Trends in uterine cancer incidence in the United States: The contribution of age, period and cohort effects.

OBJECTIVE: In the U.S., uterine cancer incidence is rising, with racial and ethnic minorities experiencing the largest increases. We performed age-period-cohort analyses using novel methods to examine the contribution of age at diagnosis (age), year of diagnosis (period), and birth cohort (cohort), to trends in uterine cancer incidence. METHODS: We used uterine cancer incidence data from the Surveillance, Epidemiology, and End Result (SEER) 12 database (1992-2019), and performed hysterectomy-correction. We generated hexamaps to visualize age, period, and cohort effects, and used mutual information to estimate the percent contribution of age, period, and cohort effects, individually and combined, on uterine cancer incidence, overall and by race and ethnicity and histology. RESULTS: Hexamaps showed an increase in uterine cancer in later time periods, and a cohort effect around 1933 showing a lower incidence compared with earlier and later cohorts. Age, period, and cohort effects combined contributed 86.6% (95% CI: 86.4%, 86.9%) to the incidence. Age effects had the greatest contribution (65.1%, 95% CI: 64.3%, 65.9), followed by cohort (20.7%, 95% CI: 20.1%, 21.3%) and period (14.2%, 95% CI: 13.7%, 14.8%) effects. Hexamaps showed higher incidence in recent years for non-Hispanic Blacks and non-endometrioid tumors. CONCLUSIONS: Age effects had the largest contribution to uterine cancer incidence, followed by cohort and period effects overall and across racial and ethnic groups and histologies. IMPACT: These findings can inform uterine cancer modeling studies on the effects of interventions that target risk factors which may vary across age, period, or cohort.

Endoscopic Screening Program for Control of Esophageal Adenocarcinoma in Varied Populations: A Comparative Cost-Effectiveness Analysis.

BACKGROUND & AIMS: Guidelines suggest endoscopic screening for esophageal adenocarcinoma (EAC) among individuals with symptoms of gastroesophageal reflux disease (GERD) and additional risk factors. We aimed to determine at what age to perform screening and whether sex and race should influence the decision. METHODS: We conducted comparative cost-effectiveness analyses using 3 independent simulation models. For each combination of sex and race (White/Black, 100,000 individuals each), we considered 41 screening strategies, including one-time or repeated screening. The optimal strategy was that with the highest effectiveness and an incremental cost-effectiveness ratio <$100,000 per quality-adjusted life-year gained. RESULTS: Among White men, 536 EAC deaths were projected without screening, and screening individuals with GERD twice at ages 45 and 60 years was optimal. Screening the entire White male population once at age 55 years was optimal in 26% of probabilistic sensitivity analysis runs. Black men had fewer EAC deaths without screening (n = 84), and screening those with GERD once at age 55 years was optimal. Although White women had slightly more EAC deaths (n = 103) than Black men, the optimal strategy was no screening, although screening those with GERD once at age 55 years was optimal in 29% of probabilistic sensitivity analysis runs. Black women had a very low burden of EAC deaths (n = 29), and no screening was optimal, as benefits were very small and some strategies caused net harm. CONCLUSIONS: The optimal strategy for screening differs by race and sex. White men with GERD symptoms can potentially be screened more intensely than is recommended currently. Screening women is not cost-effective and may cause net harm for Black women.

Yield of Repeat Endoscopy for Barrett's Esophagus After Normal Index Endoscopy.

