Decision Analysis of Colorectal Cancer Screening Tests by Age to Begin, Age to End, and Screening Intervals:
Report to the United States Preventive Services Task Force from the Cancer Intervention and Surveillance Modeling
Network (CISNET)
Agency for Healthcare Quality and ResearchSeptember 8, 2008
MISCAN
Memorial Sloan-Kettering Cancer Center -Ann Zauber
Erasmus MC - Marjolein van Ballegooijen, Iris Lansdorp-Vogelaar, Janneke Wilschut
SimCRCUniversity of Minnesota – Karen Kuntz
Massachusetts General Hospital – Amy Knudsen
What CMS reimbursement for a new CRC test? 2003 and 2007
Stool DNA test?
$ to be determined
$4.54 $22.22
National Coverage Determination (NCD) on stool DNA (PreGen-Plus test, version 1.1 every 5 years for average risk population)
Questions addressed by CISNET for USPSTF 2007
USPSTF addresses updates for 2002 colorectal cancer screening recommendations
Evidence based literature review
Task Force requested a decision analysis for recommended CRC screening tests for age to begin age to end rescreening interval Should the current recommendations be changed?
Microsimulation models (MISCAN and SimCRC) of CISNET consortium used for the decision analysis to inform health policy
Adenoma to Carcinoma Pathway
NormalEpithelium
SmallAdenoma
ColorectalCancer
AdvancedAdenoma
Microsimulation Modeling of Adenoma Carcinoma Sequence
with Potential Interventions
adenoma6-9 mm
adenoma>=10 mm
ADENOMAPreclinical
screen-detectable adenoma phase
No lesion
adenoma<=5 mm
preclinicalstage I
preclinicalstage II
preclinicalstage III
preclinicalstage IV
PreclinicalCANCER
screen-detectablecancer phase
clinicalstage I
clinicalstage II
clinicalstage III
clinicalstage IV
ClinicalCANCER
phase
deathcolorectal
cancer
Datasources:Adenoma
Autopsy studiesColonoscopy studies
Preclinical CancerDwell time
Clinical CancerSEER Incidence
DeathUS Mortality
Screening
Colorectal Cancer Screening StrategiesCurrent Age and Interval Recommendations*
Age Begin
50
Screening Tests
Hemoccult II
Hemoccult SENSA
FIT
Flex Sig
Flex Sig + SENSA
Colonoscopy
Rescreening Intervals
1 – FOBT
5 – Flex Sig
10 - Colonoscopy
Age End
None
Surveillance No stop age
* MultiSociety and ACS
Colorectal Cancer Screening StrategiesCohort of 40 year olds in 2005
Age Begin
40
50
60
Screening Tests
Hemoccult II
Hemoccult SENSA
FIT
Flex Sig*
Flex Sig* + SENSA
Colonoscopy
(No Screening)
* With biopsy
Rescreening Intervals
1,2,3 – FOBT
5,10,20- Endos
Age End
75
85
Surveillance** No stop age
Adherence 100%
** 3 year for advanced adenomas, 5-10 (5) for non-advanced adenomas
145 Test Strategies
>10mm 6-9mm <5mm
CRC Sensitivity Specificity
Pe
rce
nt
Pe
rce
nt
Hemoccult II
Hemoccult SENSAFIT
Sigmoidoscopy
Sig + Hemoccult SENSAColonoscopy
Adenoma Sensitivity by Size
Sensitivity and Specificity of Testsfrom Literature Review
$0
$50,000
$100,000
$150,000
$200,000
$250,000
$300,000
$350,000
$400,000
$450,000
$500,000
$550,000
$600,000
$650,000
$700,000
$750,000
$800,000
$850,000
$900,000
$950,000
$1,000,000
NoScreening
HII HS FIT sDNA-5(v1.1)
SIG HS + SIG COL
No Screening
HII
HS
FIT
sDNA-5 (v1.1)
SIG
HS + SIG
COL
Sigmoidoscopy sensitivity for lesions within range
Screening Test Costs $ per Test
4.54 4.54 22.22 161 498 649
USPSTF requested NOT to use costs
Outcome Measures
Most effective = Greatest life years gained relative to no screening
Weigh effectiveness against resources required and exposure to risks: Colonoscopy as resource and risk indicator
Endoscopy resourcesPerforation risk
Life years gained (LYG) vs Total colonoscopies in lifetime
(per 1000 persons in population).
