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Multicancer detection (MCD) tests use a single, easily obtainable biospecimen, such as blood, to screen for more than one cancer concurrently. MCD tests can potentially be used to improve early cancer detection, including cancers that currently lack effective screening methods. However, these tests have unknown and unquantified benefits and harms. MCD tests differ from conventional cancer screening tests in that the organ responsible for a positive test is unknown, and a broad diagnostic workup may be necessary to confirm the location and type of underlying cancer. Among two prospective studies involving greater than 16,000 individuals, MCD tests identified those who had some cancers without currently recommended screening tests, including pancreas, ovary, liver, uterus, small intestine, oropharyngeal, bone, thyroid, and hematologic malignancies, at early stages. Reported MCD test sensitivities range from 27% to 95% but differ by organ and are lower for early stage cancers, for which treatment toxicity would be lowest and the potential for cure might be highest. False reassurance from a negative MCD result may reduce screening adherence, risking a loss in proven public health benefits from standard-of-care screening. Prospective clinical trials are needed to address uncertainties about MCD accuracy to detect different cancers in asymptomatic individuals, whether these tests can detect cancer sufficiently early for effective treatment and mortality reduction, the degree to which these tests may contribute to cancer overdiagnosis and overtreatment, whether MCD tests work equally well across all populations, and the appropriate diagnostic evaluation and follow-up for patients with a positive test., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA. CA: A Cancer Journal for Clinicians published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: The European Randomized Study of Screening for Prostate Cancer (ERSPC) demonstrated that prostate-specific antigen (PSA) screening significantly reduced prostate cancer mortality (rate ratio, 0.79; 95% confidence interval, 0.69-0.91). The US Prostate, Lung, Colorectal, and Ovarian (PLCO) trial indicated no such reduction but had a wide 95% CI (rate ratio for prostate cancer mortality, 1.09; 95% CI, 0.87-1.36). Standard meta-analyses are unable to account for key differences between the trials that can impact the estimated effects of screening and the trials' point estimates., Methods: The authors calibrated 2 microsimulation models to individual-level incidence and mortality data from 238,936 men participating in the ERSPC and PLCO trials. A cure parameter for the underlying efficacy of screening was estimated by the models separately for each trial. The authors changed step-by-step major known differences in trial settings, including enrollment and attendance patterns, screening intervals, PSA thresholds, biopsy receipt, control arm contamination, and primary treatment, to reflect a more ideal protocol situation and differences between the trials., Results: Using the cure parameter estimated for the ERSPC, the models projected 19% to 21% and 6% to 8%, respectively, prostate cancer mortality reductions in the ERSPC and PLCO settings. Using this cure parameter, the models projected a reduction of 37% to 43% under annual screening with 100% attendance and biopsy compliance and no contamination. The cure parameter estimated for the PLCO trial was 0., Conclusions: The observed cancer mortality reduction in screening trials appears to be highly sensitive to trial protocol and practice settings. Accounting for these differences, the efficacy of PSA screening in the PLCO setting is not necessarily inconsistent with ERSPC results. Cancer 2018;124:1197-206. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

