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Cancer. Author manuscript; available in PMC 2017 August 15. Published in final edited form as: Cancer. 2016 August 15; 122(16): 2560–2570. doi:10.1002/cncr.30091.
Cost-effectiveness of Alternative Colonoscopy Surveillance Strategies to Mitigate Metachronous Colorectal Cancer Incidence FATIH SAFA ERENAY, Ph.D.1, OGUZHAN ALAGOZ, Ph.D.2, RITESH BANERJEE, Ph.D.3, ADNAN SAID, M.D.4, and ROBERT CIMA, M.D., M.A.5,6
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1Department
of Management Sciences, University of Waterloo, Waterloo-ON
2Department
of Industrial and Systems Engineering, University of Wisconsin-Madison, Madison-
WI 3Astellas
Pharmaceuticals, Northbrook-IL
4Gastroenterology
and Hepatology, School of Medicine and Public Health, University of Wisconsin, Madison-WI
5Division
of Colon and Rectal Surgery, Mayo Clinic, Rochester-MN
6Robert
D. and Patricia E. Kern Center for the Science of Health Care Delivery, Surgical Outcomes Program, Mayo Clinic, Rochester-MN
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Abstract BACKGROUND—Metachronous Colorectal Cancer (MCRC) incidence amongst colorectal cancer (CRC) survivors varies significantly and the optimal colonoscopy surveillance practice to mitigate MCRC incidence is unknown. METHODS—We conducted a cost-effectiveness analysis by comparing performances of the US Multi-Society Task Force guideline and all clinically-reasonable colonoscopy surveillance strategies among 50–79-year-old post-treatment CRC patients using a computer-simulation model.
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RESULTS—The US guideline [(1,3,5)] recommends the first colonoscopy 1-year after treatment while the second and third colonoscopies are repeated with 3- and 5-year intervals. We identified some promising alternative cost-effective strategies. Compared to the US guideline under various scenarios for 20-year period, 1) reducing the surveillance interval of the guideline after the first colonoscopy by 1-year [(1,2,5)] saves/prevents up to 78 discounted-life-years and 23 MCRCs per
CORRESPONDING AUTHOR: Oguzhan Alagoz, Department of Industrial and Systems Engineering, University of WisconsinMadison, 1513 University Avenue, Madison-WI 53706, [email protected], Phone:608/890-0399, Fax:608/262-8454. CONFLICT OF INTEREST DISCLOSURES: R.B. is an employee of Astellas Pharmaceuticals. F.S.E, O.A., A.S., and R.C declare no conflict of interest. Author Contributions: FATIH SAFA ERENAY: Conceptualization, methodology, software, validation, formal analysis, investigation, writing – original draft, writing – review and editing, visualization, supervision, project administration, and funding acquisition. OGUZHAN ALAGOZ: Conceptualization, methodology, writing – review and editing, supervision, project administration, and funding acquisition. RITESH BANERJEE: Conceptualization, methodology, investigation, and writing – review and editing. ADNAN SAID: Conceptualization, writing – review and editing, visualization, and supervision. ROBERT CIMA: Validation, investigation, and writing – review and editing.
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1000-patients (incremental cost-effectiveness ratio (ICER)≤$23,270/life-year); 2) reducing the intervals after the first and second negative colonoscopy by 1-year [(1,2,4)] saves/prevents up to 109 discounted-life-years and 36 MCRCs (ICER≤$52,155/life-year); 3) (1,2,3) saves/prevents up to 141 discounted-life-years and 50 MCRCs (ICER≤$68,822/life-year). These strategies require up to 1100 additional colonoscopies per 1000-patients. Although, the US guideline may not be costeffective compared to less-intensive oncology guideline (3,3,5) (ICER can be as high as $140,000/ LY), the promising strategies are cost-effective compared to such less-intensive guidelines unless cumulative MCRC incidence is very low. CONCLUSIONS—The US guideline might be improved by slightly increasing the surveillance intensity at the expense of moderately increased cost. More research is warranted to explore the benefits/harms of such practices.
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Keywords Cancer Surveillance; Second Primary Cancer; Economic Evaluation; Discrete-event Simulation; Cost-effectiveness
INTRODUCTION
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There is a growing colorectal cancer (CRC) survivor (post-treatment CRC) population in the US (1.16-million in 2011)1. Patients are recommended to undergo intensive colonoscopy surveillance after CRC treatment because of the high incidence of metachronous CRC (MCRC)2–4. Although indirect evidence exists for its effectiveness5, the actual benefit and the optimal frequency of colonoscopy surveillance among post-treatment CRC patients are unknown4,6. Reported long-term cumulative MCRC incidence (defined over a follow-up period of up to 20 years) varies significantly in the range of 2%–12%* and is associated with several risk-factors (age, family history, CRC stage/location) reflecting the heterogeneity in MCRC progression rates among the post-treatment CRC population5,7–9. Therefore, evaluating the effectiveness of post-treatment CRC surveillance in MCRC prevention/earlydetection and determining the optimal colonoscopy surveillance strategies for different cumulative MCRC incidence scenarios are imperative.
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Although similar issues for primary CRC are well-addressed through economic evaluations using computer-models10–13, such research is limited on post-treatment CRC surveillance. Only two studies analyzed the performances of a few surveillance strategies using computer models14,15. However, they either considered a limited horizon or used only data from the literature with significant assumptions. Erenay et al. (2011) developed an MCRC natural history (MCRC-NH) simulation model using a dataset from the Mayo Clinic, Rochester16. Using the MCRC-NH model, we conducted a cost-effectiveness analysis from the societal perspective for all clinically-reasonable colonoscopy surveillance strategies among 50–79year-old US post-treatment CRC population who recently completed their initial treatment. We identified effective colonoscopy surveillance strategies under various cost, colonoscopy sensitivity, and cumulative MCRC incidence scenarios.
*This cumulative incidence range may seem high compared to the MCRC incidence rates reported in some guidelines and studies as those rates may be defined over a shorter follow-up period (e.g., 2–5-year).