Effectiveness-Risk Analysis
Determine efficient strategies for each test Plot life years gained versus colonoscopies required
If strategy requires more colonoscopies but has fewer life years gained (LYG) (ie less effective) then eliminate
Of the remaining strategies, rank by increasing effectiveness (LYG) Derive relative to each other: Incremental number of colonoscopies = ΔCol Incremental LYG = ΔLYG Incremental number colonoscopies to gain a life yr = ΔCol/ ΔLYG
Efficiency Ratio of measure of the additional number of colonoscopies required to gain one year of benefit when considering a more effective strategy relative to the next less effective strategy
Efficiency frontier – all strategies NOT dominated (eliminated) Near the efficiency frontier – those strategies that are with 98% of the LYG
on the frontier
Colonoscopy-MISCAN
0
50
100
150
200
250
300
0 1,000 2,000 3,000 4,000 5,000 6,000 7,000 8,000 9,000
Colonoscopies per 1,000 persons
Life
-yea
rs g
aine
d pe
r 1,
000
pers
ons
Colonoscopy Strategies Frontier Start age 40 Frontier 40
60-75,20
50-75,20
50-75,10 50-85,10
Colonoscopy-SimCRC
0
50
100
150
200
250
300
350
0 1,000 2,000 3,000 4,000 5,000 6,000 7,000 8,000 9,000
Colonoscopies per 1,000 persons
Life
-yea
rs g
aine
d pe
r 1,
000
pers
ons
Colonoscopy strategies Frontier Start age 40 Frontier 40
60-75,20
50-75,20
50-75,10 50-85,10
Efficient Colonoscopy Strategies
Strategy* # Col(per 1000)
# LYG(per 1000)
Col(per 1000)
LYG(per 1000)
Col/LYG
MISCAN
1 COL, 60-75, 20 2,175 156 ---
2 COL, 50-75, 20 3,325 203 1,150 47 24.7
3 COL, 50-75, 10 4,136 230 811 27 29.6
4 COL, 50-85, 10 4,534 236 398 5 72.9
5 COL, 50-75, 5 5,895 254 1,362 18 74.8
6 COL, 50-85, 5 6,460 257 565 4 156.1
SimCRC
1 COL, 60-75, 20 1,780 165 ---
2 COL, 50-75, 20 2,885 246 1,106 82 13.5
3 COL, 50-75, 10 3,756 271 871 25 34.7
4 COL, 50-85, 10 4,114 273 358 2 Dominated
5 COL, 50-75, 5 5,572 281.6 1,816 10 178.8
6 COL, 50-85, 5 6,031 282 459 0.5 975.7* Test, begin age – end age, intervalCol = incremental number of colonoscopies compared with the next best strategyLYG = incremental number of life years gained compared with the next best strategy
Age to End Screening
No prior recommendations on stop age for CRC screening
Age 75 and 85 considered
Comorbidity and life expectancy rather than chronological age important
Example for colonoscopy: If start screening at age 50 and stop at age 75 Negative colonoscopy at age 50, 60, and 70 3 negative exams before stopping Those with adenomas or colorectal cancer detected at screening
colonoscopy would be in a surveillance program with no stopping age
Hemoccult II-MISCAN
0
50
100
150
200
250
300
0 500 1,000 1,500 2,000 2,500 3,000
Colonoscopies per 1,000 persons
Life
-yea
sr g
aine
d pe
r 1,
000
pers
ons
Hem II Strategies Frontier Start age 40 Frontier 40
60-75,3
50-75,3
50-75,1
50-85,1
Hemoccult SENSA-MISCAN
0
50
100
150
200
250
300
0 500 1,000 1,500 2,000 2,500 3,000 3,500 4,000 4,500 5,000
Colonoscopies per 1,000 persons
Life
-yea
sr g
aine
d pe
r 1,
000
pers
ons
Sensa® Strategies Frontier Start age 40 Frontier 40
60-75,3
50-75,3
50-75,1
50-85,1
FIT-MISCAN
0
50
100
150
200
250
300
0 500 1,000 1,500 2,000 2,500 3,000 3,500 4,000 4,500
Colonoscopies per 1,000 persons
Life
-yea
sr g
aine
d pe
r 1,
000
pers
ons
FIT Strategies Frontier Start age 40 Frontier 40
60-75,3
50-75,3
50-75,150-85,1
Flexible Sigmoidoscopy-MISCAN
0
50
100
150
200
250
300
0 500 1,000 1,500 2,000 2,500
Colonoscopies per 1,000 persons
Life
-yea
sr g
aine
d pe
r 1,
000
pers
ons
flexible sigmoidoscopy strategies Frontier start age 40 Frontier 40
60-75,20
60-75,5
50-75,550-85,5
Combination-MISCAN
0
50
100
150
200
250
300
0 1000 2000 3000 4000 5000 6000
Colonoscopies per 1,000 persons
Life
-yea
sr g
aine
d pe
r 1,
000
pers
ons
Fsig+Sensa® strategies Frontier Startage 40 Frontier 40
50-75,5,3
60-75,20,3
50-85,5,1
Comparisons Among Testswithout comparator of costs
To compare among tests, it is important to consider that tests other than colonoscopy are required (ie, FOBT, Flex Sig)
To pick an efficient strategy for each test we would expect to find an ordering to the efficiency ratios as follows:
COL > SENSA > [FIT, HII] > [FSig, FSig+SENSA]
Eg, SENSA should require fewer colonoscopies to gain a benefit of 1 year compared with COL because of the added number of FOBTs needed in addition to the colonoscopies to achieve that benefit.
