Association Between Intermediate End Points, Progression-free Survival, and Overall Survival in First-line Advanced or Recurrent Endometrial Cancer.

PURPOSE: Advanced/recurrent endometrial cancer is associated with poor long-term outcomes. Clinical studies of novel regimens are ongoing, but given that data on overall survival (OS) take a long time to mature, surrogate end points are often used to support clinical-research interpretation. The aim of this study was to explore the correlation between progression-free survival (PFS)/time to progression (TTP) and OS across multiple time points in the first-line treatment of advanced/recurrent endometrial cancer. METHODS: This study comprised meta-analyses of Phase 2/3 randomized, controlled trials of first-line treatments in patients with advanced primary or first-recurrent endometrial cancer identified via systematic literature review. The strength of the surrogacy relationship was assessed by correlation analyses (estimated with Spearman and Pearson correlation coefficients) and weighted linear regression. FINDINGS: Data from 15 studies were included. PFS and TTP (TTP was reported in one study only) were highly correlated with future OS at multiple time points (Spearman values, 0.83-0.90; Pearson values, 0.86-0.93), suggesting that a change in PFS/TTP would likely be correlated with a change in OS in the same direction. On weighted linear regression, a 10% increase in PFS/TTP probability was significantly associated with a 9.3% to 13.3% increase in the probability of future OS. The strong positive association between PFS/TTP and OS was supported by findings from sensitivity analyses based on identified sources of interstudy heterogeneity. IMPLICATIONS: PFS/TTP is a good potential candidate for predicting long-term OS outcomes in trials of first-line treatment in patients with advanced/recurrent endometrial cancer. The findings from this report may help to inform health-authority and clinical decision makers that PFS/TTP improvements are likely to translate into subsequent OS improvements once data mature.

Challenges in conducting fractional polynomial and standard parametric network meta-analyses of immune checkpoint inhibitors for first-line advanced renal cell carcinoma.

Aim: Network meta-analyses (NMAs) increasingly feature time-varying hazards to account for non-proportional hazards between different drug classes. This paper outlines an algorithm for selecting clinically plausible fractional polynomial NMA models. Methods: The NMA of four immune checkpoint inhibitors (ICIs) + tyrosine kinase inhibitors (TKIs) and one TKI therapy for renal cell carcinoma (RCC) served as case study. Overall survival (OS) and progression free survival (PFS) data were reconstructed from the literature, 46 models were fitted. The algorithm entailed a-priori face validity criteria for survival and hazards, based on clinical expert input, and predictive accuracy against trial data. Selected models were compared with statistically best-fitting models. Results: Three valid PFS and two OS models were identified. All models overestimated PFS, the OS model featured crossing ICI + TKI versus TKI curves as per expert opinion. Conventionally selected models showed implausible survival. Conclusion: The selection algorithm considering face validity, predictive accuracy, and expert opinion improved the clinical plausibility of first-line RCC survival models.

Estimating and Extrapolating Survival Using a State-Transition Modeling Approach: A Practical Application in Multiple Myeloma.

OBJECTIVES: State-transition models (STMs) applied in oncology have given limited considerations to modeling postprogression survival data. This study presents an application of an STM focusing on methods to evaluate the postprogression transition and its impact on survival predictions. METHODS: Data from the lenalidomide plus dexamethasone arm of the ASPIRE trial was used to estimate transition rates for an STM. The model accounted for the competing risk between the progression and preprogression death events and included an explicit structural link between the time to progression and subsequent death. The modeled transition rates were used to simulate individual disease trajectories in a discrete event simulation framework, based on which progression-free survival and overall survival over a 30-year time horizon were estimated. Survival predictions were compared with the observed trial data, matched external data, and estimates obtained from a more conventional partitioned survival analysis approach. RESULTS: The rates of progression and preprogression death were modeled using piecewise exponential functions. The rate of postprogression mortality was modeled using an exponential function accounting for the nonlinear effect of the time to progression. The STM provided survival estimates that closely fitted the trial data and gave more plausible long-term survival predictions than the best-fitting Weibull model applied in a partitioned survival analysis. CONCLUSIONS: The fit of the STM suggested that the modeled transition rates accurately captured the underlying disease process over the modeled time horizon. The considerations of this study may apply to other settings and facilitate a wider use of STMs in oncology.

