COLORECTAL CANCER SCREENINGCOLORECTAL CANCER SCREENING

Alan N. BarkunAlan N. BarkunProfessor, Division of Gastroenterology

Chairholder of the DG Kinnear Chair in Gastroenterology, Chief Quality Officer, Division of Gastroenterology,

McGill University and the McGill University Health Centre

Chair of the Clinical Standards and of the Evaluation of Endoscopic Competence Committees,

Quebec Colorectal Cancer Screening Program

ObjectivesObjectives

At the end of the presentation, participants At the end of the presentation, participants should should

Understand the different screening options for Understand the different screening options for colorectal cancer available to patientscolorectal cancer available to patients

have become familiar with the test have become familiar with the test performance characteristics of the different performance characteristics of the different screening approachesscreening approaches

be able to explain to patients their benefits be able to explain to patients their benefits and disadvantagesand disadvantages

Why is CRC uniquely suited for screening?Why is CRC uniquely suited for screening?Why is CRC uniquely suited for screening?Why is CRC uniquely suited for screening?

CRC is common + highly lethal if caught lateCRC is common + highly lethal if caught late

CRC has a long asymptomatic pre-clinical phaseCRC has a long asymptomatic pre-clinical phase

Accurate screening tests widely availableAccurate screening tests widely available

Early detection of CRC & polyps improves survivalEarly detection of CRC & polyps improves survival

The benefits outweigh the harms/costsThe benefits outweigh the harms/costs

CRC is common + highly lethal if caught lateCRC is common + highly lethal if caught late

CRC has a long asymptomatic pre-clinical phaseCRC has a long asymptomatic pre-clinical phase

Accurate screening tests widely availableAccurate screening tests widely available

Early detection of CRC & polyps improves survivalEarly detection of CRC & polyps improves survival

The benefits outweigh the harms/costsThe benefits outweigh the harms/costs

Epidemiology Epidemiology Epidemiology Epidemiology

Colorectal cancer is a leading cause of death in the Colorectal cancer is a leading cause of death in the Western WorldWestern World

In Canada, it is the third most common cancer in both sexesIn Canada, it is the third most common cancer in both sexes

Colorectal cancer is a leading cause of death in the Colorectal cancer is a leading cause of death in the Western WorldWestern World

In Canada, it is the third most common cancer in both sexesIn Canada, it is the third most common cancer in both sexes

In 2010

Quebec

New Cases

5900

(3rd)

Deaths

2500

(2nd)CUMULATIVE LIFETIME RISK IN USA/Canada: 1:21/1:22 and 1:49/1:54

2011 Digestive Health Summit for Health Care Professionals

CDHF.ca

Colorectal Cancer – biology

• 60% will die if cancer spreads to lymph nodes

• 95% will die if cancer spreads to distant organs

• If diagnosed early 95% will survive; presently only 35% of cases diagnosed at this stage

Polyp-cancer sequence 8-12 yrs (80%)

CRC a perfect diseaseparadigm for screening

IT IS PREVENTABLE

2011 Digestive Health Summit for Health Care Professionals

CDHF.ca

The most common risk factor: AGE

Canadian Cancer Statistics 2011

Screening for CRC - so far:Screening for CRC - so far:Screening for CRC - so far:Screening for CRC - so far:

CRC is CRC is amenableamenable to screening to screening

AgeAge is the main risk factor for average risk screening is the main risk factor for average risk screening

Need to start screening at Need to start screening at age 50age 50

Should screen Should screen every 10 yearsevery 10 years (if good test available) (if good test available)

CRC is CRC is amenableamenable to screening to screening

AgeAge is the main risk factor for average risk screening is the main risk factor for average risk screening

Need to start screening at Need to start screening at age 50age 50

Should screen Should screen every 10 yearsevery 10 years (if good test available) (if good test available)

FOBT- Meta-analysis of these trials FOBT- Meta-analysis of these trials FOBT- Meta-analysis of these trials FOBT- Meta-analysis of these trials

4 trials totaling almost 4 trials totaling almost 450,000450,000 patients patients

