Epidemiology of

Colorectal Cancer and

Overview of Screening Modalities

Ala Sharara, M.D., FACG, AGAFProfessor & Head, Division of Gastroenterology

American University of Beirut Medical Center, Lebanon

Which of the following is best suited for population-based screening for CRC?

1. Colonoscopy

2. CT colonography

3. Videocapsule colonoscopy

4. Stool guaiac test

5. Fecal DNA test

6. Fecal immunochemical test (FIT)

Question

Age-Adjusted Cancer Death Rates, *Males by Site, US, 1930-2002

Age-Adjusted Cancer Death Rates, *Females by Site, US, 1930-2002

0

Age

Ra

te p

er

10

0,0

00

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

100

200

300

400

500

Incidence of Colon Cancer

Data from Surveillance, Epidemiology, and End Results (SEER) Program, 1973-1992.

Life-time risk

~5-6%

50-60%

Sporadic

colon cancer

1%

Genetic

polyposis

3-5%

Non-polyposis

syndromes

30-40%

Familial colon cancer

Incidence of Types of Colon Cancer

About 10% of the

population aged

30–70 has at least

one first-degree

relative with CRC

de Jong AE, Vasen HF. Neth J Med 2006; 64(10):367-70.

Mitchell RJ, et al. Br J Surg. 2005; 92(9):1161-4.

General

Population

1 FDR(>60y) 1 FDR(<60y) 2 FDR 2 SDR 1 SDR 1 FDR with

adenomatous polyp

0

55

1010

1515

2020

Pro

ba

bili

ty (

%)

FDR: First degree relative

SDR: Second degree relative

Family History & Colon Cancer

Burt RW. Gastroenterology 2000;119:837-53

Johns LE, Houlston RS. Am J Gastroenterol 2001;96:2992-3003

Colorectal Cancer Risk Factors

Age

Gender

Race/Ethnicity

Personal history of IBD, adenomatous polyps or colon cancer

Family history of adenomatous polyps, colon cancer and genetic syndromes

Other Risk Factors

Diet (red or processed meat RR 1.2)

DM & insulin resistance (RR 1.3)*

Acromegaly

Renal transplantation

Smoking, heavy alcohol use

*Larsson, SC, Orsini, N, Wok, A. J Natl Cancer Ist 2005; 97:1679.

*Chiou HM. Clin Gastroenterol Hepatol 2007;5:221–229.

Theodoros R et al. World J Gastroenterol 2008 June 14; 14(22): 3484-3489.

Webster et al. Am J Transplant. 2007;7(9):2140

0

Age

Ra

te p

er

10

0,0

00

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

100

200

300

400

500

Incidence of Colon Cancer

Data from Surveillance, Epidemiology, and End Results (SEER) Program, 1973-1992.

Life-time risk

~5-6%

The Ideal Screening Test

• Safe

• Widely available

• High sensitivity & specificity

• Acceptable to Population

• Cheap

• Cost-effective

Need a Simple & Safe Test suitable for

Population Screening

• NOT…

- Selective… what you can afford!

- ad hoc…enthusiastic ‘GPs’ or ‘motivated patients’

- at risk… family history, predisposing disease

- symptomatic… blood in stool, etc.

• Everyone within a selected age group

Screening for Colon Cancer

• Fecal occult blood testing

• Barium enema

• Fecal DNA testing

• Flexible sigmoidoscopy

• Colonoscopy

• CT colonography

• Others

Sensitivity of ACBE is 48%*

*Rockey DC et al. Lancet 2005;365:305-11.

Guaiac-Based Fecal Occult

Blood Testing

• Cheap & simple

• Widely available

• Sensitivity 30-50%

• PPV 3-10%

• Yearly FOBT – ↓ CRC deaths by 33%*

– After 30 years still 32%**

• Biennial FOBT:– Both 13* and 30** years about 22%

Turnip

horseradish

Human or

animal blood

Vitamin C

X

*Mandel JS, et al. N Engl J Med 1993;328:1365-71.