INTRODUCTION: Guidelines suggest 1-time screening with esophagogastroduodenoscopy (EGD) for Barrett's esophagus (BE) in individuals at an increased risk of esophageal adenocarcinoma (EAC). We aimed to estimate the yield of repeat EGD performed at prolonged intervals after a normal index EGD. METHODS: We conducted a national retrospective analysis within the U S Veterans Health Administration, identifying patients with a normal index EGD between 2003 and 2009 who subsequently had a repeat EGD. We tabulated the proportion with a new diagnosis of BE, EAC, or esophagogastric junction adenocarcinoma (EGJAC) and conducted manual chart review of a sample. We fitted logistic regression models for the odds of a new diagnosis of BE/EAC/EGJAC. RESULTS: We identified 71,216 individuals who had a repeat EGD between 1 and 16 years after an index EGD without billing or cancer registry codes for BE/EAC/EGJAC. Of them, 4,088 had a new billing or cancer registry code for BE/EAC/EGJAC after the repeat EGD. On manual review of a stratified sample, most did not truly have new BE/EAC/EGJAC. A longer duration between EGD was associated with greater odds of a new diagnosis (adjusted odds ratio [aOR] for each 5 years 1.31; 95% confidence interval [CI] 1.19-1.44), particularly among those who were younger during the index EGD (ages 19-29 years: aOR 3.92; 95% CI 1.24-12.4; ages 60-69 years: aOR 1.19; 95% CI 1.01-1.40). DISCUSSION: The yield of repeat EGD for BE/EAC/EGJAC seems to increase with time after a normal index EGD, particularly for younger individuals. Prospective studies are warranted to confirm these findings.

The Optimal Age to Stop Endoscopic Surveillance of Patients With Barrett's Esophagus Based on Sex and Comorbidity: A Comparative Cost-Effectiveness Analysis.

BACKGROUND AND AIMS: Current guidelines recommend surveillance for patients with nondysplastic Barrett's esophagus (NDBE) but do not include a recommended age for discontinuing surveillance. This study aimed to determine the optimal age for last surveillance of NDBE patients stratified by sex and level of comorbidity. METHODS: We used 3 independently developed models to simulate patients diagnosed with NDBE, varying in age, sex, and comorbidity level (no, mild, moderate, and severe). All patients had received regular surveillance until their current age. We calculated incremental costs and quality-adjusted life-years (QALYs) gained from 1 additional endoscopic surveillance at the current age versus not performing surveillance at that age. We determined the optimal age to end surveillance as the age at which incremental cost-effectiveness ratio of 1 more surveillance was just less than the willingness-to-pay threshold of $100,000/QALY. RESULTS: The benefit of having 1 more surveillance endoscopy strongly depended on age, sex, and comorbidity. For men with NDBE and severe comorbidity, 1 additional surveillance at age 80 years provided 4 more QALYs per 1000 patients with BE at an additional cost of $1.2 million, whereas for women with severe comorbidity the benefit at that age was 7 QALYs at a cost of $1.3 million. For men with no, mild, moderate, and severe comorbidity, the optimal ages of last surveillance were 81, 80, 77, and 73 years, respectively. For women, these ages were younger: 75, 73, 73, and 69 years, respectively. CONCLUSIONS: Our comparative modeling analysis illustrates the importance of considering comorbidity status and sex when deciding on the age to discontinue surveillance in patients with NDBE.

Modeling historic incidence trends implies early field cancerization in esophageal squamous cell carcinoma.

Patterns of cancer incidence, viewed over extended time periods, reveal important aspects of multistage carcinogenesis. Here we show how a multistage clonal expansion (MSCE) model for cancer can be harnessed to identify biological processes that shape the surprisingly dynamic and disparate incidence patterns of esophageal squamous cell carcinoma (ESCC) in the US population. While the dramatic rise in esophageal adenocarcinoma (EAC) in the US has been largely attributed to reflux related increases in the prevalence of Barrett's esophagus (BE), the premalignant field in which most EAC are thought to arise, only scant evidence exists for field cancerization contributing to ESCC. Our analyses of incidence patterns suggest that ESCC is associated with a premalignant field that may develop very early in life. Although the risk of ESCC, which is substantially higher in Blacks than Whites, is generally assumed to be associated with late-childhood and adult exposures to carcinogens, such as from tobacco smoking, alcohol consumption and various industrial exposures, the temporal trends we identify for ESCC suggest an onset distribution of field-defects before age 10, most strongly among Blacks. These trends differ significantly in shape and strength from field-defect trends that we estimate for US Whites. Moreover, the rates of ESCC-predisposing field-defects predicted by the model for cohorts of black children are decreasing for more recent birth cohorts (for Blacks born after 1940). These results point to a potential etiologic role of factors acting early in life, perhaps related to nutritional deficiencies, in the development of ESCC and its predisposing field-defect. Such factors may explain some of the striking racial differences seen in ESCC incidence patterns over time in the US.

