Cost-utility of colorectal cancer screening at 40 years old for average-risk patients

Journal Pre-proof Cost-utility of colorectal cancer screening at 40 years old for average-risk patients

Nilofer S. Azad, Ira L. Leeds, Waruguru Wanjau, Eun J. Shin, William V. Padula PII:

S0091-7435(20)30027-X

DOI:

https://doi.org/10.1016/j.ypmed.2020.106003

Reference:

YPMED 106003

To appear in:

Preventive Medicine

Received date:

2 July 2019

Revised date:

10 January 2020

Accepted date:

25 January 2020

Please cite this article as: N.S. Azad, I.L. Leeds, W. Wanjau, et al., Cost-utility of colorectal cancer screening at 40 years old for average-risk patients, Preventive Medicine(2020), https://doi.org/10.1016/j.ypmed.2020.106003

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© 2020 Published by Elsevier.

Journal Pre-proof Cost-utility of colorectal cancer screening at 40 years old for average-risk patients Nilofer S. Azad, MD1*, Ira L. Leeds, MD, MBA, ScM2*, Waruguru Wanjau, MD, MPH3, Eun J. Shin, MD4, William V. Padula, MS, MSc, PhD3,5

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* Authors contributed equally to this manuscript

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1 – Sidney Kimmel Comprehensive Cancer Center, Gastrointestinal Oncology Division, The Johns Hopkins University School of Medicine, Baltimore, MD, USA 2 – Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA 3 – Department of Health Policy and Management, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA 4 – Division of Gastroenterology and Hepatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA 5 – Department of Pharmaceutical & Health Economics, Leonard D. Schaeffer Center for Health Policy & Econmoics, University of Southern California, Los Angeles, CA, USA

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Corresponding author (please use this address and phone number for all author inquiries): Nilofer Azad, MD 1650 Orleans Street Suite 4M10 Baltimore, Maryland 21287 410-955-8893 [email protected]

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Co-author email addresses: I.L.L. – [email protected] W.W. – [email protected] E.J.S. – [email protected] W.V.P. – [email protected]

Running Title: CRC screening at 40 years old Prior Presentation: None. Abstract Word Count: 245 Manuscript Word Count: 3,449 Tables: 2 Figures: 3 CONFLICT OF INTERESTS No author has any conflict of interest to disclose.

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Journal Pre-proof Funding Support: I.L.L. received salary support during the conduct of this study from a National Institutes of Health National Cancer Institute institutional training grant (5T32CA126607). This funding body had no role in the design, data use, or reporting of this

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study.

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Journal Pre-proof ABSTRACT

The incidence of colorectal cancer (CRC) is increasing in patients under the age of 50. The purpose of this study was to assess the cost-utility of available screening modalities starting at 40 years in the general population compared to standard screening at 50 years old. A decision tree modeling average-risk of the CRC in the United States population was constructed for the

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cost per quality-adjusted life year (QALY) of the five most common and effective CRC

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screening modalities in average-risk 40-year olds versus deferring screening until 50 years old

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(standard of care) under a limited societal perspective. All parameters were derived from existing

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literature. We evaluated the incremental cost-utility ratio of each comparator at a willingness-topay threshold of $50,000/QALY and included multivariable probabilistic sensitivity analysis.

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All screening modalities assessed were more cost-effective with increased QALYs than current

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standard care (no screening until 50). The most favorable intervention by net monetary benefit was flexible sigmoidoscopy ($3,284 per person). Flexible sigmoidoscopy, FOBT, and FIT all

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dominated the current standard of care. Colonoscopy and FIT-DNA were both cost-effective

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(respectively, $4,777 and $11,532 per QALY). The cost-effective favorability of flexible sigmoidoscopy diminished relative to colonoscopy with increasing willingness-to-pay. Regardless of screening modality, CRC screening at 40 years old is cost-effective with increased QALYs compared to current screening initiation at 50 years old, with flexible sigmoidoscopy most preferred. Consideration should be given for a general recommendation to start screening at age 40 for average risk individual.

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Journal Pre-proof Keywords: colorectal cancer; screening; secondary prevention; economic evaluation; cost-

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benefit analysis; endoscopy; decision trees

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Journal Pre-proof INTRODUCTION

Colorectal cancer (CRC) is the second leading cause of cancer death, with 50,630 American deaths expected this year.1 The step-wise transformation of normal colonic cells into premalignant lesions and finally into a malignant phenotype occurs through a series of acquired molecular abnormalities that have been well elucidated.2 These molecular changes correlate with

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a visible transformation in the colonic epithelium with formation of polyps and these precursor

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findings afford an opportunity to screen and prevent the development of CRC in these patients.

