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Gastric adenocarcinoma (GAC) is the fourth-leading global cause of cancer mortality and leading infection-associated cancer. High incidence regions include Latin America and Eastern Asia. Immigrants from high incidence regions maintain their GAC risk. GAC is a major U.S. cancer disparity, incidence rates are 2-10 time higher in non-white populations. Emerging guidelines recommend 3-year surveillance endoscopy for patients with high-risk gastric premalignant conditions (GPMCs). Clinical trials of GPMC chemoprevention agents are lacking. We conducted an NCI Division of Cancer Prevention-funded, phase II placebo-controlled chemoprevention trial in patients with GPMCs (atrophic gastritis, intestinal metaplasia) with a highly bioavailable preparation of curcuminoids (Meriva®). The trial sites in Puerto Rico and rural Honduras had important characteristics: (1) representative Caribbean and Mesoamerican populations, linked to large U.S. immigrant populations; (2) high prevalence of H. pylori infection and GPMCs; (3) absence of turmeric and curcuminoids in the local diets; (4) proven bidirectional collaboration with U.S. academic institutions. H. pylori-negative GPMC patients were randomized to study drug (500 mg po bid) or placebo for 180 days (NCT02782949), with primary outcomes based upon histologic parameters. Principal study challenges included: (1) international regulatory environment; (2) research infrastructure strengthening, particularly in Central America; (3) participant recruitment in Honduras wherein only 10-15% are H. pylori negative; (4) the Covid-19 pandemic; and (5) natural disasters (3 hurricanes). There were no losses to follow-up related to the pandemic or natural disasters. In conclusion, the south-south partnership provides a model for chemoprevention and translational studies in Latino populations with prevalent cancers such as GAC.
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Background and Aims: Effective approaches for prevention of hepatocellular carcinoma (HCC) will have a significant impact on HCC-related mortality. There are strong preclinical data and rationale to support targeting epidermal growth factor receptor (EGFR) for HCC chemoprevention. Small molecule inhibitors of EGFR have been Food and Drug Administration-approved for cancer therapy, which provides an opportunity to repurpose one of these drugs for chemoprevention of HCC. Unfortunately, the frequency of side effects associated with administration of these drugs at oncology doses renders them ineffective for chemoprevention. This clinical trial assesses whether lower doses of one of these inhibitors, erlotinib, still engages EGFR in the liver to block signaling (eg, EGFR phosphorylation). The objective of this clinical trial was determination of a safe and minimum effective dose of erlorinib for which ≥ 50% reduction phospho-EGFR immunohistochemical staining in the liver was observed. Methods: Forty six participants were preregistered and 25 participants were registered in this multicenter trial. By dose de-escalation trial design, cohorts of participants received a 7-day course of erlotinib 75 mg/day, 50 mg/day or 25 mg/day with liver tissue acquisition prior to and after erlotinib. Results: A ≥50% reduction phospho-EGFR immunohistochemical staining in the liver was observed in a minimum of 40% of participants (predetermined threshhold) at each of the dose levels. Erlotinib was very well tolerated with few side effects observed, particularly at the dose of 25 mg/day. Favorable modulation of the Prognostic Liver Signature was observed in participants who received erlotinib. Conclusion: These data support the selection of erlotinib doses as low as 25 mg/day of for a longer intervention to assess for evidence of efficacy as an HCC chemoprevention drug (ClinicalTrials.govNCT02273362).
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BACKGROUND: The benefits of colorectal cancer (CRC) screening programs rely on completing follow-up colonoscopy when a noncolonoscopy test is abnormal and on quality of colonoscopy screening as measured by the endoscopists' adenoma detection rate. Existing data demonstrate substantially lower follow-up colonoscopy rates and adenoma detection rate for Black Americans than White Americans. However, the contributions of racial differences in follow-up colonoscopy and adenoma detection rate on CRC outcomes have not been rigorously evaluated. METHODS: We used established and validated CRC-Adenoma Incidence and Mortality (CRC-AIM) model as our analysis platform, with inputs from published literature that report lower follow-up colonoscopy rates and adenoma detection rate in Black adults compared with White adults (15% and 10% lower, respectively). We simulated screening with annual fecal immunochemical test, triennial multitarget stool DNA, and colonoscopy every 10 years between ages 45 and 75 years using real-world utilization of the screening modalities vs no screening. We reported lifetime outcomes per 1000 Black adults. RESULTS: Elimination of Black-White disparities in follow-up colonoscopy rates would reduce CRC incidence and mortality by 5.2% and 9.3%, respectively, and improve life-years gained with screening by 3.4%. Elimination of Black-White disparities in endoscopists' adenoma detection rate would reduce CRC incidence and mortality by 9.4% and improve life-years gained by 3.7%. Elimination of both disparities would reduce CRC incidence and mortality by 14.6% and 18.7%, respectively, and improve life-years gained by 7.1%. CONCLUSIONS: This modeling study predicts eliminating racial differences in follow-up colonoscopy rates, and quality of screening colonoscopy would substantially reduce Black-White disparities in CRC incidence and mortality.