An Innovative Approach to Modelling the Optimal Treatment Sequence for Patients with Relapsing-Remitting Multiple Sclerosis: Implementation, Validation, and Impact of the Decision-Making Approach.

INTRODUCTION: An innovative computational model was developed to address challenges regarding the evaluation of treatment sequences in patients with relapsing-remitting multiple sclerosis (RRMS) through the concept of a 'virtual' physician who observes and assesses patients over time. We describe the implementation and validation of the model, then apply this framework as a case study to determine the impact of different decision-making approaches on the optimal sequence of disease-modifying therapies (DMTs) and associated outcomes. METHODS: A patient-level discrete event simulation (DES) was used to model heterogeneity in disease trajectories and outcomes. The evaluation of DMT options was implemented through a Markov model representing the patient's disease; outcomes included lifetime costs and quality of life. The DES and Markov models underwent internal and external validation. Analyses of the optimal treatment sequence for each patient were based on several decision-making criteria. These treatment sequences were compared to current treatment guidelines. RESULTS: Internal validation indicated that model outcomes for natural history were consistent with the input parameters used to inform the model. Costs and quality of life outcomes were successfully validated against published reference models. Whereas each decision-making criterion generated a different optimal treatment sequence, cladribine tablets were the only DMT common to all treatment sequences. By choosing treatments on the basis of minimising disease progression or number of relapses, it was possible to improve on current treatment guidelines; however, these treatment sequences were more costly. Maximising cost-effectiveness resulted in the lowest costs but was also associated with the worst outcomes. CONCLUSIONS: The model was robust in generating outcomes consistent with published models and studies. It was also able to identify optimal treatment sequences based on different decision criteria. This innovative modelling framework has the potential to simulate individual patient trajectories in the current treatment landscape and may be useful for treatment switching and treatment positioning decisions in RRMS.

Identifying key factors for the effectiveness of pancreatic cancer screening: A model-based analysis.

Pancreatic cancer (PC) survival is poor, as detection usually occurs late, when treatment options are limited. Screening of high-risk individuals may enable early detection and a more favorable prognosis. Knowledge gaps prohibit establishing the effectiveness of screening. We developed a Microsimulation Screening Analysis model to analyze the impact of relevant uncertainties on the effect of PC screening in high-risk individuals. The model simulates two base cases: one in which lesions always progress to PC and one in which indolent and faster progressive lesions coexist. For each base case, the effect of annual and 5-yearly screening with endoscopic ultrasonography/magnetic resonance imaging was evaluated. The impact of variance in PC risk, screening test characteristics and surgery-related mortality was evaluated using sensitivity analyses. Screening resulted in a reduction of PC mortality by at least 16% in all simulated scenarios. This reduction depended strongly on the natural disease course (annual screening: -57% for "Progressive-only" vs -41% for "Indolent Included"). The number of screen and surveillance tests needed to prevent one cancer death was impacted most by PC risk. A 10% increase in test sensitivity reduced mortality by 1.9% at most. Test specificity is important for the number of surveillance tests. In conclusion, screening reduces PC mortality in all modeled scenarios. The natural disease course and PC risk strongly determines the effectiveness of screening. Test sensitivity seems of lesser influence than specificity. Future research should gain more insight in PC pathobiology to establish the true value of PC screening in high-risk individuals.

What Did Time Tell Us? A Comparison and Retrospective Validation of Different Survival Extrapolation Methods for Immuno-Oncologic Therapy in Advanced or Metastatic Renal Cell Carcinoma.