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DATA AND METHODS MCRC-NH Simulation Model and MCRC Progression
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The MCRC-NH model, coded in Java, is a discrete-event micro-simulation model which mimics MCRC development in a post-treatment CRC population by simulating one patient at-a-time based on gender (male and female) and age-group (50–59, 60–69, and 70–79-yearold). That is, MCRC progression parameters used in the model vary among different patientgroups while these parameters (thus, the average MCRC incidence and mortality) are similar among those in the same patient-group. The model was calibrated and validated using longitudinal data from Mayo Clinic, Rochester16. We ran the MCRC-NH model for 500,000 patients for each gender/age-group for 20 years after the initial treatment to evaluate each surveillance strategy based on prevented MCRCs, saved life-years (LYs), number of required colonoscopies, and total costs (details about their derivation are given in Supplementary-Materials I).
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As a common practice, we defined any new cancer diagnosed after the first six months from the primary CRC treatment as an MCRC5,7. Assuming a successful and complete treatment, post-treatment CRC patients are cancer- and polyp-free when the model initiates MCRC progression. A patient may develop multiple colorectal lesions in 20 years and each lesion independently progresses through the polyp-to-CRC sequence following the annual Markovian state-transition pattern illustrated in Figure 1a. We divided the cancer state into MCRC (local/regional cancer) and M-MCRC (metastatic/distant cancer) stages. M-MCRCs are symptomatically detected within a year while MCRCs are detected by surveillance colonoscopies. Patients diagnosed with metachronous lesions undergo appropriate treatment after which, they may develop new lesions. Although we did not explicitly model CRC recurrence, its effect is incorporated into the estimated treatment mortality probabilities. More details about the MCRC-NH model are available elsewhere16. Input Parameters
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Table 1 presents the input parameters of the MCRC-NH simulation model whose baseline MCRC progression parameters (within 5 years after primary CRC treatment) were derived from a longitudinal dataset of around 300 patients diagnosed and treated at Mayo Clinic, Rochester during 1992–2006. These patients are randomly selected among approximately 600 local post-treatment CRC patients resided within or immediately surrounding Olmsted County to eliminate missing data issues. We excluded patients with genetic conditions such as familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC) as well as those younger than 50 and older than 80 years. We did not exclude patients with family history of colorectal cancer. The data included colonoscopy histories, polyp/MCRC incidents, and mortalities from MCRC and other causes over a 5-year period after CRC treatment. The details about the data and derivation of parameters are described elsewhere16. In order to better represent the general population and extend the analysis horizon to 20 years for accurate long-term performance evaluation, we recalibrated the baseline probability of mortality from other causes and lesion progression probabilities while our results comply
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with particular trends in the Surveillance, Epidemiology, and End Results (SEER) reports and literature. The methodology for recalibrating these parameters is described in Supplementary-Materials II. We derived age/gender distribution of the recently treated 50–79-year-old post-treatment CRC population using SEER (1975–2008) CRC incidence rates and 2008 US census estimates1,17. We derived the characteristics of colonoscopy and perforation risk from the primary CRC literature10,13,18,19. The total cost includes costs of MCRC treatment, colonoscopy surveillance, and terminal care which are derived from the primary CRC literature and updated to 2013 US dollars using Consumer Price Index20. The high- and lowcost scenarios are estimated based on Ramsey et al. (2010)11,12. We used a 3% annual discount rate for costs and health-outcomes21.
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The US Guideline and Alternative Surveillance Strategies We assumed that a colonoscopy may independently detect different colorectal lesions. US Multi-Society Task Force guideline recommends undergoing the first colonoscopy surveillance 1 year after CRC treatment and increasing the surveillance interval to 3 and 5 years after the first and second negative colonoscopy, respectively3. This surveillance guideline can be represented in the form of (I1=1,I2=3,I3=5). Figure 1b illustrates how (1,3,5) specifies the US guideline’s colonoscopy surveillance intervals for a 60-year-old post-treatment CRC patient.
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We evaluated the performance of all strategies in the form of (I1,I2,I3) where I1≤I2≤I3≤5(full list is given in Supplementary-Materials V). Among them, we identified a set of promising strategies that may improve the US guideline. We first identified the Pareto-efficient strategies. Strategy A dominates B, if A both improves health-outcomes and reduces costs compared to B. When all dominated strategies are removed from the set of feasible strategies, the remaining ones are the Pareto-efficient strategies for which no other alternative strategy may lead to better health-outcomes with less cost. Some Pareto-efficient surveillance strategies like (1,1,1) may require too many additional colonoscopies than the US guideline. Therefore, we reported detailed performance of “promising strategies”, a subset of Pareto-efficient or close-to-Pareto-efficient strategies that require at most 40% (i.e., around 1/patient) additional colonoscopies compared to the existing guideline in the baseline case. Sensitivity Analysis
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We only considered baseline, high, and low values for colonoscopy sensitivity and costs, whereas we used 20-year MCRC incidence rate scenarios of 1.7%, 3%, 5.5%, 7.2%, 9.6%, and 12.8% to represent the long-term MCRC incidence range reported in the literature (2%– 12%)5,9. The baseline input parameters of the MCRC-NH model represents the high-end of this range with a 20-year MCRC incidence of 12.8%. In order to derive these scenarios, we multiplied the annual MCRC progression probabilities with a set of progression rate multipliers representing how fast and commonly MCRC is developed. We selected these
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multipliers by matching the estimated cumulative MCRC incidences to those reported in existing cohort studies (See Supplementary-Materials IV for details).
RESULTS Among 50–79-year-old post-treatment CRC population, the US guideline is associated with 1.7%–12.8% cumulative MCRC incidence, 7.75–8.13 discounted LYs per patient, and a total cost of $49,101–$55,162/patient while requiring 2.97–3.34 colonoscopies/patient over a 20year period under various parameter scenarios. Performances of Alternative Strategies in the Baseline Scenario
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Figure 2 presents the incremental performance of alternative strategies compared to the US guideline in the baseline scenario. Most strategies in Regions I and IV require more intensive surveillance than the guideline; thus, they are associated with reduced MCRC incidence and treatment costs which offset the increase in colonoscopy surveillance cost for strategies in Region IV. Therefore, strategies in Region IV dominate the guideline, while those in Region I are more effective but more costly. Excluding strategies generating less life-years than the US guideline, Regions I and IV contain all of the Pareto-efficient strategies which are cost-effective for the baseline scenario (See Supplementary-Materials VI). Because most Pareto-efficient strategies in Region IV move to Region I as cumulative MCRC incidence increases, we analyze the promising strategies from both Region I and IV rather than only those from IV.
