Introduction

Colorectal Cancer (CRC) is the second most common cause of cancer deaths [1]. The United States Preventive Services Task Force (USPSTF) recommends screening for CRC among average-risk adults beginning at age 45 [2] as screening has long been established in reducing both the incidence of and death from CRC [3]. While recommended CRC screening use has increased since 2000 [4], rates remain below the National Colorectal Cancer Roundtable goal of screening 80% of eligible adults [5]. Despite studies estimating that increasing screening by 10 percentage points would reduce the number of deaths from CRC by 15 percentage points [6], CRC screening remains underutilized [2,7].

Multiple options for CRC screening are supported by evidence of net benefit, including stool-based tests [2]. Stoolbased tests have multiple advantages: they are non-invasive; they are accessible in resource-constrained settings and they do not rely on traveling to a health centre to perform. Two commonly used stool-based tests include Fecal Immunochemical Test (FIT) and multi-target stool DNA (mt-sDNA). FIT is recommended to be performed annually while mt-sDNA is recommended to be repeated every three years [8] and includes patient navigation with every test [9], which has been found to be a key factor in increasing adherence [10]. While patient navigation is not routinely included with FIT tests, mailed outreach programs have been found to increase use and adherence to FIT among eligible screeners enrolled in Medicare Advantage [11].

CRC screening varies based on the type of insurance coverage, including Medicare with private insurance versus Medicare with no supplementary insurance or Medicare and Medicaid [12]. Medicare Advantage is provided through providesector health insurers and was chosen by nearly 40% of Medicare enrollees in 2020 [13]. Despite the inclusion of preventive health services within the Medicare Advantage program, CRC screening remains underutilized by enrollees. To better understand the health and economic consequences of mt-sDNA versus a FIT mailed outreach program, this study examined the cost-effectiveness of these stool-based screening tests in a Medicare Advantage population due for screening using a microsimulation model.

Methods

Overview

This analysis examined the cost-effectiveness of mt-sDNA versus a FIT mailed outreach program from the perspective of Medicare Advantage. The validated CRC-AIM model was used [14,15], and included average-risk US adults aged 65 to 75 (Medicare Advantage eligible years for screening). Individuals were assumed to be due for CRC screening; that is, they were previously screened and it had been one year since their previous negative FIT test, 5 years after a previous normal sigmoidoscopy and/or 10 years after a previous normal colonoscopy. Screening modalities included in the model were either annual FIT, or triennial mt-sDNA until age 75, as per the latest guidelines [2]. Individuals who did not undergo follow-up colonoscopy in the model were assumed to be non-adherent until they become symptomatic. A lifetime horizon was chosen to assess the impact of screening; costs and Quality-Adjusted Life Years (QALYs) were discounted at 3% [16].

Inputs

Screening strategies performance parameters were based on the 2021 USPSTF modeling study (Supplementary Table 1) [2]. Cost inputs were based on Medicare fee for service and were inflated to November 2021 using the Medical Care Services component of the Consumer Price Index (Supplementary Table 2) [17]. FIT does not include the cost of an outreach program, thus, the cost of outreach was taken from a randomized controlled trial, which consisted of a mailed postcard and call, followed by a mailed FIT kit, and then a reminder phone call if the kit was not returned [18]. As patient navigation is included with every mt-sDNA, no additional cost for outreach was necessary. Utility inputs for patients not experiencing colonoscopy complications or utility loss due to complications were included at baseline, adjusted for age, and based on general US population utility values (Supplementary Table 3) [19]. Utility loss for all colonoscopies and complications from colonoscopy were included as utility decrements per event [20]. Utility loss for CRC was stratified by the level of CRC care and stage of CRC; these utility decrements were applied on a per patient per year basis [20].