BACKGROUND: The immuno-oncologic (IO) mechanism of action may lead to an overall survival (OS) hazard that changes over time, producing shapes that standard parametric extrapolation methods may struggle to reflect. Furthermore, selection of the most appropriate extrapolation method for health technology assessment is often based on trial data with limited follow-up. OBJECTIVE: To examine this problem, we fitted a range of extrapolation methods to patient-level survival data from CheckMate 025 (NCT01668784, CM-025), a phase III trial comparing nivolumab with everolimus for previously treated advanced renal cell carcinoma (aRCC), to assess their predictive accuracy over time. METHODS: Six extrapolation methods were examined: standard parametric models, natural cubic splines, piecewise models combining Kaplan-Meier data with an exponential or non-exponential distribution, response-based landmark models, and parametric mixture models. We produced three database locks (DBLs) at minimum follow-ups of 15, 27, and 39 months to align with previously published CM-025 data. A three-step evaluation process was adopted: (1) selection of the distribution family for each method in each of the three DBLs, (2) internal validation comparing extrapolation-based landmark and mean survival with the latest CM-025 dataset (minimum follow-up, 64 months), and (3) external validation of survival projections using clinical expert opinion and long-term follow-up data from other nivolumab studies in aRCC (CheckMate 003 and CheckMate 010). RESULTS: All extrapolation methods, with the exception of mixture models, underestimated landmark and mean OS for nivolumab compared with CM-025 long-term follow-up data. OS estimates for everolimus tended to be more accurate, with four of the six methods providing landmark OS estimates within the 95% confidence interval of observed OS as per the latest dataset. The predictive accuracy of survival extrapolation methods fitted to nivolumab also showed greater variation than for everolimus. The proportional hazards assumption held for all DBLs, and a dependent log-logistic model provided reliable estimates of longer-term survival for both nivolumab and everolimus across the DBLs. Although mixture models and response-based landmark models provided reasonable estimates of OS based on the 39-month DBL, this was not the case for the two earlier DBLs. The piecewise exponential models consistently underestimated OS for both nivolumab and everolimus at clinically meaningful pre-specified landmark time points. CONCLUSIONS: This aRCC case study identified marked differences in the predictive accuracy of survival extrapolation methods for nivolumab but less so for everolimus. The dependent log-logistic model did not suffer from overfitting to early DBLs to the same extent as more complex methods. Methods that provide more degrees of freedom may accurately represent survival for IO therapy, particularly if data are more mature or external data are available to inform the long-term extrapolations.

Mortality Prediction of the CHA2DS2-VASc Score, the HAS-BLED Score, and Their Combination in Anticoagulated Patients with Atrial Fibrillation.

BACKGROUND AND OBJECTIVES: Atrial fibrillation (AF) is associated with increased mortality, predictors of which are poorly characterized. We investigated the predictive power of the commonly used CHA2DS2-VASc score (congestive heart failure, hypertension, age ≥ 75 years [doubled], diabetes, stroke/transient ischemic attack/thromboembolism [doubled], vascular disease [prior myocardial infarction, peripheral artery disease, or aortic plaque], age 65-75 years, sex category [female]), the HAS-BLED score (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio [INR], elderly [age ≥ 65 years], drugs/alcohol concomitantly), and their combination for mortality in AF patients. METHODS: The PREvention oF thromboembolic events-European Registry in Atrial Fibrillation (PREFER in AF) was a prospective registry including AF patients across seven European countries. We used logistic regression to analyze the relationship between the CHA2DS2-VASc and HAS-BLED scores and outcomes, including mortality, at one year. We evaluated the performance of logistic regression models by discrimination measures (C-index and DeLong test) and calibration measures (Hosmer and Lemeshow goodness-of-fit and integrated discrimination improvement (IDI), with bootstrap techniques for internal validation. RESULTS: In 5209 AF patients with complete information on both scores, average one-year mortality was 3.1%. We found strong gradients between stroke/systemic embolic events (SSE), major bleeding and-specifically-mortality for both CHA2DS2-VASc and HAS-BLED scores, with a similar C-statistic for event prediction. The predictive power of the models with both scores combined, removing overlapping components, was significantly enhanced (p < 0.01) compared to models including either CHA2DS2-VASc or HAS-BLED alone: for mortality, C-statistic: 0.740, compared to 0.707 for CHA2DS2-VASc or 0.646 for HAS-BLED alone. IDI analyses supported the significant improvement for the combined score model compared to separate score models for all outcomes. CONCLUSIONS: Both the CHA2DS2-VASc and the HAS-BLED scores predict mortality similarly in patients with AF, and a combination of their components increases prediction significantly. Such combination may be useful for investigational and-possibly-also clinical purposes.

