5-6 July 2013, Barcelona

Population-based CRC screening: the FIT approach

Dr Antoni Castells

Director of the Institute of Digestive

Disease, The Hospital Clinic

Barcelona, Spain

Population-based CRCscreening: the FIT approach

Antoni Castells, MD, PhDGastroenterology Department

Hospital Clínic, Barcelona(castells@clinic.cat)

Colorectal cancer prevention

Normalmucosa

Adenoma Carcinoma

Primary prevention

Secondary prevention(screening)

Tertiary prevention(surveillance)

Colorectal cancer: epidemiology

Piñol et al. JAMA 2005

Factores de riesgo personal

y/o familiar

No

Edad

< 50 años ≥≥≥≥ 50 años

AbstenciónCribado

Si

Factor de riesgo personal

Adenoma Enfermedad inflamatoria

intestinal

Vigilancia Vigilancia

Factor de riesgo familiar

PAF CCHNP CCRfamiliar

Cribado

Cribado

Cribado

CRC prevention: risk stratification

0

100

200

300

400

500

20-24 30-34 40-44 50-54 60-64 70-74 80-84

Age (years old)

Ra

te /

10

0.0

00

in

ha

bit

an

ts

Colorectal cancer screening: average-risk population

Conditions for a population-basedscreening (Frame and Carlson, 1975)

� Relevant health care problem

� Well-established natural history ���� early detection diminishes morbi-mortality

� Effective and well-accepted treatment

� Adequate screening test

� Cost-effective strategy

Cancer incidence in Spain

13.212

14.477

15.979

18.821

25.665

0 5.000 10.000 15.000 20.000 25.000 30.000

Próstata

Vejiga

Mama

Pulmón

Colorrectal

Centro Nacional de Epidemiología

Casos nuevos /año

EUROCARE 4

CRC mortality in Spain

Normal mucosa

Adenoma Carcinoma

Natural history of CRC

Advanced adenoma:• Size �1 cm• Villous component• High-grade dysplasia

Advanced adenoma:• Size �1 cm• Villous component• High-grade dysplasia

5 years 5 years

� Mainly located in the proximal colon

� Frequently flat or sessile, covered by mucus

� Predominantly in women, associated with aging

� BRAF mutation, microsatellite instability, CIMP

� Rapidly progressing lesions

Serrated lesions as precursors of CRC

Endoscopic polypectomy: CRC incidence

Winawer et al. NEJM 1993

5

4

3

2

1

4 6 82 años

Incid

en

cia

acu

mu

lad

a

de C

CR

(%

)Polipectomía

SEER

St. Mark

Mayo Clinic

Evidence: 1bRecommendation: A

Endoscopic polypectomy: CRC mortality

Zauber et al. NEJM 2012

�� 47%

CRC screening in average-risk population

Personal and/or familial

risk factors

No

Age

< 50 years ≥≥≥≥ 50 years

No screenAnnual or biennial FOBT and/or

sigmoidoscopy / 5 years, ocolonoscopy / 10 years

• U.S. Preventive Services Task Force• U.S. Multi-Society Task Force on Colorectal Cancer• American Cancer Society• AEG – semFYC - Cochrane

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Cancer screening: cost-effectiveness

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1Mandel et al. NEJM 19932Hardcastle et al. Lancet 19963Kronborg et al. Lancet 1996

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CRC mortality reduction

Screening in average-risk population:fecal occult blood testing (FOBT)

Evidence: 1aRecommendation: A

1970Hemoccult®

Guaiac-based methods

Immunochemical methods (FIT)

Quantitative tests

OC-Sensor®, SENTiFOB®Immudia RPH (Magstream 1000)®

2005

Qualitative testsInmunoCare®FlexSure OBT®Immudia Hem SP®OC-Hemodia®Monohaem®

2000

Qualitative testsInSure®Instant View®Hemeselect, Hemoccult-ICT®OC-Light®

1988Hemoccult-Sensa®

FOBT’s history

Van Rossum et al. Gastroenterology 2008

Guaiac (Hemoccult II®)

FIT

(OC-Sensor®)p

Invitated population 10,301 10,322

Dietary restrictions No No

Stool samples 3 1

Participation –no. (%) 4,836 (47%) 6,157 (60%) <0.01

Test positivity 2.4% 5.5% <0.01

Adv. adenomas –no. (%) 46 (0.4%) 121 (1.1%) <0.01

CRC –no. (%) 11 (0.1%) 24 (0.2%) <0.01

FOBT vs. FIT

Barcelona’s Colorectal CancerScreening Program

Screening in average-risk population:colonoscopy

Baxter et al. Ann Intern Med 2009

Association between colonoscopy and CRC mortality reduction

Evidence: 2bRecommendation: B

CRC screening in average-risk population

Personal and/or familial

risk factors

No

Age

< 50 years ≥≥≥≥ 50 years

No screenAnnual or biennial FOBT and/or

sigmoidoscopy / 5 years, ocolonoscopy / 10 years

• U.S. Preventive Services Task Force• U.S. Multi-Society Task Force on Colorectal Cancer• American Cancer Society• AEG – semFYC - Cochrane

Which one is the best?

