Tailoring Colorectal Cancer Screening Based on Risk

Thomas F. Imperiale, MD

Indiana University Medical Center

6th Annual Cancer Care Engineering Retreat

May 27, 2011

Colorectal Cancer

3rd most prevalent cancer in the U.S.

150,000 new cases per year

55,000 deaths per year – 3rd most common cause of cancer-death– 2nd among non-smokers

Screening is effective in reducing morbidity and mortality

How best to screen is unclear

Where is the colon?

Until 2008 - Recommended Screening Tests and

Intervals for Average-Risk Persons

ACG ACS USPSTF GI Consort

Year of Rec. 2000 2001 2002 2003

3-sample FOBT Annual Annual Annual Annual

Sigmoidoscopy Q5Y Q5Y Q5Y Q5Y

FOBT & Sig Q1,5Y Q1,5Y Q1,5Y Q1,5Y

DCBE Q5Y Q5Y Q5Y Q5Y

Colonoscopy Q10Y Q10Y Q10Y Q10Y

(“preferred”)

Screening Tests and Intervals: 2009

TestACS/

MSTFACR USPSTF ACGReimbursem

entHemoccult II NR Annually NR Yes

HS-FOBT/FIT Annually Annually Annually Yes

Sigmoidoscopy Q 5 y Q 5 y (suboptimal)

Q 5-10 y Yes(suboptimal)

FOBT & Sig Q 1, 5 y Mid-interval, Q 5 y

Q 1, 5-10 y

Yes

DCBE Q 5 y NR NR Yes

Fecal DNA Yes, ? Interval

NR Q 3 y +/-

CTC Q 5 y NR Q 5 y Mostly not

Colonoscopy Q 10 y Q 10 Y Q 10 Y Yes

Micro-simulation (MISCAN) Model of CRC

Ages 50-75Test, Interval

Outcomes per 1000 Persons________ CY Non-CY Tests LYG Mortality

CY, 10 4136 0 230 65%

HOS, 1 3350 9541 230 66%

FIT, 1 2949 11773 227 65%

HO II, 1 1982 16232 194 55%

FSIG, 5 1911 4139 203 59%

FSIG + HOS; 5,3 2970 5822 230 66%

Simulation Model of CRC (SimCRC)Ages 50-75Test, Interval

Outcomes per 1000 Persons . CY Non-CY Tests LYG Mortality

CY, 10 3756 0 271 84%

HOS, 1 2654 9573 259 81%

FIT, 1 2295 11830 256 80%

HO II, 1 1456 16239 218 69%

FSIG, 5 995 4483 199 62%

FSIG + HOS;

5,31655 11623 257 79%

Sigmoidoscopy: Case-control studies

Odds Ratio (95% CI)

1st Author, Year

StudyN

OutcomeN

DistalColon

Proximal Colon

Selby, 1992 1129Mortality

2610.41

(0.25-0.69)0.96

(0.61-1.51)

Newcomb, 1992

262Mortality

660.05

(0.01-0.43)0.36

(0.11-1.20)

Newcomb, 2003

2992Incidence

16680.24

(0.17-0.33)0.89

(0.68-1.16)

Results of Flex Sig TrialsNORCCAP U.K. SCORE

N 55,736 170,432 34,292

Mean follow up 6, 7 yrs 11.2 yrs 10.5, 11.4 yrs

Mortality

-ITT 27% NS 31% 22% NS

-per protocol 59% overall76% distal

43% overall 38% overall52% distal

Incidence

-ITT 23% overall36% distal

18% overall24% distal

-per protocol 27% distal (NS)

33% overall50% distal

31% overall40% distal

Colonoscopy

No RCTs (in progress)

Indirect evidence– Mechanism of incidence / mortality reduction

with FOBT– Sigmoidoscopy works, so….

Cohort studies (observed vs. expected)

Case-control studies

Winawer SJ et al. N Engl J Med 1993;329:1977-1981

Cumulative Incidence of CRC in the NPS Cohort.

