Design of randomized controlled trials to estimate cancer-mortality reductions from multicancer detection screening.

Background: Determining whether screening with multicancer detection (MCD) tests saves lives requires randomized controlled trials (RCTs). To inform RCT design, we estimated cancer-mortality outcomes from hypothetical MCD RCTs.

Methods: We used the Hu-Zelen model, previously used to plan the National Lung Screening Trial (NLST), to estimate mortality reductions, sample size, and power for 9 cancers for different RCT design parameters and MCD test parameters.

Increasing power in screening trials by testing control-arm specimens: application to multicancer detection screening.

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.

Increasing power in screening trials by testing control-arm specimens: application to multicancer detection screening.

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.

Study design considerations for trials to evaluate multicancer early detection assays for clinical utility.

Blood-based assays using various technologies and biomarkers are in commercial development for the purpose of detecting multiple cancer types concurrently at an early stage of disease. These multicancer early detection (MCED) assays have the potential to improve the detection of cancers, particularly those for which no current screening modality exists. However, the unknown clinical benefits and harms of using MCED assays for cancer screening necessitate the development and implementation of a randomized controlled trial (RCT) to ascertain their clinical effectiveness.

Effect of Metformin and Lifestyle Interventions on Mortality in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study.

Objective: To determine whether metformin or lifestyle modification can lower rates of all-cause and cause-specific mortality in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study.

Research Design And Methods: From 1996 to 1999, 3,234 adults at high risk for type 2 diabetes were randomized to an intensive lifestyle intervention, masked metformin, or placebo. Placebo and lifestyle interventions stopped in 2001, and a modified lifestyle program was offered to everyone, but unmasked study metformin continued in those originally randomized.

Results of the cancer screening feasibility study in China: a multicentered randomized controlled trial of lung and colorectal cancer screening.

Background: To provide an understanding of important aspects of the participant recruitment and data collection, become aware of any potential problems, and obtain necessary information in order to design a large-scale randomized controlled trial (RCT) for lung cancer and colorectal cancer (CRC) screening in China.

Methods: This feasibility study was a multicentered, open-label, pilot randomized trial. A total of 2696 participants who were at high risk of lung cancer were recruited from three screening centers and randomly allocated to arm 1 ( = 894), annual low-dose computed tomography (LDCT) plus a baseline colonoscopy; arm 2 ( = 902), biennial LDCT plus annual fecal immunochemical test (FIT) with OC-Sensor (OC-FIT); and arm 3 ( = 900), annual Insure-FIT plus Septin 9 blood test.

Breast cancer overdiagnosis in stop-screen trials: More uncertainty than previously reported.

Objective: According to the Independent UK Panel on Breast Cancer Screening, the most reliable estimates of overdiagnosis for breast cancer screening come from stop-screen trials Canada 1, Canada 2, and Malmo. The screen-interval overdiagnosis fraction is the fraction of cancers in a screening program that are overdiagnosed. We used the cumulative incidence method to estimate screen-interval overdiagnosis fraction.

Effect of flexible sigmoidoscopy screening on colorectal cancer incidence and mortality: long-term follow-up of the randomised US PLCO cancer screening trial.

Background: Screening flexible sigmoidoscopy reduces incidence and mortality of colorectal cancer. Previously reported results from the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) screening trial had a median follow-up of 12 years. Whether the benefit is sustained over the long term and remains so in both sexes and all age groups is uncertain.

Extended follow-up for prostate cancer incidence and mortality among participants in the Prostate, Lung, Colorectal and Ovarian randomized cancer screening trial.

Objective: To examine prostate cancer (PCa) incidence and mortality by arm in the randomized Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial.

Patients And Methods: Patients aged 55-74 years at 10 screening centres were randomized between 1993 and 2001 to an intervention or usual care arm. Patients in the intervention arm received six annual prostate-specific antigen (PSA) tests and four annual digital rectal examinations.

Overall and Multiphasic Findings of the Prostate, Lung, Colorectal and Ovarian (PLCO) Randomized Cancer Screening Trial.

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.

Data sharing in clinical trials: An experience with two large cancer screening trials.

Paul Pinsky of the US National Cancer Institute and colleagues describe the implementation and outcomes of web-based data sharing from the PLCO and NLST cancer screening trials.

Extended mortality results for prostate cancer screening in the PLCO trial with median follow-up of 15 years.

Background: Two large-scale prostate cancer screening trials using prostate-specific antigen (PSA) have given conflicting results in terms of the efficacy of such screening. One of those trials, the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, previously reported outcomes with 13 years of follow-up. This study presents updated findings from the PLCO trial.

Extended mortality results for ovarian cancer screening in the PLCO trial with median 15years follow-up.

Background: The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial originally reported no mortality benefit of ovarian cancer screening after a median of 12.4years of follow-up. The UKCTOCS screening trial failed to show a statistically significant mortality reduction in the primary analysis but reported an apparent increased mortality benefit in trial years 7-14 compared to 0-7.

Breast-Cancer Tumor Size, Overdiagnosis, and Mammography Screening Effectiveness.

Background: The goal of screening mammography is to detect small malignant tumors before they grow large enough to cause symptoms. Effective screening should therefore lead to the detection of a greater number of small tumors, followed by fewer large tumors over time.

Methods: We used data from the Surveillance, Epidemiology, and End Results (SEER) program, 1975 through 2012, to calculate the tumor-size distribution and size-specific incidence of breast cancer among women 40 years of age or older.

PLCO: Evolution of an Epidemiologic Resource and Opportunities for Future Studies.

The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), a large-scale, multi-institutional, randomized controlled trial, was launched in 1992 to evaluate the effectiveness of screening modalities for prostate, lung, colorectal, and ovarian cancer. However, PLCO was additionally designed to serve as an epidemiologic resource and the National Cancer Institute has invested substantial resources over the years to accomplish this goal. In this report, we provide a summary of changes to PLCO's follow-up after conclusion of the screening phase of the trial and highlight recent data and biospecimen collections, including ancillary studies, geocoding, administration of a new medication use questionnaire, consent for linkage to Medicare, and additional tissue collection that enhance the richness of the PLCO resource and provide further opportunities for scientific investigation into the prevention, early detection, etiology and treatment of cancer.

Managing Multi-Center Recruitment in the PLCO Cancer Screening Trial.

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.

Study designs for determining and comparing sensitivities of disease screening tests.

Objective: To investigate the capability of various study designs to determine the sensitivity of a disease screening test.

Methods: Quantities that can be calculated from these designs were derived and examined for their relationship to true sensitivity (the ability to detect unrecognized disease that would surface clinically in the absence of screening) and overdiagnosis.

Results: To examine the sensitivity of one test, the single cohort design, in which all participants receive the test, is particularly weak, providing only an upper bound on the true sensitivity, and yields no information about overdiagnosis.