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Background: Cancer screening trials have required large sample sizes and long time-horizons to demonstrate cancer mortality reductions, the primary goal of cancer screening. We examine assumptions and potential power gains from exploiting information from testing control-arm specimens, which we call the "intended effect" (IE) analysis that we explain in detail herein. The IE analysis is particularly suited to tests that can be conducted on stored specimens in the control arm, such as stored blood for multicancer detection (MCD) tests., Methods: We simulated hypothetical MCD screening trials to compare power and sample size for the standard vs IE analysis. Under two assumptions that we detail herein, we projected the IE analysis for 3 existing screening trials (National Lung Screening Trial [NLST], Minnesota Colon Cancer Control Study [MINN-FOBT-A], and Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial-colorectal component [PLCO-CRC])., Results: Compared with the standard analysis for the 3 existing trials, the IE design could have reduced cancer-specific mortality P values 6-fold (NLST), 33-fold (MINN-FOBT-A), or 260 000-fold (PLCO-CRC) or, alternately, reduced sample size (90% power) by 25% (NLST), 47% (MINN-FOBT-A), or 63% (PLCO-CRC). For potential MCD trial designs requiring 100 000 subjects per arm to achieve 90% power for multicancer mortality for the standard analysis, the IE analysis achieves 90% power for only 37 500-50 000 per arm, depending on assumptions concerning control-arm test-positives., Conclusions: Testing stored specimens in the control arm of screening trials to conduct the IE analysis could substantially increase power to reduce sample size or accelerate trials and could provide particularly strong power gains for MCD tests., (Published by Oxford University Press 2024.)

Background: Cancer screening trials have required large sample sizes and long time-horizons to demonstrate cancer mortality reductions, the primary goal of cancer screening. We examine assumptions and potential power gains from exploiting information from testing control-arm specimens, which we call the "intended effect" (IE) analysis that we explain in detail herein. The IE analysis is particularly suited to tests that can be conducted on stored specimens in the control arm, such as stored blood for multicancer detection (MCD) tests., Methods: We simulated hypothetical MCD screening trials to compare power and sample size for the standard vs IE analysis. Under two assumptions that we detail herein, we projected the IE analysis for 3 existing screening trials (National Lung Screening Trial [NLST], Minnesota Colon Cancer Control Study [MINN-FOBT-A], and Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial-colorectal component [PLCO-CRC])., Results: Compared with the standard analysis for the 3 existing trials, the IE design could have reduced cancer-specific mortality P values 5-fold (NLST), 33-fold (MINN-FOBT-A), or 14 160-fold (PLCO-CRC) or, alternately, reduced sample size (90% power) by 26% (NLST), 48% (MINN-FOBT-A), or 59% (PLCO-CRC). For potential MCD trial designs requiring 100 000 subjects per arm to achieve 90% power for multicancer mortality for the standard analysis, the IE analysis achieves 90% power for only 37 500-50 000 per arm, depending on assumptions concerning control-arm test-positives., Conclusions: Testing stored specimens in the control arm of screening trials to conduct the IE analysis could substantially increase power to reduce sample size or accelerate trials and could provide particularly strong power gains for MCD tests., (Published by Oxford University Press 2024.)

Background: Screening tests are typically evaluated for a single disease, but multiple tests for multiple diseases are performed in practice. The Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial assessed testing for four cancers simultaneously and can be viewed as a multiphasic cancer intervention. This paper presents overall and multiphasic findings of this trial., Methods: The PLCO trial was a randomized multi-center trial conducted at ten screening centers in the US. Participants were 76,682 men and 78,215 women ages 55 - 74 and free of the target cancers at trial entry. Screening tests were PSA and digital rectal examination for prostate cancer, chest x-ray for lung cancer, flexible sigmoidoscopy for colorectal cancer, CA125 and transvaginal ultrasound for ovarian cancer. Outcomes and harms of screening were assessed including compliance, test results, incidence, mortality, false positives and overdiagnosis., Results: Screening compliance was 82%, 72,820 (8%) of 906,064 exams were positive, the overall PPV was 4.2% and the cancer detection rate was 3.38/1000. A mortality reduction was observed only for colorectal cancer (RR 0.72, 95% CI 0.61 - 0.85) with no effect on all-cause mortality. Ninety-six percent of positive exams were falsely positive and there was a suggestion of overdiagnosis of prostate and possibly ovarian cancers. Multiphasic testing resulted in 7374 men and 2748 women experiencing multiple false positive results from multiple types of tests., Conclusion: Multiphasic cancer screening led to reduced mortality for one target cancer and imposed a burden on the health care system that included substantial false positives and likely overdiagnosis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Biomedical research cannot succeed without funding, knowledgeable staff, and appropriate infrastructure. There are however equally important but intangible factors that are rarely considered in planning large multidisciplinary endeavors or evaluating their success. The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial required extensive collaborations between individuals from many fields, including clinicians, clinical trialists, and administrators; it also addressed questions across the spectrum of cancer prevention and control. In this manuscript, we examine the experiences and opinions of trial staff regarding the building of successful relationships in PLCO. We summarize, in narrative form, data collected using open-ended questionnaires that were administered to the National Cancer Institute project officers, coordinating center staff, screening center principal investigators, and screening center coordinators in 2015, about 3 years after publication of the final primary trial manuscript. Trust, respect, listening to others, and in-person interaction were frequently mentioned as crucial to building successful relationships.

