Screening and chemoprevention of CRC

1
Screening and chemoprevention of CRC

• Yaron Niv, M.D.
• Rabin Medical Center
• Tel-Aviv University

2
Primary Vs. Secondary Prevention
3
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

4
FOBT

5
Published FOBT Prospective, Randomized,
Controlled Studies

• Series Minnesota Funen Nottingham
  Gothenburg
• Biennial Annual Biennial
  Biennial 2 screens
• Period 13 y 13 y 10 y 8
  y 8y
• Colono 28 38 4 4
  7
• Mortality reduction
• 21 33 18 15
  12

6
Screening for CRC - FOBT Israel 1985-1998
Average Risk Population

• Series A n C()
  P() NL
• Slater 85 mail, FP 3233 17-42
  4.6 9 0.28
• Bat 86 FP 1339 46
  2.3 4 0.30
• Rozen 87 volunteers 1176 100
  3.6 10 4.19
• 92 volunteers 2868 100
  4.0 69 2.41
• Eliakim 88 mail 20251 35
  2.0 50 0.25
• Krieger 92 FP 1057 100
  1.9 0 0.00
• Niv 92 FP 2590 71
  4.0 34 1.32
• Total 32514 46
  2.9 176 0.54
• Aapproach Ccompliance Ppositive NLneoplastic
  lesion

7
Survival CurveScreening of Colorectal
CancerPercentage of the Population
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Sigmoidoscopy

9
Screening Sigmoidoscopy Reduced Rectal Cancer
Mortality

• Direct evidence from 3 case control studies
• Selby, NEJM 1992326653
• - 59
• Newcomb, JNCI 1992841572
• - 80
• Muller, Arch Intern Med 19951551741
  - 60

10 years protection
10
Screening FS in Israel(decrease in incidence
1982-1998, 16 to 10/100000)
Neoplastic lesion Compliance () n year Series
28 (4.7) 48 600 1986 Kiriat Uno (Bat)
45 (3.8) 100 1176 1987 Tel Aviv (Rozen)
42 (7.9) 14 529 1992 Beer Sheva (Niv)
24 (5.7) 95 420 1996 Dimona (Niv Fraser)
8 (1.8) 51 446 1996 Shouval Nirim (Fraser Niv)
8 (4.0) 50 200 1998 Hagoshrim (Niv)
4 (4.0) 10 100 1999 Chazor (Ilani, Pade Niv)
16(13.5) 10 118 2000 Beilinson (Niv)
175 (4.9) 47 3589 Total
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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 lt46 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 x 4

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Colonoscopy

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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 lt 750)

14
National polyp study 1978-1993

• A cohort of gt1400 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 19933291977

15
Preventive Effect of Colonoscopy

• 5-year incidence of adenomas after negative
  colonoscopy in asymptomatic average-risk persons
• 154 repeated colonoscopies (median 66m),
• 41 (27) patients with adenoma,
• only one gt 1 cm, no cancer!
• Rex, Gastroenterology 1996 1111178-81

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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 lt 750)

70
50
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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

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A distal significant polyp may predict a proximal
lesion

• Advanced Proximal Neoplasm (APN) (size,
  histology, no.)
• Source distal
  APN
• NEJM 92, GE 94 TAlt1cm 0.8
• 
  TAgt1cm 11.8
• NEJM 97 TAlt1cm
  16.0
• 
  TAgt1cm 29.0
• Ann Int Med 98 TAlt1cm 5.4
• 
  TAgt1cm 7.9
• JAMA 99 Tubular
  4.8
• 
  Villous 11.7

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Factors associated with an increased risk of
APNLevin, JAMA 19992811611Lieberman, N Engl J
Med 2000343162Imperiale, N Engl J Med
2000343169

• Age gt 65 years
• Villous histology in distal adenoma
• Distal adenoma gt 1cm
• Multiple distal adenomas
• Positive family history of CRC

20
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 lt 750)

21
Published FOBT Prospective, Randomized,
Controlled Studies

• Series Minnesota Funen Nottingham
  Gothenburg
• Biennial Annual Biennial
  Biennial 2 screens
• Period 13 y 13 y 10 y 8
  y 8y
• Colono 28 38 4 4
  7
• Mortality reduction
• 21 33 18 15
  12

22
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 lt 750)

23
Positivity Rates of FOBT ()St John, DDW, 1998
Rozen, Dig Dis Sci 1997.
24
FOBT - The Importance of Proper EvaluationNiv Y,
JCG 199012393

• Kibbutz A Kibbutz B P
• Population 700 750
• gt 40 y 223 173
  
• FOBT 33(25) 8( 6)
  lt0.01
• Adenomasgt1cm 2( 6) 2(25) lt0.05

25
Simulation Model - WinawerPopulation of 100,000
- 4988 CRC cases, 2391 deaths expected

• Cases Deaths
  Complication
• reduction
  reduction deaths
• Annual FOBT 2378(48) 1330(56) 52
• Colonoscopy every 10 y
• 3570(72)
  1763(74) 73
• 
  433 21
  

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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 lt 750)

27
Compliance is the single most important
determinant of effectivenessLieberman,
Gastroenterology 19951091781.

• For the same decrease in mortality
• FOBT 80
• FOBT FlEX. SIG. 60
• COLONOSCOPY 50

28
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 lt 750)

29
Cost-effectiveness Model for Colon Cancer
Screening Markov model Amnon Sonnenberg
(Sheba 2002)( per year of life saved)
FOBT every year, Sigmo every 5 years, Colono once
in a lifetime
30
Inappropriate CRC screeningFisher, AJGE
20051002526 (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

31
Primary prevention

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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

33
Chemoprevention preventionstudies

• 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

34
Effect of a diet high in diary foods upon
proliferation (early marker)Holt, JAMA
19982801074

• 70 post polypectomy patients
• Group A diet containing 1200mg Ca/day, Group B
  baseline diet
• Rectal biopsy 0,6,12 months 3Hthymidine
  incorporation into DNA, differentiation markers
• Significant lower proliferation, higher
  differentiation

35
Effect of calcium supplements on recurrence of
adenomas (late marker)Baron, Ann NY Acad Sci
1999889138

• 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