Optimizing Management of Patients With Barrett's Esophagus and Low-Grade or No Dysplasia Based on Comparative Modeling.

BACKGROUND & AIMS: Endoscopic treatment is recommended for patients with Barrett's esophagus (BE) with high-grade dysplasia, yet clinical management recommendations are inconsistent for patients with BE without dysplasia (NDBE) or with low-grade dysplasia (LGD). We used a comparative modeling analysis to identify optimal management strategies for these patients. METHODS: We used 3 independent population-based models to simulate cohorts of 60-year-old individuals with BE in the United States. We followed up each cohort until death without surveillance and treatment (natural disease progression), compared with 78 different strategies of management for patients with NDBE or LGD. We determined the optimal strategy using cost-effectiveness analyses, at a willingness-to-pay threshold of $100,000 per quality-adjusted life-year (QALY). RESULTS: In the 3 models, the average cumulative incidence of esophageal adenocarcinoma was 111 cases, with costs totaling $5.7 million per 1000 men with BE. Surveillance and treatment of men with BE prevented 23% to 75% of cases of esophageal adenocarcinoma, but increased costs to $6.2 to $17.3 million per 1000 men with BE. The optimal strategy was surveillance every 3 years for men with NDBE and treatment of LGD after confirmation by repeat endoscopy (incremental cost-effectiveness ratio, $53,044/QALY). The average results for women were consistent with the results for men for LGD management, but the optimal surveillance interval for women with NDBE was 5 years (incremental cost-effectiveness ratio, $36,045/QALY). CONCLUSIONS: Based on analyses from 3 population-based models, the optimal management strategy for patient with BE and LGD is endoscopic eradication, but only after LGD is confirmed by a repeat endoscopy. The optimal strategy for patients with NDBE is endoscopic surveillance, using a 3-year interval for men and a 5-year interval for women.

The impact of overdiagnosis on the selection of efficient lung cancer screening strategies.

The U.S. Preventive Services Task Force (USPSTF) recently updated their national lung screening guidelines and recommended low-dose computed tomography (LDCT) for lung cancer (LC) screening through age 80. However, the risk of overdiagnosis among older populations is a concern. Using four comparative models from the Cancer Intervention and Surveillance Modeling Network, we evaluate the overdiagnosis of the screening program recommended by USPSTF in the U.S. 1950 birth cohort. We estimate the number of LC deaths averted by screening (D) per overdiagnosed case (O), yielding the ratio D/O, to quantify the trade-off between the harms and benefits of LDCT. We analyze 576 hypothetical screening strategies that vary by age, smoking, and screening frequency and evaluate efficient screening strategies that maximize the D/O ratio and other metrics including D and life-years gained (LYG) per overdiagnosed case. The estimated D/O ratio for the USPSTF screening program is 2.85 (model range: 1.5-4.5) in the 1950 birth cohort, implying LDCT can prevent ∼3 LC deaths per overdiagnosed case. This D/O ratio increases by 22% when the program stops screening at an earlier age 75 instead of 80. Efficiency frontier analysis shows that while the most efficient screening strategies that maximize the mortality reduction (D) irrespective of overdiagnosis screen through age 80, screening strategies that stop at age 75 versus 80 produce greater efficiency in increasing life-years gained per overdiagnosed case. Given the risk of overdiagnosis with LC screening, the stopping age of screening merits further consideration when balancing benefits and harms.

Cost Effectiveness of Screening Patients With Gastroesophageal Reflux Disease for Barrett's Esophagus With a Minimally Invasive Cell Sampling Device.

