tailoring colorectal cancer screening based on risk thomas f. imperiale, md indiana university...
TRANSCRIPT
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Tailoring Colorectal Cancer Screening Based on Risk
Thomas F. Imperiale, MD
Indiana University Medical Center
6th Annual Cancer Care Engineering Retreat
May 27, 2011
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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
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Where is the colon?
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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”)
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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
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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%
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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%
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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)
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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
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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
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Winawer SJ et al. N Engl J Med 1993;329:1977-1981
Cumulative Incidence of CRC in the NPS Cohort.
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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)
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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.
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“…..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
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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%
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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?
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Outcomes to Target for CRC Screening
CRC mortality
CRC incidence
Advanced neoplasia
NOT just any adenoma
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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).
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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
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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”)
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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
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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
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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
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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
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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
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Where is the colon?
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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)
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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
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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)
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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
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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
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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
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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
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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
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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%
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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?
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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
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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)
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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
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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
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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
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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%
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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
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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
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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
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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
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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
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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)
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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
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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.
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Thank you!
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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
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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