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Over the past 20 years, multiple clinical trials have demonstrated the efficacy of

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screening for CRC in a normal risk population.3,4 Guidelines from multiple national and

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international organizations have previously agreed that screening for CRC should begin at age 50 and a variety of modalities are supported, including colonoscopy every 10 years as the gold

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standard for both diagnosis and treatment of precancerous lesions.4–11 Recently, data suggested

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that the incidence of CRC is increasing in patients under the age of 50. Siegel et al examined Surveillance, Epidemiology, and End Results (SEER) data and reported an increased incidence

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of CRC in patients between 20-50 years old.12 This increase was most dramatic in patients with rectal cancer, with a 2-3% increase per year in incidence for this younger patient population and one-third of rectal cancer now being diagnosed in patients under the age of 55. Similar findings have been reported in other national datasets.13–15 Moreover, while early-onset CRC has often been associated with familial cancer syndromes or germline mutations, more than 80% of CRC in patients less than 50 years old do not have an identifiable genetic predisposition.16 Therefore, selective screening strategies relying on family history or known mutations would miss most cancers in this population.

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Current evidence supports the cost-effectiveness, and potentially cost-saving, of routine CRC screening at age 50.17–19 But is starting screening at age 50 sufficient? Considering the changing incidence of CRC in younger patients, it may be beneficial both in terms of screening efficacy and cost-utility to begin screening for CRC before the age of 50, or even 45 years old as has been previously studied.15,20 While prior studies have suggested an efficacy benefit to earlier

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screening paradigms,4,21,22 such measures have not been considered with current prevalence in a

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cost-constrained health system. Given these previous research efforts, the next logical step is to

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ask if even earlier screening starts may be appropriate. The purpose of this study was to assess

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the cost-utility of available screening modalities starting at 40 years old in the average-risk general population compared to the current recommended standard of care to start CRC

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Study Design

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METHODS

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screening at 50 years old.

We developed a decision tree to assess the incremental cost-utility of five CRC screening modalities in average-risk 40-year olds versus deferring screening for CRC until 50 years old (current standard of care as the reference scenario). This model represented the U.S. societal perspective, that is, how the value of CRC screen at greater than 40 years would be valued among patients, providers, payers, and the community at large. Model comparators included: (a) colonoscopy; (b) flexible sigmoidoscopy; (c) fecal occult blood test (FOBT) with colonoscopy for initial positive screening; (d) fecal immunochemical test (FIT) with colonoscopy for initial

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Journal Pre-proof positive screening; and e) fecal immunochemical DNA testing (Cologuard®) for initial positive screening (Figure 1). All potential follow-on events from one’s initial decision and results were included in this model and described in more detail under Base Case Probabilities below. We used the current reporting standards of the Second Panel on Cost-Effectiveness in Health and Medicine (Appendix, eTable1).23 The main outcome measure was the incremental costeffectiveness ratio (ICER), that is, the incremental cost divided by incremental quality-adjusted

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life year (QALY) of each intervention relative to current standard care. Costs and QALYs were

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discounted at 3%.

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Journal Pre-proof CRC Death CRC Survive CRC No Polyp or CRC Detected

Death from Other Cause No CRC Survive without Issue CRC Death Progression to CRC Survive CRC Lesion Detected

Death from Other Cause

No Progression to Cancer

Survive without Issue

Colonic Polyp CRC Death Progression to CRC

Death from Other Cause

Survive without Issue

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No Progression to Cancer

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Survive CRC Lesion Missed

CRC Death

Progression to CRC Lesion Detected

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Survive CRC

CRC Screen*

Rectal Polyp

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No Progression to Cancer

Death from Other Cause Survive without Issue CRC Death

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Progression to CRC Survive CRC

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Lesion Missed

No Progression to Cancer

Death from Other Cause Survive without Issue

CRC Death

Lesion Detected Survive CRC

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Colon Cancer

CRC Death Lesion Missed Survive CRC

CRC Death Lesion Detected Survive CRC

Rectal Cancer CRC Death Lesion Missed Survive CRC

Figure 1. Decision tree depicting the clinical pathways for the 5 comparative forms of colorectal cancer screening in the U.S. based on current clinical guidelines. This decision model is pertinent to the following screening methods: standard care (no screen), colonoscopy, flexible sigmoidoscopy, fecal occult blood test, fecal immunochemical test, and FIT-DNA Test (i.e. “Cologuard®”). Depending on the sensitivity, specificity and anatomical range of each test, patients, providers may have the ability to detect polyps or cancers in the patient’s colonic and rectal regions. Early-detection of these outcomes leads to higher-probabilities of survival with less invasive treatments that cost relatively less overall. Later detection or missed opportunities to detect these outcomes can lead to lower survival rates, as well as higher costs to treat patients and maintain a lower quality of life. Abbreviations: CRC – colorectal cancer