There were significant recruitment challenges specific to the PLCO Cancer Screening Trial. Large numbers of participants were to be randomized from ten catchment areas nationwide within time and budgetary constraints. The eligible population was elderly and had to meet health and behavioral thresholds. Informed consent was required to participate and be randomized to screening for three cancers at periodic clinic visits or to a usual care arm that included no clinical visits. Consenting required special efforts to fully explain the trial and its potential scientific benefit to future patients with potentially no benefits but possible harms to PLCO participants. Participation would include continued follow-up for at least 13 years after randomization. Strong collaborative investments were required by the NCI and screening centers (SCs) to assure timely recruitment and appropriate racial participation. A trial-wide pilot phase tested recruitment and protocol follow through at SCs and produced a vanguard population of 11,406 participants. NCI announced the trial nationally in advance of the pilot and followed with an even more intense collaborative role with SCs for the main phase to facilitate trial-wide efficient and timely recruitment. Special efforts to enhance recruitment in the main phase included centralized and local monitoring of progress, cross-linking SCs to share experiences in problem solving, centralized training, substantial additional funding dedicated to recruitment and retention, including specialized programs for minority recruitment, obtaining national endorsement by the American Cancer Society, launching satellite recruitment and screening centers, including minority focused satellites, and adding a new SC dedicated to minority recruitment.

The randomized PLCO trial was designed to answer four primary questions: does screening for these cancers using often promoted tests reduce cancer-specific mortality? Nearly 155,000 men and women were allocated to screening or usual care arms in a 1:1 ratio under a centralized, secure randomization algorithm at ten competitively selected screening centers nationwide. Screened men received PSA blood tests and digital rectal examinations. Screened women received CA125 blood tests and trans-vaginal ultrasound. Both men and women in the screened arm received anterolateral view chest x-ray and 60 cm flexible sigmoidoscopy. Blood specimens were collected at each screening visit and buccal cell DNA was collected once from the usual care participants. Histology slides were collected for cancer cases. Participants completed a baseline questionnaire covering health and risk factors and a dietary questionnaire. Data collected on standardized machine-readable forms were scanned remotely at screening and laboratory sites utilizing PLCO dedicated, NCI provided and configured computer systems for quality checks, archiving, and analysis. Comprehensive quality assurance was implemented over recruitment, consenting, randomization, screening, data management, records keeping, patient-specific screening results reporting, follow-up, and data analysis. Performance and data quality were monitored on-site and remotely by data edits, site visits, and random record audits. Specially trained and certified professionals performed screening procedures and medical record abstracting. An independent committee of medical specialists reviewed and certified case-specific cause of death. Scientific leadership was provided by NCI Project Officers, PLCO principal investigators, external consultants, and an independent data and safety monitoring board.

