Cancer screening with multicancer detection tests: A translational science review.

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.

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. We then calculated the size-specific cancer case fatality rate for two time periods: a baseline period before the implementation of widespread screening mammography (1975 through 1979) and a period encompassing the most recent years for which 10 years of follow-up data were available (2000 through 2002). RESULTS: After the advent of screening mammography, the proportion of detected breast tumors that were small (invasive tumors measuring <2 cm or in situ carcinomas) increased from 36% to 68%; the proportion of detected tumors that were large (invasive tumors measuring ≥2 cm) decreased from 64% to 32%. However, this trend was less the result of a substantial decrease in the incidence of large tumors (with 30 fewer cases of cancer observed per 100,000 women in the period after the advent of screening than in the period before screening) and more the result of a substantial increase in the detection of small tumors (with 162 more cases of cancer observed per 100,000 women). Assuming that the underlying disease burden was stable, only 30 of the 162 additional small tumors per 100,000 women that were diagnosed were expected to progress to become large, which implied that the remaining 132 cases of cancer per 100,000 women were overdiagnosed (i.e., cases of cancer were detected on screening that never would have led to clinical symptoms). The potential of screening to lower breast cancer mortality is reflected in the declining incidence of larger tumors. However, with respect to only these large tumors, the decline in the size-specific case fatality rate suggests that improved treatment was responsible for at least two thirds of the reduction in breast cancer mortality. CONCLUSIONS: Although the rate of detection of large tumors fell after the introduction of screening mammography, the more favorable size distribution was primarily the result of the additional detection of small tumors. Women were more likely to have breast cancer that was overdiagnosed than to have earlier detection of a tumor that was destined to become large. The reduction in breast cancer mortality after the implementation of screening mammography was predominantly the result of improved systemic therapy.

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. The patients were followed for PCa incidence and for mortality via active follow-up processes and by linkage to state cancer registries and the National Death Index. For cancers identified through active follow-up, trial abstractors recorded the mode of diagnosis (screen-detected, symptomatic, other). RESULTS: A total of 38 340 patients were randomized to the intervention arm and 38 343 to a usual care arm. The median follow-up for mortality was 16.9 (intervention) and 16.7 years (usual care). There were 333 (intervention) and 352 (usual care) PCa cancer deaths, giving rates (per 10 000 person-years) of 5.5 and 5.9, respectively, and a rate ratio (RR) of 0.93 (95% confidence interval [CI] 0.81-1.08; P = 0.38). The RR for overall PCa incidence was 1.05 (95% CI 1.01-1.09). The RRs by Gleason category were 1.17 (95% CI 1.11-1.23) for Gleason 2-6, 1.00 (95% CI 0.93-1.07) for Gleason 7 and 0.89 (95% CI 0.80-0.99) for Gleason 8-10 disease. By mode of detection, during the trial's screening phase, 13% of intervention arm vs 27% of usual care arm cases were symptomatic; post-screening, these percentages were 18% in each arm. CONCLUSION: After almost 17 years of median follow-up, there was no significant reduction in PCa mortality in the intervention compared with the usual care arm. There was a significant increase in Gleason 2-6 disease and a significant reduction in Gleason 8-10 disease in the intervention compared with the usual care arm.

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. 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.

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. Here we report an updated analysis of PLCO with extended mortality follow-up. METHODS: Participants were randomized from 1993 to 2001 at ten U.S. centers to an intervention or usual care arm. Intervention arm women were screened for ovarian cancer with annual trans-vaginal ultrasound (TVU) (4years) and CA-125 (6years), with a fixed cutoff at 35U/mL for CA-125. The original follow-up period was for up to 13years (median follow-up 12.4years); in this analysis follow-up for mortality was extended by up to 6years. RESULTS: 39,105 (intervention) and 39,111 (usual care) women were randomized, of which 34,253 and 34,304, respectively, had at least one ovary at baseline. Median follow-up was 14.7years in each arm and maximum follow-up 19.2years in each arm. A total of 187 (intervention) and 176 (usual care) deaths from ovarian cancer were observed, for a risk-ratio of 1.06 (95% CI: 0.87-1.30). Risk-ratios were similar for study years 0-7 (RR=1.04), 7-14 (RR=1.06) and 14+ (RR=1.09). The risk ratio for all-cause mortality was 1.01 (95% CI: 0.97-1.05). Ovarian cancer specific survival was not significantly different across trial arms (p=0.16). CONCLUSION: Extended follow-up of PLCO indicated no mortality benefit from screening for ovarian cancer with CA-125 and TVU.

