Minnesota Colon Cancer Control Study Research Articles

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

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. 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]). 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. 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.

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

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. 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]). 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. 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.

Issue Highlights

Issue Highlights

Colonoscopy With Polypectomy Reduces Long-Term Incidence of Colorectal Cancer in Both Men and Women: Extended Results From the Minnesota Colon Cancer Control Study

Colonoscopy With Polypectomy Reduces Long-Term Incidence of Colorectal Cancer in Both Men and Women: Extended Results From the Minnesota Colon Cancer Control Study

Validation of Microsimulation Models against Alternative Model Predictions and Long-Term Colorectal Cancer Incidence and Mortality Outcomes of Randomized Controlled Trials.

Background. This study aimed to assess the validity of 2 microsimulation models of colorectal cancer (CRC), Policy1-Bowel and ASCCA.Methods. The model-estimated CRC risk in population subgroups with different health statuses, "dwell time" (time from incident precancerous polyp to symptomatically detected CRC), and reduction in symptomatically detected CRC incidence after a one-time complete removal of polyps and/or undetected CRC were compared with published findings from 3 well-established models (MISCAN, CRC-SPIN, and SimCRC). Furthermore, 6 randomized controlled trials (RCTs) that provided screening using a guaiac fecal occult blood test (Funen trial, Burgundy trial, and Minnesota Colon Cancer Control Study [MCCCS]) or flexible sigmoidoscopy (NORCCAP, SCORE, and UKFSST) with long-term follow-up were simulated. Model-estimated long-term relative reductions of CRC incidence (RRinc) and mortality (RRmort) were compared with the RCTs' findings. Results. The Policy1-Bowel and ASCCA estimates showed more similarities to CRC-SPIN and SimCRC. For example, overall dwell times estimated by Policy1-Bowel (24.0 years) and ASCCA (25.3) were comparable to CRC-SPIN (25.8) and SimCRC (25.2) but higher than MISCAN (10.6). In addition, ∼86% of Policy1-Bowel's and ∼74% of ASCCA's estimated RRinc and RRmort were consistent with the RCTs' long-term follow-up findings. For example, at 17 to 18 years of follow-up, the MCCCS reported RRmort of 0.67 (95% confidence interval [CI], 0.51-0.83) and 0.79 (95% CI, 0.62-0.97) for the annual and biennial screening arm, respectively, and the UKFSST reported RRmort of 0.70 (95% CI, 0.62-0.79) for CRC at all sites and 0.54 (95% CI, 0.46-0.65) for distal CRC. The corresponding model estimates were 0.65, 0.74, 0.81, and 0.61, respectively, for Policy1-Bowel and 0.65, 0.70, 0.75, and 0.58, respectively, for ASCCA. Conclusion. Policy1-Bowel and ASCCA's estimates are largely consistent with the data included for comparisons, which indicates good model validity.

Screening For Colorectal Cancer in the Age of Simulation Models: A Historical Lens

Screening For Colorectal Cancer in the Age of Simulation Models: A Historical Lens

BMI Is a Risk Factor for Colorectal Cancer Mortality.

The relationship between dietary and lifestyle risk factors and long-term mortality from colorectal cancer is poorly understood. Several factors, such as obesity, intakes of red meat, and use of aspirin, have been reported to be associated with risk of colorectal cancer mortality, though these findings have not been replicated in all studies to date. In the Minnesota Colon Cancer Control Study, 46,551 participants 50-80years old were randomly assigned to usual care (control) or annual or biennial screening by fecal occult blood testing. Colon cancer mortality was assessed after 30 years of follow-up. Dietary intake and lifestyle risk factors were assessed by questionnaire at baseline. Age [hazard ratio (HR) 1.09; 95% CI 1.07, -1.11], male sex (HR 1.25; 95% CI 1.01, 1.57), and higher body mass index (BMI) (HR 1.03; 95% CI 1.00-1.05) increased the risk of CRC mortality, while undergoing screening for CRC was associated with a reduced risk of colorectal cancer mortality (HR 0.76; 95% CI 0.61-0.94 and 0.67; 95% CI 0.53-0.83 for biennial and annual screening, respectively). Intakes of grains, meats, proteins, coffee, alcohol, aspirin, fiber, fruits, and vegetables were not associated with colorectal cancer mortality. Our study confirms the relationship between BMI and long-term colorectal cancer mortality. Modulation of BMI may reduce risk of CRC mortality.