The Impact of the Policy-Practice Gap on Costs and Benefits of Barrett's Esophagus Management.

INTRODUCTION: Clinical guidelines recommend surveillance of patients with Barrett's esophagus (BE). However, the surveillance intervals in practice are shorter than policy recommendations. We aimed to determine how this policy-practice gap affects the costs and benefits of BE surveillance. METHODS: We used the Netherlands as an exemplary Western country and simulated a cohort of 60-year-old patients with BE using the Microsimulation Screening Analysis model-esophageal adenocarcinoma (EAC) microsimulation model. We evaluated surveillance according to the Dutch guideline and more intensive surveillance of patients without dysplastic BE and low-grade dysplasia. For each strategy, we computed the quality-adjusted life years (QALYs) gained and costs compared with no surveillance. We also performed a budget impact analysis to estimate the increased costs of BE management in the Netherlands for 2017. RESULTS: Compared with no surveillance, the Dutch guideline incurred an additional &OV0556;5.0 ($5.7) million per 1,000 patients with BE for surveillance and treatment, whereas 57 esophageal adenocarcinoma (EAC) cases (>T1a) were prevented. With intensive and very intensive surveillance strategies for both nondysplastic BE and low-grade dysplasia, the net costs increased by another &OV0556;2.5-5.6 ($2.8-6.5) million while preventing 10-19 more EAC cases and gaining 33-60 more QALYs. On a population level, this amounted to &OV0556;21-47 ($24-54) million (+32%-70%) higher healthcare costs in 2017. DISCUSSION: The policy-practice gap in BE surveillance intervals results in 50%-114% higher net costs for BE management for only 10%-18% increase in QALYs gained, depending on actual intensity of surveillance. Incentives to eliminate this policy-practice gap should be developed to reduce the burden of BE management on patients and healthcare resources.

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.

Health-related quality of life and mortality in patients with pulmonary embolism: a prospective cohort study in seven European countries.

PURPOSE: Little is known about the quality of life following pulmonary embolism (PE). The aim of the study was to assess the 12-month illness burden in terms of health-related quality of life (HrQoL) and mortality, in relation to differences in patient characteristics. METHODS: The PREFER in VTE registry, a prospective, observational study conducted in seven European countries, was used. Within 2 weeks following an acute symptomatic PE, patients were recruited and followed up for 12 months. Associations between patient characteristics and HrQoL (EQ-5D-5L) and mortality were examined using a regression approach. RESULTS: Among 1399 PE patients, the EQ-5D-5L index score at baseline was 0.712 (SD 0.265), which among survivors gradually improved to 0.835 (0.212) at 12 months. For those patients with and without active cancer, the average index score at baseline was 0.658 (0.275) and 0.717 (0.264), respectively. Age and previous stroke were significant factors for predicting index scores in those with/without active cancer. Bleeding events but not recurrences had a noticeable impact on the HrQoL of patients without active cancer. The 12-month mortality rate post-acute period was 8.1%, ranging from 1.4% in Germany, Switzerland, and Austria to 16.8% in Italy. Mortality differed between patients with active cancer and those without (42.7% vs. 4.7%). CONCLUSION: PE is associated with a substantial decrease in HrQoL at baseline which normalizes following treatment. PE is associated with a high mortality rate especially in patients with cancer, with significant country variation. Bleeding events, in particular, impact the burden of PE.