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The ICER was assessed at U.S. societal willingness-to-pay threshold of $50,000/QALY, which represents the threshold at which interventions would be deemed cost-effective. We also assessed the net monetary benefit for each decision alternative, which was calculated as

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incremental cost minus average willingness-to- pay multiplied by the incremental QALYs. We

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intentionally selected a conservative willingness-to-pay threshold given the far-reaching

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conclusions if further population-wide testing were found to be cost-effective. In reporting

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results below, we elected to compare all screening methods to the current standard of care, no early screening. Although some cost-effectiveness methodologies will step-wise compare ICERs

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and net monetary benefits of the most competitive decision strategies, we found it most clinically

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applicable to consider each of these strategies in the context of current practice. This study’s use of exclusively published data only did not require institutional review

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under guidelines of the Johns Hopkins Medicine Institutional Review Board.

Perspective and Time Horizon The U.S. societal perspective (Appendix, eTable2) included all health sector costs and direct costs related to decreased patient productivity due to endoscopic screening procedures. The time horizon of events stemming from the decision node were modeled for ten years with the assumption that all individuals would obtain current standard of care CRC screening at 50 years old regardless of their decision to screen at 40 years old. We assessed the time horizon of the consequences of screening extending to the full life expectancy of a healthy 40 year old

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Journal Pre-proof individual (80.5 total years of life).24 The decision node represented a commitment by the decision-maker to follow their selected screening approach to its ten-year conclusion and we assumed complete adherence to a 10-year screening paradigm.

Parameter Estimates Parameter estimates were derived for the model’s needed probabilities, costs, and utility

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functions. In the next three sections, we describe how each category of parameter estimates was

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derived, and the estimates are reported together in Table 1 with suppoting appendices where

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noted.

Probabilities

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Parameter estimates of conditional probabilities came from previously published sources

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and their derivatives. Cancer epidemiology data regarding CRC prevalence came from the National Cancer Institute SEER Program 2014 results (Table 1). Given that our research question

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was posed to the average-risk individual, we did not incorporate high-risk screening paradigms

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(e.g., serial repeat testing) for those with individual or familial risk factors for CRC. We excluded the risk of a complication from screening due to the risk of a complication in the highest-risk procedure, colonoscopy, having been shown to have neglible rates of complication in those less than 50 years old and further ruled out as a consideration with sensitivity analysis prior to exclusion (Appendix, eTable 2 and eText 1).25 False positive screening results for firstline tests (e.g., FIT, FIT-DNA, FOBT) were included as a cost in the model as the cost of those screened who went on to receive a colonoscopy but then never developed nor were treated cancer. The modality-specific false positive probabilities of these tests were not directly modeled

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Journal Pre-proof as once these tests were either true- or false-positive, their subtree of the model was identical to

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the colonoscopy subtree that they effectively mirrored.

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Journal Pre-proof Table 1. Probabilities, costs, and utilities for cost-effectiveness analysis comparing screening starting at 50 years old versus multiple screening modalities starting at 40 years old. Mean

S.D.

Distr

Source

PROBABILITIES Mortality 10-year Mortality for CRC in 40yo, Prevalence-Weighted Average by Stage 10-year Mortality for CRC in 40yo, Stage I 10-year Mortality for CRC in 40yo, Symptomatic on Initial Presentation 10-year Mortality in 40yo, All-Cause

38.3% 11.1% 55.0% 2.30%

5.745% 1.665% 8.25% 0.345%

Beta Beta Beta Beta

U.S. SEER, 2014 U.S. SEER, 2014 Pande, et al. Colorect Dis. 2013 U.S. Social Security Admin., 2013

Neoplasia Risk Probability of Colon Polyp at 40yo Probability of Colon Cancer at 40yo Probability of Rectal Polyp at 40yo Probability of Rectal Cancer at 40yo Reduction in Probability of Cancer After High-Risk Polyp Excision (OR) Reduction in Probability of Cancer After Negative Screen (OR) 10-year Probability of Cancer for Missed Polyp

2.0% 0.15% 1.0% 0.09995% 0.16667 0.16667 25.4%

0.50% 0.0225% 0.25% 0.0150% 0.03 0.03 3.81%

Beta Beta Beta Beta Beta Beta Beta

Probability of Detection Colonoscopy Fecal immunochemical test (FIT) FIT-DNA (Cologuard®) Fecal occult blood test Flexible Sigmoidoscopy, colon cancer COSTS (all updated to 2015 US$) Screening Costs Colonoscopy Fecal immunochemical test (FIT) FIT-DNA (Cologuard®) Fecal occult blood test Flexible Sigmoidoscopy Endoscopy Day, Personal Work Lost Endpoint Treatment Costs Sudden Death (Last Six Months of Life) Colon Cancer with Survival Colon Cancer with 5-year Mortality Rectal Cancer with Survival Rectal Cancer with 5-year Mortality Utilities (Quality-adjusted Life Years) Cancer Death, Midpoint of 40th Decade Non-cancer Death, Midpoint of 40th Decade Discounted Full Life Expectancy at 40 years old

5.00% 9.24% 10.38% 2.45% 2.00%

Beta Beta Beta Beta Beta

Than, et al. Ann Gastroenterol. 2015. Imperiale, et al. N Engl J Med. 2014. Imperiale, et al. N Engl J Med. 2014. Collins, et al. Ann Int Med. 2005. Schoenfeld, et al. NEJM, 2005.