The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial is a large-scale research effort conducted by the National Cancer Institute. PLCO offers an example of coordinated research by both the extramural and intramural communities of the National Institutes of Health. The purpose of this article is to describe the PLCO research resource and how it is managed and to assess the productivity and the costs associated with this resource. Such an in-depth analysis of a single large-scale project can shed light on questions such as how large-scale projects should be managed, what metrics should be used to assess productivity, and how costs can be compared with productivity metrics. A comprehensive publication analysis identified 335 primary research publications resulting from research using PLCO data and biospecimens from 2000 to 2012. By the end of 2012, a total of 9679 citations (excluding self-citations) have resulted from this body of research publications, with an average of 29.7 citations per article, and an h index of 45, which is comparable with other large-scale studies, such as the Nurses' Health Study. In terms of impact on public health, PLCO trial results have been used by the US Preventive Services Task Force in making recommendations concerning prostate and ovarian cancer screening. The overall cost of PLCO was $454 million over 20 years, adjusted to 2011 dollars, with approximately $37 million for the collection, processing, and storage of biospecimens, including blood samples, buccal cells, and pathology tissues.

Lung cancer is the major cause of cancer mortality. One of the aims of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) was to determine if annual screening chest radiographs reduce lung cancer mortality. We enrolled 154,900 individuals, aged 55-74 years; 77,445 were randomized to the intervention arm and received an annual chest radiograph for 3 or 4 years. Participants with a positive screen underwent diagnostic evaluation under guidance of their primary physician. Methods of diagnosis or exclusion of cancer, interval from screen to diagnosis, and factors predicting diagnostic testing were evaluated. One or more positive screens occurred in 17% of participants. Positive screens resulted in biopsy in 3%, with 54% positive for cancer. Biopsy likelihood was associated with a mass, smoking, age, and family history of lung cancer. Diagnostic testing stopped after a chest radiograph or computed tomography/magnetic resonance imaging in over half. After a second or subsequent positive screen, evaluation stopped after comparison to prior radiographs in over half. Of 308 screen-detected cancers, the diagnosis was established by thoracotomy/thoracoscopy in 47.7%, needle biopsy in 27.6%, bronchoscopy in 20.1% and mediastinoscopy in 2.9%. Eighty-four percent of screen-detected lung cancers were diagnosed within 6 months. Diagnostic evaluations following a positive screen were conducted in a timely fashion. Lung cancer was diagnosed by tissue biopsy or cytology in all cases. Lung cancer was excluded during evaluation of positive screening examinations by clinical or radiographic evaluation in all but 1.4% who required a tissue biopsy., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Context: The effect on mortality of screening for lung cancer with modern chest radiographs is unknown., Objective: To evaluate the effect on mortality of screening for lung cancer using radiographs in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial., Design, Setting, and Participants: Randomized controlled trial that involved 154,901 participants aged 55 through 74 years, 77,445 of whom were assigned to annual screenings and 77,456 to usual care at 1 of 10 screening centers across the United States between November 1993 and July 2001. The data from a subset of eligible participants for the National Lung Screening Trial (NLST), which compared chest radiograph with spiral computed tomographic (CT) screening, were analyzed., Intervention: Participants in the intervention group were offered annual posteroanterior view chest radiograph for 4 years. Diagnostic follow-up of positive screening results was determined by participants and their health care practitioners. Participants in the usual care group were offered no interventions and received their usual medical care. All diagnosed cancers, deaths, and causes of death were ascertained through the earlier of 13 years of follow-up or until December 31, 2009., Main Outcome Measures: Mortality from lung cancer. Secondary outcomes included lung cancer incidence, complications associated with diagnostic procedures, and all-cause mortality., Results: Screening adherence was 86.6% at baseline and 79% to 84% at years 1 through 3; the rate of screening use in the usual care group was 11%. Cumulative lung cancer incidence rates through 13 years of follow-up were 20.1 per 10,000 person-years in the intervention group and 19.2 per 10,000 person-years in the usual care group (rate ratio [RR]; 1.05, 95% CI, 0.98-1.12). A total of 1213 lung cancer deaths were observed in the intervention group compared with 1230 in usual care group through 13 years (mortality RR, 0.99; 95% CI, 0.87-1.22). Stage and histology were similar between the 2 groups. The RR of mortality for the subset of participants eligible for the NLST, over the same 6-year follow-up period, was 0.94 (95% CI, 0.81-1.10)., Conclusion: Annual screening with chest radiograph did not reduce lung cancer mortality compared with usual care., Trial Registration: clinicaltrials.gov Identifier: NCT00002540.