Comparison of quality of life measurements: EQ-5D-5L versus disease/treatment-specific measures in pulmonary embolism and deep vein thrombosis.

INTRODUCTION: There is a lack of performance comparisons of the generic quality of life tool EQ-5D-5L against disease- and treatment-specific measures in venous thromboembolism (VTE). The aim of this study was to compare EQ-5D-5L against the pulmonary embolism (PE)-specific PEmb-QoL and the deep vein thrombosis (DVT)-specific VEINES-QOL/Sym, and PACT-Q2 (treatment-specific) questionnaires in five language settings. METHODS: PREFER in VTE was a non-interventional disease registry conducted between 2013 and 2014 in primary and secondary care across seven European countries with five languages, including English, French, German, Italian and Spanish. Consecutive patients with acute PE/DVT were enrolled and followed over 12 months. Only patients who completed all three questionnaires at baseline were included in the study sample. The psychometric properties examined included acceptability (missing, ceiling and floor effects), validity (convergent and known-groups validity), and responsiveness. Known groups validity and responsiveness were assessed using both effect size (Cohen's d) and relative efficiency (F-statistic). All analyses were conducted in each language version and the total sample across all languages. RESULTS: A total of 1054 PE and 1537 DVT patients were included. 14% of PE and 10% of DVT patients had the maximum EQ-5D-5L index score. EQ-5D-5L was low to moderately correlated with other measures (r < 0.5). EQ-5D-5L was associated with larger effect size/relative efficiency in most of known group comparisons in both VTE groups. Similar results were observed for responsiveness. EQ-5D-5L performed relatively better in French, Italian and Spanish language versions. CONCLUSION: Overall EQ-5D-5L is comparable to PEmb-QoL, VEINES-QOL/Sym and PACT-Q2 in terms of acceptability, validity and responsiveness in both PE and DVT populations in English, French, German, Italian and Spanish language version. Nevertheless, it should be noted that each measure is designed to capture different aspects of health-related quality of life.

The impact of co-morbidity on the disease burden of VTE.

Venous thromboembolism (VTE) is often accompanied by co-morbidities, which complicate and confound data interpretation concerning VTE-related mortality, costs and quality of life. We aimed to assess the contribution of co-morbidities to the burden of VTE. The PREFER in VTE registry, across seven European countries, documented and followed acute VTE patients over 12 months. Patients with co-morbidities were grouped in major co-morbidity groups: cancer, cardiovascular (CV) comorbidity (other than VTE), CV risks, venous, renal, liver, respiratory, bone and joint diseases, and lower extremity paralysis. Mortality rates and health-related quality of life (HrQoL) utility values grouped per co-morbidity were compared to the UK general population. Regression analyses were performed to determine the impact of co-morbidities on mortality and HrQoL. VTE were analyzed together and separately as pulmonary embolism (PE) and deep vein thrombosis (DVT). In total, 3455 patients were included, 40.5% with PE and 59.5% with DVT. 13% and 16% of the PE and DVT patients had no co-morbidities and had a 12-month mortality rate of 1.8% and 1.7%, respectively. Frequency and severity of co-morbidities increased mortality rates up to 30%. The EQ-5D-5L index in patients without co-morbidities were 0.826 and 0.838 for PE and DVT. These scores decreased to 0.638 and 0.555 in the presence of co-morbidities. Co-morbidities in VTE patients are common. VTE had an impact on mortality and HrQoL, and additional impact of co-morbidities was seen. Awareness of the presence of co-morbidities is important when making VTE-related treatment decisions. The presence of co-morbidities in PE and DVT patients is common and their frequency and severity in VTE patients have a substantial impact on mortality rates and HrQoL. When adjusting for co-morbidities, the impact of VTE on mortality as well as health-related quality of life remains present. Assessing patients without consideration of co-morbidities might lead to misinterpretations of the disease burden of PE and DVT.