**Nishihara et al. N Engl J Med 2013;369:1095-1105.

Guaiac – Fecal Occult Blood Test

England’s Program 2 yearly (2006-April 2013)

60-74 year olds invited

Test Kits Out 20.0 million

Test Kits In 11.6 million

+ve Screens 214,000

Colonoscopies 210,000

Cancers 17,114 (PPV 8.2%)

Advanced Adenomas 19,384Early cancer

detection

Cancer

Prevention

Dukes

Stage

Symptomatic England

Screening

A 11% 36%

B 35% 40%

C 26% 20%

‘D’ 29% 4%

From Halloran S. UEGW 2013 PG Course

2

4

6

Me

an

Blo

od

Lo

ss (

ml/

da

y)

Polyp Size <10 mm 10-20 mm >20 mm

Overt bleeding

No overt bleeding

Mean Blood Loss from

Adenomatous Polyps

Macrae FA, et al. Gastroenterology 1982;82:981-8.

only 24% of patients

with advanced neoplasia

have a positive FOBTLieberman DA, et al. N Engl J Med 2000;343:162–168.

Guaiac Test vs. Fecal

Immunochemical Test (FIT)

Test Sensitivity (%)

Cancer Advanced Neoplasia

Standard gFOBT

(3 stool samples)

33-50 11

Sensitive gFOBT

(3 stool samples)

50-75 20-25

iFOBT (FIT)

(1 to 3 stool samples)

60-85 20-50

Lieberman DA. N Engl J Med 2009;361:1179-87

Study Cohort

Invited gFOBT

5004

FIT

5007

15,011

2,351

(49.5%)

2,979

(61.5%)Participation

65

(2.8%)

14

(0.5%)

6

(0.3%)

64

(47%)

34

(55)

143

(4.8%)

62

(95%)

137

(96%)

28

(1.2%)

73

(2.5%)

Positive test

Follow-Up

Examination

Advanced

Adenomas &

Cancers

Detected

Cancers

False

Positives

Study Cohort

Invited

Participation

Positive test

Follow-Up

Examination

Advanced

Adenomas &

Cancers

Detected

Cancers

False

Positives

20,623

gFOBT

10,301

FIT

10,322

6,157

(60%)

4,836

(47%)

339

(5.5%)

117

(2.4%)

103

(88%)

280

(83%)

57

(0.6%)

145

(1.4%)

24

(0.2%)

11

(0.1%)

135

(48%)

46

(45%)

L Hal et al. GUT

2010,59:62-68

Van Rossum et al

Gastroenterology

2008; 35: 82-90

Study relation OC Sensor FIT concentration

and outcome at colonoscopy

Outcome

No. of

Patient

Outcomes

Positive

gFOBT

Mean FIT Conc.

ng/ml

Positives at

75ng/ml

Cut-off

Positives at

100ng/ml

Cut-off

Normal 479 (62.2%) 35 (7.3%) 51 (5-100) 36 (7.5%) 35 (6.9%)

All

Adenoma219 (28.4%) 14 (6.5%) 69 (22-116) 24 (11.2%) 20 (9.3%)

Adv.

Adenoma 59 (7.7%) 8 (13.6%) 404 (183-624) 22 (37.3%) 20 (34.5%)

Cancer 13 (1.7%) 4 (30.8%) 846 (447-1262) 12 (92.3%) 11 (84.6%)

Hemoccult-II and OC-SENSA MICRO

From Halloran S. UEGW 2013 PG Course

Study relation OC Sensor FIT concentration

and outcome at colonoscopy

Endoscopic

Classification

No. of

Patient

Outcomes

Positive

gFOBT

Mean FIT

Conc. ng/ml

Positives at

75ng/ml

Cut-off

Positives

at 100

ng/ml

Cut-off

Histology

LGD 276 (99%) 21 (7.6%) 134 (75-194) 44 (15.9%) 39 (14.1%)

HGD 2 (0.7%) 1 (50.0%) 986 2 (100%) 1 (50.0%)

Size

< 10 mm 222 (80%) 15 (6.8%) 58 (9-224) 24 (10.8%) 20 (9.0%)

≥ 10 mm 56 (20%) 7 (12.5%) 493 (246-740) 22 (39.3%) 20 (36.4%)

Number

< 3 Adenoma 203 (73%) 18 (9.0%) 71 (23-118) 25 (12.6%) 20 (10.0%)

≥3 Adenoma 75 (27%) 4 (5.3%) 327 (144-510) 21 (28.4%) 20 (26.7%)

Hemoccult-II and OC-SENSA MICRO

Effect of Test Cut-off on Number needed to

Scope to detect CRC

0

2

4

6

8

10

12

14

16

18

50 75 100 125 150 175 200 225

Colorectal Cancer

Incr

ea

sin

g p

rop

ort

ion

of

fals

e +

ve

Cut-off threshold for Hemoglobin ng/ml

No

. o

f C

olo

no

sco

pie

s

Van Rossum L, et al. Br J Cancer 2009;100:259-165.

