for CT screening. The remaining 3,642 persons, the study population, completed the initial CT screening a median 53 days (range, 2–604 d) after the initial telephone contact. Among eligible persons (n = 5,034), CT screening occurred more frequently in men than women (74.6 vs. 70.2%), more frequently in ex–cigarette smokers than current cigarette smokers (76.7 vs. 69.7%), and more frequently in younger than older persons (72.5, 73.9, and 66.5% in 50- to 59-, 60- to 69-, and 70- to 79-yr-old persons, respectively). Otherwise, CT-screened and unscreened eligible persons were similar with respect to age started smoking, duration of cigarette smoking, and duration quit (among ex-smokers).
Screening CT Imaging Protocol
The lung cancer screening protocol used a single-breath-hold, helical, low-dose technique (40–60 mA, 140 kVp) to obtain axial images reconstructed with a high spatial frequency (lung) algorithm at contiguous 2.5-mm intervals. One of two study radiologists (CRF and SNF) used standard lung windows (1,496/-555) to view images (2.5 mm section thickness) on a PACS monitor display system (Stentor; Radiology Informatics Business Group of Phillips Medical Systems, Foster City, CA). Radiologists adjusted window width and level, as appropriate, to detect calcification in nodules and to evaluate mediastinal structures.
Protocol for Primary Interpretation of the Initial Screening CT
A single study radiologist identified and characterized lung nodules according to size, presence and type of calcification (complete, central target, speckled, or peripheral), attenuation (solid, nonsolid, or mixed), border characteristic (smooth, spiculated, or lobulated), and lobar location. The radiologist used the axial image showing the nodule to its fullest extent to measure maximum nodule diameter and nodule diameter perpendicular to this maximum. Analyses averaged these two diameter measurements to obtain a summary measure of nodule size, the average diameter. The category of calcified nodule included all completely calcified nodules and nodules (≤ 2.0 cm average diameter) with central target or lamellate calcification. Procedures further divided noncalcified nodules into low (< 0.5 cm average diameter or 0.5–0.9 cm average diameter with nonspiculated border) and moderate or high lung cancer suspicion categories (0.5–0.9 cm average diameter with spiculated border or ≥ 1.0 cm average diameter). Finally, the interpreting radiologist used subjective criteria to classify larger noncalcified nodules (≥ 1.0 cm average diameter) into moderate and high lung cancer suspicion categories. The initial CT study received a preliminary summary nodule interpretation (low, moderate, or high lung cancer suspicion) based on the rating of the most suspicious nodule. The radiologist used a locally developed computer database application (programmed in Microsoft Office Access 2003) to enter visual CT findings. The application used pre-programmed algorithms to map the visual findings into lung nodule ratings and summary interpretations, as defined above and summarized in Table E1. Intended to encompass less than 5%, 5 to 50%, and greater than 50% pre-biopsy lung cancer probabilities, respectively, we conceived the low, moderate, and high lung cancer suspicion categories to guide referral recommendations and subsequent diagnostic activity.
Protocol for Primary Interpretation of the Repeat Screening CT
The primary interpretation of the repeat screening CT also included a direct visual comparison of initial and repeat CT images. Specifically, a single study radiologist relocated each noncalcified lung nodule noted at baseline and applied subjective criteria to interpret temporal change according to a forced-choice format (suspicious change vs. no significant change vs. partial resolution vs. complete resolution), with suspicious change defined as increase in size or density of a pre-existing nodule. The radiologist also identified and characterized noncalcified lung nodules, visible on repeat CT images, but not enumerated at baseline. The radiologist used the same forced-choice format to report temporal change in nodules, first identified on the repeat CT images, but visible, in retrospect, on the initial CT images.
A computer algorithm, programmed into our Access database application, assigned the moderate lung cancer suspicion rating to every noncalcified lung nodule that either first appeared on repeat CT or showed suspicious change from baseline. The radiologist was allowed to use subjective criteria to assign a high lung cancer suspicion rating to nodules in this category. The algorithm assigned the low lung cancer suspicion rating to nodules showing no significant change between initial and repeat CT. The repeat screening received a preliminary summary nodule interpretation (low, moderate, or high lung cancer suspicion) based on the rating of the most suspicious nodule.
Secondary Review Procedures
By protocol, a committee that included study radiologists, pulmonologists, and other investigators met in conference and reviewed all CT studies with preliminary moderate or high suspicion nodule interpretations and some low suspicion CT studies with larger (≥ 0.5 cm) nodules. Using subjective clinical criteria and the totality of findings present on all available CT studies, the committee reached consensus regarding a final summary nodule interpretation (no, low, moderate, or high lung cancer suspicion).
For each screening CT study, the investigators prepared a written report containing detailed radiologic findings and final summary interpretations. The subject and one personal physician received the written report, by mail, along with a cover letter and explanatory information. Based on the final summary nodule interpretation, written materials advised physician-directed diagnostic follow-up for persons with moderate to high lung cancer suspicion and interval diagnostic CT follow-up for persons with low lung cancer suspicion. Subjects could also receive a recommendation for physician-directed diagnostic follow-up for central airway abnormalities, thoracic lymph enlargements, or other clinically significant incidental findings.
To coincide with the postal delivery of written reports, a nurse practitioner telephoned every subject with any CT finding that generated a follow-up recommendation. The nurse practitioner summarized relevant CT findings and referral recommendations and described follow-up options, options that could include either a consultation visit with the study pulmonologist (D.O.W.) or a no-fee physician office visit with the principal investigator (JLW). Again, based on the final summary nodule interpretation, the investigators generally advised thoracoscopy with excisional biopsy or mediastinoscopy for persons with high suspicion; additional diagnostic imaging studies (thoracic CT, positron emission tomography [PET], or PET-CT) after no greater than 3-month delay for persons with moderate suspicion; and interval periodic thoracic CT for persons with low suspicion, in accordance with published guidelines. During the first year of our study, we advised repeat CT in 6 months for persons with only small (< 0.4 cm) low suspicion nodules and repeat CT in 3 to 6 months for persons with larger (≥ 0.4 cm) low suspicion nodules. After the first year, we responded to evolving opinion regarding the management of small CT screen-detected nodules (4
) and began to recommend annual repeat CT screening for persons with only micro-nodules (< 0.4 cm) and 6-month CT follow-up for persons with larger (≥ 0.4 cm) nodules.
Tracking/Surveillance of Study Endpoints
To document diagnostic events and outcomes, the nurse practitioner maintained telephone contact with persons who had received a follow-up recommendation. At annual intervals, the investigators used brief telephone interviews and/or mailed questionnaires to update the vital and cancer status of study subjects and to ascertain interval lung biopsy procedures. Follow-up was 99%, 98%, and 80% complete at the 1-, 2-, and 3-year time points, respectively. Using information obtained over the telephone and signed consents, the investigators identified, acquired, and reviewed relevant medical records, including images and reports from imaging studies (thoracic CT, PET, or PET-CT), biopsy procedure reports, pathology reports, and death certificates.
Focusing on clinical indications and outcomes, one author (D.O.W.) reviewed the assembled medical records of (1) every subject who received a lung cancer diagnosis and (2) every subject with a follow-up recommendation who subsequently experienced an invasive diagnostic procedure. The same author and a certified tumor registrar independently staged every lung cancer case and met in conference to reconcile disagreements. We report only lung cancer diagnoses and invasive diagnostic procedures that occurred within 2 years of the repeat CT or, for persons without repeat CT, within 3 years of the initial CT.
The institutional review board for the University of Pittsburgh approved the research.