Introduction: Identification of individuals at high risk for lung cancer should be of value to individuals, patients, clinicians, and researchers. Existing prediction models have only modest capabilities to classify persons at risk accurately., Methods: Prospective data from 70 962 control subjects in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) were used in models for the general population (model 1) and for a subcohort of ever-smokers (N = 38 254) (model 2). Both models included age, socioeconomic status (education), body mass index, family history of lung cancer, chronic obstructive pulmonary disease, recent chest x-ray, smoking status (never, former, or current), pack-years smoked, and smoking duration. Model 2 also included smoking quit-time (time in years since ever-smokers permanently quit smoking). External validation was performed with 44 223 PLCO intervention arm participants who completed a supplemental questionnaire and were subsequently followed. Known available risk factors were included in logistic regression models. Bootstrap optimism-corrected estimates of predictive performance were calculated (internal validation). Nonlinear relationships for age, pack-years smoked, smoking duration, and quit-time were modeled using restricted cubic splines. All reported P values are two-sided., Results: During follow-up (median 9.2 years) of the control arm subjects, 1040 lung cancers occurred. During follow-up of the external validation sample (median 3.0 years), 213 lung cancers occurred. For models 1 and 2, bootstrap optimism-corrected receiver operator characteristic area under the curves were 0.857 and 0.805, and calibration slopes (model-predicted probabilities vs observed probabilities) were 0.987 and 0.979, respectively. In the external validation sample, models 1 and 2 had area under the curves of 0.841 and 0.784, respectively. These models had high discrimination in women, men, whites, and nonwhites., Conclusion: The PLCO lung cancer risk models demonstrate high discrimination and calibration.

Background: The 5-year overall survival rate of lung cancer patients is approximately 15%. Most patients are diagnosed with advanced-stage disease and have shorter survival rates than patients with early-stage disease. Although screening for lung cancer has the potential to increase early diagnosis, it has not been shown to reduce lung cancer mortality rates. In 1993, the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was initiated specifically to determine whether screening would reduce mortality rates from PLCO cancers., Methods: A total of 77 464 participants, aged 55-74 years, were randomly assigned to the intervention arm of the PLCO Cancer Screening Trial between November 8, 1993, and July 2, 2001. Participants received a baseline chest radiograph (CXR), followed by three annual single-view CXRs at the 10 US screening centers. Cancers were classified as screen detected and nonscreen detected (interval or never screened) and according to tumor histology. The positivity rates of screen-detected cancers and positive predictive values (PPVs) were calculated. Because 51.6% of the participants were current or former smokers, logistic regression analysis was performed to control for smoking status. All statistical tests were two-sided., Results: Compliance with screening decreased from 86.6% at baseline to 78.9% at the last screening. Overall positivity rates were 8.9% at baseline and 6.6%-7.1% at subsequent screenings; positivity rates increased modestly with smoking risk categories (P(trend) < .001). The PPVs for all participants were 2.0% at baseline and 1.1%, 1.5%, and 2.4% at years 1, 2, and 3, respectively; PPVs in current smokers were 5.9% at baseline and 3.3%, 4.2%, and 5.6% at years 1, 2, and 3, respectively. A total of 564 lung cancers were diagnosed, of which 306 (54%) were screen-detected cancers and 87% were non-small cell lung cancers. Among non-small cell lung cancers, 59.6% of screen-detected cancers and 33.3% of interval cancers were early (I-II) stage., Conclusions: The PLCO Cancer Screening Trial demonstrated the ability to recruit, retain, and screen a large population over multiple years at multiple centers. A higher proportion of screen-detected lung cancers were early stage, but a conclusion on the effectiveness of CXR screening must await final PLCO results, which are anticipated at the end of 2015.

Background: : Two randomized controlled trials of lung cancer screening initiated in the 1970s, the Johns Hopkins Lung Project and the Memorial Sloan-Kettering Lung Study, compared 1 arm that received annual chest X-ray and 4-monthly sputum cytology (dual-screen) to a second arm that received annual chest X-ray only. Previous publications from these trials reported similar lung cancer mortality between the 2 groups. However, these findings were based on incomplete follow-up, and each trial on its own was underpowered to detect a modest mortality benefit., Methods: : The authors estimated the efficacy of lung cancer screening with sputum cytology in an intention-to-screen analysis of lung cancer mortality, using combined data from these trials (n = 20,426)., Results: : Over (1/2) of squamous cell lung cancers diagnosed in the dual-screen group were identified by cytology; these cancers tended to be more localized than squamous cancers diagnosed in the X-ray only arm. After 9 years of follow-up, lung cancer mortality was slightly lower in the dual-screen than in the X-ray only arm (rate ratio [RR], 0.88; 95% confidence interval [CI], 0.74-1.05). Reductions were seen for squamous cell cancer deaths (RR, 0.79; 95% CI, 0.54-1.14) and in the heaviest smokers (RR, 0.81; 95% CI, 0.67-1.00). There were also fewer deaths from large cell carcinoma in the dual-screen group, although the reason for this is unclear., Conclusions: : These data are suggestive of a modest benefit of sputum cytology screening, although we cannot rule out chance as an explanation for these findings. Cancer 2009. (c) 2009 American Cancer Society.

