Screening and
chemoprevention of CRC
Yaron Niv, M.D.
Rabin Medical Center
Tel-Aviv University
Primary Vs. Secondary
Prevention
Western Diet (fat, bief)
Increased transit time
Carcinogen (DMH)
Promotor (cholate, cholecystectomy)
Bran
Decreased transit time
Calcium, vitamin D
Selenium
NSAID, aspirin
Coxibs
Proliferation
Differentiation
Apoptosis
Polyp to Cancer
Secondary prevention
Polypectomy
Colorectal Cancer
Screening Guide-lines
For those at average risk (choosing from the
following):
 Annual FOBT
 A sigmoidoscopy every 5 years
 A combination of FOBT and sigmoidoscopy
 A colonoscopy every 10 years or once in a
life-time
For those at increased risk: a colonoscopy
FOBT
Published FOBT Prospective,
Randomized, Controlled Studies
Series
Minnesota
Funen Nottingham Gothenburg
Biennial Annual Biennial Biennial
2 screens
13 y
38%
10 y
4%
8y
4%
8y
7%
Mortality reduction
21% 33%
18%
15%
12%
Period
Colono
13 y
28%
Screening for CRC - FOBT
Israel 1985-1998
Average Risk Population
Series
Slater
Bat
Rozen
85
86
87
92
Eliakim 88
Krieger 92
Niv
92
Total
A
n
mail, FP 3233
FP
1339
volunteers 1176
volunteers 2868
mail
20251
FP
1057
FP
2590
32514
C(%)
P(%)
17-42
46
100
100
35
100
71
46
4.6
2.3
3.6
4.0
2.0
1.9
4.0
2.9
NL
9 0.28%
4 0.30%
10 4.19%
69 2.41%
50 0.25%
0 0.00%
34 1.32%
176 0.54%
A=approach C=compliance P=positive NL=neoplastic lesion
Survival Curve
Screening of Colorectal Cancer
Percentage of the Population
100.5
100
99.5
99
98.5
Screened
98
Refusers
97.5
Controls
97
88
89
90
91
92
93
94
95 Year
Sigmoidoscopy
Screening Sigmoidoscopy
Reduced Rectal Cancer
Mortality
Direct evidence from 3 case
control studies:
 Selby, NEJM 1992;326:653
- 59%
 Newcomb, JNCI 1992;84:1572
- 80%
 Muller, Arch Intern Med
1995;155:1741
- 60%
10 years
protection
Screening FS in Israel
(decrease in incidence 1982-1998, 16 to 10/100000)
Series
year
n
Compliance
(%)
Kiriat Uno (Bat)
1986
600
48
28 (4.7%)
Tel Aviv (Rozen)
1987
1176
100
45 (3.8%)
Beer Sheva (Niv)
1992
529
14
42 (7.9%)
Dimona (Niv & Fraser)
1996
420
95
24 (5.7%)
Shouval & Nirim (Fraser & Niv)
1996
446
51
8 (1.8%)
Hagoshrim (Niv)
1998
200
50
8 (4.0%)
Chazor (Ilani, Pade & Niv)
1999
100
10
4 (4.0%)
Beilinson (Niv)
2000
118
10
16(13.5%)
3589
47
175 (4.9%)
Total
Neoplastic
lesion
Screening for CRC - Comparison of FS and
FOBT, Israel 1982-1998, Average Risk
Population (FOBT 7,FS 5 papers)
Method
N Compliance Adenoma
CRC
%
n
%
n
%
FOBT 32514 <46
141 0.44 40 0.12
Sigmo
3171
47
132 4.16 15 0.47
Total
35685
273 0.77 55 0.15
--------------------------------------------------------------S/F
1/10
x 10
x4
Colonoscopy
Screening Colonoscopy in the Average
Risk Population






Visualization of the entire colon,
biopsy and removal of all polyps
Proximal distribution of colonic
neoplasm
Positive FOBT or sigmoidoscopy
lead to total colonoscopy
FOBT alone may prevent fewer
cancer deaths than colonoscopy
Effectiveness: 80% compliance by
FOBT = 50% to colonoscopy
Once in a lifetime colonoscopy may
be preferred (cost < $750)
National polyp study
1978-1993