Long-Term Mortality after Screening for Colorectal Cancer

BackgroundIn randomized trials, fecal occult-blood testing reduces mortality from colorectal cancer. However, the duration of the benefit is unknown, as are the effects specific to age and sex.MethodsIn the Minnesota Colon Cancer Control Study, 46,551 participants, 50 to 80 years of age, were randomly assigned to usual care (control) or to annual or biennial screening with fecal occult-blood testing. Screening was performed from 1976 through 1982 and from 1986 through 1992. We used the National Death Index to obtain updated information on the vital status of participants and to determine causes of death through 2008.ResultsThrough 30 years of follow-up, 33,020 participants (70.9%) died. A total of 732 deaths were attributed to colorectal cancer: 200 of the 11,072 deaths (1.8%) in the annual-screening group, 237 of the 11,004 deaths (2.2%) in the biennial-screening group, and 295 of the 10,944 deaths (2.7%) in the control group. Screening reduced colorectal-cancer mortality (relative risk with annual screening, 0.68; 95% confidence interval [CI], 0.56 to 0.82; relative risk with biennial screening, 0.78; 95% CI, 0.65 to 0.93) through 30 years of follow-up. No reduction was observed in all-cause mortality (relative risk with annual screening, 1.00; 95% CI, 0.99 to 1.01; relative risk with biennial screening, 0.99; 95% CI, 0.98 to 1.01). The reduction in colorectal-cancer mortality was larger for men than for women in the biennial-screening group (P=0.04 for interaction).ConclusionsThe effect of screening with fecal occult-blood testing on colorectal-cancer mortality persists after 30 years but does not influence all-cause mortality. The sustained reduction in colorectal-cancer mortality supports the effect of polypectomy. (Funded by the Veterans Affairs Merit Review Award Program and others.)

Evaluating the long-term effect of FOBT in colorectal cancer screening

Background Cancer screening has been effective in detecting tumors early before symptoms appear. However, the effectiveness of the regular fecal occult blood test (FOBT) in colorectal cancer in the long term has not been quantified. Methods We applied the statistical method developed by Wu and Rosner [1] using data from the Minnesota Colon Cancer Control Study (MCCCS). All initially asymptomatic participants were classified into four mutually exclusive groups: true-early-detection, no-early-detection, over-diagnosis, and symptom-free life; human lifetime was treated as a random variable and is subject to competing risks. All participants in the screening program will eventually fall into one of the four outcomes above. Predictive inferences on the percentages of the four outcomes for both genders were made using the Minnesota study data. Results Depending on gender, screening frequency and age at the initial screening, for all participants the probability of “symptom-free-life” varies between 95.3% and 96.6%; the probability of “true-early-detection” is 1.9–3.8%; the probability of no-early-detection is 0.3–2.0%; the probability of over-diagnosis is 0.16–0.3%. Among those with colorectal cancer detected by regular FOBT, the probability of over-diagnosis is lower than expected and is between 6% and 9%, with 95% CI (2.5%, 21.3%) for females and (1.9%, 44.7%) for males. The probability of true-early-detection increases as screening interval decreases. The probability of no-early-detection decreases as screening interval decreases. Conclusion The probability of over-diagnosis among the screen-detected cases is not as high as previously thought. We hope this outcome can provide valuable information on the effectiveness of the FOBT in colorectal cancer detection in the long term.

Mathematical models and cost-effective screening strategies for colorectal cancer

See related research article by Telford and colleagues, page [1307][1] , and see also research article by Simunovic and colleagues, page [1301][2] In 1993 the results of the Minnesota Colon Cancer Control Study provided clear evidence of the efficacy of screening for colorectal cancer with a

Colorectal Cancer Screening in the Elderly: The Need for Informed Decision Making

Colorectal Cancer Screening in the Elderly: The Need for Informed Decision Making

Probabilistic cost-effectiveness comparison of screening strategies for colorectal cancer