Introduction: Chest radiographs are routinely employed in clinical practice. Radiographic findings that are abnormal suspicious (AS) for lung cancer occur commonly. The majority of AS radiographic abnormalities are not cancer. This study identifies predictors of true positive (TP) AS and presents models for estimating the probability of lung cancer., Methods: This is a prospective cohort study nested in the randomized National Cancer Institute's Prostate Lung Colorectal Ovarian Cancer Screening Trial (PLCO). First-time AS screens in the screening arm of the PLCO were studied. Associations between nonradiographic and radiographic factors, and TP AS were evaluated by multiple logistic regression., Results: The PLCO intervention arm had 77,465 individuals, of whom 12,314 were AS and of these 232 (1.9%) had lung cancer (were TP). Important independent predictors of TP were older age, lower education, greater pack years and duration smoking history, body mass index <30, family history of lung cancer, lung nodule, lung mass, unilateral mediastinal or hilar lymphadenopathy, lung infiltrate, and upper/middle chest AS location. The model including these variables had a receiver operator characteristic area under the curve (ROC AUC) of 86.4%. This model excluding the smoking variables had an ROC AUC of 77.1% and excluding all nonradiographic variables had an ROC AUC of 73.3% (p < 0.0001 for all these model differences). Smoking and nonsmoking nonradiographic variables significantly added to prediction., Conclusion: This study identifies important nonradiographic and radiographic predictors of lung cancer, and presents an accurate model for estimating the probability of lung cancer in individuals with suspicious radiographs. These findings may be of value for screening, research, and patient and clinician decision-making.

Purpose: Multiple cancer screening tests have been advocated for the general population; however, clinicians and patients are not always well-informed of screening burdens. We sought to determine the cumulative risk of a false-positive screening result and the resulting risk of a diagnostic procedure for an individual participating in a multimodal cancer screening program., Methods: Data were analyzed from the intervention arm of the ongoing Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, a randomized controlled trial to determine the effects of prostate, lung, colorectal, and ovarian cancer screening on disease-specific mortality. The 68,436 participants, aged 55 to 74 years, were randomized to screening or usual care. Women received serial serum tests to detect cancer antigen 125 (CA-125), transvaginal sonograms, posteroanterior-view chest radiographs, and flexible sigmoidoscopies. Men received serial chest radiographs, flexible sigmoidoscopies, digital rectal examinations, and serum prostate-specific antigen tests. Fourteen screening examinations for each sex were possible during the 3-year screening period., Results: After 14 tests, the cumulative risk of having at least 1 false-positive screening test is 60.4% (95% CI, 59.8%-61.0%) for men, and 48.8% (95% CI, 48.1%-49.4%) for women. The cumulative risk after 14 tests of undergoing an invasive diagnostic procedure prompted by a false-positive test is 28.5% (CI, 27.8%-29.3%) for men and 22.1% (95% CI, 21.4%-22.7%) for women., Conclusions: For an individual in a multimodal cancer screening trial, the risk of a false-positive finding is about 50% or greater by the 14th test. Physicians should educate patients about the likelihood of false positives and resulting diagnostic interventions when counseling about cancer screening.