Approach to ChoosingEfficient Strategies
Assume that a single start and end age would be recommended for screening
Select strategies from all tests (including combination of tests) that:1. are efficient (or near efficient) within the test2. have efficiency ratios with expected ordering (to
account for the burden of other testing)3. have comparable effectiveness (LYG)
Example: start age = 50; stop age = 75; anchored with 10-year colonoscopy (as a starting strategy)
Efficient (near efficient) strategies for start age 50 and stop age 75-(Table 9 bolded strategies)
Strategy*# Col
(per 1000)# LYG
(per 1000)Col/LYG # FOBT # Fsig
MISCAN
COL, 50-75, 10 4,136 230 29.6 0 0
SENSA®, 50-75, 1 3,350 230 30.9 9,541 0
FIT, 50-75, 1 2,949 227 25.9 11,772 0
Hem II®, 50-75, 1 1,982 194 14.3 16,232 0
Fsig, 50-75, 5 1,911 203 9.7 0 4,139
FsigSENSA®, 50-75, 5,3 2,870 230 16.3 6,145
SimCRC
COL, 50-75, 10 3,756 271 34.7 0 0
SENSA®, 50-75,1 2,654 259 22.9 9,573 0
FIT, 50-75,1 2,295 256 19.7 11,830 0
Hem II®, 50-75, 1 1,456 218 9.6 16,239 0
Fsig, 50-75, 5 995 199 8.4 0 4,483
FsigSENSA®, 50-75, 5,3 1,655 257 7.0 9,679
Sensitivity Analysis
Comparative modeling (2 models) give similar results
Similar rankings of strategies even if assume better or worse estimates on sensitivity and specificity
Adherence varied from 100%, 80%, 50%
MISCAN Adherence Plot
0
50
100
150
200
250
0 1000 2000 3000 4000 5000
Colonoscopies per 1,000 screened
life
yea
rs g
ain
ed p
er 1
,000
scr
een
ed
COL
SENSA
FIT
HemII
FSIG
FSIG-SENSA
Adherence 50%
Adherence 80%
Adherence 100%
CONCLUSIONS
Current recommended guidelines* are on or close to the efficiency frontier
Beginning at age 50 balances life years gained and number of colonoscopies required and associated risk of perforation
To increase efficiency of current guidelines*, stop screening at age 75 should depend on life expectancy of person
rather than strict chronological age
*MultiSociety and ACS
CONCLUSIONS (Continued 1)
Annual SENSA or FIT have similar LYG as colonoscopy every 10 years but with lower colonoscopy requirements – PROVIDED high compliance for all tests
FlexSig every 5 years with annual FOBT with Sensitive FOBT not recommended (high efficiency ratio) Original strategy for Flex Sig+ FOBT was for Hemoccult II with
lower sensitivity Combination of Flex Sig and Hemoccult SENSA® could have
one mid-interval FOBT between the 5 year repeat Flex Sig screening rather than annual FOBT
FlexSig every 5 years and Hemoccult II not as good in terms of effectiveness
CONCLUSIONS for Adherence
Adherence conclusions Life years gained and colonoscopies decreased with decreased
adherence BUT The overall conclusions did not change substantially as
adherence varied from 50% to 100%.
