Transcript Hepatitis C

Colorectal Cancer
Prevention & Screening
Rajeev Jain, M.D.
2007 Estimated US Cancer Cases*
Men
766,860
Women
678,060
Prostate
29%
26%
Breast
Lung & bronchus
15%
15%
Lung & bronchus
Colon & rectum
10%
11%Colon & rectum
Urinary bladder
7%
6%
Uterine corpus
Non-Hodgkin
lymphoma
4%
4%
Non-Hodgkin
lymphoma
Melanoma of skin
4%
4%
Melanoma of skin
Kidney
4%
4%
Thyroid
Leukemia
3%
3%
Ovary
Oral cavity
3%
3%
Kidney
Pancreas
2%
3%
Leukemia
19%
21%
All Other Sites
*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.
All Other Sites
Source: American Cancer Society, 2007.
2007 Estimated US Cancer Deaths*
Lung & bronchus
31%
Men
289,550
Women
270,100
26%
Lung & bronchus
15%
Breast
Colon & rectum
Prostate
9%
Colon & rectum
9%
10%
Pancreas
6%
6%
Pancreas
Leukemia
4%
6%
Ovary
Liver & intrahepatic
bile duct
4%
4%
Leukemia
3%
Esophagus
4%
Non-Hodgkin
lymphoma
Urinary bladder
3%
3%
Uterine corpus
Non-Hodgkin
lymphoma
3%
2%
Brain/ONS
2%
Kidney
3%
Liver & intrahepatic
bile duct
All other sites
24%
23%
All other sites
ONS=Other nervous system.
Source: American Cancer Society, 2007.
Colorectal Tumorogenesis
APC/ß-Catenin
Normal
Early
Adenoma
K-ras
p53
18q LOH
Late
Adenoma
Carcinoma
Fearon & Vogelstein. Cell 1990.
Colorectal Cancer
Risk Factors
 Age > 50 years
 Inflammatory Bowel
Disease
 Familial Adenomatous
Polyposis (FAP)
Syndromes
 Hereditary Nonpolyposis Colon Cancer
(HNPCC)
 Family History
– Polyps
– Cancer
 Past History
–
–
–
–
–
Polyps
Colon Cancer
Ovarian Cancer
Uterine Cancer
Breast Cancer
Winawer, et al. Gastro 1997.
Colorectal Cancer
Risk Factors
IBD FAP HNPCC
1% 1%
5%
FAM HX
15-20%
SPORADIC
75%
Winawer et al. J Natl Cancer Inst 1991.
Familial Adenomatous Polyposis
(FAP)
 Autosomal dominant
– Mutant APC gene
 > 100 polyps
 Avg age of adenoma
appearance: 16 yrs
 Avg age of CRC
diagnosis: 39 yrs
 Risk of CRC ~ 100%
Winawer, et al. Gastro 2003.
Hereditary Nonpolyposis
Colorectal Cancer
(HNPCC or Lynch Syndrome)
 Autosomal dominant
– Mutations in DNA mismatch repair genes
 In comparison to sporadic CRC:
– Earlier age of onset (mean, 44 yrs)
– Right-sided
– Synchronous or metachronous lesions
– Poorly differentiated histology
CRC Incidence Rate, %
CRC & Ulcerative Colitis
20
18
15
10
8
5
2
0
10
20
30
Duration of colitis, years
Eaden, et al. Gut 2001.
Colorectal Cancer
Ulcerative colitis & Crohn’s colitis
 Risk of developing CRC increases with:
– Duration of disease
– Young age at diagnosis
– Extent of disease
– Primary sclerosing cholangitis (PSC)
– Familial association
Munkholm P. Aliment Pharmacol Ther 2003.
Colorectal Cancer
Age-Specific Incidence
Rate Per 100,000
500
400
300
200
100
0
20-24
30-34
40-44
50-54
60-64
70-74
80-84
Age (years)
SEER 1973-1992.
Colorectal Cancer
Incidence with Positive Family History
Cumulative Incidence (%)
10
<45
45-54
>55
Controls
5
0
40
50
60
70
80
Age of Relatives (years)
Mecklin et al. Gastro 1986.
Colon Cancer
Familial Risk
Risk of Colon Cancer
5
4
3
2
1
0
1 1st
1 1st <50 yrs
2 1st
1 2nd/3rd
2 2nd
Familial Setting
Burt. Gastro 2000.
Colon Cancer
Risk After Gynecologic Cancer
Risk of Colon Cancer
4
3
25 - 49 yrs
50 - 64 yrs
> 65 yrs
2
1
0
Cervical
Endometrial
Ovarian
Gynecologic Cancer
Weinberg et al. Ann Intern Med 1999.