16%16% risk reduction in CRC related mortality (23% risk reduction in CRC related mortality (23%

in compliant patients)in compliant patients)

RR=0.84; CI: 0.77-0.93RR=0.84; CI: 0.77-0.93

NN to screen to prevent 1 death: NN to screen to prevent 1 death: 11731173

4 trials totaling almost 4 trials totaling almost 450,000450,000 patients patients

16%16% risk reduction in CRC related mortality (23% risk reduction in CRC related mortality (23%

in compliant patients)in compliant patients)

RR=0.84; CI: 0.77-0.93RR=0.84; CI: 0.77-0.93

NN to screen to prevent 1 death: NN to screen to prevent 1 death: 11731173

Fecal Immunochemical TestingFecal Immunochemical TestingFecal Immunochemical TestingFecal Immunochemical Testing

The FIT detects more specifically human hemoglobin that The FIT detects more specifically human hemoglobin that arises from the arises from the lowerlower GI tract GI tract

Easier to use, more quantifiable; high throughput Easier to use, more quantifiable; high throughput technologytechnology

4 trials performed in a populational setting; only first-round 4 trials performed in a populational setting; only first-round screening and no cancer registry follow-up as of yet (Italy, screening and no cancer registry follow-up as of yet (Italy, Netherlands); additional trial out of China – very preliminary Netherlands); additional trial out of China – very preliminary datadata

FIT outperforms gFOBT with a lower level of reported FIT outperforms gFOBT with a lower level of reported discomfort and overall burdendiscomfort and overall burden

The FIT detects more specifically human hemoglobin that The FIT detects more specifically human hemoglobin that arises from the arises from the lowerlower GI tract GI tract

Easier to use, more quantifiable; high throughput Easier to use, more quantifiable; high throughput technologytechnology

4 trials performed in a populational setting; only first-round 4 trials performed in a populational setting; only first-round screening and no cancer registry follow-up as of yet (Italy, screening and no cancer registry follow-up as of yet (Italy, Netherlands); additional trial out of China – very preliminary Netherlands); additional trial out of China – very preliminary datadata

FIT outperforms gFOBT with a lower level of reported FIT outperforms gFOBT with a lower level of reported discomfort and overall burdendiscomfort and overall burden

Fecal Immunochemical Testing vs GuaiacFecal Immunochemical Testing vs GuaiacFecal Immunochemical Testing vs GuaiacFecal Immunochemical Testing vs Guaiac

FIT Positive Rate of 3.5 to 8.1% (decreases with increasing FIT Positive Rate of 3.5 to 8.1% (decreases with increasing threshold value 50-200 ng/ml) vs 2.8% Guaiacthreshold value 50-200 ng/ml) vs 2.8% Guaiac

More patients referred to colonoscopy at every threshold More patients referred to colonoscopy at every threshold with FIT vs Guaiacwith FIT vs Guaiac

Detection rates greater for FIT 2-3.1% vs Guaiac 1.2% for Detection rates greater for FIT 2-3.1% vs Guaiac 1.2% for significant lesionssignificant lesions

PPV greater for FIT: 62% vs 45% (FIT=75ng/ml)PPV greater for FIT: 62% vs 45% (FIT=75ng/ml)

Inferior specificity for FIT: 92.9 vs 97.6%Inferior specificity for FIT: 92.9 vs 97.6%

FIT Positive Rate of 3.5 to 8.1% (decreases with increasing FIT Positive Rate of 3.5 to 8.1% (decreases with increasing threshold value 50-200 ng/ml) vs 2.8% Guaiacthreshold value 50-200 ng/ml) vs 2.8% Guaiac

More patients referred to colonoscopy at every threshold More patients referred to colonoscopy at every threshold with FIT vs Guaiacwith FIT vs Guaiac

Detection rates greater for FIT 2-3.1% vs Guaiac 1.2% for Detection rates greater for FIT 2-3.1% vs Guaiac 1.2% for significant lesionssignificant lesions