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Colorectal cancer is the second leading cause of cancer-related mortality in adults in the United States. Despite compelling evidence of improved outcomes in colorectal cancer, screening rates are not optimal. This study aimed to characterize colorectal cancer screening trends over the last two decades and assess the impact of various screening modalities on overall colorectal cancer screening rates. Using National Health Interview Survey data from 2005 to 2021, we examined colorectal cancer screening [colonoscopy, multitarget stool DNA (mt-sDNA), fecal occult blood test (FOBT)/fecal immunochemical test, sigmoidoscopy, CT colonography] rates among adults ages 50-75 years (n = 85,571). A pseudo-time-series cross-sectional (pseudo-TSCS) analysis was conducted including a random effects generalized least squares regression model to estimate the relative impact of each modality on changes in colorectal cancer screening rates. Among 50 to 75 year olds, the estimated colorectal cancer screening rate increased from 47.7% in 2005 to 69.9% in 2021, with the largest increase between 2005 and 2010 (47.7%-60.7%). Rates subsequently plateaued until 2015 but increased from 63.5% in 2015 to 69.9% in 2018. This was primarily driven by the increased use of mt-sDNA (2.5% in 2018 to 6.6% in 2021). Pseudo-TSCS analysis results showed that mt-sDNA contributed substantially to the increase in overall screening rates (77.3%; P < 0.0001) between 2018 and 2021. While colorectal cancer screening rates increased from 2005 to 2021, they remain below the 80% goal. The introduction of mt-sDNA, a noninvasive screening test may have improved overall rates. Sustained efforts are required to further increase screening rates to improve patient outcomes and offering a range of screening options is likely to contribute to achieving this goal. PREVENTION RELEVANCE: This retrospective study highlights the importance of convenient stool-based colorectal cancer screening options to achieve the national goal of 80% for overall colorectal cancer screening rates. Empowering screening-eligible individuals with a choice for their colorectal cancer screening tests is imperative.
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Neoplasias Colorrectales , Detección Precoz del Cáncer , Sangre Oculta , Sigmoidoscopía , Humanos , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/prevención & control , Persona de Mediana Edad , Detección Precoz del Cáncer/estadística & datos numéricos , Detección Precoz del Cáncer/métodos , Detección Precoz del Cáncer/tendencias , Masculino , Femenino , Anciano , Estados Unidos/epidemiología , Sigmoidoscopía/estadística & datos numéricos , Estudios Transversales , Colonoscopía/estadística & datos numéricos , Colonografía Tomográfica Computarizada/estadística & datos numéricos , Tamizaje Masivo/estadística & datos numéricos , Tamizaje Masivo/métodos , Tamizaje Masivo/tendencias , Heces/química , Encuestas EpidemiológicasRESUMEN
OBJECTIVE: This analysis estimated the outcomes of triennial blood-based colorectal cancer (CRC) screening at various adherence, including perfect adherence, compared with triennial multi-target stool DNA (mt-sDNA) screening at the reported real-world adherence rate. METHODS: The validated CRC-AIM model simulated a US cohort of average-risk individuals receiving triennial screening with mt-sDNA or blood-based test from ages 45 to 75 years. Modeled specificity and sensitivity were based on reported data. Adherence was set at a real-world rate of 65.6% for mt-sDNA and at 65.6%, relative 10% incremental increases from 65.6%, or 100% for the blood-based test. Costs of mt-sDNA and the blood-based test were based on prices for clinically available tests ($508.87 and $895, respectively). Value-based pricing was estimated at a willingness-to-pay threshold of $100,000. RESULTS: Both tests resulted in life-years gained (LYG), reduced CRC cases, and reduced deaths versus no screening. With adherence for mt-sDNA set at 65.6% and for blood-based test set at 100%, mt-sDNA resulted in 30% more LYG, 52% more averted CRC cases, and 32% more averted CRC deaths. At reported sensitivity and specificity rates, mt-sDNA at 65.6% adherence dominates (is more effective and less costly) the blood-based test at any adherence. There was no price at which triennial screening with the blood-based test at any adherence was cost-effective compared with mt-sDNA at 65.6% adherence. CONCLUSIONS: Triennial screening with mt-sDNA resulted in better clinical outcomes at a lower cost compared with the modeled blood-based test even at perfect adherence, supporting application of blood-based tests only as a secondary screening option.