Colonoscopy and CRC

Risk Ratio (95% Confidence Interval)

1st author, yrStudy design

StudyN

Outcome N

Overall Distal Proximal

Baxter, ’09, CCS

61752 Mortality 10292

0.63(0.57-0.69)

0.33(0.28-0.39)

0.99(0.86-1.14)

Brenner, ’10, CCS

3287 Incidence214

0.52(0.37-0.73)

0.33(0.21-0.53)

1.05(0.63-1.76)

Singh, ’10, Cohort

45985 Incidence300

Men: 0.59(0.50-0.70)

0.44(0.34-0.57)

0.88(0.69-1.12)

Incidence2524

Women: 0.71

(0.61-0.83)

0.44(0.33-0.58)

0.99(0.82-1.19)

Brenner, ’11, CCS

2622 Incidence1688

0.23(0.19-0.27)

0.16(0.12-0.20)

0.44 (0.35-0.55)

Questions to Consider

Can use of screening colonoscopy be made more efficient?

Can CRC screening – in general – be made more efficient?

Can concepts of risk improve efficiency?

“Efficient” (def) – productive of results with a minimum of wasted effort.

“…..the millions who undergo screening for no apparent gain – the denominator – (who) are subject to the harms that could cumulatively outweigh the benefits to the smaller group in the numerator.”

Woolf SH. N Engl J Med 2000;343:1641-3

Neoplasia Prevalence - Screening

First au, year

Study N Mean age, yr

Non-advanced neoplasia

Advanced neoplasia

Adeno-CA

Morikawa2005

21,805 48.2 16% 4.9% 0.1%

Lin, 2006 1,244 56.2 12.1% 4.4% 0.2%

Regula, 2006

43,032 NA 8.9% 5.9% 0.9%

Strul, 2006

994 47 15.6% 7.2% 1.3%

Kim, 2007 4,491 53 17.9% 3.4% 0%

Tailoring CRC Screening

Intensity of screening (and surveillance) is suited to a person’s risk

Requires knowing about risk

Currently done for “high-risk” groups– FAP & HNPCC– Strong family history of CRC– IBD

Can tailoring be extended to “average-risk” persons?

Outcomes to Target for CRC Screening

CRC mortality

CRC incidence

Advanced neoplasia

NOT just any adenoma

Risk stratification could affect screening decisions

Risk stratification – a system or process by which clinically-

meaningful separation of risk is achieved in a group of

otherwise similar persons.

For high-risk (or not low-risk) persons

– Education about need for screening

– Suggestion that aggressive screening is indicated

For low-risk persons

– Defer screening until no longer low-risk

– Screen less aggressively (? non-invasively).

Risk Factors for CRC:What we use vs. what we “know”

What we use

Age – 50 is the threshold

Family history - > 1 FDR with CRC / AP

– When to begin

– How to screen

What we know: CRC risk factors

Strong risk factors (RR > 4.0)

– Age

Moderate risk factors (RR = 2.1 – 4.0)

– High red meat diet

– Pelvic irradiation – after 15 years

– Waist-to-hip ratio > 0.99 vs. < 0.90, > 0.90 vs. < 0.81

– Waist circumference (> 43” vs. < 35”)

Modest Risk Factors(RR = 1.1 – 2.0)

High fat diet

Alcohol – daily use, > 5 beers / week

Cigarette smoking: > 20 years, remote use

Obesity – BMI

Tall stature: > 73” vs. < 68”

Cholecystectomy

Weight gain of > 40 lbs since age 21

Male gender

Modest Protective Factors(RR = 0.9 – 0.6)

High fruit / vegetable diet

High fiber diet

High folate intake

High calcium intake

Post-menopausal HRT – any use, > 5yr,

current use

Moderate Protective Factors(RR < 0.6)

High physical activity– Decreases transit time– Highest vs. lowest quintiles of MET-hr/wk

score

Aspirin / NSAIDs– Inhibition of COX-2 (?)– > 2 times per week– Duration; > 10 – 20 years (NHS) - ? 5 years

Advanced neoplasia

Factor PAF (95% CI)

Male gender (50%)

23% (9-36%)

Current smoking(10%)

9% (-2 to 20%)

FDR with CRC (12%) 4% (-1 to 8%)

• Male gender and smoking have a larger impact on the prevalence of colorectal neoplasia than family history• Suggests CRC-based risk stratification based on gender and smoking status.