Background: Some non-small cell lung cancers (NSCLC) progress to distant lymph nodes or metastasize while relatively small. Such small aggressive NSCLCs (SA-NSCLC) are no longer resectable with curative intent, carry a grave prognosis, and may involve unique biological pathways. This is a study of factors associated with SA-NSCLC., Methods: A nested case-case study was embedded in the National Cancer Institute's Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. SA-NSCLC cases had stage T1, N3, and/or M1 NSCLC (n = 48) and non-SA-NSCLC cases had T2 to T3, N0 to N2, and M0 NSCLC (n = 329). Associations were assessed by multiple logistic regression., Results: SA-NSCLCs were associated with younger age at diagnosis [odds ratio (OR)(>or=65 versus <65), 0.44; 95% confidence interval (95% CI), 0.22-0.88], female gender, family history of lung cancer, and the interaction gender*family history of lung cancer and were inversely associated with ibuprofen use (OR(yes versus no), 0.29; 95% CI, 0.11-0.76). The ORs for associating gender (women versus men) with SA-NSCLC in those with and without a family history of lung cancer were 11.76 (95% CI, 2.00-69.22) and 1.86 (95% CI, 0.88-3.96), respectively. These associations held adjusted for histology and time from screening to diagnosis and when alternative controls were assessed., Conclusion: SA-NSCLC was associated with female gender, especially in those with a family history of lung cancer. If these exploratory findings, which are subject to bias, are validated as causal, elucidation of the genetic and female factors involved may improve understanding of cancer progression and lead to preventions and therapies. Ibuprofen may inhibit lung cancer progression.

Background: The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial was initiated in 1992 to examine cause-specific mortality reduction from screening for these four cancers in men and women. We report lung cancer detection results of the baseline screening round., Methods: Of the 154,942 participants enrolled, who were aged 55-74 years with no history of PLCO cancers, 77,465 were randomly assigned to the intervention arm. Current or former smokers and never smokers in this arm received an initial single-view posterior-anterior chest radiograph., Results: In the initial screen, 5991 (8.9%, 95% confidence interval [CI] = 8.7% to 9.2%) of radiographs were suspicious for lung cancer: 8.2% (95% CI = 7.9% to 8.5%) for women and 9.6% (95% CI = 9.3% to 10.0%) for men. Rates were highest for older age groups and for smokers. Among those 5991 participants with a positive screen, 206 (3.4%, 95% CI = 3.0% to 3.9%) underwent biopsy examination, 126 (61.2%, 95% CI = 54.5% to 67.8%) of whom were diagnosed with lung cancer within 12 months of the screen (59 in women and 67 in men). The positive predictive value was 2.1% (95% CI = 1.7% to 2.5%), and 1.9 lung cancers were detected per 1000 screens. Among these cancers, 44% (95% CI = 35% to 52%) were stage I non-small-cell lung cancer. High rates of lung cancer were found in current smokers (6.3 per 1000 screens) and in former smokers who had smoked within the past 15 years (4.9 per 1000 screens). The lung cancer detection rate among never smokers was 0.4 per 1000 screens; this group accounted for 11% (95% CI = 5.6% to 16.6%) of the cancers identified., Conclusions: In the baseline screen, nearly half the cancers were stage I. Whether this experience results in a reduction in lung cancer mortality is yet to be seen.

The Lung Screening Study (LSS) was a pilot study designed to assess the feasibility of conducting a large scale randomized controlled trial (RCT) of low radiation dose spiral computed tomography (LDCT) versus chest X-ray (CXR) for lung cancer screening. Baseline results of LSS have been previously reported. Here, we report on the findings at the year one screen and on the final results of the LSS study. A total of 1660 subjects were randomized to the LDCT arm and 1658 to the CXR arm. Compliance with screening declined from 96% at baseline to 86% at year one in the LDCT arm and declined from 93% at baseline to 80% at year one in the CXR arm. Positivity rates for the year one screen were 25.8% for LDCT and 8.7% for CXR. Cancer yield was significantly less at year one for LDCT, 0.57%, than at baseline, 1.9%; cancer yield for CXR increased from 0.45% at baseline to 0.68% at year one. Forty lung cancers in the LDCT arm and 20 in the CXR arm were diagnosed over the study period. Stage I cancers comprised 48% of cases in the LDCT arm and 40% in the CXR arm. A total of 16 stage III-IV cancers were observed in the LDCT arm versus nine in the CXR arm. The LSS has established the feasibility of a RCT comparing annual spiral CT to chest X-ray for lung cancer screening.