Colorectal-cancer incidence and mortality with screening flexible sigmoidoscopy.

BACKGROUND: The benefits of endoscopic testing for colorectal-cancer screening are uncertain. We evaluated the effect of screening with flexible sigmoidoscopy on colorectal-cancer incidence and mortality. METHODS: From 1993 through 2001, we randomly assigned 154,900 men and women 55 to 74 years of age either to screening with flexible sigmoidoscopy, with a repeat screening at 3 or 5 years, or to usual care. Cases of colorectal cancer and deaths from the disease were ascertained. RESULTS: Of the 77,445 participants randomly assigned to screening (intervention group), 83.5% underwent baseline flexible sigmoidoscopy and 54.0% were screened at 3 or 5 years. The incidence of colorectal cancer after a median follow-up of 11.9 years was 11.9 cases per 10,000 person-years in the intervention group (1012 cases), as compared with 15.2 cases per 10,000 person-years in the usual-care group (1287 cases), which represents a 21% reduction (relative risk, 0.79; 95% confidence interval [CI], 0.72 to 0.85; P<0.001). Significant reductions were observed in the incidence of both distal colorectal cancer (479 cases in the intervention group vs. 669 cases in the usual-care group; relative risk, 0.71; 95% CI, 0.64 to 0.80; P<0.001) and proximal colorectal cancer (512 cases vs. 595 cases; relative risk, 0.86; 95% CI, 0.76 to 0.97; P=0.01). There were 2.9 deaths from colorectal cancer per 10,000 person-years in the intervention group (252 deaths), as compared with 3.9 per 10,000 person-years in the usual-care group (341 deaths), which represents a 26% reduction (relative risk, 0.74; 95% CI, 0.63 to 0.87; P<0.001). Mortality from distal colorectal cancer was reduced by 50% (87 deaths in the intervention group vs. 175 in the usual-care group; relative risk, 0.50; 95% CI, 0.38 to 0.64; P<0.001); mortality from proximal colorectal cancer was unaffected (143 and 147 deaths, respectively; relative risk, 0.97; 95% CI, 0.77 to 1.22; P=0.81). CONCLUSIONS: Screening with flexible sigmoidoscopy was associated with a significant decrease in colorectal-cancer incidence (in both the distal and proximal colon) and mortality (distal colon only). (Funded by the National Cancer Institute; PLCO ClinicalTrials.gov number, NCT00002540.).

Occurrence of Distal Colorectal Neoplasia Among Whites and Blacks Following Negative Flexible Sigmoidoscopy: An Analysis of PLCO Trial.

BACKGROUND: It is unclear whether the higher rate of colorectal cancer (CRC) among non-Hispanic blacks (blacks) is due to lower rates of CRC screening or greater biologic risk. OBJECTIVE: We aimed to evaluate whether blacks are more likely than non-Hispanic whites (whites) to develop distal colon neoplasia (adenoma and/or cancer) after negative flexible sigmoidoscopy (FSG). DESIGN: We analyzed data of participants with negative FSGs at baseline in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial who underwent repeat FSGs 3 or 5 years later. Subjects with polyps or masses were referred to their physicians for diagnostic colonoscopy. We collected and reviewed the records of diagnostic evaluations. PARTICIPANTS: Our analytic cohort consisted of 21,550 whites and 975 blacks. MAIN MEASURES: We did a comparison by race (whites vs. blacks) in the findings of polyps or masses at repeat FSG, the follow-up of abnormal test results and the detection of colorectal neoplasia at diagnostic colonoscopy. KEY RESULTS: At the follow-up FSG examination, 304 blacks (31.2 %) and 4183 whites (19.4 %) had abnormal FSG, [adjusted relative risk (RR) = 1.00; 95 % confidence interval (CI), 0.90-1.10]. However, blacks were less likely to undergo diagnostic colonoscopy (76.6 % vs. 83.1 %; RR = 0.90; 95 % CI, 0.84-0.96). Among all included patients, blacks had similar risk of any distal adenoma (RR = 0.86; 95 % CI, 0.65-1.14) and distal advanced adenoma (RR = 1.01; 95 % CI, 0.60-1.68). Similar results were obtained when we restricted our analysis to compliant subjects who underwent diagnostic colonoscopy (RR = 1.01; 95 % CI, 0.80-1.29) for any distal adenoma and (RR = 1.18; 95 % CI, 0.73-1.92) for distal advanced adenoma. CONCLUSIONS: We did not find any differences between blacks and whites in the risk of distal colorectal adenoma 3-5 years after negative FSG. However, follow-up evaluations were lower among blacks.