Dutch Recommendations

January 2010

Start January 2014

Biennial single-sample FIT testing:

for all 55-75 years old using 15ug/g cut-off

€2,200 per life-year gained

(€ 11,300 cervical screening )

FIT: What Cut-off & Sample Number?

• Is a one sample device screen adequate? Kuipers

• What ‘cut-off’ concentration is best (OC-Sensor)

– Netherland/ New Zealand (15ug/g) Kuipers/ Rossum

– Italy (20ug/g) Zappa Zorzi

– Scotland Study (80ug/g) Fraser, Steele

– England Surveillance Study (50ug/g) Atkin/ Halloran

• Different FIT sensitivity for men and women

McDonald PJ. Clin Chem Lab Med 2012:50(5).

• Adjust positively to meet colonoscopy resource

Droste. Neth J Med 2006;64(10):371-373.

From Halloran S. UEGW 2013 PG Course

Preliminary evidence of FIT

reducing CRC incidence

• Organised biennial single FIT screening program

in Florence

• Initial screen during 1993-99

• 26,285 unscreened and 6,961 screened

• Average follow-up period 11 years

• 56 cancers prevented for every 10,000 screened

• 22% reduction of colorectal cancer incidence

Ventura L, Mantellini P, Grazzini G: The effect of introduction of immunochemical faecal occult blood testing on colorectal cancer incidence. International Cancer Screening Network Biennial Meeting, Sydney

Australia. October 23-25, 2012.

Screening Colonoscopy

Aim: Interrupt the Adenoma-Carcinoma sequence

40 50 60 70 80

10

20

30

40

50

60

Age

Pe

rce

nt

Prevalence of Adenomatous Polyps

Williams AR, et al. Gut 1982; 123:835-42.

• Three large studies (Veterans Affairs CSP-380 study1,

Women study2, Polish study3)

• End-point: prevalence of advanced neoplasia

(adenomas ≥ 10 mm, villous histology, high-grade

dysplasia, CIS, or invasive cancer)

• All 3 studies did not exclude individuals with FH of

CRC or adenomatous polyps

1Lieberman DA, et al. N Engl J Med 2000;343:162–168.2Schoenfeld P, et al. N Engl J Med 2005;352:2061–8.

3Regula J, et al. N Engl J Med 2006;355:1863-72.

Advanced Neoplasia

Prevalence

4.9% to 10.5%1-3

1Lieberman DA, et al. N Engl J Med 2000;343:162–168.2Schoenfeld P, et al. N Engl J Med 2005;352:2061–8.

3Regula J, et al. N Engl J Med 2006;355:1863-72.

0

40-49

50-54

55-59

60-66

Ag

e (

yr)

Number Needed to Screen (95% Cl)

5 10 15 20 25 30 35 40 45

10 (9-11) 18 (17-20)

12 (11-13) 22 (20-25)

17 (15-19)

23 (19-27)

28 (26-32)

36 (31-44)

Men

Women

Advanced Neoplasia on Screening

Compliance

% C

an

cers

Pre

ve

nte

d

75%100% 50%

20

40

60

80

100

Lieberman DA. Gastroenterology 1995;109:1781-1790.

Efficacy of Screening Programs

FOBT

FS

FOBT/FS

Colonoscopy

FS = flexible sigmoidoscopy

Cost Effectiveness

• CRC screening is cost-effective or even cost-saving

when compared with no screening

• Is colonoscopy the most cost-effective?

The costs of CRC screening per added year of life

is comparable to that of hypertension screening & less

than that of mammography & cholesterol testing

Lieberman DA, Atkin W. Aliment Pharmacol Ther 2004;19:71-6.

Colonoscopic Polypectomy

and Prevention of CRC Deaths

Zauber AG, et al. N Engl J Med 2012;366:687-96

Test Sensitivity (%) Specificity (%)

Cancer Advanced Neoplasia

Old stool DNA test

(1 stool sample)

51 18

93-97New stool DNA test

(1 stool sample)

>80 40

Imperiale TF, et al. N Engl J Med 2004;351:2704-14.

Ahlquist DA, et al. Ann Intern Med 2008;149:441-50.

Allison JE, et al. J Natl Cancer Inst 2007;99:1462-70.