The ColonPrev Study

Hypothesis

� Fecal immunochemical testing (FIT):

� Better sensitivity than gFOBT

� Less effective but potentially better accepted than colonoscopy

� Higher acceptance may counteract its lower efficacy in a population-based approach

FIT-based screening should not be inferior to colonoscopy-based strategies in terms of CRC-

related mortality in average-risk individuals.

Primary end-point

� To compare the efficacy of one-time colonoscopy vs. biennial FIT for the reduction of CRC-related mortality at 10 years in average-risk population

Secondary end-points

� Participation (1st round) and adherence (at 10 years) rates

� Diagnostic rate and diagnostic yield (1st round and cumulative at 10 years) of advanced colorectal neoplasia

� Complication rate (1st round and cumulative at 10 years)

� Cost-efficacy

Aims

Study design

Multicenter, randomized controlled trial in 8 Spanish

regions and 15 participating centers

ClinicalTrials.gov number: NCT00906997

Regions withinstitutional CRC population-based screening program

Regions withoutinstitutional CRC population-based screening program

Eligible population(grouped by address)

Randomization 1:1

Group I: Biennial FIT (n= 27,749)

Group II: Colonoscopy(n= 27,749)

Information + invitation � reminding letters

Appointment: Local Screening Office(questionnaire, post-randomization consent)

Study flow chart

Inclusion criteria� Men and women aged 50-69 years

Exclusion criteria

� Personal history of CRC, colorectal adenoma or colorectal polyposis

� Personal history of inflammatory bowel disease

� Family history of colorectal polyposis, Lynch syndrome or familial CRC (>2 FDR with CRC, or 1 FDR with CRC diagnosed <60 years of age)

� Severe comorbidity

� Previous total colectomy

� Not signed informed consent to participate

Methodology (I)

Methodology (II)

� Cross-over between study groups is allowed

� Incomplete colonoscopy: CT-colonography

� Quality-assurance program:

� Colonoscopy

� Recruitment process

� Online database (www.coloncrib.org)

� Communication plan

���������ABCA

Chronogram

Inclusion period(1st round)

June 2009 2011

FIT FIT FIT FIT

Analysis of participation and

detection rate

Screening (continued)

2021

Analysis of mortality

Cost-efficacy

Analysis of CRC incidence

End of 2nd round

Participation and cross-over rates(intention-to-screen analysis)

24,60%

34,20%

0%

5%

10%

15%

20%

25%

30%

35%

Colonoscopy FIT

p=0.0001

OR, 0.63 (95% CI, 0.60-0.65)

Participation rate

6,20%

0,40%

0%

1%

2%

3%

4%

5%

6%

7%

Colonoscopy > FIT FIT > colonoscopy

p=0.0001

OR, 16.8; 95% CI, 13.9-20.2)

Cross-over rate

Diagnostic yield(intention-to-screen analysis)

Cancer

0 1 2 3 4 5 6 7 8 9 10 11 12

1.0

FIT Colonoscopy

Odds ratio(adjusted by age, gender and participating center)

30 (0.1%)33 (0.1%)

2.3514 (1.9%)231 (0.9%)

Advanced adenoma

9.8

Non-advanced adenoma

1109 (4.2%)119 (0.4%)

Colorectal cancer staging(as-screened analysis)

19

24

66

2

6

0

5

10

15

20

25

Stage I Stage II Stage III

Colonoscopy FIT

p=0.52

Number needed to screen(per protocol analysis)

191

281

1036

0

50

100

150

200

250

300

Ind

ivid

uals

need

ed

to s

cre

en

Cancer Advanced

neoplasia

Colonoscopy FIT

Number needed to scope(per protocol analysis)

191

18 10 2

0

50

100

150

200

250

300

Ind

ivid

uals

need

ed

to s

co

pe

Cancer Advanced

neoplasia

Colonoscopy FIT

Summary of ColonPrev results (1st round)

� Subjects in the FIT group were more likely to participate in CRC screening than subjects in the colonoscopy group

� On the baseline screening examination, the number of subjects in whom CRC was detected was similar in the two study groups, but more adenomas were detected in the colonoscopy group

� The comparative effectiveness of FIT and colonoscopy for preventing death from CRC will be assessed at the completion of this 10-year trial

Quintero & Castells et al. N Engl J Med 2012

“The best test is the one that gets done." “The best test is the one that gets done."

Sidney Winawer, MD

Grant support

Local grant support

Population-based CRC screening: the FIT approach

Antoni Castells, MD, PhDGastroenterology Department

Hospital Clínic, Barcelona(castells@clinic.cat)

5-6 July 2013, Barcelona