Quantification of length-bias in screening trials with covariate-dependent test sensitivity.

Length-biased sampling exists in screening programs where longer duration disease is detected during the preclinical stage because a longer sojourn time (preclinical duration) has a higher probability of being screen detected. By modeling the course of disease, we quantify the effect of length-biased sampling on clinical duration when cases are subject to periodic screening with variable test sensitivity. We use the highly flexible bivariate lognormal density to jointly model preclinical and clinical durations, and we model screening test sensitivity as a function of the sojourn time and number of previous false negative screens. We show that the mean clinical duration among screen-detected cases can be up to 40% higher, with shrinking standard deviation, than those among nonscreen-detected cases, due to biased sampling alone, irrespective of any possible benefit (increased survival time arising from earlier detection or reduction in mortality). These findings will aid in the design and interpretation of screening trials.

Considerations in the design of randomized trials to screen for type 2 diabetes.

Background Randomized controlled trials (RCTs) are the most robust and valid approach to evaluate screening for diseases. Many in the diabetes research community have advocated sole reliance on RCTs for designing diabetes screening policies. However, the challenges of conducting RCTs of screening for type 2 diabetes may have been underappreciated. Purpose Discuss the key theoretical concepts and practical challenges of designing and conducting RCTs of diabetes screening. Methods Narrative and critical review of the literature pertaining to the theory and practice of designing and conducting RCTs of diabetes screening. Results We present the theoretical basis of a diabetes screening trial, using concepts developed mainly in studies of cancer screening and illustrations from the Cambridge component of the Anglo Danish Dutch Study of Intensive Treatment In peOple with screeN-detected diabetes in primary care (ADDITION-Cambridge), the only extant trial of diabetes screening. We examine design issues, including the appropriate trial question, choice of design, and duration of follow-up, and address aspects of trial implementation, including recruitment, randomization, endpoint determination, sample size requirements, and screening interval. Limitations The limited number of trials of diabetes screening did not permit us to illustrate many of the practical difficulties one encounters when implementing theoretical concepts. Conclusion When diabetes screening trials are planned, we suggest careful consideration to potential areas of practical difficulty, especially the need for particularly large sample sizes and extended follow-up, and the choice of appropriate outcomes and screening intervals.

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. 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 to 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 multi-cancer 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 provide particularly strong power gains for 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. This was the consensus of experts at a National Cancer Institute-hosted workshop to discuss initial design concepts for such a trial. Using these assays to screen simultaneously for multiple cancers poses novel uncertainties for patient care compared with conventional screening tests for single cancers, such as establishing the diagnostic workup to confirm the presence of cancer at any organ site; clarifying appropriate follow-up for a positive assay for which there is no definitive diagnosis; identifying potential harms such as overdiagnosis of indolent disease; determining clinically effective and efficient strategies for disseminating MCED screening in real-world practice; and understanding the ethical implications, such as potentially alleviating or exacerbating existing health disparities. These assays present new and complex challenges for designing an RCT. Issues that emerged from the meeting centered around the need for a flexibly designed, clinical utility RCT to rigorously capture the evidence required to fully understand the net benefit of this promising technology. Specific topic areas were endpoints, screening protocols, recruitment, diagnostic pathway, pilot phase, data elements, specimen collection, and ethical considerations.

Mortality results from a randomized prostate-cancer screening trial.