Hoffmeister M, et al. Clin Gastro Hepatol 2010; 8: 870-6

Risk factor Category Points

Age (years) 50-54 0

55-59 1

60-64 2

> 65 3

Gender Women 0

Men 1

Distal finding No polyps 0

Hyperplastic polyps 1

> 1 tubular adenoma < 1 cm 2

Advanced neoplasia 3

A risk index previously developed

• Age, gender, and distal colorectal findings used to stratify risk for advanced proximal neoplasia (APN)

Scores ranged from 0 to 7

Imperiale, et al. Ann Intern Med 2003; 139:959-65

Where is the colon?

Previous Risk Index for APN

Risk Group(Score)

N % of total N

Risk of APN (%)(95% CI)

Low (0, 1)

1222 (40) 0.82 (0.39-1.50)

Intermediate(2, 3)

1221 (40) 2.05 (1.33-3.01)

High(4-7)

582 (20) 8.59 (6.44-11.2)

Application to Clinical PracticeColonoscopy for APN

DetectedN (%)

Persons having colonoscopy

N (%)

Number needed

to screen

Any distal polyp 41 (49) 641 (21) 27

Any distal neoplasm

32 (39) 341 (11) 11

All 83 (100) 3,025 (100) 36

Intermediate & high risk 76 (92) 1,808 (60) 24

Imperiale TF, et al. Ann Intern Med 2003

External Validation of the IndexOriginal

Validation Group

Caucasian African-American

Hispanic

N 1031 1481 1329 689

Prevalence of APN - % (CI)

1.5% (0.8-2.4%)

2.4% (1.7-3.3%)

2.1% (1.4-3.0%)

1.5%(0.8-2.4%)

Low-risk 0.4% (0.1-1.5%)

1.0% 1.0% 0.6%

Intermediate risk

1.9% (0.8-3.8%)

2.8% (1.0-7.6%)

2.2% (0.8-6.2%)

1.9% (0.6-15.9%)

High-risk 3.8% (1.2-8.6%)

3.8%(1.3-10.6%)

4.2% (1.4-12.7%)

3.7% (1.1-34%)

% APN in low-risk group

13% 17% 18% 18%aROC 0.74

(0.62-0.84)0.62

(0.54-0.70)0.63

(0.54-0.73)0.68

(0.53-0.82)

Lin O. Am J Gastroenterol 2011 (in press)

A predictive model for advanced adenoma

• 2210 persons > 40 years – screening CY• Logistic model risk score ROC curve• 617 (28%) had neoplasia

– 259 (11.7%) had adv adenoma; 11 CRC• Variables –

– Age: 0 to 4 by decade– Sex: 0 for women, 2 for men– BMI: 0 for < 25 kg/m2 to 2 for > 35 kg/m2

Betés M, et al. Am J Gastroenterol 2003; 98:2648-54

Yield of Colonoscopy for advanced adenomaaROC=0.67

Score n/N (%) NNS

0 0/41 (0) ---

1 1/117(1) 14

2 4/201 (2) 13

3 20/408 (5) 12

4 45/487 (9) 10

5 37/359 (10) 8.7

6 11/71 (15) 6.0

7 2/6 (33) 3.0

Limitations

• Potential for selection bias

– 11 years to achieve N

– Medium-to-high SES

– Motivated to screening CY

• Model and score not validated

• No information about location (proximal / distal)

by score

Models for Future Risk of CRC

• Physicians’ Health Study – 21,851 U.S. Physicians, ages 40-84 years– 20-year follow-up ….. 485 cases of CRC

• Independent predictors– Age (by decade) -- Alcohol use (> 1/wk)– Smoking hx (yes/no) -- BMI (< 25, 25-9, > 30)