A stochastic discrete-event simulation model of the natural history of Colorectal Cancer (CRC) is augmented with screening technology representations to create a base for simulating various screening strategies for CRC. The CRC screening strategies recommended by the American Gastroenterological Association (AGA) and the newest screening strategies for which clinical efficacy has been established are simulated. In addition to verification steps, validation of screening is pursued by comparison with the Minnesota Colon Cancer Control Study. The model accumulates discounted costs and quality-adjusted life-years. The natural variability in the modeled random variables for natural history is conditioned using a probabilistic sensitivity analysis through a two-stage sampling process that adds other random variables representing parametric uncertainty. The analysis of the screening alternatives in a low-risk population explores both deterministic and stochastic dominance to eliminate some screening alternatives. Net benefit analysis, based on willingness to pay for quality-adjusted life-years, is used to compare the most cost-effective strategies through acceptability curves and to make a screening recommendation. Methodologically, this work demonstrates how variability from the natural variation in the development, screening, and treatment of a disease can be combined with the variation in parameter uncertainty. Furthermore, a net benefit analysis that characterizes cost-effectiveness alternatives can explicitly depend on variation from all sources producing a probabilistic cost-effectiveness analysis of decision alternatives.

The Effect of Fecal Occult-Blood Screening on the Incidence of Colorectal Cancer

Mandel, Jack S.; Church, Timothy R.; Bond, John H.; Ederer, Fred; Geisser, Mindy S.; Mongin, Steven J.; Snover, Dale C.; Schuman, Leonard M.

Colorectal Cancer Deaths as Determined by Expert Committee and from Death Certificate: A Comparison. The Minnesota Study

For deaths during the first 13 years of follow-up of the Minnesota Colon Cancer Control Study, an expert committee using numerous medical documents, and a nosologist using only the death certificate independently determined whether colorectal cancer caused the death and, if not, whether the disease was present at death. Deaths due to colorectal cancer numbered 318 according to the nosologist and 323 according to the committee, a discrepancy of 1.5%, which is similar in magnitude to that in three previous studies. The nosologist and committee agreed that colorectal cancer caused the death in each of 290 individual cases; they disagreed widely on the number of deaths from other causes but with colorectal cancer. If it is important to know only the gross number of deaths from colorectal cancer, then the death certificate alone appears to be sufficiently accurate; if it is important to know the cause of death of individual subjects or the number dying from other causes but with colorectal cancer, then the expert committee method provides more accurate information.

Fecal occult blood screening in the Minnesota study: role of chance detection of lesions.

In the Minnesota Colon Cancer Control Study, annual fecal occult blood testing reduced mortality from colorectal cancer by at least 33.4%. Some attribute a large part of this reduction to chance detection of cancers by colonoscopies; rehydration of guaiac test slides greatly increased positivity and consequently the number of colonoscopies performed. This study was conducted to determine how much of the reduction resulted from chance detection. We used a mathematical model developed by Lang and Ransohoff to estimate the proportion of the 33.4% mortality attainable by chance alone. Applying the model requires the specification of five parameters: duration of follow-up, rate of compliance with fecal occult blood testing, rate of compliance with colonoscopy, positivity rate, and efficacy of colonoscopy in reducing colorectal cancer mortality. We took values for four of the five parameters directly from the Minnesota study. For the fifth parameter, efficacy of colonoscopy, we selected a value of 60%, based on the conclusions of another study. Whereas the Lang-Ransohoff model selects persons for colonoscopy by chance alone, those with bleeding cancers would also be selected by sensitive fecal occult blood testing. We therefore adjusted the result of the Lang-Ransohoff model for this dual detectability. We found that 16%-25% of the reduction in colorectal cancer deaths effected by fecal occult blood testing in the Minnesota study was due to chance detection; the remainder was due to sensitive detection. Chance played a minor role in the detection of colorectal cancers by fecal occult blood testing in the Minnesota study.