Hemoccult II and flexible sigmoidoscopy every 5 years remained the least two attractive alternatives re life years gained
Colonoscopy every 10 years improved a bit relative to the other strategies when adherence was 80% but lost its health benefit advantage when adherence as 50%
Limitations
Analyses for whole population – not specific by sex or race Potential of more proximal disease in older women and blacks Age of onset may vary by sex and race Inadequate data on adenoma prevalence age 40
Chronological age rather than life expectancy Life expectancy of men: 10.5 at age 75 and 5.9 at 85 Life expectancy of women: 12.5 at age 75 and 7.0 at 85
Simulation models rely on assumptions of natural history of disease Comparing two models provides sensitivity analysis of natural history
assumptions
‘Best’ Test is the One Which Gets Done- SJ Winawer re Adherence
Thank You
Mary Barton, William Lawrence of AHRQ
Diana Pettit, Michael LeFevre, George Isham, and Steve Teutsch of USPSTF
Acknowledgements
Screening and Treatment Costs by Screening Strategy
$0
$1,000,000
$2,000,000
$3,000,000
$4,000,000
$5,000,000
NonTreatment
Treatment
Hemoccult II
Hemoccult SENSAFIT
No Screening
Sigmoidoscopy
Sig + Hemoccult SENSA
Colonoscopy
Per 1000 screened
Hemoccult II
Screening Test Polyp Resection and Pathology Follow-up of Positive Test
Surveillance Complications
Hemoccult SENSAFIT
Sigmoidoscopy
Sig + Hemoccult SENSA
Colonoscopy
Components of Screening Costs (per 1000 screened) (CMS analysis age 65+)
Model Calibrations
Process of matching model output with data
Useful when data aren’t available to estimate certain model parameters but are available on model outcomes
Compare model output with empirical data
1.Prevalence and number of adenomas(autopsy studies)
2.Location and size of lesions(colonoscopy studies)
3. Incidence, location, and stage of diagnosed CRC (SEER)
SENSA®, 50-75,1 Specificity of 92.5% (base case) vs 87% (ER)Colonoscopy 50-75,10 given as comparator
Strategy MISCAN# Col (per 1000)
# LYG (per 1000)
Colonoscopy, 50-75, 10 4,136 230
SENSA®, 50-75,1 (basecase) 3,350 230
SENSA®, 50-75,1 (SA at 87% specificity)
3,832 (+14%) 233 (+1%)
Strategy SimCRC # Col (per 1000)
# LYG (per 1000)
Colonoscopy, 50-75, 10 3,756 271
SENSA®, 50-75,1 (basecase) 2,654 259
SENSA®, 50-75,1 (SA at 87% specificity)
3,104 (+17%) 263 (+1.5%)
Efficient Strategiesfor start age of 50 and stop age of 75
(Table 9 Page 31)
Strategy* # Col(per 1000)
# LYG(per 1000)
Col(per 1000)
LYG(per 1000)
Col/LYG
MISCAN
COL, 50-75, 10 4,136 230 811 27 29.6
SENSA®, 50-75, 1 3,350 230 766 25 30.9
FIT, 50-75, 1 2,949 227 765 30 25.9
Hem II®, 50-75, 1 1,982 194 647 45 14.3
Fsig, 50-75, 5 1,911 203 864 89 9.7
FsigSENSA®, 50-75, 5,3 2,870 230 839 52 16.3
SimCRC
COL, 50-75, 10 3,756 271 871 25 34.7
SENSA®, 50-75,1 2,654 259 698 31 22.9
FIT, 50-75,1 2,295 256 681 35 19.7
Hem II®, 50-75, 1 1,456 218 536 56 9.6
Fsig, 50-75, 5 995 199 187 22 8.4
FsigSENSA®, 50-75, 5,3 1,655 257 611 88 7.0* Test, begin age – end age, interval Col = incremental number of colonoscopies compared with the next best strategyLYG = incremental number of life years gained compared with the next best strategy
Efficient Strategiesfor start age of 50 and stop age of 75
Rank order of strategies
Strategy* # Col(per 1000)
# LYG(per 1000)
Col/LYG
MISCAN
COL, 50-75, 10 4,136 (1) 230 (1) 29.6
SENSA®, 50-75, 1 3,350 (2) 230 (1) 30.9
FIT, 50-75, 1 2,949 (3) 227 (4) 25.9
Hem II®, 50-75, 1 1,982 (5) 194 (6) 14.3
Fsig, 50-75, 5 1,911 (6) 203 (5) 9.7
FsigSENSA®, 50-75, 5,3 2,870 (4) 230 (1) 16.3
SimCRC
COL, 50-75, 10 3,756 (1) 271 (1) 34.7
SENSA®, 50-75,1 2,654 (2) 259 (2) 22.9
FIT, 50-75,1 2,295 (3) 256 (4) 19.7
Hem II®, 50-75, 1 1,456 (5) 218 (5) 9.6
Fsig, 50-75, 5 995 (6) 199 (6) 8.4
FsigSENSA®, 50-75, 5,3 1,655 (4) 257 (3) 7.0* Test, begin age – end age, interval Col = incremental number of colonoscopies compared with the next best strategyLYG = incremental number of life years gained compared with the next best strategy
Comparisons
First compare strategies within a screening test
Efficient frontier derived for each screening test or combination test
Col/LYG – ‘Efficiency Ratio’ A measure of the additional number of colonoscopies
required to gain one year of benefit when considering a more effective strategy relative to the next less effective strategy
Colonoscopy resources across tests are comparable but burden of all testing is not
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