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Table 2 shows improvements associated with the Pareto-efficient alternative strategies compared to the guideline for the baseline scenario. Strategies such as annual colonoscopy [(1,1,1)], annual colonoscopy until the second negative surveillance and biennial afterwards [(1,1,2)], and (1,2,2) improve health-outcomes significantly; however, require at least two additional colonoscopies/patient compared to the guideline. The other Pareto-efficient strategies (excluding (1,1,3)) may incur up to two-fifth of the achievable baseline life-year savings and number of prevented MCRCs at the expense of less than 1.2 additional colonoscopies/patient (< 35% increase in the number of colonoscopies). Sensitivity Analysis Results
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As illustrated in Supplementary-Materials VII, 5–10% variation in colonoscopy sensitivity minimally affects the performances and composition of set of Pareto-efficient strategies. Figure 3 shows that changes in cost and cumulative MCRC incidence lead to significant variation in health-outcomes and incremental cost-effectiveness ratios (ICERs) of Paretoefficient strategies. As expected, the improvements in saved life-years and prevented MCRCs decrease as the cumulative MCRC incidence decreases and ICERs exponentially increase with the surveillance intensity. Note that, most Pareto-efficient alternative strategies are cost-effective (i.e., ICERs < $50,000/LY) compared to the guideline except very intensive ones (e.g., (1,1,1), (1,1,2)). Supplementary-Materials VI provides detailed evaluation of the strategies in Figure 3. Although the composition of set of Pareto-efficient strategies varies significantly based on the cumulative MCRC incidence, (1,1,1), (1,1,2), (1,2,3), (2,2,2), (2,2,3), (2,2,4), and (2,2,5) Cancer. Author manuscript; available in PMC 2017 August 15.
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are amongst the Pareto-efficient strategies for almost all parameter scenarios. Among these, we refer to (1,2,3), (2,2,2), (2,2,3), (2,2,4) and (2,2,5) as “promising strategies” because they improve health-outcomes by moderately increasing required number of colonoscopies compared to the US guideline. We have also included (1,2,4) and (1,2,5) among them due to their similar performance to (2,2,3) and (2,2,4), respectively. Table 3 illustrates the performances of the promising strategies compared to the guideline for both baseline and high-cost scenarios. Only Strategy (2,2,5) is always both more effective and cost-saving than the guideline. However, in all scenarios, (2,2,5) only generates around 17–35% and 10% of achievable saved life-years and prevented MCRCs (e.g., the performance difference between (1,1,1) and (1,3,5)), respectively.
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Strategy (2,2,4) is biennial surveillance until the second negative colonoscopy followed by colonoscopies every four years thereafter while (1,2,5) refers to reducing the surveillance interval of the US guideline after the first negative colonoscopy by one year. In all scenarios, these strategies require up to 330 additional colonoscopies per 1000-patients while incurring around 25–50% of achievable saved LYs and 20% of achievable prevented MCRCs compared to the guideline. Strategy (2,2,3) and (1,2,4) require up to 675 additional colonoscopies per 1000-patients while generating 35–60% of achievable saved life-years and 30–35% of achievable prevented MCRCs. These strategies are cost-effective for all cost and incidence scenarios (ICER$50,000/LY compared to the guideline.
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Table 1
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Estimates, Ranges, and Sources of Input Parameters Parameters
Baseline
Low
High
Source
Annual MCRC progression probabilities Adenomatous polyp-onset
12%*
Adenomatous polyp-to-MCRC progression
16%*
MCRC-to-M-MCRC progression
27%*
Mortality after MCRC treatment
3%*
Mortality from undetected MCRC
8%*
Mortality after M-MCRC treatment
11%*
Mortality from other causes
1%*
16
Varies based on cumulative MCRC incidence scenario (see Supplementary-Materials IV)
Adenoma number at polyp-onset 1, 2, and 3 polyps
16
78%,13%,9%
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Inputs related to colonoscopy surveillance 10,13
Colonoscopy sensitivity: for adenomatous polyps
85%
80%
90%
for MCRC
90%
85%
95%
Colonoscopy specificity
100%
10,13
Probability of detecting/biopsying other lesions (e.g., inflammation, hyperplastic polyp)
16%
30
Probability of major complication with and without polypectomy/biopsy
7/1000, 8/10000
18
Probability of mortality from perforation with and without polypectomy/biopsy
1.6/10000*, 1/10000*
18,19
Costs (USD) Colonoscopy
$865
Polypectomy/biopsy plus pathology lab
$430
$1,725
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$240
$120
$480
$6,750
$3,400
$13,500
$51,100*
$42,000*
$62,000*
M-MCRC treatment (costs within the first year after the treatment)
$84,500*
$70,000
$132,600*
Annual continuing care after CRC/MCRC treatment
$5,300*
$4,350*
$6,475*
Annual continuing care after M-MCRC treatment
$13,600*
$11,250*
$16,600*
Terminal care for MCRC deaths (last year of life)
$69,000*
$56,500*
$83,000*
Terminal care for M-MCRC deaths (last year of life)
$96,000*
$78,700*
$116,000*
Terminal care for deaths from other causes (last year of life)
$23,200*
$19,000*
$28,400*
Colonoscopy complication treatment MCRC treatment (costs within the first year after the treatment)
11,12,31
Costs (USD)
11,12,31
Other parameters
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Gender/age distribution among US post-treatment CRC population Cancer stage distribution to restructure costs from the literature to comply with our stage definition Discount rate Consumer Price Index in 2007–2013 (medical care component)
Varies by age and gender
1,17
Varies by stage
32
3%
11,21
3.4%**
20
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Parameters MCRC progression rate multiplier
Baseline
Low
High
Source
1
0.32
1
Supl.-Materials IV
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M-MCRC, metastatic/distant MCRC. The table presents only the average values. The inputs with * vary by age and gender while those with ** vary by year (See Supplementary-Materials III for the derivation and details).
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Author Manuscript 88.3%
2945
6243 187.2%
63.9%
82
119 92.7%
3.0%
237
4.1%
323
62.7%
2092
50.8%
65
2.3%
183
(1,2,2)
50.9%
1698
40.6%
52
1.8%
142
(1,1,3)
34.4%
1148
39.0%
50
1.8%
141
(1,2,3)
11.8%
395
27.0%
35
1.4%
113
(2,2,3)
20.2%
675
27.8%
36
1.4%
109
(1,2,4)
1.2%
40
17.1%
22
1.0%
82
(2,2,4)
−7.5%
−252
9.0%
12
0.7%
56
(2,2,5)
The guideline requires 3335 colonoscopies (CLs), and results in 128 MCRC incidents and 7842 LYs (life-years) per 1000 post-treatment CRC patients for baseline parameters. Rows 1, 3, and 5 show performance differences compared to the guideline. Rows 2, 4, and 6 present the proportion of these differences, e.g., (1,1,1) saves 323 more discounted life-years (4.1%=100×323/7848), prevents 119 MCRCs (92.7%=100×119/128), and requires 6,243 more colonoscopies (187.2%=100×6243/3335).