Distribution of Polyps &
Cancer
Adenomatous Polyps
Adenocarcinoma
11%
11%
13%
9%
18%
7%
6%
13%
52%
55%
Winawer, et al. Gastro 1997.
Colorectal Cancer
Summary of Risk Factors
 Highest Risk
– Genetic syndromes (FAP &
HNPCC)
– Inflammatory bowel disease
 High Risk
– Family history of polyps and/or
CRC
 Average Risk
Colorectal Cancer
PREVENTION
Dietary
Habits
Medical
Therapy
Colorectal Cancer
 Western countries have 10x risk
for colon cancer in comparison to
Asian & other developing
countries.
 Rapid increases in rates of colon
cancer are found in:
– migrants from low-risk to high-risk
areas.
– Japan since World War II.
Colorectal Cancer
Dietary Hypotheses
Excretion of
bile acids
Conversion to
secondary bile acids
deoxycholic & lithocolic
acid
Colorectal
carcinogenesis
Fiber
Animal
Fat
RISK
Colon Cancer &
Animal Fat Intake
2
Relative Risk
Nurses' Health Study
1.5
1
1
2
3
4
5
Intake of Animal Fat (quintile)
Willet et al. NEJM 1990.
Colon Cancer & Dietary Fiber
Possible Mechanisms of Action
 Increased bulk of stool
– Dilution of potential carcinogens
– Decrease in transit time




Binding with potential carcinogens
Lowers fecal pH
Alters colonic flora
Fermentation by fecal flora to
SCFA’s
Kim. Gastro 2000.
Colon Cancer & Dietary Fiber
 Current evidence (epidemiological, animal,
and interventional studies) is supportive of
an inverse association between dietary
fiber intake and CRC risk.
 Protective effects seen at 30-35 gm/d
(US mean 11.1 gm/d)
 Intervention should begin 10-20 yrs
before the peak age for CRC incidence.
Kim. Gastro 2000.
Colon Cancer & Diet
What should we tell our patients ?
 Nutritional education
– Low animal fat
– High fiber
 Fiber supplementation (goal of 25
– 35 gm fiber/day)
 Other lifestyle modifications
– Weight loss
– Physical activity
– Avoid tobacco
Colorectal Cancer
Protective Micronutrients ?





Calcium and Vitamin D
Folic acid
Vitamins A, C, and E
Selenium
Curcumin
Colorectal Cancer
Chemopreventive Agents




ASA & NSAIDs
Folate
Calcium
Estrogens
Chemoprevention with ASA
U.S. Preventive Services Task Force
 Colonic adenomas
– RR 0.82 [95%CI, 0.70 – 0.95] RCTs
– RR 0.87 [95%CI, 0.77 – 0.98] Case-control
– RR 0.72 [95%CI, 0.61 – 0.85] Cohort
 Colon cancer
– 22% RR in cohort studies
– 2 RCTs no protective benefit at low doses
 Benefits seen with higher doses and for periods
longer than 10 years
 The USPSTF recommends against the routine
use of ASA/NSAIDs to prevent CRC in average
risk patients.
Dube C et al. Ann Int Med 146:365-75, 2007.
Chemoprevention
Folate
 Mechanism unknown
 Colorectal adenomas
– Prospective cohort study (25,474 pts)
– Folate 400 ug QD
– 29% risk reduction
 Colorectal cancer
– Prospective cohort study (88,756 pts)
– Folate in a multivitamin preparation
– 75% risk reduction after 15 yrs
Chemoprevention
Calcium
 Mechanism
– binding of bile and fatty acids
– inhibit colorectal epithelium proliferation
 Case-control and cohort studies show inverse
relationship between calcium intake and CRC
– imprecise assessment of calcium intake
– confounding factors
 RCT
–
–
–
–
930 pts with h/o adenomas
3 gm Ca carbonate (1200 mg elemental Ca)
Serial colonoscopy 1 and 4 yrs after randomization
15% reduction in adenoma formation
Baron et al. NEJM 1999.
Chemoprevention
Estrogens
– 422,373 patients
– End point – Death
 2.Nurses’ Health
Study
– 59,002 patients
– End point - Cancer
40
Risk Reduction (%)
 1.Cancer Prevention
Study II
35
30
25
20
15
10
5
0
Study 1
Study 2
Calle et al. J Natl Cancer Inst 1995.
Grodstein et al. Ann Intern Med 1998.