• Odds ratios rounded risk score - range, 0-10• Risk categories – low (0-3), intermediate (4-6),

high (7-10)

Driver JA, et al. Am J Med 2007; 120:257-63

20-year risk of CRC by score# Points # (%)

PatientsOdds Ratio (95%

CI) for CRC20-year cumulative

Risk of CRC0 977 (5) 1.00 (reference) 0.6%

1 3090 (14) 1.48 (0.61-3.59) 0.9%

2 3981 (18) 1.52 (0.64-3.61) 0.9%

3 3422 (16) 2.25 (0.96-5.29) 1.4%

4 3356 (16) 3.70 (1.61-3.82) 2.2%

5 2656 (12) 5.35 (2.33-12.29) 3.2%

6 1953 (9) 7.46 (3.25-17.12) 4.4%

7 1268 (6) 7.76 (3.33-18.05) 4.6%

8 600 (3) 11.25 (4.73-26.74) 6.5%

9-10 278 (1) 15.29 (6.19-37.81) 8.6%

Driver JA, et al. Am J Med 2007; 120:257-63

Performance of the 3 Risk Groups

Risk Group

N (%) Patients

Predicted CRC

Observed CRC

OR (CI) of CRC

Obs. 20-year risk of CRC

Low(0-3 pts)

11470 (53%)

121 118 1.0 1%

Intermed(4-6 pts)

7965(37%)

238 246 3.07(2.5-3.8)

3%

High(7-10 pts)

2146(10%)

126 121 5.75(4.4-7.4)

6%

Limitations

• No information on FHx, prior screening, others• Not validated • Uncertain generalizability• Estimated future (vs. current) risk• High-risk group is about “average” risk (6%)• Better for estimating relative, not absolute, risk• CRC, not advanced neoplasia, is the outcome

– Is this acceptable?

Absolute Risk Projection Model for CRC

• Derived from 2 population-based CCSs involving persons > 50 years

• Combined ORs & ARs from 2 CCSs with SEER data on age-specific CRC incidence to estimate CRC risk over 5, 10, & 20 years

• Identified independent RFs• Developed questionnaire and web-based

version – www.cancer.gov/colorectalcancerrisk• 1st absolute risk model for CRC

Freedman AN, et al. J Clin Oncol 2009; 27: 686-93

Factors

• Cancer-negative sig/colonoscopy < 10 years• Polyp history during previous 10 years• CRC in first-degree relative• Regular aspirin and NSAID use• Cigarette smoking• BMI• Current leisure-time vigorous activity• Vegetable consumption• Hormone-replacement therapy (HRT)

Model validation

• NIH-AARP diet and health study cohort• 567,169 persons 50-71 years completed self-

administered questionnaire• Comparison of expected vs. observed CRC• 7 years of follow-up 2,924 cases of CRC• Expected / observed ratios:

– 0.99 (CI, 0.95-1.04) for men– 1.05 (CI, 0.98-1.11) for women

• aROCs – 0.61 for both men and women• Calibrated vs. validated; limited to Caucasians

Park Y, et al. J Clin Oncol 2009; 27: 694-8

R-01 CA 1044590• 5-year grant from NCI – funded in 2004• Goal – quantify risk for advanced

neoplasia, tailor CRC screening according to risk

• Specific aims– Create a clinical prediction rule (CPR) for

advanced neoplasia anywhere in the large intestine

– Create a CPR for advanced proximal neoplasia

– Establish a blood-based biorepository

NCI study

• Multi-site, cross-sectional study• Persons 50-80 years old having their first

screening colonoscopy– Eli Lilly and Marathon Oil – several sites– IGH, MMCH, Wishard, VA

• Questionnaires, physical measures, blood• Recruitment goal: 5-6K ; 420 advanced

neoplasia• For repository only – patients with CRC

– Surgery, oncology clinics

Current status through 4/30/11

• Specific aim 3 – completed 9/30/09– 2,058 unique subjects– 1,102 - no polyps; 281 – hyperplastic only– 394 – non-adv adenomas– 92 – advanced adenomas– 5 - screen-detected adenocarcinomas– 189 subjects with known CRC