BACKGROUND & AIMS: It is important to identify patients with Barrett's esophagus (BE), the precursor to esophageal adenocarcinoma (EAC). Patients with BE usually are identified by endoscopy, which is expensive. The Cytosponge, which collects tissue from the esophagus noninvasively, could be a cost-effective tool for screening individuals with gastroesophageal reflux disease (GERD) who are at increased risk for BE. We developed a model to analyze the cost effectiveness of using the Cytosponge in first-line screening of patients with GERD for BE with endoscopic confirmation, compared with endoscopy screening only. METHODS: We incorporated data from a large clinical trial of Cytosponge performance into 2 validated microsimulation models of EAC progression (the esophageal adenocarcinoma model from Massachusetts General Hospital and the microsimulation screening analysis model from Erasmus University Medical Center). The models were calibrated for US Surveillance, Epidemiology and End Results data on EAC incidence and mortality. In each model, we simulated the effect of a 1-time screen for BE in male patients with GERD, 60 years of age, using endoscopy alone or Cytosponge collection of tissue, and analysis for the level of trefoil factor 3 with endoscopic confirmation of positive results. For each strategy we recorded the number of cases of EAC that developed, the number of EAC cases detected with screening by Cytosponge only or by subsequent targeted surveillance, and the number of endoscopies needed. In addition, we recorded the cumulative costs (including indirect costs) incurred and quality-adjusted years of life lived within each strategy, discounted at a rate of 3% per year, and computed incremental cost-effectiveness ratios (ICERs) among the 3 strategies. RESULTS: According to the models, screening patients with GERD by Cytosponge with follow-up confirmation of positive results by endoscopy would reduce the cost of screening by 27% to 29% compared with screening by endoscopy, but led to 1.8 to 5.5 (per 1000 patients) fewer quality-adjusted life years. The ICERs for Cytosponge screening compared with no screening ranged from $26,358 to $33,307. For screening patients by endoscopy compared with Cytosponge the ICERs ranged from $107,583 to $330,361. These results were sensitive to Cytosponge cost within a plausible range of values. CONCLUSIONS: In a comparative modeling analysis of screening strategies for BE in patients with GERD, we found Cytosponge screening with endoscopic confirmation to be a cost-effective strategy. The greatest benefit was achieved by endoscopic screening, but with an unfavorable cost margin.

A Molecular Clock Infers Heterogeneous Tissue Age Among Patients with Barrett's Esophagus.

Biomarkers that drift differentially with age between normal and premalignant tissues, such as Barrett's esophagus (BE), have the potential to improve the assessment of a patient's cancer risk by providing quantitative information about how long a patient has lived with the precursor (i.e., dwell time). In the case of BE, which is a metaplastic precursor to esophageal adenocarcinoma (EAC), such biomarkers would be particularly useful because EAC risk may change with BE dwell time and it is generally not known how long a patient has lived with BE when a patient is first diagnosed with this condition. In this study we first describe a statistical analysis of DNA methylation data (both cross-sectional and longitudinal) derived from tissue samples from 50 BE patients to identify and validate a set of 67 CpG dinucleotides in 51 CpG islands that undergo age-related methylomic drift. Next, we describe how this information can be used to estimate a patient's BE dwell time. We introduce a Bayesian model that incorporates longitudinal methylomic drift rates, patient age, and methylation data from individually paired BE and normal squamous tissue samples to estimate patient-specific BE onset times. Our application of the model to 30 sporadic BE patients' methylomic profiles first exposes a wide heterogeneity in patient-specific BE onset times. Furthermore, independent application of this method to a cohort of 22 familial BE (FBE) patients reveals significantly earlier mean BE onset times. Our analysis supports the conjecture that differential methylomic drift occurs in BE (relative to normal squamous tissue) and hence allows quantitative estimation of the time that a BE patient has lived with BE.

A Multiscale Model Evaluates Screening for Neoplasia in Barrett's Esophagus.