A cohort of >1400 patients who had
undergone colonoscopy and removal of
adenomas was followed by colonoscopy for a
mean of 5.9 years.
70%-90% reduction was found in the
incidence of colorectal cancers relative to
what was expected based on 3 different
historical control groups.
Winawer, N Engl J Med 1993;329:1977
Preventive Effect of
Colonoscopy
5-year incidence of adenomas after negative
colonoscopy in asymptomatic averagerisk persons
154 repeated colonoscopies (median 66m),
41 (27%) patients with adenoma,
only one > 1 cm, no cancer!
Rex, Gastroenterology 1996; 111:1178-81
Screening Colonoscopy in the Average
Risk Population






Visualization of the entire colon,
removal of all polyps
Rising proximal distribution of
colonic neoplasm
Positive FOBT or sigmoidoscopy
lead to total colonoscopy
FOBT alone may prevent fewer
cancer deaths than colonoscopy
Effectiveness: 80% compliance by
FOBT = 50% to colonoscopy
Once in a lifetime colonoscopy may
be preferred (cost < $750)
70%
50%
Screening CRC - Distribution
McCallion, Distribution of CRC in Northern
Ireland:
A 10% proximal shift, and 10% decrease in
FS diagnostic yield (1976-1994).
76-78
90-94
FS
72%
62%
A distal significant polyp may
predict a proximal lesion
Advanced Proximal Neoplasm (APN) (size,
histology, no.)
Source
distal
APN
 NEJM 92, GE 94
TA<1cm
0.8%
TA>1cm
11.8%
 NEJM 97
TA<1cm
16.0%
TA>1cm
29.0%
 Ann Int Med 98
TA<1cm
5.4%
TA>1cm
7.9%
 JAMA 99
Tubular
4.8%
Villous
11.7%
Factors associated with an
increased risk of APN
Levin, JAMA 1999;281:1611
Lieberman, N Engl J Med 2000;343:162
Imperiale, N Engl J Med 2000;343:169





Age > 65 years
Villous histology in
distal adenoma
Distal adenoma > 1cm
Multiple distal
adenomas
Positive family history
of CRC
Screening Colonoscopy in the Average
Risk Population






Visualization of the entire colon,
removal of all polyps
Proximal distribution of colonic
neoplasm
Positive FOBT or sigmoidoscopy
lead to total colonoscopy
FOBT alone may prevent fewer
cancer deaths than colonoscopy
Effectiveness: 80% compliance by
FOBT = 50% to colonoscopy
Once in a lifetime colonoscopy may
be preferred (cost < $750)
Published FOBT Prospective,
Randomized, Controlled Studies
Series
Period
Colono
Minnesota
Funen Nottingham Gothenburg
Biennial Annual Biennial Biennial
2 screens
13 y
28%
13 y
38%
Mortality reduction
21%
33%
10 y
4%
18%
8y
4%
15%
8y
7%
12%
Screening Colonoscopy in the Average
Risk Population






Visualization of the entire colon,
removal of all polyps
Proximal distribution of colonic
neoplasms
Positive FOBT or sigmoidoscopy
lead to total colonoscopy
FOBT alone may prevent fewer
cancer deaths than colonoscopy
Effectiveness: 80% compliance by
FOBT = 50% to colonoscopy
Once in a lifetime colonoscopy may
be preferred (cost < $750)
Positivity Rates of FOBT (%)
St John, DDW, 1998; Rozen, Dig Dis Sci
1997.
FOBT - The Importance of Proper
Evaluation
Niv Y, JCG 1990;12:393
Kibbutz A Kibbutz B