Additional CLs per 1000-patients
Prevented MCRCs per 1000-patients
Saved LYs per 1000-patients
(1,1,2)
(1,1,1)
The Performance of Pareto-efficient Strategies for the Baseline Parameters Compared to the Guideline
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Table 2 ERENAY et al. Page 19
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Cancer. Author manuscript; available in PMC 2017 August 15. 1104 47.2 17.5
Number of CLs per prevented MCRC
Number of CLs per saved LYs
23
Additional CLs per 1000-patients
63
Prevented MCRCs per 1000-patients
(1,2,3)
5.5% Cumulative MCRC incidence
Saved LYs per 1000-patients
$13,963
ICER compared to (1,3,5) for high-cost
13.5
Number of CLs per saved LYs $6,596
36.9
ICER compared to (1,3,5) for baseline-cost
1116
Number of CLs per prevented MCRC
30
Additional CLs per 1000-patients
83
Prevented MCRCs per 1000-patients
(1,2,3)
7.3% Cumulative MCRC incidence
Saved LYs per 1000-patients
$8,695
ICER compared to (1,3,5) for high-cost
10.3
Number of CLs per saved LYs $3,954
29.3
ICER compared to (1,3,5) for baseline-cost
1132
Number of CLs per prevented MCRC
39
Additional CLs per 1000-patients
110
Prevented MCRCs per 1000-patients
(1,2,3)
9.6% Cumulative MCRC incidence
Saved LYs per 1000-patients
$3,963
ICER compared to (1,3,5) for high-cost
8.1
Number of CLs per saved LYs $1,351
23.0
ICER compared to (1,3,5) for baseline-cost
1148
Number of CLs per prevented MCRC
50
Additional CLs per 1000-patients
141
Prevented MCRCs per 1000-patients
(1,2,3)
Saved LYs per 1000-patients
12.8% Cumulative MCRC incidence
20.9
59.1
1433
24
69
(2,2,2)
$13,518
$7,065
15.3
44.6
1354
30
89
(2,2,2)
$8,067
$4,234
11.5
32.8
1253
38
109
(2,2,2)
$3,310
$1,801
8.2
24.1
1134
47
138
(2,2,2)
13.2
37.5
614
16
46
(1,2,4)
$8,352
$3,447
10.4
29.6
628
21
60
(1,2,4)
$4,374
$1,593
7.8
23.9
650
27
83
(1,2,4)
$428
**
6.2
18.9
675
36
109
(1,2,4)
9.7
31.0
541
17
56
(2,2,3)
$4,417
$2,813
7.1
22.8
502
22
71
(2,2,3)
$1,168
$1,099
5.2
16.4
453
28
87
(2,2,3)
3.5
11.4
395
35
113
(2,2,3)
8.3
23.6
246
10
30
(1,2,5)
$1,906
**
6.2
20.3
270
13
44
(1,2,5)
5.3
17.2
297
17
56
(1,2,5)
4.2
14.2
332
23
78
(1,2,5)
2.9
12.1
132
11
45
(2,2,4)
2.0
7.8
108
14
55
(2,2,4)
1.2
4.4
77
17
65
(2,2,4)
0.5
1.8
40
22
82
(2,2,4)
−6.5
−32.3
−195
6
30
(2,2,5)
**
−5.3
−27.9
−209
7
40
(2,2,5)
**
−5.0
−24.6
−228
9
46
(2,2,5)
**
−4.5
−21.9
−252
12
56
(2,2,5)
Performances of Promising Strategies Compared to the Guideline for the Baseline Colonoscopy Sensitivity
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Table 3 ERENAY et al. Page 20
Author Manuscript $63,822
$66,238
$34,165
56.8
199.0
1670
8
29
(2,2,2)
$41,889
$21,465
38.0
110.9
1576
14
42
(2,2,2)
$20,590
$10,626
(2,2,2)
$52,155
$25,951
36.9
107.1
576
5
16
(1,2,4)
$36,620
$16,704
30.4
62.7
587
9
19
(1,2,4)
$13,457
$6,123
(1,2,4)
$33,041
$17,670
28.3
105.7
651
6
23
(2,2,3)
$20,341
$10,803
19.7
59.0
607
10
31
(2,2,3)
$8,106
$4,716
(2,2,3)
$23,270
$11,796
13.3
60.1
193
3
15
(1,2,5)
$18,115
$6,230
16.6
36.4
210
6
13
(1,2,5)
$4,857
$823
(1,2,5)
$689
$1,689
10.0
52.3
202
4
20
(2,2,4)
7.0
27.0
173
6
25
(2,2,4)
(2,2,4)
LYs, life-years; CLs, colonoscopies; ICER, incremental cost-effectiveness ratios; **, cost saving strategies.
$32,423
ICER compared to (1,3,5) for high-cost
44.0
Number of CLs per saved LYs ICER compared to (1,3,5) for baseline-cost
140.6
Number of CLs per prevented MCRC
8 1080
Additional CLs per 1000-patients
Prevented MCRCs per 1000-patients
(1,2,3)
1.7% Cumulative MCRC incidence 25
$45,309
Saved LYs per 1000-patients
$22,221
ICER compared to (1,3,5) for high-cost
33.9
Number of CLs per saved LYs ICER compared to (1,3,5) for baseline-cost
82.0
Number of CLs per prevented MCRC
13 1086
Additional CLs per 1000-patients
Prevented MCRCs per 1000-patients
3.0% Cumulative MCRC incidence 32
(1,2,3)
ICER compared to (1,3,5) for high-cost
Saved LYs per 1000-patients
$9,914 $20,479
ICER compared to (1,3,5) for baseline-cost
(1,2,3)
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12.8% Cumulative MCRC incidence
**
−13.4
−76.9
−153
2
11
(2,2,5)
**
−12.6
−48.1
−172
4
14
(2,2,5)
**
(2,2,5)
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Cancer. Author manuscript; available in PMC 2017 August 15.