Barrett's esophagus (BE) patients are routinely screened for high grade dysplasia (HGD) and esophageal adenocarcinoma (EAC) through endoscopic screening, during which multiple esophageal tissue samples are removed for histological analysis. We propose a computational method called the multistage clonal expansion for EAC (MSCE-EAC) screening model that is used for screening BE patients in silico to evaluate the effects of biopsy sampling, diagnostic sensitivity, and treatment on disease burden. Our framework seamlessly integrates relevant cell-level processes during EAC development with a spatial screening process to provide a clinically relevant model for detecting dysplastic and malignant clones within the crypt-structured BE tissue. With this computational approach, we retain spatio-temporal information about small, unobserved tissue lesions in BE that may remain undetected during biopsy-based screening but could be detected with high-resolution imaging. This allows evaluation of the efficacy and sensitivity of current screening protocols to detect neoplasia (dysplasia and early preclinical EAC) in the esophageal lining. We demonstrate the clinical utility of this model by predicting three important clinical outcomes: (1) the probability that small cancers are missed during biopsy-based screening, (2) the potential gains in neoplasia detection probabilities if screening occurred via high-resolution tomographic imaging, and (3) the efficacy of ablative treatments that result in the curative depletion of metaplastic and neoplastic cell populations in BE in terms of the long-term impact on reducing EAC incidence.

Incremental benefits of screening colonoscopy over sigmoidoscopy in average-risk populations: a model-driven analysis.

PURPOSE: Screening colonoscopy and flexible sigmoidoscopy (FSG) reduce the risk of colorectal cancer (CRC), but the magnitude and duration of protection, particularly against right-sided cancer, remain uncertain. We computed the incremental benefit of colonoscopy over FSG using a validated mathematical model, which reflects colorectal neoplasia growth characteristics while allowing uncertainty in endoscopic detection and removal of adenomas. METHODS: We calibrated models of CRC incidence within a multistage clonal expansion framework to data from: (1) San Francisco-Oakland SEER registry (reference population) and (2) FSG long-term follow-up data from 50,757 individuals after a negative FSG in the Kaiser Permanente system. We compared the residual CRC risks after FSG with full-length colonoscopy. RESULTS: Our model mirrors trial data with 10-year CRC risk reductions after FSG screening at age 50 years of approximately one-third; the optimal age for a 'once-only' FSG exam was between ages 50 and 60 years; and the greater benefit was for men compared with women. There were considerable incremental gains in reduction in CRC risk by colonoscopy compared with FSG with the greatest benefit for screening colonoscopy at age 50 years. These results held up against lowering the right-sided adenoma detection sensitivity by 30%, as well as reducing the curative efficacy of polypectomy throughout the colon. CONCLUSIONS: Mathematical modeling of CRC screening, which takes account of important aspects of tumor biology, demonstrates superior risk reductions by colonoscopy over FSG. Our predictions provide further rationale for recommending screening colonoscopy in average-risk populations before the age of 60.

Benefits and harms of computed tomography lung cancer screening strategies: a comparative modeling study for the U.S. Preventive Services Task Force.

BACKGROUND: The optimum screening policy for lung cancer is unknown. OBJECTIVE: To identify efficient computed tomography (CT) screening scenarios in which relatively more lung cancer deaths are averted for fewer CT screening examinations. DESIGN: Comparative modeling study using 5 independent models. DATA SOURCES: The National Lung Screening Trial; the Prostate, Lung, Colorectal, and Ovarian Cancer Screening trial; the Surveillance, Epidemiology, and End Results program; and the U.S. Smoking History Generator. TARGET POPULATION: U.S. cohort born in 1950. TIME HORIZON: Cohort followed from ages 45 to 90 years. PERSPECTIVE: Societal. INTERVENTION: 576 scenarios with varying eligibility criteria (age, pack-years of smoking, years since quitting) and screening intervals. OUTCOME MEASURES: Benefits included lung cancer deaths averted or life-years gained. Harms included CT examinations, false-positive results (including those obtained from biopsy/surgery), overdiagnosed cases, and radiation-related deaths. RESULTS OF BEST-CASE SCENARIO: The most advantageous strategy was annual screening from ages 55 through 80 years for ever-smokers with a smoking history of at least 30 pack-years and ex-smokers with less than 15 years since quitting. It would lead to 50% (model ranges, 45% to 54%) of cases of cancer being detected at an early stage (stage I/II), 575 screening examinations per lung cancer death averted, a 14% (range, 8.2% to 23.5%) reduction in lung cancer mortality, 497 lung cancer deaths averted, and 5250 life-years gained per the 100,000-member cohort. Harms would include 67,550 false-positive test results, 910 biopsies or surgeries for benign lesions, and 190 overdiagnosed cases of cancer (3.7% of all cases of lung cancer [model ranges, 1.4% to 8.3%]). RESULTS OF SENSITIVITY ANALYSIS: The number of cancer deaths averted for the scenario varied across models between 177 and 862; the number of overdiagnosed cases of cancer varied between 72 and 426. LIMITATIONS: Scenarios assumed 100% screening adherence. Data derived from trials with short duration were extrapolated to lifetime follow-up. CONCLUSION: Annual CT screening for lung cancer has a favorable benefit-harm ratio for individuals aged 55 through 80 years with 30 or more pack-years' exposure to smoking. PRIMARY FUNDING SOURCE: National Cancer Institute.