PPV greater for FIT: 62% vs 45% (FIT=75ng/ml)PPV greater for FIT: 62% vs 45% (FIT=75ng/ml)

Inferior specificity for FIT: 92.9 vs 97.6%Inferior specificity for FIT: 92.9 vs 97.6%

vanRoon, 2011

FIT performanceFIT performanceFIT performanceFIT performance

Participants (50-75 years) in an invitational primary Participants (50-75 years) in an invitational primary colonoscopy screening program were asked to complete colonoscopy screening program were asked to complete one sample FIT before colonoscopyone sample FIT before colonoscopy

A total of 1,256 participants underwent a FIT and screening A total of 1,256 participants underwent a FIT and screening colonoscopycolonoscopy

The positive and negative predictive values for FIT50 were The positive and negative predictive values for FIT50 were 6% (95% CI: 3-12) and almost 100% (95% CI: 99-100) for 6% (95% CI: 3-12) and almost 100% (95% CI: 99-100) for CRCCRC, and 37% (95% CI: 29-46) and 93% (95% CI: 92-95) , and 37% (95% CI: 29-46) and 93% (95% CI: 92-95) for advanced neoplasiafor advanced neoplasia

Participants (50-75 years) in an invitational primary Participants (50-75 years) in an invitational primary colonoscopy screening program were asked to complete colonoscopy screening program were asked to complete one sample FIT before colonoscopyone sample FIT before colonoscopy

A total of 1,256 participants underwent a FIT and screening A total of 1,256 participants underwent a FIT and screening colonoscopycolonoscopy

The positive and negative predictive values for FIT50 were The positive and negative predictive values for FIT50 were 6% (95% CI: 3-12) and almost 100% (95% CI: 99-100) for 6% (95% CI: 3-12) and almost 100% (95% CI: 99-100) for CRCCRC, and 37% (95% CI: 29-46) and 93% (95% CI: 92-95) , and 37% (95% CI: 29-46) and 93% (95% CI: 92-95) for advanced neoplasiafor advanced neoplasia

de Wijkerslooth , AJG, 2012

N = 19 studiesN = 19 studies

Pooled sensitivity, specificity, (+) and (-) likelihood ratio of FITs Pooled sensitivity, specificity, (+) and (-) likelihood ratio of FITs for CRC were 0.79 (95% CI, for CRC were 0.79 (95% CI, 0.69 to 0.86), 0.94 (CI, 0.92 to 0.69 to 0.86), 0.94 (CI, 0.92 to 0.95), 13.10 (CI, 10.49 to 16.35),0.95), 13.10 (CI, 10.49 to 16.35), 0.23 (CI, 0.15 to 0.33); 0.23 (CI, 0.15 to 0.33); diagnostic accuracy of 95% (CI, 93% to 97%)diagnostic accuracy of 95% (CI, 93% to 97%)

Lower thresholds yielded highest sensitivities Lower thresholds yielded highest sensitivities (for example, (for example, 0.89 [CI, 0.80 to 0.95] at a cutoff value less than 20 mcg/g vs. 0.89 [CI, 0.80 to 0.95] at a cutoff value less than 20 mcg/g vs. 0.70 [CI, 0.55 to 0.81] at cutoff values of 20 to 50 mcg/g) but 0.70 [CI, 0.55 to 0.81] at cutoff values of 20 to 50 mcg/g) but with a corresponding decrease in specificity.with a corresponding decrease in specificity.

A single-sample FIT had similar sensitivity and specificity as A single-sample FIT had similar sensitivity and specificity as several samples, independent of FIT brandseveral samples, independent of FIT brand

N = 19 studiesN = 19 studies

Pooled sensitivity, specificity, (+) and (-) likelihood ratio of FITs Pooled sensitivity, specificity, (+) and (-) likelihood ratio of FITs for CRC were 0.79 (95% CI, for CRC were 0.79 (95% CI, 0.69 to 0.86), 0.94 (CI, 0.92 to 0.69 to 0.86), 0.94 (CI, 0.92 to 0.95), 13.10 (CI, 10.49 to 16.35),0.95), 13.10 (CI, 10.49 to 16.35), 0.23 (CI, 0.15 to 0.33); 0.23 (CI, 0.15 to 0.33); diagnostic accuracy of 95% (CI, 93% to 97%)diagnostic accuracy of 95% (CI, 93% to 97%)