Blood-based colorectal cancer screening has lower diagnostic accuracy, lower clinical and health outcomes, and is more expensive than mt-sDNA, even with perfect blood-based screening participation. Although better than no screening at all, blood-based testing is unlikely to exceed performance of stool-based assessment unless a blood-based test is able to meaningfully detect precancerous growths.
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Neoplasias Colorrectales , Análisis Costo-Beneficio , Detección Precoz del Cáncer , Sangre Oculta , Humanos , Neoplasias Colorrectales/diagnóstico , Persona de Mediana Edad , Anciano , Masculino , Femenino , Detección Precoz del Cáncer/métodos , Detección Precoz del Cáncer/economía , Heces/química , Cooperación del Paciente , Sensibilidad y Especificidad , Años de Vida Ajustados por Calidad de Vida , Estados UnidosRESUMEN
This cross-sectional study estimates the number of average-risk colorectal cancer screeningeligible individuals in the US since the US Preventive Services Task Force updated its recommendations in 2021.
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Neoplasias Colorrectales , Detección Precoz del Cáncer , Humanos , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiología , Servicios Preventivos de SaludRESUMEN
BACKGROUND: A next-generation multitarget stool DNA test, including assessments of DNA molecular markers and hemoglobin level, was developed to improve the performance of colorectal cancer screening, primarily with regard to specificity. METHODS: In a prospective study, we evaluated a next-generation multitarget stool DNA test in asymptomatic adults 40 years of age or older who were undergoing screening colonoscopy. The primary outcomes were sensitivity of the test for colorectal cancer and specificity for advanced neoplasia (colorectal cancer or advanced precancerous lesions). Advanced precancerous lesions included one or more adenomas or sessile serrated lesions measuring at least 1 cm in the longest dimension, lesions with villous histologic features, and high-grade dysplasia. Secondary objectives included the quantification of sensitivity for advanced precancerous lesions and specificity for nonneoplastic findings or negative colonoscopy and comparison of sensitivities for colorectal cancer and advanced precancerous lesions between the multitarget stool DNA test and a commercially available fecal immunochemical test (FIT). RESULTS: Of 20,176 participants, 98 had colorectal cancer, 2144 had advanced precancerous lesions, 6973 had nonadvanced adenomas, and 10,961 had nonneoplastic findings or negative colonoscopy. With the next-generation test, sensitivity for colorectal cancer was 93.9% (95% confidence interval [CI], 87.1 to 97.7), and specificity for advanced neoplasia was 90.6% (95% CI, 90.1 to 91.0). Sensitivity for advanced precancerous lesions was 43.4% (95% CI, 41.3 to 45.6), and specificity for nonneoplastic findings or negative colonoscopy was 92.7% (95% CI, 92.2 to 93.1). With the FIT, sensitivity was 67.3% (95% CI, 57.1 to 76.5) for colorectal cancer and 23.3% (95% CI, 21.5 to 25.2) for advanced precancerous lesions; specificity was 94.8% (95% CI, 94.4 to 95.1) for advanced neoplasia and 95.7% (95% CI, 95.3 to 96.1) for nonneoplastic findings or negative colonoscopy. As compared with FIT, the next-generation test had superior sensitivity for colorectal cancer (P<0.001) and for advanced precancerous lesions (P<0.001) but had lower specificity for advanced neoplasia (P<0.001). No adverse events occurred. CONCLUSIONS: The next-generation multitarget stool DNA test showed higher sensitivity for colorectal cancer and advanced precancerous lesions than FIT but also showed lower specificity. (Funded by Exact Sciences; BLUE-C ClinicalTrials.gov number, NCT04144738.).