BACKGROUND: The effect of screening with prostate-specific-antigen (PSA) testing and digital rectal examination on the rate of death from prostate cancer is unknown. This is the first report from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial on prostate-cancer mortality. METHODS: From 1993 through 2001, we randomly assigned 76,693 men at 10 U.S. study centers to receive either annual screening (38,343 subjects) or usual care as the control (38,350 subjects). Men in the screening group were offered annual PSA testing for 6 years and digital rectal examination for 4 years. The subjects and health care providers received the results and decided on the type of follow-up evaluation. Usual care sometimes included screening, as some organizations have recommended. The numbers of all cancers and deaths and causes of death were ascertained. RESULTS: In the screening group, rates of compliance were 85% for PSA testing and 86% for digital rectal examination. Rates of screening in the control group increased from 40% in the first year to 52% in the sixth year for PSA testing and ranged from 41 to 46% for digital rectal examination. After 7 years of follow-up, the incidence of prostate cancer per 10,000 person-years was 116 (2820 cancers) in the screening group and 95 (2322 cancers) in the control group (rate ratio, 1.22; 95% confidence interval [CI], 1.16 to 1.29). The incidence of death per 10,000 person-years was 2.0 (50 deaths) in the screening group and 1.7 (44 deaths) in the control group (rate ratio, 1.13; 95% CI, 0.75 to 1.70). The data at 10 years were 67% complete and consistent with these overall findings. CONCLUSIONS: After 7 to 10 years of follow-up, the rate of death from prostate cancer was very low and did not differ significantly between the two study groups. (ClinicalTrials.gov number, NCT00002540.)

Colorectal cancers not detected by screening flexible sigmoidoscopy in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

BACKGROUND AND OBJECTIVE: Diagnosis of colorectal cancer after negative findings on endoscopic evaluation raises concern about the effectiveness of endoscopic screening. We contrast screening-detected cancers with cancers not detected by screening among participants assigned to flexible sigmoidoscopy (FSG) in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial to determine the reasons for the lack of detection of prevalent lesions. DESIGN: Cancers detected within 1 year of a screening FSG with abnormal findings were classified as screening detected. All other cancers were categorized, based on cancer stage and years until detection, as either not detectable or prevalent but not detected at the time of screening. SETTING/PATIENTS: A total of 77,447 subjects in the multicenter PLCO trial. MAIN OUTCOME MEASUREMENTS: A total of 977 colorectal cancers were diagnosed with a mean follow-up of 11.5 years. RESULTS: A total of 243 (24.9%) cancers were screening detected, 470 (48.1%) were not detectable at screening, and 264 (27.0%) were considered prevalent but not detected. Among prevalent nondetected lesions, 35.6% (n = 94) were attributed to problems in patient compliance (58 never screened, 34 delayed colonoscopy follow-up, and 2 inadequate bowel preparation), 43.9% (n = 116) were attributable to a limitation in the FSG procedure (97 beyond the reach of the sigmoidoscope and 19 inadequate depth of insertion on FSG), and 20.5% (n = 54) were caused by endoscopist limitation (33 missed on FSG, 21 missed at initial colonoscopy) (P < .0001). Had colonoscopy instead of FSG been used for screening, an additional 15.6% and as many as 19.0% of cancers may have been screening-detected. LIMITATIONS: These estimates are reasonable approximations, but biological variability precludes precise determinations. CONCLUSIONS: Prevalent nondetected cancers were more often attributable to problems with patient compliance or limitations in the FSG procedure than to missed lesions. Colonoscopy instead of FSG could have moderately increased the detection of cancer via screening.

Longitudinal evaluation of CA-125 velocity and prediction of ovarian cancer.

OBJECTIVE: To determine whether CA-125 velocity is a statistically significant predictor of ovarian cancer and develop a classification rule to screen for ovarian cancer. METHODS: In the ovarian component of the PLCO cancer screening trial, 28,038 women aged 55-74 had at least two CA-125 screening tests. Ovarian cancer was diagnosed in 72 (0.26%) women. A multiple logistic regression model was developed to evaluate CA-125 velocity and other related covariates as predictors of ovarian cancer. Predictive accuracy was assessed by the concordance index and measures of discrimination and calibration while the fit of the model was assessed by the Hosmer and Lemeshow's goodness-of-fit χ(2)test. RESULTS: CA-125 velocity decreased as the number of CA-125 measurements increased but was unaffected by age at baseline screen and family history of ovarian cancer. The average velocity (19.749U/ml per month) of the cancer group was more than 500 times the average velocity (0.035U/ml per month) of the non-cancer group. CONCLUSION: Among six covariates used in the model, CA-125 velocity and time intervals between baseline and second to last screening test and between last two screening tests were statistically significant predictors of ovarian cancer. The chance of having ovarian cancer increased as velocity increased, and the chance decreased when the time intervals between baseline and the second to last screening test and between last two screening tests of an individual increased.