• 123 enrolled pre-operatively• 62 post-op, 4 unknown

– Draw-to-freezer time < 6 hr for > 95%

Questionnaire part

• 4,493 subjects enrolled though 4/30/11• 2,732 (61%) normal findings• 556 (12%) with hyperplastic polyps• 867 (19%) with non-advanced adenomas• 338 (8%) with advanced neoplasia

– 17 with screen-detected CRC

Staff and Collaborators• Project Manager – Curlie Morrow• Research assistants

– Mungai Maina– Maria Cruz

• Biostatistics– Janetta Matsen – Data manager– Rebeka Tabbey – masters biostatistician– Menggang Yu, PhD –

• Collaborators – – Betsy Glowinski – IGRF– Kris Courtney, MD – Lilly – Brian Linder, MD – Marathon– David Ransohoff, MD - UNC

Thanks to…..• Oncology clinic

– Gabi Chiorean, M.D.– Paul Helft, M.D., M.P.H.– Pat Loehrer, M.D.

• Surgery clinic– Vermilio George, M.D.– Bruce Robb, M.D.– Eric Wiebke, M.D.

• Other funding sources– CTSI– Walther Foundation– IUCC and DoD grant

Yield of colonoscopy in veterans – VA funded-study – HSR&D

Objectives – – Measure, compare yield of 1st-time VA

colonoscopy for advanced neoplasia within pre-specified demographic groups

– Quantify yield by indication– Explore associations between demographic

and clinical features …and risk for CIN

Methods– 18-site, cross-sectional study of findings on

1st-time colonoscopy, ages 40-80– Remote data extraction, NLP

Results to date

IRB approval – 18 sites

Indianapolis VA data “remotely” extracted– Software “finalized” (N=198)– 92% sensitivity; 87% specificity– Reasons for misses: coding errors, h/o polyps

17 remote sites extracted 8/10 - 10/10– Independent, remote EMR review by RA– 3 samples of 60 unique records per site

ResultsExtraction software test characteristics @ Indy VA– Sensitivity = 92%– Specificity = 87%

Total N from 18 sites = 258,743

1st exclusion = 46,649 (18%; range: 9-47%)

1st inclusion = 212,094

Software performance at external sites (n=587)– 12.4% falsely excluded (no CPT code in EMR)– 15.7% falsely included (h/o polyps; prior CY)– 32.7% properly excluded– 40.2% properly included

Estimated final N = 85,000 (4,250 women)

Staff and Collaborators

• Project manager – Brian Brake• Research assistants – Jason Larson,

Maria Cruz• Data Management

– Kathy Smith - Tenesha Pennington• Biostats – Xiaochun Li, PhD• IT – Jon Cardwell, Leonard Aloi• Collaborators – Jeff Friedlin, Charles Kahi,

17 other site investigators

Conclusion

• CRC screening is effective and cost-effective, but screening the entire population with colonoscopy is not feasible, costly, may be unnecessary.

• Tailoring CRC screening based on risk, would make screening more efficient and might engage persons previously unscreened.

Thank you!

A risk index for advanced neoplasia

Retrospective cross-sectional study of 3005 persons >= 50 years – screening CY– Derivation subgroup of 1512– Validation subgroup of 1493

Age (0-3), sex (0, 1), FHx CRC (0-2) = 0-6

Compared 3 strategies– CY for all– CTC for all– CTC for low-risk (scores of 0, 1); CY for rest

Lin O, et al. Gastroenterol 2006; 131: 1011-9

ResultsUniversal

CTCUniversal

CYIndex-based

screening

# CTCs 3005 0 1146

# Colonoscopies 405 3005 1985

Total # procedures 3410 3005 3131

Both procedures 405 (13%) 0 126 (4%)

% advanced neoplasia detected

70% 94% 91%

Limitations- CTC not widely available / reimbursed- Cost and effects of radiation, incidental findings not considered