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Adenoma , Neoplasias Colorrectales , ADN , Detección Precoz del Cáncer , Heces , Inmunoquímica , Lesiones Precancerosas , Adulto , Humanos , Adenoma/diagnóstico , Neoplasias Colorrectales/diagnóstico , ADN/análisis , Detección Precoz del Cáncer/métodos , Heces/química , Lesiones Precancerosas/diagnóstico , Estudios Prospectivos , Enfermedades Asintomáticas , Colonoscopía , Sensibilidad y Especificidad , Pruebas Inmunológicas/métodos , Inmunoquímica/métodosRESUMEN
The multi-target stool DNA (mt-sDNA) test screens for colorectal cancer by analyzing DNA methylation/mutation and hemoglobin markers to algorithmically derive a qualitative result. A new panel of highly discriminant candidate methylated DNA markers (MDM) was recently developed. Performance of the novel MDM panel, with hemoglobin, was evaluated in a simulated screening population using archived stool samples weighted to early-stage colorectal cancer and prospectively collected advanced precancerous lesions (APL). Marker selection study (MSS) and separate preliminary independent verification studies (VS) were conducted utilizing samples from multi-center, case-control studies. Sample processing included targeted MDM capture, bisulfite conversion, and MDM quantitation. Fecal hemoglobin was quantified using ELISA. Samples were stratified into 75%/25% training-testing sets; model outcomes were cross-validated 1,000 times. All laboratory operators were blinded. The MSS included 232 cases (120 colorectal cancer/112 APLs) and 490 controls. The VS featured 210 cases (112 colorectal cancer/98 APLs) and 567 controls; APLs were 86.7% adenomas and 13.3% sessile serrated lesions (SSL). Average age was 65.5 (cases) and 63.2 (controls) years. Mean sensitivity in the VS from cross-validation was 95.2% for colorectal cancer and 57.2% for APLs, with specificities of 89.8% (no CRC/APLs) and 92.4% (no neoplasia). Subgroup analyses showed colorectal cancer sensitivities of 93.4% (stage I) and 94.2% (stage II). APL sensitivity was 82.9% for high-grade dysplasia, 73.4% for villous lesions, 49.8% for tubular lesions, and 30.2% for SSLs. These data support high sensitivity and specificity for a next-generation mt-sDNA test panel. Further evaluation of assay performance will be characterized in a prospective, multi-center clinical validation study (NCT04144738). PREVENTION RELEVANCE: This study highlights performance of the next-generation mt-sDNA test, which exhibits high sensitivity and specificity for detecting colorectal cancer and APLs. This noninvasive option has potential to increase screening participation and clinical outcomes. A multi-center, clinical validation trial is underway. See related commentary by Bresalier, p. 93.
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Neoplasias Colorrectales , Lesiones Precancerosas , Anciano , Humanos , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , ADN/análisis , Detección Precoz del Cáncer , Heces/química , Hemoglobinas/análisis , Lesiones Precancerosas/diagnóstico , Lesiones Precancerosas/genética , Estudios Prospectivos , Sensibilidad y Especificidad , Persona de Mediana EdadRESUMEN
Medicare coverage of a follow-up colonoscopy after a positive stool-based colorectal cancer screening test with no patient cost-sharing started January 2, 2023, which may favorably affect screening behavior. This analysis estimated the clinical and economic effects of increased colorectal cancer screening participation potentially resulting from this policy change in Medicare beneficiaries. The validated Colorectal Cancer and Adenoma Incidence & Mortality (CRC-AIM) model simulated three guideline-endorsed colorectal cancer screening strategies for average-risk individuals (colonoscopy every 10 years, annual fecal immunochemical test, triennial multitarget stool DNA) from ages 65-75 years. The base-case scenario assumed 0% coinsurance for initial screening and follow-up colonoscopy, real-world screening test use (colonoscopy = 45.3%, stool-based test = 24.4%, unscreened = 30.3%), and real-world follow-up colonoscopy rates. Comparative scenarios assumed an increase in the overall screening rate from 0% to 15% (5% increments) and an increase in the follow-up colonoscopy rate from 0% to 15% (5% increments). The base-case scenario resulted in 128 life-years gained (LYG)/1,000 individuals versus no screening and total screening and treatment costs of $7,938/person. The changes resulted in an increase of up to 26 LYG/1,000 individuals and a decrease in total screening and treatment costs by as much as $128/person. Follow-up colonoscopy at $0 coinsurance became cost-saving with any increase in either overall screening or follow-up colonoscopy. Policies that remove cost barriers to completing colorectal cancer screening may increase rates of screening participation, potentially improving economic and clinical outcomes. SIGNIFICANCE: A follow-up colonoscopy after a positive stool-based colorectal cancer screening test is necessary to complete the full screening process. Policies that remove cost barriers to completing colorectal cancer screening may lead to increases in overall participation rates and use of follow-up colonoscopy, improving clinical and economic outcomes.