Itzkowitz SH, et al. Clin Gastroenterol Hepatol 2007;5:111-7.

Fecal DNA Testing

Meta-analysis: summary sensitivities

Mulhall BP, et al. Ann Int Med 2005;142:635-50.

*Sonnenberg A, et al. Am J Gastroenterol 1999;94:2268-74

CT Colonography Trials

Markov CE analysis: CTC $24,586 per life-year saved

vs. $20,930 for colonoscopy*

Size < 6 mm 6-9 mm > 9 mm

Sensitivity

(range)

0.48

(14-86)

0.70

(30-95)

0.85

(48-100)

Colon Capsule Endoscopy

A colon capsule for colorectal cancer

screening is in clinical trials in

Europe, but its role is still uncertain

Bowel preparation is required prior to the

examination

Patients with lesions detected during the

examination typically require subsequent

colonoscopy

Significant Polyp Any Polyp

Sensitivity 69% 73%

Specificity 86% 89%

Rokkas T, et al. Gastrointest Endosc 2010;71:792-8.

Polyps >6mm Polyps >10mm

Sensitivity 84% 88%

Specificity 88% 95%

Colon Capsule Endoscopy

First Generation

Second Generation

Spada C, et al. Gastrointest Endosc 2011;74:581-9.

Study Design Results

Van Gossum et

al. 2009

PillCam Colon

(n=328)

8 European sites

• Polyps ≥ 6mm: Sens (64%), Spec (84%)

• Adv. Adenoma: Sens (73%), Spec (79%)

• Cancer: 14 out of 19 (sens = 74%)

Sachet-Huvelin

et al. 2010

PillCam Colon (n=545)

multicenter France

• Polyps ≥ 6mm:

Sens (39%), Spec (88%), PPV (47%), NPV (85%)

• Cancer: detected 3 of 5 CRC

Eliakim et al.

2009

PillCam Colon 2 (n=98) Polyps ≥ 6mm:

Sensitivity=89%

Specificity=76%

Polyps ≥ 10mm:

Sensitivity=88%

Specificity=89%

Spada et al.

2011

PillCam Colon 2

(n=117)

8 European sites

Polyps ≥ 6mm:

Sens = 84%

Spec = 64%

Polyps ≥ 10mm:

Sens = 88%

Spec = 95%

CCE compared to Colonoscopy

Van Gossum, et al. N Engl J Med 2009;361:264-70

Sachet-Huvelin, et al. Aliment Pharmacol Ther 2010; 32: 1145–1153

Eliakim R, et al. Endoscopy 2009; 41(12): 1026-1031

Spada C, et al. Gastrointest Endosc 2011;74:581-9

Epidemiology of Colorectal

Cancer in Lebanon

Colorectal Cancer in Lebanon

• CRC is the second most commonly reported

cancer in females and the fourth most

commonly reported cancer in males in

Lebanon in 2012

• CRC is diagnosed in an average of 630

individuals annually in Lebanon

• No vital statistics or information about burden

of disease in terms of morbidity & mortality

Shamseddine A et al. Middle East Journal of Cancer 2010; 1(1): 41-44.

The ASR for colon

cancer:

1998:

8.71/100,000

2007:

15.28/100,000

The ASR for colon

cancer:

1998:

8.87/100,000

2007:

10.29/100,000

Time-Trend for CRC in Lebanon

ASR= age-standardized rate

Colorectal Cancer in Lebanon

• There is no national CRC screening strategy or

education awareness program

• Screening with fecal occult blood testing is

rarely practiced

• Gastroenterologists recommend and perform

screening colonoscopy on an erratic and

opportunistic basis

Screening Colonoscopy Studies

Study

(Country)

Journal Number Adenomas Advanced

Neoplasia

Positive FH

Lieberman et al.

(USA)

NEJM 2000 3,196

96.8% ♂

37.5% 10.5% 13.9%

Schoenfeld et al

(USA)

NEJM 2005 1,463 ♀ 20.4% 4.9% 15.7%

Regula et al.

(Poland)

NEJM 2006 43,042Age 50-66

14.9% 5.9% 13.3%

Kim et al.

(USA)

NEJM 2007 6,283CTC vs. OC

study

• Not reported per

patient

• Polyps <6mm on

CTC not evaluated

3.3% ?

Only

HNPCC/FAP

excluded

Study

(Country)

Journal Number Adenomas Advanced

Neoplasia

Comments

Rex et al.