Pulmonary embolism in Europe - Burden of illness in relationship to healthcare resource utilization and return to work.

OBJECTIVES: Pulmonary embolism (PE) is associated with a substantial economic burden. However evidence from patients in Europe is scarce. The aim of this study was to report the impacts of PE on healthcare resource utilization (HCRU) and return to work using the PREFER in VTE registry. METHODS: The PREFER in VTE registry was a prospective, observational, multicenter study in seven European countries, aiming to provide data concerning treatment patterns, HCRU, mortality, quality of life and work-loss. Patients with a first-time or recurrent PE were included and followed up at 1, 3, 6 and 12 months. Treatment patterns, re-hospitalization rates, length of hospital stays (LOS), and ambulatory/office visits, as well as proportion of patients returning to work, were assessed. Subgroups by country and with/without active cancer were examined separately. Zero-inflated negative binomial and Cox regression were applied to investigate the relationship between baseline characteristics and LOS and return to work, respectively. RESULTS: Amongst 1399 patients with PE, 53.2% were male and the average age was 62.3 ±â€¯17.1 years old. Overall, patients were treated with combinations of heparin, vitamin K antagonists (VKA) and the non-VKA oral anticoagulants (NOACs) (50.0% treated with the combination of heparin with VKA). Patients with active cancer were primarily treated with heparin (84.9%). NOACs were used more frequently in DACH (Germany, Austria and Switzerland) and France (55.2% and 32.6%) compared to Italy and Spain (4.5% and 6.1%). The VTE-related re-hospitalization rate within 12 months and the average LOS varied substantially between countries, from 26.2% in UK to 12.3% in France, and from 12.9 days in Italy to 3.9 days in France. PE patients were often co-managed by general practitioners in France and DACH (>84%), and less frequently in other countries (<47%). The regression results confirmed the country variation of HCRU. Of the employed patients (n = 385), 60% returned to work at 1 month but 27.8% had not after one year. PE patients with DVT were more likely to return to work. Active cancer was a significant predictor for not returning to work, as well as smoking history. CONCLUSIONS: Medical treatment of PE differed between patients with active cancer and patients without active cancer. VTE-related resource utilization differed markedly between countries. While the reported 'not return to work' was high for patients with PE, this may at least in part reflect the presence of co-morbidities such as cancer.

Harms, benefits and costs of fecal immunochemical testing versus guaiac fecal occult blood testing for colorectal cancer screening.

BACKGROUND: The ColonCancerCheck screening program for colorectal cancer (CRC) in Ontario, Canada, is considering switching from biennial guaiac fecal occult blood test (gFOBT) screening between age 50-74 years to the more sensitive, but also less specific fecal immunochemical test (FIT). The aim of this study is to estimate whether the additional benefits of FIT screening compared to gFOBT outweigh the additional costs and harms. METHODS: We used microsimulation modeling to estimate quality adjusted life years (QALYs) gained and costs of gFOBT and FIT, compared to no screening, in a cohort of screening participants. We compared strategies with various age ranges, screening intervals, and cut-off levels for FIT. Cost-efficient strategies were determined for various levels of available colonoscopy capacity. RESULTS: Compared to no screening, biennial gFOBT screening between age 50-74 years provided 20 QALYs at a cost of CAN$200,900 per 1,000 participants, and required 17 colonoscopies per 1,000 participants per year. FIT screening was more effective and less costly. For the same level of colonoscopy requirement, biennial FIT (with a high cut-off level of 200 ng Hb/ml) between age 50-74 years provided 11 extra QALYs gained while saving CAN$333,300 per 1000 participants, compared to gFOBT. Without restrictions in colonoscopy capacity, FIT (with a low cut-off level of 50 ng Hb/ml) every year between age 45-80 years was the most cost-effective strategy providing 27 extra QALYs gained per 1000 participants, while saving CAN$448,300. INTERPRETATION: Compared to gFOBT screening, switching to FIT at a high cut-off level could increase the health benefits of a CRC screening program without considerably increasing colonoscopy demand.