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Neoplasias Colorrectales , Tamizaje Masivo , Anciano , Humanos , Estados Unidos , Estudios de Seguimiento , Detección Precoz del Cáncer , Medicare , Colonoscopía , Neoplasias Colorrectales/diagnósticoRESUMEN
AIM: The United States Preventive Services Taskforce (USPSTF) recently recommended lowering the age for average-risk colorectal cancer (CRC) screening from 50 to 45 years. While initiating screening at age 45 versus 50 provides a greater opportunity for CRC early detection and prevention, the full profile of benefits, risks, and cost-effectiveness of expanding the screen-eligible population requires further evaluation. MATERIALS AND METHODS: The costs and clinical outcomes for screening at age 45 for triennial multi-target stool DNA [mt-sDNA], and other non-invasive stool-based modalities (annual fecal immunochemical test [FIT] and annual fecal-occult blood test [FOBT]), were estimated using the validated CRC-AIM microsimulation model over a lifetime horizon. Test sensitivity and specificity inputs were based on 2021 USPSTF modeling analyses; adherence rates were based on published real-world data and the costs of the screening test, follow-up colonoscopies, complications, and CRC care were included. Outcomes are reported from the perspective of a United States payer as clinical, life-years gained (LYG), and incremental cost-effectiveness ratio (ICER); stool-based and follow-up colonoscopy adherence ranges were explored in one-way, probabilistic and threshold analyses. RESULTS: When compared to initiation of CRC screening at age 45 versus 50, all modalities reduced both the incidence of and mortality from CRC and increased LYG. Initiating CRC screening at age 45 was cost-effective with an ICER of $59,816 and $35,857 per quality-adjusted life year (QALY) for mt-sDNA versus FIT and FOBT, respectively. In the threshold analyses, at equivalent rates to stool-based screening, mt-sDNA was always cost-effective at a willingness-to-pay threshold of $100,000 per QALY versus FIT and FOBT. CONCLUSIONS: Initiating average-risk CRC screening at age 45 instead of age 50 increases the estimated clinical benefit by reducing disease burden while remaining cost-effective. Among stool-based screening modalities, mt-sDNA provides the most clinical benefit in a Commercial and Medicare population.
Screening for colorectal cancer at an earlier age can provide additional benefits in terms of reducing disease complications and death. This study looked at the occurrence of disease complications and costs related to different types of colorectal cancer screening in 45 vs. 50 year old people. A model that has previously been used to project lifetime costs and disease complications in people receiving colorectal cancer screening was used in this study. We found that beginning screening at age 45 as compared to at age 50 reduced disease complications and death. In people who started screening at age 45, one particular screening type (multitarget stool DNA) was found to provide better economic value to a greater degree relative to other strategies. These findings were consistent even when many inputs into the model were changed over reasonable ranges. Therefore, our study helps show that starting screening in people at age 45 with average risk for developing colorectal cancer is beneficial by reducing disease complications and deaths, and that multitarget stool DNA is the strategy that provides the most benefits while being economically justifiable.
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Neoplasias Colorrectales , Detección Precoz del Cáncer , Humanos , Estados Unidos , Persona de Mediana Edad , Análisis Costo-Beneficio , Sensibilidad y Especificidad , Colonoscopía , Tamizaje Masivo , Neoplasias Colorrectales/diagnóstico , MedicareRESUMEN
The Centers for Medicare & Medicaid Services (CMS) recommend covering blood-based tests meeting proposed minimum performance thresholds for colorectal cancer (CRC) screening. Outcomes were compared between currently available stool-based screening tests and a hypothetical blood-based test meeting CMS minimum thresholds. Using the Colorectal Cancer and Adenoma Incidence and Mortality Microsimulation Model (CRC-AIM), outcomes were simulated for average-risk individuals screened between ages 45 and 75 years with triennial multitarget stool DNA (mt-sDNA), annual fecal immunochemical test (FIT), and annual fecal occult blood test (FOBT). Per CMS guidance, blood-based CRC screening was modeled triennially, with 74% CRC sensitivity and 90% specificity. Although not specified by CMS, adenoma sensitivity was set between 10% and 20%. Published adenoma and CRC sensitivity and specificity were used for stool-based tests. Adherence was set at (1) 100%, (2) 30%-70%, in 10% increments, and (3) real-world rates for stool-based tests (mt-sDNA = 65.6%; FIT = 42.6%; FOBT = 34.4%). Assuming perfect adherence, a blood-based test produced ≥19 lower life-years gained (LYG) than stool-based strategies. At the best-case scenario for blood-based tests (100% adherence and 20% adenoma sensitivity), mt-sDNA at real-world adherence achieved more LYG (287.2 vs. 297.1, respectively) with 14% fewer colonoscopies. At 100% blood-based test adherence and real-world mt-sDNA and FIT adherence, the blood-based test would require advanced adenoma sensitivity of 30% to reach the LYG of mt-sDNA (297.1) and â¼15% sensitivity to reach the LYG of FIT (258.9). This model suggests that blood-based tests with CMS minimally acceptable CRC sensitivity and low advanced adenoma sensitivity will frequently yield inferior outcomes to stool-based testing across a wide range of adherence assumptions.