Lower thresholds yielded highest sensitivities Lower thresholds yielded highest sensitivities (for example, (for example, 0.89 [CI, 0.80 to 0.95] at a cutoff value less than 20 mcg/g vs. 0.89 [CI, 0.80 to 0.95] at a cutoff value less than 20 mcg/g vs. 0.70 [CI, 0.55 to 0.81] at cutoff values of 20 to 50 mcg/g) but 0.70 [CI, 0.55 to 0.81] at cutoff values of 20 to 50 mcg/g) but with a corresponding decrease in specificity.with a corresponding decrease in specificity.

A single-sample FIT had similar sensitivity and specificity as A single-sample FIT had similar sensitivity and specificity as several samples, independent of FIT brandseveral samples, independent of FIT brand

Lee, AIM, 2014

FLEXIBLE SIGMOIDOSCOPYFLEXIBLE SIGMOIDOSCOPYFLEXIBLE SIGMOIDOSCOPYFLEXIBLE SIGMOIDOSCOPY

www.edoctor.co.in

image.healthhaven.com

Flex sig meta-analysis

Littlejohn, Br J Surg, 2012

www.flickr.com

COLONOSCOPYCOLONOSCOPYCOLONOSCOPYCOLONOSCOPY

image.healthhaven.com

db2.photoresearchers.comwww.tcnj.edu

Long-Term Colorectal-Cancer Incidence and Mortality after Lower Endoscopy

Association of lower endoscopy (1998-2008) with colorectal-cancer incidence (2010) and mortality (2012) among participants in the Nurses’ Health Study and the Health Professionals Follow-up Study

88,902 participants over 22 years, 1815 incident colorectal cancers and 474 deaths from colorectal cancer

Nishihara, NEJM, 2013

Long-Term Colorectal-Cancer Incidence and Mortality after Lower Endoscopy

Nishihara, NEJM, 2013

Adenoma Detection Rate (ADR)and Risk of Colorectal Cancer and

Death

314,872 colonoscopies performed by 136 GIs w ADRs: Jan 1998 - December 2010; f-u of at least 6 mos

712 interval colorectal adenocarcinomas, including 255 advanced-stage cancers, and 147 deaths from interval colorectal cancer

Corley, NEJM, 2014

ADR and CRC

Corley, NEJM, 2014

Each 1.0% increase in ADR

associated with 3% decrease in cancer

risk(HR=0.97;

95%CI 0.96 to 0.98)

Colonoscopy vs FIT screening RCTColonoscopy vs FIT screening RCTColonoscopy vs FIT screening RCTColonoscopy vs FIT screening RCT

First of 5 RCTs of colonoscopy, 4 population-based

Higher adherence in FIT than colonoscopy (34.2% vs. 24.6%, P<0.001)Higher adherence in FIT than colonoscopy (34.2% vs. 24.6%, P<0.001)

Quintero, NEJM, 2012

CT COLOGRAPHY (virtual colonoscopy)CT COLOGRAPHY (virtual colonoscopy)CT COLOGRAPHY (virtual colonoscopy)CT COLOGRAPHY (virtual colonoscopy)

www.agfahealthcare.com

www.ultimatehealthguide.com

www.ebook3000.comlsgimaging.com

Average sensitivity and specificity of Average sensitivity and specificity of screening methodsscreening methodsAverage sensitivity and specificity of Average sensitivity and specificity of screening methodsscreening methods

Allameh et al. Iran J Cancer Prev. 2011

Systematic review included: •20 studies for colonoscopy•12 studies for sigmoidoscopy•26 studies for Barium enema•62 studies for CT colonography

Virtual colonoscopy

Not recommended for screening: - lack of data - risk of irradiation - downstream implications of incidentalomas - unfavorable cost-effectiveness