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.

Real-Time Monitoring of Results During First Year of Dutch Colorectal Cancer Screening Program and Optimization by Altering Fecal Immunochemical Test Cut-Off Levels.

BACKGROUND & AIMS: After careful pilot studies and planning, the national screening program for colorectal cancer (CRC), with biennial fecal immunochemical tests (FITs), was initiated in The Netherlands in 2014. A national information system for real-time monitoring was developed to allow for timely evaluation. Data were collected from the first year of this screening program to determine the importance of planning and monitoring for optimal screening program performance. METHODS: The national information system of the CRC screening program kept track of the number of invitations sent in 2014, FIT kits returned, and colonoscopies performed. Age-adjusted rates of participation, the number of positive test results, and positive predictive values (PPVs) for advanced neoplasia were determined weekly, quarterly, and yearly. RESULTS: In 2014, there were 741,914 persons invited for FIT; of these, 529,056 (71.3%; 95% CI, 71.2%-71.4%) participated. A few months into the program, real-time monitoring showed that rates of participation and positive test results (10.6%; 95% CI, 10.5%-10.8%) were higher than predicted and the PPV was lower (42.1%; 95% CI, 41.3%-42.9%) than predicted based on pilot studies. To reduce the burden of unnecessary colonoscopies and alleviate colonoscopy capacity, the cut-off level for a positive FIT result was increased from 15 to 47 µg Hb/g feces halfway through 2014. This adjustment decreased the percentage of positive test results to 6.7% (95% CI, 6.6%-6.8%) and increased the PPV to 49.1% (95% CI, 48.3%-49.9%). In total, the first year of the Dutch screening program resulted in the detection of 2483 cancers and 12,030 advanced adenomas. CONCLUSIONS: Close monitoring of the implementation of the Dutch national CRC screening program allowed for instant adjustment of the FIT cut-off levels to optimize program performance.

Calibrating Parameters for Microsimulation Disease Models: A Review and Comparison of Different Goodness-of-Fit Criteria.

BACKGROUND: Calibration (estimation of model parameters) compares model outcomes with observed outcomes and explores possible model parameter values to identify the set of values that provides the best fit to the data. The goodness-of-fit (GOF) criterion quantifies the difference between model and observed outcomes. There is no consensus on the most appropriate GOF criterion, because a direct performance comparison of GOF criteria in model calibration is lacking. METHODS: We systematically compared the performance of commonly used GOF criteria (sum of squared errors [SSE], Pearson chi-square, and a likelihood-based approach [Poisson and/or binomial deviance functions]) in the calibration of selected parameters of the MISCAN-Colon microsimulation model for colorectal cancer. The performance of each GOF criterion was assessed by comparing the 1) root mean squared prediction error (RMSPE) of the selected parameters, 2) computation time of the calibration procedure of various calibration scenarios, and 3) impact on estimated cost-effectiveness ratios. RESULTS: The likelihood-based deviance resulted in the lowest RMSPE in 4 of 6 calibration scenarios and was close to best in the other 2. The SSE had a 25 times higher RMSPE in a scenario with considerable differences in the values of observed outcomes, whereas the Pearson chi-square had a 60 times higher RMSPE in a scenario with multiple studies measuring the same outcome. In all scenarios, the SSE required the most computation time. The likelihood-based approach estimated the cost-effectiveness ratio most accurately (up to -0.15% relative difference versus 0.44% [SSE] and 13% [Pearson chi-square]). CONCLUSIONS: The likelihood-based deviance criteria lead to accurate estimation of parameters under various circumstances. These criteria are recommended for calibration in microsimulation disease models in contrast with other commonly used criteria.