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Adenoma , Neoplasias Colorrectales , Anciano , Humanos , Estados Unidos , Detección Precoz del Cáncer , Medicare , Sensibilidad y Especificidad , Tamizaje Masivo , Neoplasias Colorrectales/diagnóstico , Adenoma/diagnósticoRESUMEN
Objective: To evaluate the effect of hemorrhoids on noninvasive stool test performance for colorectal cancer (CRC) screening. Patients and Methods: We conducted a retrospective cohort study of test characteristics for the fecal immunochemical test (FIT) and the multitarget stool DNA (mt-sDNA) test, on the basis of hemorrhoid status, recorded at the time of colonoscopy, among patients enrolled in the pivotal prospective study for mt-sDNA that was conducted from June 2011, to May 2013. Test characteristics (sensitivity, specificity, positive, and negative predictive values) for FIT and mt-sDNA (performed < 90 days before colonoscopy) were stratified by the presence of hemorrhoids and compared. Results: Hemorrhoids were found in 51.7% (5163 of 9989) of the study cohort. Across all test characteristics, there were no statistically significant differences for FIT or mt-sDNA when stratified by hemorrhoid status. Analysis revealed mt-sDNA sensitivity of 44% and 41% for advanced precancerous lesions in nonhemorrhoidal and hemorrhoid patients, respectively (P=.41). The FIT sensitivity among the same lesion category was 24.9% in patients without hemorrhoids and 22.8% in those with hemorrhoids (P=.48). The mt-sDNA specificity was 86.4% in patients without hemorrhoids vs 87.7% in those with hemorrhoids (P=.67), although FIT specificity was 95.0% among patients without hemorrhoids vs 94.7% in those with hemorrhoids (P=.44). Conclusion: The presence of asymptomatic hemorrhoids did not adversely affect test performance in this large clinical study. These findings suggest that in the absence of overt gastrointestinal bleeding, FIT and mt-sDNA are options for CRC screening, irrespective of hemorrhoid status. Trial Registration: clinicaltrials.gov Identifier: NCT01397747.
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OBJECTIVES: Machine learning (ML)-based emulators improve the calibration of decision-analytical models, but their performance in complex microsimulation models is yet to be determined. METHODS: We demonstrated the use of an ML-based emulator with the Colorectal Cancer (CRC)-Adenoma Incidence and Mortality (CRC-AIM) model, which includes 23 unknown natural history input parameters to replicate the CRC epidemiology in the United States. We first generated 15,000 input combinations and ran the CRC-AIM model to evaluate CRC incidence, adenoma size distribution, and the percentage of small adenoma detected by colonoscopy. We then used this data set to train several ML algorithms, including deep neural network (DNN), random forest, and several gradient boosting variants (i.e., XGBoost, LightGBM, CatBoost) and compared their performance. We evaluated 10 million potential input combinations using the selected emulator and examined input combinations that best estimated observed calibration targets. Furthermore, we cross-validated outcomes generated by the CRC-AIM model with those made by CISNET models. The calibrated CRC-AIM model was externally validated using the United Kingdom Flexible Sigmoidoscopy Screening Trial (UKFSST). RESULTS: The DNN with proper preprocessing outperformed other tested ML algorithms and successfully predicted all 8 outcomes for different input combinations. It took 473 s for the trained DNN to predict outcomes for 10 million inputs, which would have required 190 CPU-years without our DNN. The overall calibration process took 104 CPU-days, which included building the data set, training, selecting, and hyperparameter tuning of the ML algorithms. While 7 input combinations had acceptable fit to the targets, a combination that best fits all outcomes was selected as the best vector. Almost all of the predictions made by the best vector laid within those from the CISNET models, demonstrating CRC-AIM's cross-model validity. Similarly, CRC-AIM accurately predicted the hazard ratios of CRC incidence and mortality as reported by UKFSST, demonstrating its external validity. Examination of the impact of calibration targets suggested that the selection of the calibration target had a substantial impact on model outcomes in terms of life-year gains with screening. CONCLUSIONS: Emulators such as a DNN that is meticulously selected and trained can substantially reduce the computational burden of calibrating complex microsimulation models. HIGHLIGHTS: Calibrating a microsimulation model, a process to find unobservable parameters so that the model fits observed data, is computationally complex.We used a deep neural network model, a popular machine learning algorithm, to calibrate the Colorectal Cancer Adenoma Incidence and Mortality (CRC-AIM) model.We demonstrated that our approach provides an efficient and accurate method to significantly speed up calibration in microsimulation models.The calibration process successfully provided cross-model validation of CRC-AIM against 3 established CISNET models and also externally validated against a randomized controlled trial.