Cancer. Author manuscript; available in PMC 2017 August 15. Published in final edited form as: Cancer. 2016 August 15; 122(16): 2560–2570. doi:10.1002/cncr.30091.
Cost-effectiveness of Alternative Colonoscopy Surveillance Strategies to Mitigate Metachronous Colorectal Cancer Incidence FATIH SAFA ERENAY, Ph.D.1, OGUZHAN ALAGOZ, Ph.D.2, RITESH BANERJEE, Ph.D.3, ADNAN SAID, M.D.4, and ROBERT CIMA, M.D., M.A.5,6
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1Department
of Management Sciences, University of Waterloo, Waterloo-ON
2Department
of Industrial and Systems Engineering, University of Wisconsin-Madison, Madison-
WI 3Astellas
Pharmaceuticals, Northbrook-IL
4Gastroenterology
and Hepatology, School of Medicine and Public Health, University of Wisconsin, Madison-WI
5Division
of Colon and Rectal Surgery, Mayo Clinic, Rochester-MN
6Robert
D. and Patricia E. Kern Center for the Science of Health Care Delivery, Surgical Outcomes Program, Mayo Clinic, Rochester-MN
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Abstract BACKGROUND—Metachronous Colorectal Cancer (MCRC) incidence amongst colorectal cancer (CRC) survivors varies significantly and the optimal colonoscopy surveillance practice to mitigate MCRC incidence is unknown. METHODS—We conducted a cost-effectiveness analysis by comparing performances of the US Multi-Society Task Force guideline and all clinically-reasonable colonoscopy surveillance strategies among 50–79-year-old post-treatment CRC patients using a computer-simulation model.
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RESULTS—The US guideline [(1,3,5)] recommends the first colonoscopy 1-year after treatment while the second and third colonoscopies are repeated with 3- and 5-year intervals. We identified some promising alternative cost-effective strategies. Compared to the US guideline under various scenarios for 20-year period, 1) reducing the surveillance interval of the guideline after the first colonoscopy by 1-year [(1,2,5)] saves/prevents up to 78 discounted-life-years and 23 MCRCs per
CORRESPONDING AUTHOR: Oguzhan Alagoz, Department of Industrial and Systems Engineering, University of WisconsinMadison, 1513 University Avenue, Madison-WI 53706, [email protected], Phone:608/890-0399, Fax:608/262-8454. CONFLICT OF INTEREST DISCLOSURES: R.B. is an employee of Astellas Pharmaceuticals. F.S.E, O.A., A.S., and R.C declare no conflict of interest. Author Contributions: FATIH SAFA ERENAY: Conceptualization, methodology, software, validation, formal analysis, investigation, writing – original draft, writing – review and editing, visualization, supervision, project administration, and funding acquisition. OGUZHAN ALAGOZ: Conceptualization, methodology, writing – review and editing, supervision, project administration, and funding acquisition. RITESH BANERJEE: Conceptualization, methodology, investigation, and writing – review and editing. ADNAN SAID: Conceptualization, writing – review and editing, visualization, and supervision. ROBERT CIMA: Validation, investigation, and writing – review and editing.
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1000-patients (incremental cost-effectiveness ratio (ICER)≤$23,270/life-year); 2) reducing the intervals after the first and second negative colonoscopy by 1-year [(1,2,4)] saves/prevents up to 109 discounted-life-years and 36 MCRCs (ICER≤$52,155/life-year); 3) (1,2,3) saves/prevents up to 141 discounted-life-years and 50 MCRCs (ICER≤$68,822/life-year). These strategies require up to 1100 additional colonoscopies per 1000-patients. Although, the US guideline may not be costeffective compared to less-intensive oncology guideline (3,3,5) (ICER can be as high as $140,000/ LY), the promising strategies are cost-effective compared to such less-intensive guidelines unless cumulative MCRC incidence is very low. CONCLUSIONS—The US guideline might be improved by slightly increasing the surveillance intensity at the expense of moderately increased cost. More research is warranted to explore the benefits/harms of such practices.
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Keywords Cancer Surveillance; Second Primary Cancer; Economic Evaluation; Discrete-event Simulation; Cost-effectiveness
INTRODUCTION
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There is a growing colorectal cancer (CRC) survivor (post-treatment CRC) population in the US (1.16-million in 2011)1. Patients are recommended to undergo intensive colonoscopy surveillance after CRC treatment because of the high incidence of metachronous CRC (MCRC)2–4. Although indirect evidence exists for its effectiveness5, the actual benefit and the optimal frequency of colonoscopy surveillance among post-treatment CRC patients are unknown4,6. Reported long-term cumulative MCRC incidence (defined over a follow-up period of up to 20 years) varies significantly in the range of 2%–12%* and is associated with several risk-factors (age, family history, CRC stage/location) reflecting the heterogeneity in MCRC progression rates among the post-treatment CRC population5,7–9. Therefore, evaluating the effectiveness of post-treatment CRC surveillance in MCRC prevention/earlydetection and determining the optimal colonoscopy surveillance strategies for different cumulative MCRC incidence scenarios are imperative.
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Although similar issues for primary CRC are well-addressed through economic evaluations using computer-models10–13, such research is limited on post-treatment CRC surveillance. Only two studies analyzed the performances of a few surveillance strategies using computer models14,15. However, they either considered a limited horizon or used only data from the literature with significant assumptions. Erenay et al. (2011) developed an MCRC natural history (MCRC-NH) simulation model using a dataset from the Mayo Clinic, Rochester16. Using the MCRC-NH model, we conducted a cost-effectiveness analysis from the societal perspective for all clinically-reasonable colonoscopy surveillance strategies among 50–79year-old US post-treatment CRC population who recently completed their initial treatment. We identified effective colonoscopy surveillance strategies under various cost, colonoscopy sensitivity, and cumulative MCRC incidence scenarios.
*This cumulative incidence range may seem high compared to the MCRC incidence rates reported in some guidelines and studies as those rates may be defined over a shorter follow-up period (e.g., 2–5-year).