The Prostate, Lung, Cancer, and Ovarian Cancer Screening Trial is a randomized, multicenter, study evaluating whether screening for prostate, lung, colon, and ovarian cancer will reduce cancer-specific mortality. More than 155,000 participants have been identified and will be monitored through 2015. A biorepository of screened individuals and control participants has been created. Together, the data derived from the intervention and control arms and material in the biorepository provide a valuable resource to allow identification and testing of novel biomarkers for human disease., (Copyright 2004 Elsevier Inc.)

The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial is enrolling 148,000 men and women ages 55-74 at ten screening centers nationwide with balanced randomization to intervention and control arms. For prostate cancer, men receive a digital rectal examination and a blood test for prostate-specific antigen. For lung cancer, men and women receive a posteroanterior view chest X-ray. For colorectal cancer, men and women undergo a 60-cm flexible sigmoidoscopy. For ovarian cancer, women receive a blood test for the CA125 tumor marker and transvaginal ultrasound. Members of the control arm continue with their usual care. Follow-up in both groups will continue for at least 13 years from randomization to assess health status and cause of death. The primary endpoint is mortality from the four PLCO cancers, which accounts for about 53% of all cancer deaths in men and 41% of cancer deaths in women in the United States each year. Blood specimens are collected from screened participants, buccal cell DNA from controls, and histology slides from cases; these are maintained in a biorepository. Participants complete a baseline questionnaire (covering health status and risk factors) and a dietary questionnaire. More than 12,000 participants were enrolled in the pilot phase (concluded in September 1994). Changes in the eligibility criteria followed. As of April 2000, enrollment exceeded 144,500. Data are scanned into designated on-site computers for uploading by participant identification number to the coordinating center for quality checks, archival storage, and preparation of analysis datasets for use by the National Cancer Institute (NCI). Scientific direction is provided by NCI scientists, trial investigators, external consultants, and an independent data safety and monitoring board. Performance and data quality are monitored via data edits, site visits, random record audits, and teleconferences. The PLCO trial is formally endorsed by the American Cancer Society and has been ranked by the American Urological Association as one of the most important prostate cancer studies being conducted. Special efforts to enroll black participants are cosponsored by the U.S. Centers for Disease Control and Prevention.

The objectives of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial are to determine in screenees ages 55-74 at entry whether screening with flexible sigmoidoscopy (60-cm sigmoidoscope) can reduce mortality from colorectal cancer, whether screening with chest X-ray can reduce mortality from lung cancer, whether screening men with digital rectal examination (DRE) plus serum prostate-specific antigen (PSA) can reduce mortality from prostate cancer, and whether screening women with CA125 and transvaginal ultrasound (TVU) can reduce mortality from ovarian cancer. Secondary objectives are to assess screening variables other than mortality for each of the interventions including sensitivity, specificity, and positive predictive value; to assess incidence, stage, and survival of cancer cases; and to investigate biologic and/or prognostic characterizations of tumor tissue and biochemical products as intermediate endpoints. The design is a multicenter, two-armed, randomized trial with 37,000 females and 37,000 males in each of the two arms. In the intervention arm, the PSA and CA125 tests are performed at entry, then annually for 5 years. The DRE, TVU, and chest X-ray exams are performed at entry and then annually for 3 years. Sigmoidoscopy is performed at entry and then at the 5-year point. Participants in the control arm follow their usual medical care practices. Participants will be followed for at least 13 years from randomization to ascertain all cancers of the prostate, lung, colorectum, and ovary, as well as deaths from all causes. A pilot phase was undertaken to assess the randomization, screening, and data collection procedures of the trial and to estimate design parameters such as compliance and contamination levels. This paper describes eligibility, consent, and other design features of the trial, randomization and screening procedures, and an outline of the follow-up procedures. Sample-size calculations are reported, and a data analysis plan is presented.

The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial is a large and complex multi-institutional, multifaceted organization with a 20-year horizon. The implementation of the trial began with the creation of an organizational structure that supports strong leadership, cooperation, and effective communication among the trial collaborators including an operational framework for the development, review, and pretest of instruments, data collection, and management procedures; the setting of high-quality standards for training of trial staff; and the development of a comprehensive assessment plan for evaluation of all trial activities. This paper describes the process and methods used in the coordination and management of the PLCO trial. These include the role of the steering committee and its subcommittees and working groups, the establishment of regular and ad hoc communications among collaborators, the training of screening center coordinators and examiners, the PLCO manual of operations and procedures, and the development and implementation of a comprehensive quality assurance plan.