Comparative analysis of 5 lung cancer natural history and screening models that reproduce outcomes of the NLST and PLCO trials.

BACKGROUND: The National Lung Screening Trial (NLST) demonstrated that low-dose computed tomography screening is an effective way of reducing lung cancer (LC) mortality. However, optimal screening strategies have not been determined to date and it is uncertain whether lighter smokers than those examined in the NLST may also benefit from screening. To address these questions, it is necessary to first develop LC natural history models that can reproduce NLST outcomes and simulate screening programs at the population level. METHODS: Five independent LC screening models were developed using common inputs and calibration targets derived from the NLST and the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). Imputation of missing information regarding smoking, histology, and stage of disease for a small percentage of individuals and diagnosed LCs in both trials was performed. Models were calibrated to LC incidence, mortality, or both outcomes simultaneously. RESULTS: Initially, all models were calibrated to the NLST and validated against PLCO. Models were found to validate well against individuals in PLCO who would have been eligible for the NLST. However, all models required further calibration to PLCO to adequately capture LC outcomes in PLCO never-smokers and light smokers. Final versions of all models produced incidence and mortality outcomes in the presence and absence of screening that were consistent with both trials. CONCLUSIONS: The authors developed 5 distinct LC screening simulation models based on the evidence in the NLST and PLCO. The results of their analyses demonstrated that the NLST and PLCO have produced consistent results. The resulting models can be important tools to generate additional evidence to determine the effectiveness of lung cancer screening strategies using low-dose computed tomography.

Chapter 13: CISNET lung models: comparison of model assumptions and model structures.

Sophisticated modeling techniques can be powerful tools to help us understand the effects of cancer control interventions on population trends in cancer incidence and mortality. Readers of journal articles are, however, rarely supplied with modeling details. Six modeling groups collaborated as part of the National Cancer Institute's Cancer Intervention and Surveillance Modeling Network (CISNET) to investigate the contribution of U.S. tobacco-control efforts toward reducing lung cancer deaths over the period 1975-2000. The six models included in this monograph were developed independently and use distinct, complementary approaches toward modeling the natural history of lung cancer. The models used the same data for inputs, and agreed on the design of the analysis and the outcome measures. This article highlights aspects of the models that are most relevant to similarities of or differences between the results. Structured comparisons can increase the transparency of these complex models.

Chapter 8: The FHCRC lung cancer model.

As a member of the Cancer Intervention and Surveillance Modeling Network (CISNET), the lung cancer (LC) group at Fred Hutchinson Cancer Research Center (FHCRC) developed a model for evaluating U.S. lung cancer mortality trends and the impact of changing tobacco consumption. Model components include a biologically based two-stage clonal expansion (TSCE) model; a smoking simulator to generate smoking histories and other cause mortality; and adjustments for period and birth cohort to improve calibration to U.S. LC mortality. The TSCE model was first calibrated to five substantial cohorts: British doctors, American Cancer Society CPS-I and CPS-II, Health Professionals' Follow-Up Study (HPFS), and Nurses' Health Study (NHS). The NHS and HPFS cohorts included the most detailed smoking histories and were chosen to represent the effects of smoking on U.S. LC mortality. The calibrated TSCE model and smoking simulator were used to simulate U.S. LC mortality. Further adjustments were necessary to account for unknown factors. This provided excellent fits between simulated and observed U.S. LC mortality for ages 30-84 and calendar years 1975-2000. The FHCRC LC model may be used to study the effects of public health information on U.S. LC trends and the impact of tobacco control policy. For example, we estimated that over 500,000 males and 200,000 females avoided LC death between 1975 and 2000 due to increasing awareness since the mid 1950s of the harmful effects of smoking. We estimated that 1.1 million male and 0.6 million female LC deaths were avoidable if smokers quit smoking in 1965.