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DATA AND METHODS MCRC-NH Simulation Model and MCRC Progression
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The MCRC-NH model, coded in Java, is a discrete-event micro-simulation model which mimics MCRC development in a post-treatment CRC population by simulating one patient at-a-time based on gender (male and female) and age-group (50–59, 60–69, and 70–79-yearold). That is, MCRC progression parameters used in the model vary among different patientgroups while these parameters (thus, the average MCRC incidence and mortality) are similar among those in the same patient-group. The model was calibrated and validated using longitudinal data from Mayo Clinic, Rochester16. We ran the MCRC-NH model for 500,000 patients for each gender/age-group for 20 years after the initial treatment to evaluate each surveillance strategy based on prevented MCRCs, saved life-years (LYs), number of required colonoscopies, and total costs (details about their derivation are given in Supplementary-Materials I).
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As a common practice, we defined any new cancer diagnosed after the first six months from the primary CRC treatment as an MCRC5,7. Assuming a successful and complete treatment, post-treatment CRC patients are cancer- and polyp-free when the model initiates MCRC progression. A patient may develop multiple colorectal lesions in 20 years and each lesion independently progresses through the polyp-to-CRC sequence following the annual Markovian state-transition pattern illustrated in Figure 1a. We divided the cancer state into MCRC (local/regional cancer) and M-MCRC (metastatic/distant cancer) stages. M-MCRCs are symptomatically detected within a year while MCRCs are detected by surveillance colonoscopies. Patients diagnosed with metachronous lesions undergo appropriate treatment after which, they may develop new lesions. Although we did not explicitly model CRC recurrence, its effect is incorporated into the estimated treatment mortality probabilities. More details about the MCRC-NH model are available elsewhere16. Input Parameters
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Table 1 presents the input parameters of the MCRC-NH simulation model whose baseline MCRC progression parameters (within 5 years after primary CRC treatment) were derived from a longitudinal dataset of around 300 patients diagnosed and treated at Mayo Clinic, Rochester during 1992–2006. These patients are randomly selected among approximately 600 local post-treatment CRC patients resided within or immediately surrounding Olmsted County to eliminate missing data issues. We excluded patients with genetic conditions such as familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC) as well as those younger than 50 and older than 80 years. We did not exclude patients with family history of colorectal cancer. The data included colonoscopy histories, polyp/MCRC incidents, and mortalities from MCRC and other causes over a 5-year period after CRC treatment. The details about the data and derivation of parameters are described elsewhere16. In order to better represent the general population and extend the analysis horizon to 20 years for accurate long-term performance evaluation, we recalibrated the baseline probability of mortality from other causes and lesion progression probabilities while our results comply
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with particular trends in the Surveillance, Epidemiology, and End Results (SEER) reports and literature. The methodology for recalibrating these parameters is described in Supplementary-Materials II. We derived age/gender distribution of the recently treated 50–79-year-old post-treatment CRC population using SEER (1975–2008) CRC incidence rates and 2008 US census estimates1,17. We derived the characteristics of colonoscopy and perforation risk from the primary CRC literature10,13,18,19. The total cost includes costs of MCRC treatment, colonoscopy surveillance, and terminal care which are derived from the primary CRC literature and updated to 2013 US dollars using Consumer Price Index20. The high- and lowcost scenarios are estimated based on Ramsey et al. (2010)11,12. We used a 3% annual discount rate for costs and health-outcomes21.
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The US Guideline and Alternative Surveillance Strategies We assumed that a colonoscopy may independently detect different colorectal lesions. US Multi-Society Task Force guideline recommends undergoing the first colonoscopy surveillance 1 year after CRC treatment and increasing the surveillance interval to 3 and 5 years after the first and second negative colonoscopy, respectively3. This surveillance guideline can be represented in the form of (I1=1,I2=3,I3=5). Figure 1b illustrates how (1,3,5) specifies the US guideline’s colonoscopy surveillance intervals for a 60-year-old post-treatment CRC patient.
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We evaluated the performance of all strategies in the form of (I1,I2,I3) where I1≤I2≤I3≤5(full list is given in Supplementary-Materials V). Among them, we identified a set of promising strategies that may improve the US guideline. We first identified the Pareto-efficient strategies. Strategy A dominates B, if A both improves health-outcomes and reduces costs compared to B. When all dominated strategies are removed from the set of feasible strategies, the remaining ones are the Pareto-efficient strategies for which no other alternative strategy may lead to better health-outcomes with less cost. Some Pareto-efficient surveillance strategies like (1,1,1) may require too many additional colonoscopies than the US guideline. Therefore, we reported detailed performance of “promising strategies”, a subset of Pareto-efficient or close-to-Pareto-efficient strategies that require at most 40% (i.e., around 1/patient) additional colonoscopies compared to the existing guideline in the baseline case. Sensitivity Analysis
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We only considered baseline, high, and low values for colonoscopy sensitivity and costs, whereas we used 20-year MCRC incidence rate scenarios of 1.7%, 3%, 5.5%, 7.2%, 9.6%, and 12.8% to represent the long-term MCRC incidence range reported in the literature (2%– 12%)5,9. The baseline input parameters of the MCRC-NH model represents the high-end of this range with a 20-year MCRC incidence of 12.8%. In order to derive these scenarios, we multiplied the annual MCRC progression probabilities with a set of progression rate multipliers representing how fast and commonly MCRC is developed. We selected these
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multipliers by matching the estimated cumulative MCRC incidences to those reported in existing cohort studies (See Supplementary-Materials IV for details).
RESULTS Among 50–79-year-old post-treatment CRC population, the US guideline is associated with 1.7%–12.8% cumulative MCRC incidence, 7.75–8.13 discounted LYs per patient, and a total cost of $49,101–$55,162/patient while requiring 2.97–3.34 colonoscopies/patient over a 20year period under various parameter scenarios. Performances of Alternative Strategies in the Baseline Scenario
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Figure 2 presents the incremental performance of alternative strategies compared to the US guideline in the baseline scenario. Most strategies in Regions I and IV require more intensive surveillance than the guideline; thus, they are associated with reduced MCRC incidence and treatment costs which offset the increase in colonoscopy surveillance cost for strategies in Region IV. Therefore, strategies in Region IV dominate the guideline, while those in Region I are more effective but more costly. Excluding strategies generating less life-years than the US guideline, Regions I and IV contain all of the Pareto-efficient strategies which are cost-effective for the baseline scenario (See Supplementary-Materials VI). Because most Pareto-efficient strategies in Region IV move to Region I as cumulative MCRC incidence increases, we analyze the promising strategies from both Region I and IV rather than only those from IV.