Background: The Mayo Lung Project (MLP) was a randomized, controlled clinical trial of lung cancer screening that was conducted in 9211 male smokers between 1971 and 1983. The intervention arm was offered chest x-ray and sputum cytology every 4 months for 6 years; the usual-care arm was advised at trial entry to receive the same tests annually. No lung cancer mortality benefit was evident at the end of the study. We have extended follow-up through 1996., Methods: A National Death Index-PLUS search was used to assign vital status and date and cause of death for 6523 participants with unknown information. The median survival for lung cancer patients diagnosed before July 1, 1983, was calculated by use of Kaplan-Meier estimates. Survival curves were compared with the log-rank test., Results: The median follow-up time was 20.5 years. Lung cancer mortality was 4.4 (95% confidence interval [CI] = 3.9-4.9) deaths per 1000 person-years in the intervention arm and 3.9 (95% CI = 3.5-4.4) in the usual-care arm (two-sided P: for difference =.09). For participants diagnosed with lung cancer before July 1, 1983, survival was better in the intervention arm (two-sided P: =.0039). The median survival for patients with resected early-stage disease was 16.0 years in the intervention arm versus 5.0 years in the usual-care arm., Conclusions: Extended follow-up of MLP participants did not reveal a lung cancer mortality reduction for the intervention arm. Similar mortality but better survival for individuals in the intervention arm indicates that some lesions with limited clinical relevance may have been identified in the intervention arm.

Objectives: To examine whether age at entry, history of cigarette smoking, exposure to non-tobacco lung carcinogens, or previous pulmonary illnesses were confounders or effect modifiers of the relation between screening and lung cancer mortality in the Mayo Lung Project., Setting: The Mayo Lung Project was a randomised, controlled, clinical trial conducted between 1971 and 1986 in 9211 male smokers over the age of 45 in Minnesota (USA). The group screened received chest x ray examination and sputum cytology every four months for six years. The unscreened group were recommended to obtain usual care (annual chest x ray examination and sputum cytology). After follow up, lung cancer mortality was similar in both groups., Methods: Proportional hazard models were used to analyse data. A variable was considered a confounder if its inclusion in a model changed the rate ratio for screening by more than 15%; a variable was considered an effect modifier if its stratum-specific rate ratio for screening differed by a factor of two., Results: None of the four aforementioned variables changed the rate ratio associated with screening (1.07) by more than 2%. The effect of screening may have differed by years smoked (rate ratio for smoking fewer than 30 years 2.4; rate ratio for smoking 30 or more years 1.0), though we suspect that this result occurred by chance., Conclusion: Adjustment for or stratification by four established lung cancer risk factors did not alter the original findings of the Mayo Lung Project.

BACKGROUND. Ovarian cancer is the fifth most common cause of cancer-related death in American women. The median age at diagnosis is about 62 years; incidence rises rapidly after age 60. Pelvic examination has been the primary method for detection of ovarian carcinoma. It is insensitive for the detection of early disease, however: most women present with disease beyond the pelvis (Stages III and IV) and are not curable with existing techniques. Two new technologies may be useful as screening tools for earlier detection of ovarian cancer. CA 125 is an antigenic determinant expressed on an ovarian cancer cell line. Transvaginal ultrasound (TVUS) images the ovaries from within the vagina and can be performed by a technician in about 10 minutes. In small preoperative studies of women with ovarian masses, serum CA 125 levels have been elevated (typically above 35 U/ml) in over two-thirds of cases and in up to 50% of Stage I cases. The test is not absolutely specific: elevations have been reported with pregnancy, endometriosis, menstruation, benign ovarian tumors, and with cancers of the breast, colon, pancreas, lung, stomach, and liver. Nevertheless, the specificity of CA 125 in postmenopausal women has been reported at about 95% or more. TVUS provides higher resolving power for ovarian abnormalities than transabdominal ultrasound or physical examination; however, experience with it is limited. CA 125 and TVUS may be complementary. CONCLUSIONS. For these reasons, the National Cancer Institute is planning a randomized trial of all three tests versus routine medical care in women of ages 60-74 years. This is part of a larger trial to determine the efficacy of screening for lung, colorectal, and ovarian cancers in women, and for lung, colorectal, and prostatic cancers in men. Seventy-four thousand women will be randomized in the study.