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., Methods: The PLCO trial randomized subjects from 1993 to 2001 to an intervention or control arm. Intervention-arm men received annual PSA tests for 6 years and digital rectal examinations for 4 years. This study used a linkage with the National Death Index to extend mortality follow-up to a maximum of 19 years after randomization., Results: Men were randomized to the intervention arm (n = 38,340) or the control arm (n = 38,343). The median follow-up time was 14.8 years (25th/75th, 12.7/16.5 years) in the intervention arm and 14.7 years (25th/75th, 12.6/16.4 years) in the control arm. There were 255 deaths from prostate cancer in the intervention arm and 244 deaths from prostate cancer in the control arm; this meant a rate ratio (RR) of 1.04 (95% confidence interval [CI], 0.87-1.24). The RR for all-cause mortality was 0.977 (95% CI, 0.950-1.004). It was estimated that 86% of the men in the control arm and 99% of the men in the intervention arm received any PSA testing during the trial, and the estimated yearly screening-phase PSA testing rates were 46% and 84%, respectively., Conclusions: Extended follow-up of the PLCO trial over a median of 15 years continues to indicate no reduction in prostate cancer mortality for the intervention arm versus the control arm. Because of the high rate of control-arm PSA testing, this finding can be viewed as showing no benefit of organized screening versus opportunistic screening. Cancer 2017;123:592-599. © 2016 American Cancer Society., (© 2016 This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Background: Two recent chemoprevention trials demonstrated significant reductions in overall prostate cancer incidence. However, a possible increase in high-grade disease has raised concerns that the harms of the drugs, including mortality because of high-grade disease, may outweigh the benefits. The authors attempted to estimate the effect of these drugs on prostate cancer mortality to be able to better evaluate the cost-benefit tradeoff., Methods: The authors analyzed prostate cancer incidence in the Prostate Cancer Prevention Trial (PCPT) and Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, which evaluated finasteride and the related compound dutasteride, respectively (both vs placebo). They used 13-year prostate cancer survival data from the Prostate, Lung, Colorectal and Ovarian (PLCO) trial to project prostate cancer mortality from incidence patterns; survival rates were applied to incident cancers according to prognostic strata, which were defined by Gleason score, prostate-specific antigen level, and clinical stage. For PCPT, the analysis was performed using both original trial results and previously published adjusted analyses that attempted to account for artifacts related to the drugs' effect on prostate volume., Results: For the PCPT trial, the estimated relative risk (RR) for prostate cancer mortality was 1.02 (95% confidence interval [95% CI], 0.85-1.23) using the original trial results and 0.87 (95% CI, 0.72-1.06) and 0.91 (95% CI, 0.76-1.09) based on the adjusted PCPT analyses. For the REDUCE trial, the RR for prostate cancer mortality was 0.93 (95% CI, 0.80-1.08)., Conclusions: Projecting a mortality outcome of the PCPT and REDUCE trials as an approach to weighing benefits versus harms suggests at most a small increase in prostate cancer mortality in the treatment arms, and possibly a modest decrease., (Copyright © 2012 American Cancer Society.)

In evaluating discriminatory performance of a new modality in a screening setting, a logistical constraint is that the prevalence of the disease of interest is typically very low. This implies that under a standard study design large numbers of subjects have to be evaluated using the new modality. However, if a predicate modality exists in clinical practice, one can base inclusion into the study of the new modality on the clinical results from the predicate to 'enrich' the population of diseased subjects in the study. If this enrichment is not accounted for when estimating sensitivity, specificity, and area under the ROC curve, these 'naive' estimates may be substantially biased compared with expected performance in the intended use population. We derive expressions for the magnitude of this bias in terms of correlations of modality scores. When such estimates are 'corrected' for the sampling weights using inverse probability weighting, the variances of the estimates of the above quantities are affected. We derive here analytic expressions for these variances. For a fixed number of diseased subjects, differential sampling increases the variance of the (corrected) estimates, all other things being equal. However, differential sampling also increases the number with disease for fixed total study size, which decreases the variance of the sensitivity and area under the ROC curve estimates, all other things being equal. The balance of these two effects determines the gain in efficiency when using enrichment and corrected estimates. These principles are illustrated with a simulation study motivated by the Digital Mammographic Imaging Screening Trial study, a trial of digital versus screen film mammography., (Copyright © 2011 John Wiley & Sons, Ltd.)

Background: Low-radiation dose spiral computed tomography (LDCT) currently is being evaluated as a screening modality for lung carcinoma in a randomized trial. Although several diagnostic algorithms for the workup of positive LDCT screens have been proposed, to the authors' knowledge there is no widely accepted standard to date and there are few nationwide data concerning how such diagnostic workups are actually being performed outside a research protocol setting., Methods: The Lung Screening Study (LSS) was a multicenter feasibility trial that randomized 1660 subjects to undergo LDCT and an equivalent number to undergo chest X-ray. Subjects with positive screens were referred to their own health care providers for diagnostic follow-up; LSS did not specify a diagnostic algorithm. LSS collected and abstracted medical records regarding procedures employed in the diagnostic workup of positive screens., Results: Of the 522 subjects with a positive LDCT screen at baseline or at Year One, 12% underwent biopsy. Biopsy was less likely to be performed in subjects with 4-9-mm nodules (5%) than in subjects with nodules measuring 10+ mm (25%) or in subjects with no nodules but other suspicious findings (15%). Among 63% of the subjects who underwent chest CT on follow-up, the median time between screening and first follow-up chest CT was 82 days. Only a minority of subjects received diagnostic workups that were consistent with published algorithms., Conclusions: The data from the current study represent the experience of subjects followed by their health care providers in five different U.S. metropolitan areas and one rural area. As such, they provide some indication of practices in the U.S. with regard to the diagnostic workup of patients with positive spiral CT screens.