Colorectal Cancer Prevention
 Dietary habits
– Increase fiber intake
– Decrease animal fat intake
 Chemoprevention
– Not enough data to firmly
recommend
Definitions
Screening: search for neoplasia in
asymptomatic population with no prior
neoplasia
Surveillance: evaluation of patients with prior
colorectal adenomas or cancer, or with IBD
Diagnosis: evaluation of symptomatic patients
and patients with positive screening tests
CRC Screening
 Only 26% of eligible population has had FOBT within 3 yrs;
33% have never had FOBT
 Most common reason given: test was never recommended
 Of those offered screening, only 4% decline
 Cancer Prevention Study (CPS) II Nutrition Cohort, crosssectional data from 1997
– Men 86,404; women 97,786
– 42% men & 31% women underwent screening FS or colonoscopy
 In pts > 50 yrs, 33% had undergone FS/C in 1999. By 2004,
52% had undergone screening FS/C.
Vernon, J Natl Cancer Inst 1997.
Leard et al, J Fam Prac 1997.
Chao, Am J Public Health 2004.
Smith,CA Cancer J Clin 2006.
CRC Screening
 Women who underwent screening
mammography and Pap smear
– 52% underwent CRC screening
 Men who underwent prostate cancer
screening with PSA
– 65% underwent CRC screening
Carlos, Acad Radiol 2005.
Carlos, J Am Coll Surg 2005.
Medicolegal Issues
 Delay in diagnosis of CRC accounts for
>50% of all litigation against PCPs for
GI disease
– Attributing rectal bleeding to hemorrhoids
– Inadequate evaluation of positive FOBT
– Failure to screen
Gerstenberger & Plumeri. Gastrointest Endosc 1993.
Risk Stratification
 Has the patient had colorectal cancer or
an adenomatous polyp?
 Does the patient have an illness that
predisposes him or her to colorectal
cancer?
 Has a family member had colorectal
cancer or an adenomatous polyp?
Winawer et al. Gastroenterology 2003.
Screening Tests
for Colorectal Cancer
 Fecal occult blood test
 Flexible sigmoidoscopy
 Double-contrast barium
enema
 Colonoscopy
Fecal Occult Blood Tests
 Rationale: colorectal cancers bleed
 Guaiac-based
– pseudoperoxidase activity of hemoglobin
 Immunochemical
– antibodies to human globin epitopes
 Heme-porphyrin
– hemoglobin derived porphyrin
Fecal Occult-Blood Tests
Test
Basis of
Reaction
Hemoccult II
Guaiac
Hemoccult
SENSA
Guaiac
HemeSelect
Ab to H Hgb
HemoQuant
Heme porphyrins
Rockey. NEJM 1999.
Fecal Occult-Blood Tests
CHARACTERISTICS
GUAIACBASED
HEMEPORPHYRIN
IMMUNOCHEMICAL
Bedside
availability
++++
0
0 to ++
Time to develop
1 min
1 hr
up to 24 hrs
Cost
$18
$33
$18-35
Rockey. NEJM 1999.
Fecal Occult-Blood Tests
REASON FOR
FALSE POSITIVE
RESULTS
GUAIACBASED
HEMEPORPHYRIN
IMMUNOCHEMICAL
Non-human
hemoglobin
++++
++++
0
Dietary peroxidases
+++
0
0
Rehydration
+++
0
0
Iron
0
0
0
Rockey. NEJM 1999.
Fecal Occult-Blood Tests
REASON FOR
GUAIACHEMEFALSE NEGATIVE
BASED
PORPHYRIN
RESULTS
IMMUNOCHEMICAL
Hemoglobin
degradation
+++
0
+++
Storage
++
0
++
Vitamin C
++
0
0
Rockey. NEJM 1999.
Guaiac-based FOBT
 2 slides from 3 consecutive bowel
movements
 Dietary & medication restrictions
 Slides should NOT be rehydrated
 Slides should be stored at room
temperature & developed within 7
days
Fecal Occult-Blood Tests
Comparison of RCTs
Mandel et al
Hardcastle et al
Kronborg et al
Kewenter et al
Minnesota
Nottingham
Funen
Gothenburg
Number of
patients
46,551
152,850
61,933
68,308
Follow-up
13 yrs
7.8 yrs
10 yrs
8.3 yrs
FOBT frequency
1 yr
2 yr
2 yr
1.5 yr
Rehydration
Yes
No
No
Yes
PPV for CRC
2%
10%
18%
5%
Mortality
reduction
33%
14%
18%
12%
Towler et al. BMJ 1998.
Screening Sigmoidoscopy
Mortality Reduction (%)
Case-Control Studies
100
80
60
40
79
60
59
20
0
San Fransisco
London
VA
Study
Selby et al. NEJM 1993.
Newcomb et al. NEJM 1993.
Muller & Sonnenberg. Arch Int Med 1995.
Cumulative Incidence (%)
Observed and Expected CRC
Incidence after Polypectomy
5
NPS
SEER
St. Mark's
Mayo
4
3
2
1
0
0
2
4
6
7
Years Followed
Winawer et al. NEJM 1993.