Multimodal T Cell Analysis with CoNGA.

Advances in single-cell technologies have made it possible to simultaneously quantify gene expression and immune receptor sequence across thousands of individual T or B cells in a single experiment. Data from such experiments are advancing our understanding of the relationship between adaptive immune receptor sequence and transcriptional profile. We recently reported a software tool, CoNGA, specifically developed to detect correlation between receptor sequence and transcriptional profile. Here we describe in detail how CoNGA can be applied to analyze a large and diverse T cell dataset featuring multiple donors and batch annotations. Our workflow illustrates new analysis modes for the detection of TCR sequence convergence into similarity clusters and of matches to literature-derived TCR databases, as well as processing of gamma-delta T cells.

Calibrating disease progression models using population data: a critical precursor to policy development in cancer control.

There are many more strategies for early detection of cancer than can be evaluated with randomized trials. Consequently, model-projected outcomes under different strategies can be useful for developing cancer control policy provided that the projections are representative of the population. To project population-representative disease progression outcomes and to demonstrate their value in assessing competing early detection strategies, we implement a model linking prostate-specific antigen (PSA) levels and prostate cancer progression and calibrate it to disease incidence in the US population. PSA growth is linear on the logarithmic scale with a higher slope after disease onset and with random effects on intercepts and slopes; parameters are estimated using data from the Prostate Cancer Prevention Trial. Disease onset, metastatic spread, and clinical detection are governed by hazard functions that depend on age or PSA levels; parameters are estimated by comparing projected incidence under observed screening and biopsy patterns with incidence observed in the Surveillance, Epidemiology, and End Results registries. We demonstrate implications of the model for policy development by projecting early detections, overdiagnosis, and mean lead times for PSA cutoffs 4.0 and 2.5 ng/mL and for screening ages 50-74 or 50-84. The calibrated model validates well, quantifies the tradeoffs involved across policies, and indicates that PSA screening with cutoff 4.0 ng/mL and screening ages 50-74 performs best in terms of overdiagnosis per early detection. The model produces representative outcomes for selected PSA screening policies and is shown to be useful for informing the development of sound cancer control policy.

Optimal Timing for Cancer Screening and Adaptive Surveillance Using Mathematical Modeling.

Cancer screening and early detection efforts have been partially successful in reducing incidence and mortality, but many improvements are needed. Although current medical practice is informed by epidemiologic studies and experts, the decisions for guidelines are ultimately ad hoc. We propose here that quantitative optimization of protocols can potentially increase screening success and reduce overdiagnosis. Mathematical modeling of the stochastic process of cancer evolution can be used to derive and optimize the timing of clinical screens so that the probability is maximal that a patient is screened within a certain "window of opportunity" for intervention when early cancer development may be observable. Alternative to a strictly empirical approach or microsimulations of a multitude of possible scenarios, biologically based mechanistic modeling can be used for predicting when best to screen and begin adaptive surveillance. We introduce a methodology for optimizing screening, assessing potential risks, and quantifying associated costs to healthcare using multiscale models. As a case study in Barrett's esophagus, these methods were applied for a model of esophageal adenocarcinoma that was previously calibrated to U.S. cancer registry data. Optimal screening ages for patients with symptomatic gastroesophageal reflux disease were older (58 for men and 64 for women) than what is currently recommended (age > 50 years). These ages are in a cost-effective range to start screening and were independently validated by data used in current guidelines. Collectively, our framework captures critical aspects of cancer evolution within patients with Barrett's esophagus for a more personalized screening design. SIGNIFICANCE: This study demonstrates how mathematical modeling of cancer evolution can be used to optimize screening regimes, with the added potential to improve surveillance regimes. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/4/1123/F1.large.jpg.