Alternative diagnostic strategies: Fecal DNA

Noninvasive, multitarget stool DNA test (KRAS mutations, aberrant NDRG4 and BMP3 methylation, and β-actin, plus a hemoglobin immunoassay) vs FIT (100ng/ml) in persons at average risk for CRC

n=9989, with 65 (0.7%) CRC and 757 (7.6%) advanced precancerous lesions (advanced adenomas or sessile serrated polyps measuring ≥1 cm in the greatest dimension) on colonoscopy

Sensitivity for CRC: 92.3% DNA testing vs 73.8% FIT (P = 0.002)

Imperiale, NEJM, 2014

Alternative diagnostic strategies: Fecal DNA

Sensitivity for advanced precancerous lesions 42.4% DNA testing vs 23.8% FIT (P<0.001)

Polyps with high-grade dysplasia was 69.2% with DNA testing vs 46.2% with FIT (P = 0.004)

Serrated sessile polyps>1cm: 42.4% vs 5.1%, (P<0.001)

Specificities 86.6% and 94.9%, respectively, among participants with nonadvanced or negative findings (P<0.001) and 89.8% and 96.4%, respectively, among those with negative results on colonoscopy (P<0.001)

NN screen to detect one cancer: 154 with colonoscopy, 166 with DNA testing, and 208 with FIT

Imperiale, NEJM, 2014

COLONIC WIRELESS CAPSULE COLONIC WIRELESS CAPSULE ENDOSCOPY ENDOSCOPY COLONIC WIRELESS CAPSULE COLONIC WIRELESS CAPSULE ENDOSCOPY ENDOSCOPY

www.endoatlas.com

www.endoatlas.commygeorgetownmd.org

www.vcharkarn.com

www.umm.edu www.bgapc.com

The colonic capsule

Spada, CGH, 2010

The role of patient preference?The role of patient preference?The role of patient preference?The role of patient preference?

Systematic review of colonoscopy vs CTC patient Systematic review of colonoscopy vs CTC patient preference showed that preference showed that most included studies reported most included studies reported preference for CTCpreference for CTC

Screening patients preferred CTC while diagnostic patients Screening patients preferred CTC while diagnostic patients showed no preferenceshowed no preference

With comprehensive information, colonoscopy and CTC With comprehensive information, colonoscopy and CTC were seen as having different advantages and were seen as having different advantages and disadvantages, disadvantages, yielding no clear preferences between yielding no clear preferences between the twothe two

Lin, J Gen Int Med, 2012; Ghanouni, Patient Educ Counsel, 2012

AN OVERALL ACCURACY OF

76%!

Altomare, Br J Surg, 2013

CONCLUSIONCONCLUSION

Any CRC screening better than noneAny CRC screening better than none

Many efficacious detection techniques for CRCMany efficacious detection techniques for CRC

Limitations:Limitations: FFeasibility (Flex sig, colonoscopy, low FIT thresholds)easibility (Flex sig, colonoscopy, low FIT thresholds) Morbidity (quality is key for efficacy and safety)Morbidity (quality is key for efficacy and safety) Technology (?CT colography, colonic WCE, ?Volatile organic compounds Technology (?CT colography, colonic WCE, ?Volatile organic compounds

detection)detection) Costs (CT colography, fecal DNA)Costs (CT colography, fecal DNA)

Most population-based programs remain FOBT-basedMost population-based programs remain FOBT-based

Colonoscopy (and CT colography) remain very popular for Colonoscopy (and CT colography) remain very popular for opportunistic screeningopportunistic screening

Need for additional head-to-head testing with adequate Need for additional head-to-head testing with adequate follow-upfollow-up

Consider “enhanced” detection methodsConsider “enhanced” detection methods

A quality colonoscopy is key!A quality colonoscopy is key!

?Down the road: A menu of available testing ?Down the road: A menu of available testing alternatives/combination thereof tailored to the patients alternatives/combination thereof tailored to the patients

risks and preference profiles?risks and preference profiles?

CONCLUSIONCONCLUSION