Multiple factors affect adherence to CRC screening. The top barriers to screening identified among respondents who had previously used stool-based screening options were lack of provider recommendations and lack of knowledge [25]. In order to address these barriers and increase adherence to screening, different outreach strategies have been proposed; these organized outreach programs have been shown to be effective to various degrees [26]. The results of this cost-effectiveness analysis are based on a mailed outreach program for FIT that included eligible Medicare Advantage patients receiving a letter containing information about CRC screening, along with a FIT kit where adherence to screening with outreach was found to be 29.0% [11]. This adherence is lower than the 69.8% reported among Medicare Advantage patients using mt-sDNA, which may be due to the fully integrated patient navigation for completion of the stool-based test which is integrated with every mt-sDNA test, including the universal outreach available in over 240 languages [9]. While a previous study in an integrated healthcare delivery system (Kaiser Permanente Northern California) found that the initiation of an organized CRC screening program significantly increased the up to date screening status from 39.0% to 82.7% over 15 years (p<0.01) [27], a claims analysis of multiple health plans found that only 23.4% of patients were adherent to FIT at year 2, and 10.6% were adherent at year 3 [28]. Outreach strategies to increase adherence to screening, including follow-up colonoscopy, need to be explored further, to determine the barriers and facilitators of screening across various populations.

Results of this study should be interpreted in the context of the assumptions. This analysis was based on the use of the CRC-AIM microsimulation model, which has previously been validated [29]. In addition, reported population-specific real-world data was used to inform adherence for both stool-based screening tests (mt-sDNA and FIT), along with the respective adherence to follow-up colonoscopies. However, as Medicare Advantagespecific adherence data are not available for the fecal occult blood test, it was excluded from this analysis. Further, only noninvasive stool tests were explored in this analysis. This analysis also only considered cross-sectional adherence rates; the impact of intermittent or longitudinal adherence on the cost-effectiveness of screening strategies was not explored. While the inputs of this analysis were based on a limited number of studies, these were tested through scenario and sensitivity analyses and results remained robust.

Conclusions

Adherence to initial stool-based CRC screening tests and follow-up colonoscopies impact both clinical and costeffectiveness outcomes. The choice of test and patient outreach can favourably impact patient adherence, thus further contributing towards the goal of attaining 80% CRC screening adherence. Future analyses should consider population-specific real-world evidence, including those living in supportive care facilities and those with chronic conditions, as well as comparisons with colonoscopies, in order to aid payer decision making.

Funding Source

This study was funded by Exact Sciences Corporation.

Competing Interests

Dr. Fendrick reports having been a consultant and expert witness for Exact Sciences, he is also a consultant for Abbvie, Amgen, Bayer, the California Health Care Foundation, CareFirst Blue Cross Blue Shield, Centivo, the Community Oncology Association, EmblemHealth, Exact Sciences, GRAIL, Health[at] Scale Technologies, HealthCorum, MedZed, Merck, Mother Goose Health, Pfizer, Sempre Health, SilverFern Healthcare, the State of Minnesota, Teladoc Health, the U.S. Department of Defense, the Virginia Center for Health Innovation, Wellth, Yale University, and Zansors, being a partner in VBIDHEALTH, and receiving research support from the Agency for Healthcare Research and Quality, Arnold Ventures, the National Pharmaceutical Council, the PatientCentered Outcomes Research Institute, Pharmaceutical Research and Manufacturers of America, the Robert Wood Johnson Foundation, the State of Michigan, West Health Policy Center, and the Centers for Medicare and Medicaid Services. Dr. Chen, Dr. Vahdat, Dr. Brooks and Dr. Ozbay were full-time employees of Exact Sciences Corporation during the conduct of the study. Dr. Bhatt as nothing to disclose. Dr. Lieberman reports being part of the Safety Advisory Board for Genescopy, Colowrap and UDX; he also reports having received consultant fees for Freenome and Ironwood. Dr. Karlitz has provided consulting services to Exact Sciences and has an equity position and is Chief Medical Officer for Gastro Girl and GI OnDEMAND.

Author’s Contributions

All authors contributed to the conception of the work, the interpretation of the data and contributed to the draft of the manuscript. JVC and VV contributed to the data analysis. All authors have approved the final version of the manuscript. All authors agree to be both personally accountable for their own contributions.

Acknowledgments

Lianne Barnieh of the Maple Health Group provided medical writing assistance.

Data Availability Statement

The data inputs for the analysis are contained within the manuscript; the modeling approach has been detailed in a prior manuscript.

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