$1,216 $149 $1,336 $280 $300 $168

$182 $22 $200 $42 $45 $25

Gamma Gamma Gamma Gamma Gamma Gamma

AHRQ, 2007. AHRQ, 2007. AHRQ, 2007. AHRQ, 2007. AHRQ, 2007. U.S. BLS, 2015.

$29,775 $74,073 $180,835 $117,536 $193,822

$4,466 $11,111 $27,125 $17,630 $29,073

Gamma Gamma Gamma Gamma Gamma

Kelley, et al. Ann Int Med. 2011. Mariotto, et al. JNCI. 2011. Mariotto, et al. JNCI. 2011 Mariotto, et al. JNCI. 2011 Mariotto, et al. JNCI. 2011

3.48 4.21 21.1

0.522 0.632 3.165

Normal Normal Normal

Butzke, et al. Acta Oncol. 2016. Brogan, et al. Hum Vacc Immunother. 2017. Brogan, et al. Hum Vacc Immunother. 2017.

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97.5% 46.2% 69.2% 23.9% 66.3%

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Rundle, et al. Gastroenterology. 2008. Siegel R, et al. JNCI. 2017. Rundle, et al. Gastroenterology. 2008. Siegel R, et al. JNCI. 2017. Brenner H, et al. J Clin Onc. 2012. Brenner H, et al. J Clin Onc. 2012. Brenner H, et al. Gut. 2007.

Table 1 Note: When available, we used the distributions provided with previously reported estimates. If a distribution was not available, we used 15% of the reported estimate in most studies and 5% of the reported estimate in nationally-representative databases (e.g., SEER) as the standard deviation and then modeled all probabilities as beta distributions, costs as gamma distributions, and utilities as normal distributions. The use of the normal distribution for utilities was based on summated utilities consistently greater than 0 with adequate sampling to justify a normal distribution. 26

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Mortality from CRC was modeled by cancer stage with prevalence weighting as appropriate. With those identified with cancer on their original screening modality, we assumed CRC mortality rates consistent with the general CRC population.27 We assumed that patients who proceeded to develop cancer after having an excised polyp would have Stage 1 cancer due to increased post-polypectomy surveillance in these populations.27 Unscreened patients who

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developed CRC would likely have late-stage cancer given the association between symptomatic

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presentation and advanced stage.28 Finally, we accounted for the background all-cause mortality

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in the U.S. during the fifth decade of life.24

To model the likelihood of neoplasia in this population, we used historical data of high-

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risk polyp (advanced adenoma) 10-year incidence in 40 year old patients29 and separately

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included the most recent evidence of high rates of colon and rectal cancer during this decade of life.12 We also accounted for the expected reduction in the risk of cancer given that a polyp was

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identified and excised.30 Furthermore, we assumed that a negative screen – after accounting for

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missed lesions below – was also probabilistically informative and reduced an individual’s known risk of cancer in a manner consistent with a polypectomy.

We individually modeled the risk of a missed lesion for each tested modality. When possible, missed lesion rates were cross-compared from multiple literature sources for enhanced reliability.31–33 For flexible sigmoidoscopy, we assumed the detection rate compared to colonoscopy was equivalent for rectal cancer while the latter had a disadvantage for detecting colon cancers due to incomplete visualization of the colonic mucosa. We assigned a 10-year risk

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Journal Pre-proof of cancer occurrence in polyp missed by a screening method that was assumed to be independent of modality employed.34

Costs CRC screening, treatment, and outcomes are defined events with relatively short followup of a few years. Therefore, we used aggregated costing methods since these events are discrete

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and sequelae of each are well-described without the need for incremental micro-costing that

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would be methodologically burdensome without any additional meaningful granularity.23 We

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identified costs of screening and cancer care from previously published sources and re-screened

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during the ten year period at the prescribed number of interval screenings for those remaining

Utility

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average risk. A complete description of the costing methodology is included as eText 1.

