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