Population
> 40 y
FOBT +
Adenomas>1cm
700
223
33(25%)
2( 6%)
P
750
173
8( 6%) <0.01
2(25%) <0.05
Simulation Model - Winawer
Population of 100,000 - 4988 CRC
cases, 2391 deaths expected
Cases
reduction
Annual FOBT
Deaths
Complication
reduction
deaths
2378(48%)
1330(56%)
52
Colonoscopy every 10 y
3570(72%)
1763(74%)
73
433
21
Screening Colonoscopy in the Average
Risk Population






Visualization of the entire colon,
removal of all polyps
Proximal distribution of colonic
neoplasms
Positive FOBT or sigmoidoscopy
lead to total colonoscopy
FOBT alone may prevent fewer
cancer deaths than colonoscopy
Compliance has a direct effect on
detection rate
Once in a lifetime colonoscopy may
be preferred (cost < $750)
Compliance is the single most
important determinant of effectiveness
Lieberman, Gastroenterology 1995;109:1781.
For the same decrease in mortality:
FOBT 80% =
= FOBT + FlEX. SIG. 60% =
= COLONOSCOPY 50%
Screening Colonoscopy in the Average
Risk Population






Visualization of the entire colon,
removal of all polyps
Proximal distribution of colonic
neoplasms
Positive FOBT or sigmoidoscopy
lead to total colonoscopy
FOBT alone may prevent fewer
cancer deaths than colonoscopy
Compliance has a direct effect on
detection rate
Once in a lifetime colonoscopy may
be preferred (cost < $750)
Cost-effectiveness Model for Colon Cancer
Screening – Markov model –
Amnon Sonnenberg (Sheba 2002)
($ per year of life saved)
35,000
30,000
25,000
20,000
15,000
FOBT
Sigmoidoscopy
Colonoscopy
10,000
5,000
0
FOBT every year, Sigmo every 5 years, Colono once in a lifetime
Inappropriate CRC screening
Fisher, AJGE 2005;100:2526 (North Carolina)
500 consecutive primary care patients for
whom FOBT had been ordered
 35% - inappropriate (at least one reason)
 18% - severe co morbid illness
13% - GI bleeding
7% - history of CRC or IBD
5% - had undergone colonoscopy within
prior 5 years
3% - younger than 50 yr

‫‪Primary prevention‬‬
‫‪ ‬תזונה דלת שומן ועשירה בפירות‪ ,‬ירקות וסיבים‬
‫‪ ‬משקל תקין‬
‫‪ ‬המנעות מעישון ואלכוהול‬
‫‪ ‬תוספת סידן ‪ 1500‬מג' ליום‬
‫‪ ‬עדויות בלתי ישירות‪ :‬אספירין‪,NSAIDs ,‬‬
‫סלניום‪ ,‬חומצה פולית‪ ,‬ויטמין ‪D‬‬
Proliferation, Differentiation,
Apoptosis



High fat diet – soluble
fatty acids, bile acids –
colonic epithelium cell
damage – proliferation
Calcium precipitate
fatty and bile acids
Calcium decreases
cell proliferation and
induces differentiation
Chemoprevention – prevention
studies

Intermediate biomarkers –
1. Early – change in proliferation –
number of crypt-proliferating cells
and an upward shift of the
proliferative zone
2. Late - recurrence of adenomatous
polyps after polypectomy
Effect of a diet high in diary foods upon
proliferation (early marker)
Holt, JAMA 1998;280:1074




70 post polypectomy
patients
Group A – diet containing
1200mg Ca/day, Group B
– baseline diet
Rectal biopsy – 0,6,12
months – [3H]thymidine
incorporation into DNA,
differentiation markers
Significant lower
proliferation, higher
differentiation
100
Study
Control
10
1
Prol.
Diff.
Effect of calcium supplements on
recurrence of adenomas (late marker)
Baron, Ann NY Acad Sci 1999;889:138




930 post-polypectomy
patients
Group A – 1200mg
Ca/day, Group B –
placebo
Colonoscopy – 1y, 2y
19% decrease in
recurrent adenoma,
24% decrease in the
average number
50
45
40
35
30
25
20
15
10
5
0
Study
Control
Rec. rate Number