Colonoscopy
Case-Control Study
Mortality Reduction (%)
100
80
60
40
20
39
52
0
Colonoscopy
Polypectomy
Muller & Sonnenberg. Ann Intern Med 1995.
Screening Colonoscopy
VA
Indiana
Patients
3121
1994
Age
50-75 yrs
>50 yrs
Men
97%
?
FHx CRC
14%
?
Cancer
1%
1%
Lieberman et al. NEJM 2000.
Imperiale et al. NEJM 2000.
Major Complication Rates of
Screening Tests
Screening test
Perforation &
Hemorrhage
Death
Barium enema
1/10,000
1/50,000
Sigmoidoscopy
1-2/10,000
<1/10,000
Colonoscopy
1-3/1,000
1-3/10,000
Winawer, et al. Gastro 1997.
Colorectal Cancer
Innovative Screening Techniques
 Targeting exfoliated markers
– Fecal
• colonocytes
• DNA
– Immunochemical assays
• p53
• CEA
Colorectal Cancer
Innovative Screening Techniques
 Virtual colonoscopy (computed
tomographic colonography).
– Thin-section helical CT & air insufflation
generating 2-D images converted to 3-D
images.
 Results of recent study (100 pts)
–
–
–
–
Cancer:
Polyps > 10 mm:
Polyps 6 – 9 mm:
Polyps < 5:
100%
91%
82%
55%
Fenlon, et al. NEJM 1999.
Colorectal Cancer
Screening Guidelines




American Cancer Society
American College of Gastroenterology
American Gastroenterological Association
American Society of Colon & Rectal
Surgeons
 American Society for Gastrointestinal
Endoscopy
Winawer, et al. Gastro 1997.
Latest Guidelines
 Original panel reconvened to review latest literature
 Endorsed by:
–
–
–
–
–
–
–
–
American Academy of Family Practice
American Cancer Society
American College of Gastroenterology
American College of Physicians-American Society of Internal
Medicine
American College of Radiology
American Gastroenterological Association
American Society of Colon & Rectal Surgeons
American Society for Gastrointestinal Endoscopy
Winawer, et al. Gastro 2003.
CRC Screening Guidelines
Average Risk
 Asymptomatic
 Age > 50 years
 No other risk factors for
CRC
Winawer, et al. Gastro 2003.
CRC Screening Guidelines
Average Risk
TEST
FREQUENCY
Fecal occult blood test*
Annually
Flexible sigmoidoscopy*
Every 5 years
Double-contrast barium enema*
Every 5 years
Colonoscopy
Every 10 years
* Positive result leads to colonoscopy
Winawer, et al. Gastro 2003.
CRC Screening Guidelines
Familial Risk
CATEGORY
RECOMMENDATIONS
First-degree relative with CRC or an
adenomatous polyp at age >60 yrs
Same as average risk but
starting at age 40 yrs
2 second-degree relatives with CRC
2 or more first degree relatives with
colon cancer
Colonoscopy every 5 yrs beginning
at the 40 yrs or 10 yrs younger than
the earliest diagnosis in the family
First-degree relative with CRC or
adenomatous polyp < 60 yrs
1 ≥2nd degree relative with CRC
Same as average risk
Winawer, et al. Gastro 2003.
CRC Screening Guidelines
Genetic Syndromes
CATEGORY
RECOMMENDATION
Familial adenomatous
polyposis (FAP)
Sigmoidoscopy beginning
at age 10-12 yrs
Hereditary nonpolypsosis
colorectal cancer (HNPCC)
Colonoscopy , every 1-2
yrs, beginning at age 20-25
yrs or 10 yrs younger than
earliest case in the family
Winawer, et al. Gastro 2003.
Colorectal Cancer
Cost-Effectiveness of Screening
 5 studies: less than $50,000 per lifeyear saved.
 Cost-utility of one-time colonoscopic
screening (50-54 yrs): $69,000 per
QALYs
 Compares favorably to other
interventions
– Mammograms
– Seat belts
– Airbags
$168,400 (40-69 yrs)
$100,000
$750,000
When Not to Screen?
When to Stop Screening?
 Patients who are to frail to
tolerate
– bowel preparation
– sedation
– colonoscopy
 Life expectancy less than 3 to 5
years
 Colonoscopy within past 5
years
Colorectal Cancer
Prevention & Screening
 Colorectal cancer is a major cause of
cancer related death in the US.
 Dietary counseling to minimize animal
fat and increase fiber intake.
 Chemoprevention needs further study.
 Colonoscopy has become the dominant
screening strategy.
 Overall screening rates remain poor.