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Table 2 shows improvements associated with the Pareto-efficient alternative strategies compared to the guideline for the baseline scenario. Strategies such as annual colonoscopy [(1,1,1)], annual colonoscopy until the second negative surveillance and biennial afterwards [(1,1,2)], and (1,2,2) improve health-outcomes significantly; however, require at least two additional colonoscopies/patient compared to the guideline. The other Pareto-efficient strategies (excluding (1,1,3)) may incur up to two-fifth of the achievable baseline life-year savings and number of prevented MCRCs at the expense of less than 1.2 additional colonoscopies/patient (< 35% increase in the number of colonoscopies). Sensitivity Analysis Results
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As illustrated in Supplementary-Materials VII, 5–10% variation in colonoscopy sensitivity minimally affects the performances and composition of set of Pareto-efficient strategies. Figure 3 shows that changes in cost and cumulative MCRC incidence lead to significant variation in health-outcomes and incremental cost-effectiveness ratios (ICERs) of Paretoefficient strategies. As expected, the improvements in saved life-years and prevented MCRCs decrease as the cumulative MCRC incidence decreases and ICERs exponentially increase with the surveillance intensity. Note that, most Pareto-efficient alternative strategies are cost-effective (i.e., ICERs < $50,000/LY) compared to the guideline except very intensive ones (e.g., (1,1,1), (1,1,2)). Supplementary-Materials VI provides detailed evaluation of the strategies in Figure 3. Although the composition of set of Pareto-efficient strategies varies significantly based on the cumulative MCRC incidence, (1,1,1), (1,1,2), (1,2,3), (2,2,2), (2,2,3), (2,2,4), and (2,2,5) Cancer. Author manuscript; available in PMC 2017 August 15.
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are amongst the Pareto-efficient strategies for almost all parameter scenarios. Among these, we refer to (1,2,3), (2,2,2), (2,2,3), (2,2,4) and (2,2,5) as “promising strategies” because they improve health-outcomes by moderately increasing required number of colonoscopies compared to the US guideline. We have also included (1,2,4) and (1,2,5) among them due to their similar performance to (2,2,3) and (2,2,4), respectively. Table 3 illustrates the performances of the promising strategies compared to the guideline for both baseline and high-cost scenarios. Only Strategy (2,2,5) is always both more effective and cost-saving than the guideline. However, in all scenarios, (2,2,5) only generates around 17–35% and 10% of achievable saved life-years and prevented MCRCs (e.g., the performance difference between (1,1,1) and (1,3,5)), respectively.
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Strategy (2,2,4) is biennial surveillance until the second negative colonoscopy followed by colonoscopies every four years thereafter while (1,2,5) refers to reducing the surveillance interval of the US guideline after the first negative colonoscopy by one year. In all scenarios, these strategies require up to 330 additional colonoscopies per 1000-patients while incurring around 25–50% of achievable saved LYs and 20% of achievable prevented MCRCs compared to the guideline. Strategy (2,2,3) and (1,2,4) require up to 675 additional colonoscopies per 1000-patients while generating 35–60% of achievable saved life-years and 30–35% of achievable prevented MCRCs. These strategies are cost-effective for all cost and incidence scenarios (ICER$50,000/LY compared to the guideline.
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Table 1
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Estimates, Ranges, and Sources of Input Parameters Parameters
Baseline
Low
High
Source
Annual MCRC progression probabilities Adenomatous polyp-onset
12%*
Adenomatous polyp-to-MCRC progression
16%*
MCRC-to-M-MCRC progression
27%*
Mortality after MCRC treatment
3%*
Mortality from undetected MCRC
8%*
Mortality after M-MCRC treatment
11%*
Mortality from other causes
1%*
16
Varies based on cumulative MCRC incidence scenario (see Supplementary-Materials IV)
Adenoma number at polyp-onset 1, 2, and 3 polyps
16
78%,13%,9%
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Inputs related to colonoscopy surveillance 10,13
Colonoscopy sensitivity: for adenomatous polyps
85%
80%
90%
for MCRC
90%
85%
95%
Colonoscopy specificity
100%
10,13
Probability of detecting/biopsying other lesions (e.g., inflammation, hyperplastic polyp)
16%
30
Probability of major complication with and without polypectomy/biopsy
7/1000, 8/10000
18
Probability of mortality from perforation with and without polypectomy/biopsy
1.6/10000*, 1/10000*
18,19
Costs (USD) Colonoscopy
$865
Polypectomy/biopsy plus pathology lab
$430
$1,725
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$240
$120
$480
$6,750
$3,400
$13,500
$51,100*
$42,000*
$62,000*
M-MCRC treatment (costs within the first year after the treatment)
$84,500*
$70,000
$132,600*
Annual continuing care after CRC/MCRC treatment
$5,300*
$4,350*
$6,475*
Annual continuing care after M-MCRC treatment
$13,600*
$11,250*
$16,600*
Terminal care for MCRC deaths (last year of life)
$69,000*
$56,500*
$83,000*
Terminal care for M-MCRC deaths (last year of life)
$96,000*
$78,700*
$116,000*
Terminal care for deaths from other causes (last year of life)
$23,200*
$19,000*
$28,400*
Colonoscopy complication treatment MCRC treatment (costs within the first year after the treatment)
11,12,31
Costs (USD)
11,12,31
Other parameters
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Gender/age distribution among US post-treatment CRC population Cancer stage distribution to restructure costs from the literature to comply with our stage definition Discount rate Consumer Price Index in 2007–2013 (medical care component)
Varies by age and gender
1,17
Varies by stage
32
3%
11,21
3.4%**
20
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Parameters MCRC progression rate multiplier
Baseline
Low
High
Source
1
0.32
1
Supl.-Materials IV
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M-MCRC, metastatic/distant MCRC. The table presents only the average values. The inputs with * vary by age and gender while those with ** vary by year (See Supplementary-Materials III for the derivation and details).