HemeSelect and a combination of HemeSelect with Hemoccult II Sensa accurately screened for colorectal cancer

DiagnosisMay 1, 1996HemeSelect and a combination of HemeSelect with Hemoccult II Sensa accurately screened for colorectal cancerRobert H. Fletcher, MD, MScRobert H. Fletcher, MD, MScHarvard Medical School, Boston, Massachusetts, USA (R.H.F.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJC-1996-124-3-074 SectionsAboutFull Text ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinkedInRedditEmail Source CitationAllison JE, Tekawa IS, Ransom LJ, Adrain AL. A comparison of fecal occult-blood tests for colorectal-cancer screening. N Engl J Med. 1996 Jan 18;334:155-9. https://pubmed.ncbi.nlm.nih.gov/8531970References1 Mandel JS, Rond JH, Church TR, et al. Reducing mortality from colorectal cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study. N Engl J Med. 1993;328:1365-71. Google Scholar2 Office of Technology Assessment. Congress of the United States. Cost-effectiveness of colorectal cancer screening in average-risk adults. April 1995 (BH-H-146). Google Scholar Author, Article, and Disclosure InformationAffiliations: Harvard Medical School, Boston, Massachusetts, USA (R.H.F.) PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails May 1, 1996Volume 124, Issue 3Page: 74KeywordsCancer detection and diagnosisCancer preventionCancer screeningColonoscopyColorectal cancerColorectal cancer screeningDietHematologic testsHemoglobinPeroxidasesSpecificity ePublished: 9 March 2020 Issue Published: May 1, 1996 Copyright & PermissionsCopyright © 1996 by American College of Physicians. All Rights Reserved.Loading ...

Longitudinal Compliance with Annual Screening for Fecal Occult Blood

In a randomized, controlled trial of fecal occult blood screening for colorectal cancer, the Minnesota Colon Cancer Control Study carried out 11 annual mail screens in two phases between 1976 and 1992. This long-term compliance record of 15,476 individuals is summarized and related to demographic characteristics as well as to the screening experience of the participants. There was a strong and consistent effect of age, with peak compliance among participants about 70 years old, and lower compliance among the youngest (< or = 55 years) and oldest (> or = 80 years) participants. There was a significantly higher rate of screen compliance among participants who lived with other participants, compared with households where only one individual participated in the study. Finally, participants who underwent a diagnostic colorectal examination with negative results had significantly lower odds of compliance.

Screening for Colorectal Cancer: Which Test Is Best?

To the Editor. —We found the article by Drs Lang and Ransohoff 1 on the utility of the FOBT screening for CRC very interesting. Their results suggest that one third to one half of the mortality reduction observed in the widely cited Minnesota Colon Cancer Control Study of FOBT screening using rehydrated slides 2 may be attributable to chance selection for colonoscopy. They further assert that with long-term annual FOBT screening with rehydration the chance of undergoing colonoscopy approaches 100% and, therefore, it may be a more effective strategy to simply screen everyone directly with colonoscopy (eg, when a person reaches a certain age). We agree that universal endoscopic screening would be a more direct approach to screening for CRC. Such a direct approach would eliminate the annual costs of laboratory processing, record keeping, and follow-up associated with doing annual FOBT screening. We would further suggest that any universal endoscopic

Screening for Colorectal Cancer: Which Test Is Best?-Reply

In Reply. —Dr Mandel and colleagues provide new data from the Minnesota Colon Cancer Control Study and observe correctly that these data could be used to further elucidate the mechanism by which FOBT screening with slide rehydration reduces CRC mortality. We agree that the cumulative rate of colonoscopy in the screened group will have an important effect on any projection of the degree to which random screening colonoscopy, done for workup of false-positive FOBT results, contributes to CRC mortality reductions. The values used in our model were based on the published data. 1 We agree that the results also depend on the degree and duration of protective effect from endoscopy screening, so we provided tables showing results for different durations and degrees of protection from endoscopy screening. New insights from the Minnesota study's data might be obtained by considering the types of neoplasms detected in the screened group (ie, early

Fecal Occult Blood Screening for Colorectal Cancer

Annual fecal occult blood test (FOBT) screening using rehydrated Hemoccult slides has been reported in the Minnesota Colon Cancer Control Study to reduce colorectal cancer mortality by about 33%. However, some of the benefit of FOBT screening may come from "chance" selection of persons for colonoscopic examination because of the high positivity rate of FOBT (about 10%) that may occur for reasons other than a bleeding cancer or polyp. To determine how much this mechanism could account for the benefit of FOBT screening, we used a simple mathematical model to simulate the course of a cohort of screened persons, incorporating published data including those from the Minnesota study. The results suggest that one third to one half of the mortality reduction observed from FOBT screening in the Minnesota study may be attributable to chance selection for colonoscopy. We conclude that annual FOBT screening with rehydration is a haphazard method for selecting persons for colonoscopy.