Sign of lung cancer

Background: Low-radiation-dose spiral CT (LDCT) scanning is capable of detecting lung neoplasms in asymptomatic individuals. To determine whether such detection can reduce lung cancer mortality, a randomized controlled trial (BCT) of LDCT scanning is necessary.

Methods: The feasibility of conducting an RCT in asymptomatic individuals who are at high risk for lung cancer was explored in the Lung Screening Study (LSS), a 12-month special project of the ongoing Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial During the fall of 2000, six PLCO screening centers recruited a total of 3,318 heavy or long-term smokers who were not participants in the PLCO trial and randomized them to receive either a screening LDCT scan (1,660 participants) or screening posteroanterior view chest radiograph (CXR) [1,658 participants].

Results: The screens were completed on 96% of subjects in the LDCT scan arm and 93% of subjects in the CXR arm. A total of 20.5% of screened subjects in the LDCT scan arm and 9.8% of those in the CXR arm had findings that were suspicious for lung cancer. Thirty lung cancers in subjects in the LDCT arm and 7 lung cancers in patients in the CXR arm were diagnosed following a positive screening result. Additional data from the LSS indicated that, among persons who were at elevated risk for lung cancer, CT scan use was not pervasive, interest in participating in an RCT of LDCT scanning was strong, and few subjects randomized to CXR either refused their examination or sought a CT scan after their study CXR.

Interpretation: The results of the LSS demonstrated convincingly the feasibility of an RCT of LDCT scanning in the United States.

(CHEST 2004; 126:114-121)

Key words: chest radiograph; lung cancer: randomized trial; screening; spiral CT scan

Abbreviations: CXR = chest radiograph; ELCAP = Early Lung Cancer Action Project: HU = Hounsfield units; LDCT = low-radiation-dose spiral CT; LSS = Lung Screening Study; NCI = National Cancer Institute; NLST = National Lung Screening Trial; OR = odds ratio: PLCO = Prostate, Lung, Colorectal, and Ovarian; RCT = randomized controlled trial

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Lung cancer is the leading cause of cancer-related mortality in both men and women in the United States. (1) Although the overwhelming majority of lung cancer cases have a known and potentially preventable cause (ie, tobacco use), it is estimated that currently about one half of all lung cancer eases in the United States occur in former tobacco smokers, who remain at elevated risk for lung cancer years after quitting smoking. (2) Thus, although the control of tobacco use is a critical component in the fight against lung cancer (and other diseases), in the foreseeable future successful chemoprevention or early detection of lung cancer in persons with a history of tobacco use or other high-risk exposure will be necessary if lung cancer morbidity and mortality rates are to decline substantially.

Although several approaches for the early detection of lung cancer have been investigated in clinical trials, (3-6) to date none has been shown to be effective in reducing lung cancer mortality. The lung component of the ongoing Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial (7) is currently evaluating the effect of posteroanterior chest radiograph (CXR) screening vs usual care on lung cancer mortality, however, the final results may not be available for several years. Low-radiation-dose spiral CT (LDCT) scanning, an advance in CT scan technology that was introduced in the mid-1990s, offers rapid image acquisition at radiation doses substantially below that of standard CT scanning, although at higher doses than a CXR. (8) Findings from the Early Lung Cancer Action Project (ELCAP) (9) published in 1999 and from a mass screening program in Japan reported in 1998 (10) demonstrated that LDCT scanning could detect lung cancer in asymptomatic subjects with greater sensitivity than could CXRs. The National Cancer Institute (NCI) began deliberations on the feasibility and design of a randomized controlled trial (RCT) to assess the impact on mortality of LDCT scan lung screening in 1999.

To assess the feasibility of conducting a definitive RCT of LDCT scanning, the Division of Cancer Prevention at the NCI conducted the Lung Screening Study (LSS), a pilot RCT of LDCT vs CXR. The primary goals of this project were to determine the following: (1) the feasibility of rapidly accruing high-risk participants who were not actively being screened with spiral CT scans into a study of lung cancer screening, (2) the willingness of study participants to be randomized to either an LDCT scan or a CXR arm and to undergo the appropriate examinations, (3) the likelihood that participants randomized to a CXR would subsequently receive a spiral CT scan examination on their own (and vice versa), (4) the prevalence of abnormal findings on baseline screening, and (5) the extent of diagnostic follow-up subsequent to abnormal screening findings.

MATERIALS AND METHODS

The LSS began as a 1-year special project of the PLCO cancer trial. (7) The PLCO cancer trial provided an established infrastructure, resulting in an acceleration of LSS activities and rapid data collection. The following 6 of 10 PLCO screening centers were chosen, in a competitive fashion, to participate in the LSS: Georgetown University Medical Center/Lombardi Cancer Center (Washington, DC); Henry Ford Health System (Detroit, MI); Marshfield Medical Research and Education Foundation (Marshfield, WI); University of Minnesota School of Public Health/Virginia Piper Cancer Center (Minneapolis, MN); Washington University School of Medicine (St. Louis, MO); and the University of Alabama at Birmingham (Birmingham, AL). Screening centers were responsible for all day-to-day study activities, including recruitment, screening, follow-up, and quality assurance. The NCI was responsible for scientific oversight and data analysis, Mille Westat, Inc (Rockville, MD), the coordinating Renter, was responsible for data management, including titans development, data entry, and systems development.

The LSS sought to recruit, randomize, and screen 3,000 persons who were at elevated risk for lung cancer in a short period of time. Recruitment was accomplished primarily by mass mailings, although other sources, such as posters, advertisements, and recommendations from practitioners, were employed. To be eligible for the LSS, an individual had to be between 55 and 74 years old at the time of randomization, to be either a current cigarette smoker or a former smoker who had quit within the previous 10 years, and to have at least a 30-pack-year history of cigarette smoking. Exclusion criteria included a history of a spiral CT scan examination of the lungs or thorax in the previous 24 months, a history of lung cancer, currently receiving treatment for any cancer other than non-melanoma skin cancer, removal of a portion of a lung or an entire lung, and participation in another cancer screening trial (including the PLCO cancer trial) or a primary cancer prevention trial other than a smoking cessation study. In addition, all persons were required to sign an institutional review board-approved consent from before undergoing randomization.

Once eligibility was established and consent was obtained, participants were randomized, using a secure web-based system that was maintained by the coordinating center, to one of the two study arms, LDCT scan or CXR. Randomization was stratified by age (in 5-year categories), sex, and screening center, using blocks of varying sizes.

LDCT scan examinations were obtained using the following technical parameters: 120 to 140 kilovolt peak, 60 mA, scan time of 1 s, 5-mm collimation, a pitch of 2 or equivalent (depending on the model and type of scanner), and continous reconstructions. In the case of obese participants, the milliampere setting could he raised as high as 120 mA. Images were obtained using a standard algorithm or were reconstructed using a high-resolution bone or lung algorithm. Lung windows (standard width, 1500 Hounsfield units [HU]; standard level -650 HU) and mediastinal windows (standard width, 400 to 500 HU; standard level, 10 to 30 HU) were provided for review, although standard settings could be adjusted to optimize viewings. The use of filters was optional, and, when filmed, a 15 to 20 on one format was used. CXR examinations consisted of a single posteroanterior view and were obtained using equipment with a high kilovolt potential (ie, 110 to 150 kilowatt peak) at a tube-to-receiver distance of 6 to 10 feet. Wide-latitude film with a 12:1 standard grid or higher was used. Screening film and computed radiography systems were used to perform the CXR examinations.