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Author Manuscript 88.3%
2945
6243 187.2%
63.9%
82
119 92.7%
3.0%
237
4.1%
323
62.7%
2092
50.8%
65
2.3%
183
(1,2,2)
50.9%
1698
40.6%
52
1.8%
142
(1,1,3)
34.4%
1148
39.0%
50
1.8%
141
(1,2,3)
11.8%
395
27.0%
35
1.4%
113
(2,2,3)
20.2%
675
27.8%
36
1.4%
109
(1,2,4)
1.2%
40
17.1%
22
1.0%
82
(2,2,4)
−7.5%
−252
9.0%
12
0.7%
56
(2,2,5)
The guideline requires 3335 colonoscopies (CLs), and results in 128 MCRC incidents and 7842 LYs (life-years) per 1000 post-treatment CRC patients for baseline parameters. Rows 1, 3, and 5 show performance differences compared to the guideline. Rows 2, 4, and 6 present the proportion of these differences, e.g., (1,1,1) saves 323 more discounted life-years (4.1%=100×323/7848), prevents 119 MCRCs (92.7%=100×119/128), and requires 6,243 more colonoscopies (187.2%=100×6243/3335).
Additional CLs per 1000-patients
Prevented MCRCs per 1000-patients
Saved LYs per 1000-patients
(1,1,2)
(1,1,1)
The Performance of Pareto-efficient Strategies for the Baseline Parameters Compared to the Guideline
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Cancer. Author manuscript; available in PMC 2017 August 15. 1104 47.2 17.5
Number of CLs per prevented MCRC
Number of CLs per saved LYs
23
Additional CLs per 1000-patients
63
Prevented MCRCs per 1000-patients
(1,2,3)
5.5% Cumulative MCRC incidence
Saved LYs per 1000-patients
$13,963
ICER compared to (1,3,5) for high-cost
13.5
Number of CLs per saved LYs $6,596
36.9
ICER compared to (1,3,5) for baseline-cost
1116
Number of CLs per prevented MCRC
30
Additional CLs per 1000-patients
83
Prevented MCRCs per 1000-patients
(1,2,3)
7.3% Cumulative MCRC incidence
Saved LYs per 1000-patients
$8,695
ICER compared to (1,3,5) for high-cost
10.3
Number of CLs per saved LYs $3,954
29.3
ICER compared to (1,3,5) for baseline-cost
1132
Number of CLs per prevented MCRC
39
Additional CLs per 1000-patients
110
Prevented MCRCs per 1000-patients
(1,2,3)
9.6% Cumulative MCRC incidence
Saved LYs per 1000-patients
$3,963
ICER compared to (1,3,5) for high-cost
8.1
Number of CLs per saved LYs $1,351
23.0
ICER compared to (1,3,5) for baseline-cost
1148
Number of CLs per prevented MCRC
50
Additional CLs per 1000-patients
141
Prevented MCRCs per 1000-patients
(1,2,3)
Saved LYs per 1000-patients
12.8% Cumulative MCRC incidence
20.9
59.1
1433
24
69
(2,2,2)
$13,518
$7,065
15.3
44.6
1354
30
89
(2,2,2)
$8,067
$4,234
11.5
32.8
1253
38
109
(2,2,2)
$3,310
$1,801
8.2
24.1
1134
47
138
(2,2,2)
13.2
37.5
614
16
46
(1,2,4)
$8,352
$3,447
10.4
29.6
628
21
60
(1,2,4)
$4,374
$1,593
7.8
23.9
650
27
83
(1,2,4)
$428
**
6.2
18.9
675
36
109
(1,2,4)
9.7
31.0
541
17
56
(2,2,3)
$4,417
$2,813
7.1
22.8
502
22
71
(2,2,3)
$1,168
$1,099
5.2
16.4
453
28
87
(2,2,3)
3.5
11.4
395
35
113
(2,2,3)
8.3
23.6
246
10
30
(1,2,5)
$1,906
**
6.2
20.3
270
13
44
(1,2,5)
5.3
17.2
297
17
56
(1,2,5)
4.2
14.2
332
23
78
(1,2,5)
2.9
12.1
132
11
45
(2,2,4)
2.0
7.8
108
14
55
(2,2,4)
1.2
4.4
77
17
65
(2,2,4)
0.5
1.8
40
22
82
(2,2,4)
−6.5
−32.3
−195
6
30
(2,2,5)
**
−5.3
−27.9
−209
7
40
(2,2,5)
**
−5.0
−24.6
−228
9
46
(2,2,5)
**
−4.5
−21.9
−252
12
56
(2,2,5)
Performances of Promising Strategies Compared to the Guideline for the Baseline Colonoscopy Sensitivity
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Table 3 ERENAY et al. Page 20
Author Manuscript $63,822
$66,238
$34,165
56.8
199.0
1670
8
29
(2,2,2)
$41,889
$21,465
38.0
110.9
1576
14
42
(2,2,2)
$20,590
$10,626
(2,2,2)
$52,155
$25,951
36.9
107.1
576
5
16
(1,2,4)
$36,620
$16,704
30.4
62.7
587
9
19
(1,2,4)
$13,457
$6,123
(1,2,4)
$33,041
$17,670
28.3
105.7
651
6
23
(2,2,3)
$20,341
$10,803
19.7
59.0
607
10
31
(2,2,3)
$8,106
$4,716
(2,2,3)
$23,270
$11,796
13.3
60.1
193
3
15
(1,2,5)
$18,115
$6,230
16.6
36.4
210
6
13
(1,2,5)
$4,857
$823
(1,2,5)
$689
$1,689
10.0
52.3
202
4
20
(2,2,4)
7.0
27.0
173
6
25
(2,2,4)
(2,2,4)
LYs, life-years; CLs, colonoscopies; ICER, incremental cost-effectiveness ratios; **, cost saving strategies.
$32,423
ICER compared to (1,3,5) for high-cost
44.0
Number of CLs per saved LYs ICER compared to (1,3,5) for baseline-cost
140.6
Number of CLs per prevented MCRC
8 1080
Additional CLs per 1000-patients
Prevented MCRCs per 1000-patients
(1,2,3)
1.7% Cumulative MCRC incidence 25
$45,309
Saved LYs per 1000-patients
$22,221
ICER compared to (1,3,5) for high-cost
33.9
Number of CLs per saved LYs ICER compared to (1,3,5) for baseline-cost
82.0
Number of CLs per prevented MCRC
13 1086
Additional CLs per 1000-patients
Prevented MCRCs per 1000-patients
3.0% Cumulative MCRC incidence 32
(1,2,3)
ICER compared to (1,3,5) for high-cost
Saved LYs per 1000-patients
$9,914 $20,479
ICER compared to (1,3,5) for baseline-cost
(1,2,3)
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12.8% Cumulative MCRC incidence
**
−13.4
−76.9
−153
2
11
(2,2,5)
**
−12.6
−48.1
−172
4
14
(2,2,5)
**
(2,2,5)
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