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Effectiveness was measured in terms of QALYs according to EQ-5D (EuroQol Group)

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estimates of chronic conditions based on a combination of survival and quality-of-life weights for U.S. preferences. These QALYs were estimated from 40 years old to expected death for each of the possible screening modalities under assessment using previously published estimates (Table 1). We assumed that cancer deaths occurred on average at the mid-point of the decade with a diminished quality of life due to cancer metastases and its sequelae.35 Those without cancer were each attributed a near-complete life-year for their total expected lifetime (40.5 years for further full life expectancy; 5 years for premature death proportion).24,36

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Journal Pre-proof Model Validation We obtained face validity on the model structure and parameters from multiple experts: a practicing medical oncologist specializing in CRC; and a gastroenterologist with training in advanced endoscopy. These experts compared existing estimates and models to the incremental findings of this analysis .21,31,37,38 We also used this group to perform step-wise internal validation of the model by assuring that conclusions from each screening modality were

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internally consistent and within the expected ranges of intermediate results. Because of the

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ubiquity of high-quality CRC screening literature and meta-analyses,4,30,32,37 we elected to use

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existing literature estimates for parameters rather than our own generated data or a new

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systematic evidence search, which effectively provided an additional degree of cross-validation. The use of existing, large U.S. population studies ensured internal and external validity of the

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parameters used. This approach also lessened the need for independent validation or calibration

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studies given the use of previously reviewed and published data. Such a validation approach combining face validity, internal validation, and external validation has been recommended by

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the Second Panel on Cost-effectiveness in Health and Medicine.39

Sensitivity Analysis

We tested all of the expected parameters values described above using multivariable probabilistic sensitivity analysis (see note on probability distributions in Table 1). The final model cost-utility uncertainty was assessed with 100,000 MonteCarlo iterations of this probabilistic distribution of parameter estimates. We also compared cost-utility acceptability across all modalities for a range of willingness-to-pay thresholds from $0 to $300,000 per QALY.

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Modeling Population Impact We determined how a change in practice to the screening approach favored by the model would impact a population of 100,000 individuals compared to current standard of care. This estimate was performed using the component elements of the ICER and multiplying times an

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affected population of 100,000.

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Journal Pre-proof RESULTS

Cost-utility of screening starting at age 40 All screening modalities assessed were more cost-effective than current standard of care of no screening for average risk patients at 40 years-old (Table 2). The most favorable intervention by net monetary benefit (i.e., excess cost savings compared to maximum willingness

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to pay threshold) was flexible sigmoidoscopy ($3,284 per person), and it was both cheaper and

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more effective than no early screening. Flexible sigmoidoscopy, FOBT, and FIT all dominated

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(i.e., lower total costs, higher QALYs) current standard of care. Colonoscopy and FIT-DNA

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willingness-to-pay of $50,000 per QALY.

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were both cost-effective (respectively, ICER = $4,777/QALY and $11,532/QALY) against a

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Journal Pre-proof Table 2. Expected results of the base case cost-effectiveness analysis comparing screening starting at 50 years old versus multiple screening modalities starting at 40 years old (ordered by net monetary benefit in comparsion to the current standard of no early screening).

Strategy

Cost (US$ 2015)

Utility (QALYs)

No Early Screening

$2,116

Flexible Sigmoidoscopy

$1,562

-$554

20.6720

0.0546

Colonoscopy

$2,459

$343

20.6892

0.0718

Fecal Immunochemical Test

$1,689

-$427

20.6490

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FIT-DNA (Cologuard®)

$2,688

$572

20.6670

Fecal Occult Blood Test

$2,003

-$113

20.6316

 Cost

ICER ($ per QALY)

 Utility

20.6174

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Net Monetary Benefit

Dominant

$3,284

$4,777

$3,247

Dominant

$2,007

0.0496

$11,532

$1,908

0.0142

Dominant

$823

0.0316

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Journal Pre-proof Sensitivity analysis for endoscopic screening at age 40 versus no screening until age 50 When testing the reliability of model results with variation of individual parameter estimates, univariate sensitivity analysis demonstrated two variables to have the greatest impact on the model’s conclusions: 1) the probability of a flexible sigmoidoscopy identifying all the lesions that a colonoscopy would, and 2) the degree of risk reduction following polypectomy for an advanced adenoma (results not shown). For all ranges of parameter variation tested and

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reported in the preceding tables, the incremental cost-effectiveness ratio favored either one of the

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endoscopic approaches over no early screening. Further sensitivity analysis for flexible

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sigmoidoscopy versus no early screening was performed with extreme outlier estimates and still

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maintained no observed ICER above the willingness-to-pay threshold of $50,000/QALY

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favoring a robust conclusion from this analysis (Appendix, eFigure1).