(USA)

GIE 2000 121 35% 4.8% African Americans

Scott et al.

(Australia)

AJG 2005 184 Unclear from

report

8.7% FH of 1st degree

relative excluded

Chiu et al.

(China)

GIE 2005 1741 15.4% 3.0% FH of 1st degree

relative excluded

Strul et al.

(Israel)

AJG 2006 994 21.3% 6.7% Retrospective

Graser et al.

(Germany)

Gut 2009 311 36.8%

CTC (+3%)

9.6% One 1°<60 or two 1°

at any age excluded

Screening Colonoscopy in True Average Risk

SCREENING COLONOSCOPY IN

AVERAGE-RISK ADULTS IN LEBANON

• Patients with ANY known family history of CRC or

large adenomas were EXCLUDED

• Potential risk and protective factors for developing

adenomatous polyps & advanced neoplasia

• Withdrawal time & adenoma detection recorded

• 1000 patients enrolled

• Complete data analysis on 980 patients

All Adenomas= 42.8%

Advanced Neoplasia = 5.1%

Cancer = 0.8%

0%

10%

20%

30%

40%

50%6.5 %

3.8%

45.5 %30.1 %

RESULTS (n=980)

Mean age = 61.1 y

n = 249 (51.9%)*Mean age = 60.6 y

n = 170 (33.9 %)

Pre

va

len

ce o

f A

de

no

ma

s

Male (n=479) Female (n=501)

▀ Advanced Neoplasia

▀ Adenomas

•Sharara AI, et al. Gastroenterology 2013 (Abstract)

0

10

20

30

40

50

60

70

50-54 55-59 60-64 65-69 70-74 >75

Female Male

Pe

rce

nt

(%)

Age group (years)

Prevalence of Adenomasby Age and Gender

0

2

4

6

8

10

12

50-54 55-59 60-64 65-69 70-74 >75

Female Male

Pe

rce

nt

(%)

Age group (years)

Prevalence of Advanced Neoplasiaby Age and Gender

Number Needed To Screen to Identify

Adenomas &/or Advanced Neoplasia

Adenomas

(95% CI)

Advanced Neoplasia

(95% CI)

Total population 2.7

(2.5-2.9)

18.2

(14.4-24.8)

50-59yo 3.3

(3.0-3.6)

24

(19-36.4)

60-69yo 2.3

(2.2-2.9)

14.1

(11.5-18.3)

≥70yo 2.1

(1.9-2.2)

14.9

12.1-19.6

Characteristics β ± S.E. p-value Odds RatioAge (years) 0.035 ± 0.018 0.048 1.036 (1–1.073)

BMI 0.018

Overweight 0.794 ± 0.417 0.057 2.211 (0.978–5.003)

Obese 1.265 ± 0.447 0.005 3.544 (1.475–8.514)

Smoking status 0.002

<40 pack-years 0.697 ± 0.353 0.048 2.01 (1.01–4.01)

≥40 pack-years 1.376 ± 0.385 0 3.96 (1.86–8.42)

Daily red meat 0.702 ± 0.4 0.079 2.017 (0.921–4.419)

Multivariate Logistic Regression Model

Predicting the Risk of Advanced Neoplasia

•Sharara AI, et al. Gastroenterology 2013 (Abstract)

Model for Predicting Advanced Neoplasia

according to Risk Factors against BMI

•Sharara AI, et al. Gastroenterology 2013 (Abstract)

65

68 170

0

0

x

2.0

65

74 170

1

20

x

14.

0

65

84 155

1

40

x

41.

5

AUC=0.722

Accuracy of Model for Predicting

Advanced Neoplasia

•Sharara AI, et al. Gastroenterology 2013 (Abstract)

Average Risk

Age 50-70

Average Risk

Score

Multivariate Colon Cancer

Risk Score(Age, BMI, Smoking, Red meat)

High Risk

Score

Annual or biennial FIT

(cut off TBD)

Stop at age 70Positive FIT

Colonoscopy

Surveillance according to

existing guidelines

High Risk

(positive FH)

Proposed Algorithm

Colorectal Cancer in Lebanon

• CRC is common in Lebanon and appears

associated with a significant burden

• The prevalence of colon adenomas and

advanced neoplasia is similar to rates published

in Europe and North America

• Risk factors may help stratify risk, chief amongst

these are BMI and heavy smoking

• A national screening strategy is a priority

No National Program for Colorectal

Cancer Screening