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Adenoma , Neoplasias Colorrectales , Humanos , Incidencia , Calibración , Neoplasias Colorrectales/diagnóstico , Redes Neurales de la Computación , Adenoma/diagnósticoRESUMEN
We utilized the population-based New Hampshire Colonoscopy Registry to calculate false discovery rates (FDR) and positive predictive values (PPVs) using three 'positive' colonoscopy definitions. Understanding the frequency of meaningful 'true positive' mt-sDNA and Fecal Immunochemical Test (FIT) results can optimize the use of these colorectal cancer (CRC) screening tests. We calculated FDR (positive stool test followed by negative colonoscopy divided by all positive stool tests) and PPV for mt-sDNA and FIT cohorts using the following definitions: 1) DeeP-C Study (CRC, adenomas/serrated polyps ≥ 1 cm, villous/High Grade Dysplasia); 2) < 10 year US Multi-Society Task Force (USMSTF) follow-up: DeeP-C findings & ≥1 sessile serrated polyps (SSPs) < 1 cm (with/without dysplasia) or ≥ 1 tubular adenomas < 1 cm. 3) Clinically Significant: DeeP-C + USMSTF + clinically significant serrated polyps: traditional serrated adenomas, SSPs, hyperplastic polyps (HPs) > 1 cm, and 5-9 mm proximal HPs. The sample included 549 mt-sDNA + and 410 FIT + and patients (mean age 66.4, 43.0% male). Using the most limited definition of positive colonoscopy, DeeP-C, FDR was 71.9% for mt-sDNA + and 81.7% for FIT +. Using the USMSTF definition, FDR decreased substantially: mt-sDNA+:33.2% and FIT+:47.6%. Adding all CSSPs resulted in the lowest FDR: mt-sDNA+:32.2% and FIT+:47.1%. Decreasing FDRs corresponded to increasing PPVs: mt-sDNA+:28.1% and FIT+:18.3% (DeeP-C definition) and mt-sDNA+:67.8% and FIT+:52.9% (DeeP-C + USMSTF + CSSP) (Table 1). FDRs decreased substantially when the definition of positive exams included all significant precancerous findings. These data present a comprehensive understanding of false positive outcomes at colonoscopies following positive stool tests, which to our knowledge is the first such analysis.
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BACKGROUND: To assess patient and primary care provider (PCP) factors associated with adherence to American Cancer Society (ACS) and United States Preventive Services Task Force (USPSTF) guidelines for average risk colorectal cancer (CRC) screening. METHODS: Retrospective case-control study of medical and pharmacy claims from the Optum Research Database from 01/01/2014 - 12/31/2018. Enrollee sample was adults aged 50 - 75 years with ≥ 24 months continuous health plan enrollment. Provider sample was PCPs listed on the claims of average-risk patients in the enrollee sample. Enrollee-level screening opportunities were based on their exposure to the healthcare system during the baseline year. Screening adherence, calculated at the PCP level, was the percent of average-risk patients up to date with screening recommendations each year. Logistic regression modelling was used to examine the association between receipt of screening and enrollee and PCP characteristics. An ordinary least squares model was used to determine the association between screening adherence among the PCP's panel of patients and patient characteristics. RESULTS: Among patients with a PCP, adherence to ACS and USPSTF screening guidelines ranged from 69 to 80% depending on PCP specialty and type. The greatest enrollee-level predictors for CRC screening were having a primary/preventive care visit (OR = 4.47, p < 0.001) and a main PCP (OR = 2.69, p < 0.001). CONCLUSIONS: Increased access to preventive/primary care visits could improve CRC screening rates; however, interventions not dependent on healthcare system contact, such as home-based screening, may circumvent the dependence on primary care visits to complete CRC screening.
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Neoplasias Colorrectales , Detección Precoz del Cáncer , Adulto , Humanos , Estados Unidos , Estudios Retrospectivos , Estudios de Casos y Controles , Atención Primaria de Salud , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/prevención & control , Tamizaje MasivoRESUMEN
BACKGROUND AND AIMS: The FDA-approved multitarget stool-DNA [mt-sDNA] test is a successful colorectal cancer [CRC] screening tool in average-risk individuals but is not indicated for patients with inflammatory bowel disease [IBD]. We determined the performance of the mt-sDNA assay without the haemoglobin component [mt-sDNAHgb-] in patients with IBD, while measuring sensitivity for colorectal cancer and advanced colorectal neoplasia [ACRN]. METHODS: This was a multi-centre, proof-of-concept investigation in persons aged 18-84 years with a diagnosis of IBD, or primary sclerosing cholangitis [PSC] with IBD. Enrolment occurred between March 2013 and May 2016. Stool was tested with the mt-sDNA molecular markers only, minus the immunochemical haemoglobin component. RESULTS: The analysis set contained 355 samples. The median age was 52 [range 39-62] years, 45.6% were female and 93% were White. Two-thirds [63%] had ulcerative colitis [UC] and 10.1% had PSC/IBD. Colonoscopy revealed cancer in 8.5% [Nâ =â 30], advanced precancerous lesions [APLs] in 9.3% [Nâ =â 33] and non-advanced precancerous lesions in 7.6% [Nâ =â 27], and three-quarters [74.7%, Nâ =â 265] had negative findings. mt-sDNAHgb- sensitivity was 73.3% for any stage cancers, and 76.2% for ACRN. Sensitivity was highest for IBD-associated high-grade dysplasia at 100% and 84.6% for IBD-associated low-grade dysplasia ≥1 cm. The test showed higher sensitivity and lower specificity in UC than in Crohn's disease. Increasing inflammation score was associated with a significant decrease in mt-sDNAHgb- test score [â =â 0.028] amongst neoplasia-negative individuals, but not in patients with ACRN. CONCLUSIONS: These data highlight the potential of multitarget stool-DNA marker testing as an important addition to colorectal cancer surveillance by complementing colonoscopic evaluations in IBD patients.