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Flexible sigmoidoscopy under multivariate analysis When assessing the combined effects of varying multiple parameters simultaneously in

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the model, multivariable probabilistic sensitivity analysis maintained the findings. The cross-

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favorability of flexible sigmoidoscopy versus other modalities is demonstrated on equally-scaled graphs in Figure 2 and Appendix, eFigure2. Even when adjusting for variation in all parameter estimates at the chosen, conservative willingness to pay of $50,000/QALY, flexible sigmoidoscopy was favored 59.3% of the time with the remaining simulations split between colonoscopy (38.9%), FIT(1.3%), and FIT-DNA (0.1%). The favorability of flexible sigmoidoscopy diminished with increasing willingness-to-pay due to the superiority of colonoscopy in the cost-utility acceptability curve (i.e., crossing of cost-utility acceptability

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Journal Pre-proof lines, since increasing willingness to pay favored the more expensive endoscopic option and its increased probability of finding all colorectal lesions (Figure 3).

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B)

Figure 2. Multivariable probabilistic sensitivity analysis of incremental cost-effectiveness ratios for 100,000 Monte Carlo simulations. Two panels demonstrating the ICER distribution against early screening for the two most favored modalities: flexible sigmoidoscopy at low willingness to pay ratios (Panel A), and colonoscopy at high willingness to pay ratio (Panel B). Other ICER comparisons to no early screening are reported as Appendix, eFigure2. (Units: cost in 2015 US$, effectiveness in discounted QALYs). Figure 2 Note: Diagonal dotted line represents willingness to pay threshold of $50,000 per QALY. Quadrant I (NE) and Quadrant III (SW) represent cost-effective strategies if a modalities incremental-utility falls to the appropriate side of the willingness to pay line. Quadrant II (NW)

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and Quadrant IV (SE) represents strategies that dominate early screening with less costs and more QALYs.

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Figure 3. Cost-utility acceptability curve across multiple willingness to pay thresholds (100,000 Monte Carlo iterations).

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Figure 3 Note: Cost-utility acceptability curves display multivariable sensitivity analysis across a range of willingness to pay thresholds. Each set of vertical markers on the graph demonstrates the proportion of Monte Carlo iterations that favored the labeled screening modality compared to all others at a given willingness to pay threshold. The marker with the greatest y-value among each vertical set is the preferred strategy at that willingness to pay threshold. Commonly used willingness to pay thresholds in industrialized countries are $50,000 to $150,000 per qualityadjusted life year.

Population-based impact of early screening with flexible sigmoidoscopy When considering the results of the early screening proposed by this model in a hypothetical population of 100,000 40 to 49 year-olds. Flexible sigmoidoscopy would save an additional 5,460 QALYs through prevention (i.e., pre-malignant polyp excision) and earlier detection of CRC while also reducing total healthcare costs of this population by $55.4 million. These findings reflect approximately 800 less cases of CRC and 500 cancer deaths prevented from a 10-year cancer incidence of 1,000 baseline cases.

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DISCUSSION The purpose of this study was to assess the cost-utility and potential increased survival of starting CRC screening in the general, average-risk population at 40 years old versus the current recommendations, in the context of increasing rates of rectal cancer observed in the population younger than 50 years old. Given that current guidelines recommend screening starting at 50

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years old, the increasing incidence of CRC being identified in those less than 50 suggests this is

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not simply increased screening practices leading to surveillance bias. Indeed, these early-onsent

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CRC cases have worsening mortality rates while those of CRC overall continue to fall suggesting again that the cancer epidemiology is evolving with a potential need for earlier detection of these

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early-onset CRC cases.40

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We demonstrated that under a wide-range of estimated parameters, flexible

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sigmoidoscopy and FITsts dominated the current screening recommendations, resulting in more QALYs and lower total costs; flexible sigmoidoscopy was preferred to FIT under most scenarios.

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All screening modalities were cost-effective when compared to no early screening, even under

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liberal sensitivity analysis. The primary driver of the superior cost-utility of early screening compared to the current standard of care was that early detection led to less costly treatment (e.g., polypectomy rather than colectomy; colectomy alone rather than multimodality therapy for advanced cancer) as well as improved overall survival rates. At willingness to pay thresholds greater than $50,000 per QALY, relevant for high healthcare spending countries such as the United States, colonoscopy was superior to flexible sigmoidoscopy and FIT testing. Even compared to flexible simgiodoscopy in high income countries, the additional costs of colonoscopy were justified by the increased rate of detection and treatment of premalignant

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Journal Pre-proof lesions, thus preventing the development of malignancy, in the face of known negligible risks of morbidity and mortality. Although an exact estimate of the size of average risk population of 40 to 49 year olds in the United States is not available, using the total 40 to 49 year old population in the United States (approximately 39 million individuals), earlier screening suggests a potential savings of 2.1 million QALYs and $21 billion over the lifetime of the age group.

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These results support the potential change of CRC screening recommendations for the

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general, average-risk population. Routine CRC screening is well-known to be cost-effective, and

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potentially cost-saving.17–19 While prior studies have suggested that screening benefits outweigh harms in younger populations, this study is the first to demonstrate the economic superiority of

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screening from a societal perspective.4,21,22 Unlike in other common cancers such as breast

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cancer, there have not been randomized, prospective studies assessing the cost-effectiveness or

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efficacy in commencing screening for CRC at different ages. The United States Preventive Services Task Force has considered an earlier age for CRC screening initiation noting that some

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models have produced favorable clinical results; however, these models did not include the

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effects of cost.5,21 When incorporating the cost savings of earlier screening (i.e., low costs of universal screening compared to the high costs of the fraction requiring cancer care) with known incremental clinical benefit of earlier screening, the complete argument for early screening is even more favorable by traditional standards of cost-effectiveness. The robustness of these findings under multivariable sensitivity analysis encourages liberalizing screening guidelines for average risk patients to begin screening patients at 40 years old. Screening studies in average risk populations are expensive and resource-heavy, but changing screening guidelines has enormous implications for patients and the medical community at large. This complicated discussion has

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Journal Pre-proof already begun in the medical community and will require consensus from the major guidelinecreating entities as to how to best proceed. Importantly, the American Cancer Society has just released its new guidelines for CRC screening with a new recommendation to start screening at 45 for healthy, average-risk patients.40

The primary limitation of this study is related to the nature of the research question and

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the study designs that are practically available. Cost-effectiveness studies are attractive because

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they allow for scenario testing of clinical conditions and trials that are not practical to perform.

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However, conclusions of these studies can be highly sensitive to the model assumptions and the

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tested uncertainty of estimate parameters. The model employed in this study balanced comprehensive scenario testing and model simplicity that was easy to understand but maintained

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fidelity to real-world settings. We recognize that a number of complex scenarios were not

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included in our model (individual-specific disease progression versus population averages; linear effect of polyp count on cancer risk; variation in cancer risk over the fifth decade of life;

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variation in costs of cancer care versus overall estimates, incomplete adherence to screening

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assignment), but we found that such complexity might improve precision of estimates without changing the comparative conclusions and relative superiority of certain screening strategies that we report here. This decision model and cost-effectiveness approaches in general rely on estimates with general face validity rather than conventional diagnostic and therapy effectiveness estimates that stem from heavily-resourced, randomized clinical trials. Therefore, we elected to use a simplified model that passes face validity while acknowledging that highly individualized cases or scenarios may not apply. We designed the model for this study with our own tertiary care institution’s gastroenterologists, medical oncologists, surgeons, and healthcare economists

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Journal Pre-proof for a multidisciplinary perspective of CRC care. We also compared our own model assumptions and estimates to similar cost-effectiveness and simulation studies reported in the literature.16,19,28,41

A related assumption in our model that remains to be determined with existing literature is whether the clinical phenotype of early-onset CRC is similar to historical CRC. The

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limitations of existing literature prohibited the use of probabilities for the specific target

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population (i.e., 40 to 49 year olds) in many instances during model design. Importantly, if polyp

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prevalence and polyp progression are indeed underestimated in 40 year olds compared to

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historical data, it would only increase the strength of our conclusions many screening modalities are cost-effective at early age initiation. In general for those parameter estimates not available in

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our target population, we have opted to use general population estimates which should lead to

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more conservative results. In addition, these conclusions reported here should be tested further in

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population.

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the future when new data becomes available specific to the newly identified young, CRC

In addition to the vulnerabilities of an incomplete or incorrect model design, one must consider the relative importance of the accuracy of our estimates on our conclusions. In Appendix, eFigure1, we provide further evidence of the robustness of our results where, even at extreme ranges of estimates (e.g., polyp-to-cancer risk progression 5 times lower than predicted, cost of colonoscopy 3 times higher than current reported averages), all scenarios demonstrated early screening with flexible sigmoidoscopy remained cost-effective compared to the current standard of care.

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The potential impact of our findings must also be acknowledged to be likely overestimates of any real-world impact. In our Discussion above, we noted the potential QALY and cost savings to society associated with early screening for CRC using flexible sigmoidoscopy. However, we must acknowledge that these reported savings assume all eligible individuals would seek early screening for CRC and use the most preferred modality. Although

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no data exists predicting how younger populations would exist to a new screening

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recommendation, current CRC screening adherence and modality usage rates would suggest a

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lower real-world impact.42

The increasing incidence of CRC in the under 50 year-old population and reported

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findings such as those presented here suggests that a shift in screening recommendations affords

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us a real opportunity to decrease the burden of suffering and death from this major cause of

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CONCLUSIONS

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mortality, while also improving the efficiency of healthcare resource utilization and costs.