RESUMEN
PURPOSE: To assess whether MUC1 peptide vaccine produces an immune response and prevents subsequent colon adenoma formation. PATIENTS AND METHODS: Multicenter, double-blind, placebo-controlled randomized trial in individuals age 40 to 70 with diagnosis of an advanced adenoma ≤1 year from randomization. Vaccine was administered at 0, 2, and 10 weeks with a booster injection at week 53. Adenoma recurrence was assessed ≥1 year from randomization. The primary endpoint was vaccine immunogenicity at 12 weeks defined by anti-MUC1 ratio ≥2.0. RESULTS: Fifty-three participants received the MUC1 vaccine and 50 placebo. Thirteen of 52 (25%) MUC1 vaccine recipients had a ≥2-fold increase in MUC1 IgG (range, 2.9-17.3) at week 12 versus 0/50 placebo recipients (one-sided Fisher exact P < 0.0001). Of 13 responders at week 12, 11 (84.6%) responded to a booster injection at week 52 with a ≥2-fold increase in MUC1 IgG measured at week 55. Recurrent adenoma was observed in 31 of 47 (66.0%) in the placebo group versus 27 of 48 (56.3%) in the MUC1 group [adjusted relative risk (aRR), 0.83; 95% confidence interval (CI), 0.60-1.14; P = 0.25]. Adenoma recurrence occurred in 3/11 (27.3%) immune responders at week 12 and week 55 (aRR, 0.41; 95% CI, 0.15-1.11; P = 0.08 compared with placebo). There was no difference in serious adverse events. CONCLUSIONS: An immune response was observed only in vaccine recipients. Adenoma recurrence was not different than placebo, but a 38% absolute reduction in adenoma recurrence compared with placebo was observed in participants who had an immune response at week 12 and with the booster injection.
Asunto(s)
Adenoma , Neoplasias del Colon , Neoplasias Colorrectales , Adulto , Anciano , Humanos , Persona de Mediana Edad , Adenoma/prevención & control , Neoplasias Colorrectales/prevención & control , Inmunoglobulina G , Vacunas de SubunidadRESUMEN
Background: Gastroesophageal reflux disease (GERD) is a risk factor for Barrett's esophagus (BE) and BE-related neoplasia (BERN). Objectives: This study aimed to evaluate healthcare resource utilization (HRU) and costs associated with GERD, BE, and BERN in the United States. Methods: Adult patients with GERD, nondysplastic BE (NDBE), and BERN (including indefinite for dysplasia [IND], low-grade dysplasia [LGD], high-grade dysplasia [HGD] or esophageal adenocarcinoma [EAC]), were identified from a large US administrative claims database, the IBM Truven Health MarketScan® databases (Q1/2015-Q4/2019). Patients were categorized into the corresponding mutually exclusive EAC-risk/diagnosis cohorts based on the most advanced stage from GERD to EAC using diagnosis codes in medical claims. Disease-related HRU and costs (2020 USD) were calculated for each cohort. Results: Patients were categorized into the following EAC-risk/diagnosis cohorts: 3â¯310â¯385 into GERD, 172â¯481 into NDBE, 11â¯516 into IND, 4332 into LGD, 1549 into HGD, and 11â¯676 into EAC. Disease-related annual mean number of inpatient admissions, office visits, and emergency department visits by cohort were 0.09, 1.45, and 0.19 for GERD; 0.08, 1.55, and 0.10 for NDBE; 0.10, 1.92, and 0.13 for IND; 0.09, 2.05, and 0.10 for LGD; 0.12, 2.16, and 0.14 for HGD; and 1.43, 6.27, and 0.87 for EAC. Disease-related annual mean total healthcare costs by cohort were $6955 for GERD, $8755 for NDBE, $9675 for IND, $12â¯241 for LGD, $24â¯239 for HGD, and $146â¯319 for EAC. Discussion: Patients with GERD, BE, and BERN had important HRU and costs, including inpatient admissions and office visits. As patients progressed to more advanced stages, there was substantially higher disease-related resource utilization, with associated costs being 16 times higher in patients with EAC than those with NDBE. Conclusions: Findings suggest the need for early identification of high-risk individuals prior to progression to EAC to potentially improve clinical and economic outcomes in this population.