Regardless of screening modality, CRC screening at 40 years old is cost-effective compared to current screening initiation at 50 years old, with flexible sigmoidoscopy being the preferred modality compared to others. The superiority of flexible sigmoidoscopy to colonoscopy decreases with increasing willingness to pay thresholds.

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SUPPLEMENTAL DIGITAL CONTENT LISTING

eTable1 eTable2

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eText1

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eFigure1

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eFigure2

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eTable1. Second Panel on Cost-effectiveness Reporting Standards (JAMA, 2016)

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Journal Pre-proof eTable2. Impact inventory for cost-effectiveness analysis comparing early screening versus current standard of care.

Sector

Type of impact (units)

Notes / Sources of Evidence

Longevity (life years)

Butzke, et al. Acta Oncol. 2016. U.S. SEER, 2014. Pande, et al. Colorectal Dis. 2013.

Health-related quality of life (incremental QALYs)

Butzke, et al. Acta Oncol. 2016. Brogan, et al. Hum Vacc Immunother. 2017.

Adverse events of early screening

Negligible in less than 50 year old patients. Rutter, et al. Cancer Causes Control, 2012.

Patient time costs

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Health, Informal

U.S. BLS, 2015. Negligible for independent, general U.S. population during 5th decade of life.

Transportation costs

Negligible due to widespread ubiquity of community-based endoscopy clinics.

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Unpaid caregiver time costs

Earnings lost

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Productivity

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Health, Formal

Uncompensated household production lost

Excluded due to study population being older than peak productivity with limited future contributions to societal economic output (conservative approach favoring current standard of care).42 Excluded due to study population being older than peak productivity with limited future contributions to societal output (conservative approach favoring current standard of care).42

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Journal Pre-proof eText1. Costing Methodology in Detail All estimates were updated to 2015 United States dollars for comparison using the U.S. Bureau of Labor Statistics Consumer Price Index for healthcare costs.43 To ensure cross-comparability, we used screening cost estimates previously used in cost analysis studies from a major technology assessment study commissioned by the United States government and updated to present day prices.44,45 We increased costs of screening for endoscopic procedures to account for a day of lost work (8 hours of work, median hourly wage),46 and we assumed lost work to be negligible for office-based tests. We assumed the risk of perforation or other clinically relevant event attributable to endoscopy was negligible based on prior reports of the event rate for young patients observed in endoscopy studies.25

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We used previously accepted phases of cancer care costs in assessing total costs of care with cancer over a presumed 5-year treatment period. In those with CRC who survived, phases of care included an initial, 1-year treatment phase and four years of continuation follow-up care. Those who died from CRC had a 1-year initial treatment phase, three years of continuation care, and 1year of terminal high-cost care. We attributed costs of phases of cancer care independently for colon and rectal cancer due to the distinct therapies and healthcare utilization heterogeneity between the two.47,48

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Costs of death from non-CRC mortality during the fifth decade of life were presumed to be short-course illnesses (e.g., cardiovascular mortality, trauma). We used recent assessments of costs in the last 6-months of life for the general population to estimate these non-CRC deaths in our model.49

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eFigure1. Multiple one way sensitivity analysis (Tornado Diagram) demonstrating robustness of flexible sigmoidoscopy superiority to no screening in 40 year-old average risk patients across.

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Variable descriptions listed next to each sensitivity interval bar plotted on ICER number line. Author-specified sensitivity intervals listed in parentheses following description. Dashed line identifies expected value of ICER using deterministic values provided in manuscript. Red portion of sensitivity interval demonstrates ICER change for values greater than deterministic estimate. Blue portion of sensitivity interval demonstrates ICER change for values less than deterministic estimate. Willingness to pay ($50,000 per QALY) not shown since entire range of observed ICER values were below the specified threshold.

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Journal Pre-proof eFigure2. Multivariable probabilistic sensitivity analysis of incremental cost-effectiveness ratios for 100,000 Monte Carlo simulations. Other ICER comparisons to no early screening: fecal occult blood test (Panel A), fecal immunochemical test (Panel B), and fecal immunochemicalDNA test (Panel C). (Units: cost in 2015 US$, effectiveness in discounted QALYs).

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Journal Pre-proof CREDIT AUTHOR STATEMENT Azad: conceptualization; writing – reviewing and editing; supervision Leeds: methodology; data curation; formal analysis; writing – original draft ; writing – reviewing and editing Wanjau: data curation; writing – reviewing and editing Shin: conceptualization; writing – reviewing and editing

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Padula: methodology; conceptualization; writing – reviewing and editing; supervision

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Journal Pre-proof Highlights:



Flexible sigmoidoscopy is the optimal, cost-saving colorectal cancer screening for 40 year olds.

Regardless of modality, colorectal cancer screening at 40 years old is cost-effective.

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Consider a recommendation to start screening at age 40 for average risk individual.

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