Upload
jola
View
22
Download
0
Tags:
Embed Size (px)
DESCRIPTION
Epidemiology of Colorectal Cancer. Edward Giovannucci, M.D., Sc.D. Harvard School of Public Health Brigham and Women’s Hospital and Harvard Medical School Boston, MA USA. Colorectal Cancer (CRC). Second leading cause of cancer death in the United States 10% of cancer deaths - PowerPoint PPT Presentation
Citation preview
Epidemiologyof
Colorectal Cancer
Edward Giovannucci, M.D., Sc.D.
Harvard School of Public HealthBrigham and Women’s Hospital
and Harvard Medical SchoolBoston, MA USA
Colorectal Cancer (CRC)
• Second leading cause of cancer death in the United States
10% of cancer deaths
105,000 colon cancer and 42,000 rectal cancer cases annually in U.S.
57,000 people die annually of CRC in the U.S.
1,000,000 cases annually worldwide
Group Approximate lifetime cancer risk (%)
Normal population 5 Past history of breast or female genital cancer 7-20 Past history of colorectal cancer 15 Family history of colorectal cancer 15 a Adenomas 10-20 b Ulcerative colitis 5-50 c Cancer family syndrome (HNCC) 50 Familial polyposis coli 100
Risk of Colorectal Carcinoma in General Populationand in High-Risk Groups
a Risk increases with number of relatives affected.b Risk depends on number, size, and histology of adenomas.c Risk depends on extent and duration of disease; the 50 percent figure applies to subjects with universal colitis of >30 years duration.
Modified from Ron & Lubin, 1986.
Colorectal Cancer: Natural History
• Process takes several decades
• Molecular lesions fairly well characterized
• Empirical stages:small adenomalarge adenomacarcinoma
APCmutation
K-rasmutation
COX-2 over-expression
MLH1 hypermethylation
MSI
p27 lossp53 mutation
IncreasedCell
Growth
AdenomaI
CancerAdenoma
IIAdenoma
IIINormal
Cell
Small Large
>30 - 40 years
Sub-Type Classification of CRC
Clinical: proximal vs. distal
Pathological: mucinous vs. non-mucinouspoorly vs. well-differentiated
Molecular: chromosomal instability (CIN)microsatellite instability (MSI)CpG island methylation
phenotype (CIMP)
Ogino S & Goel A, J Mol Diagn 2008
Prevention of Colorectal Cancer
• Primary:Prevent cancers from occurring through diet, lifestyle, drugs
• Secondary: Prevent cancers by removing precursor lesions (adenomas)
Prevent mortality by discovering cancers at early treatable stage
ScreeningAmerican Cancer Society Guidelines
• For average risk persons, screeningis recommended beginning at age 50 yrs
• Colonoscopy is recommended every10 years (if no polyps are found)
Primary Prevention
Factors That Increase Risk
• Smoking (esp. at early ages)
• Alcohol (>2 drinks/day)
• Red or processed meats
• Obesity (esp. central adiposity)
• Sedentary lifestyle
• “Western” diet in general
Smoking and Alcohol
Smoking and Colorectal CancerNHS and HPFS
Years Since Starting Smoking
0
0.5
1
1.5
2
2.5
3
3.5
4
NeverSmokers
1-19 Yrs 20-29 Yrs 30-34 Yrs 35-39 Yrs 40-44 Yrs 45 Yrs
Giovannucci et al., JNCI 1994
Mul
tivar
iate
Rel
ativ
e R
isk
Alcohol and Colorectal CancerAnalysis of 8 Cohort Studies
Cho e et al., Ann Intern Med 2004
Intake (g / day)
0.5
1
1.5
2
0 >0-<5 5-<15 15-<30 30-<45 >45
Mul
tivar
iate
Rel
ativ
e R
isk
Why are colon cancer rates invariably high
in populations that undergo “Westernization”?
Factors That Increase Risk
• Smoking (esp. at early ages)
• Alcohol (>2 drinks/day)
Red or processed meats
Obesity (esp. central adiposity)
Sedentary lifestyle
“Western” diet in general
Increased risk of colon cancer in Western countries
is primarily due to hyperinsulinemia and corresponding
increase in insulin and insulin-like growth factor-1 (IGF-1)
resulting from excess energy intake, central obesity,
physical inactivity, and Western dietary pattern.
Giovannucci, CCC 1995; JNCI 2002
Pituitary GH SecretionTallness
Insulin ResistanceDiabetes
Red & Processed Meats,Saturated Fat, Sweets,
Refined Grains
Insulin IGF-1
Competent -CellsInsulin Treatment
Physical InactivityAbdominal Obesity
Energy,Protein, Minerals
Acromegaly
Colon Tumor Growth
Proliferation; Apoptosis
Risk Factors* for Colon Cancer and AdenomaCompatible with Insulin/IGF Hypothesis
• circulating C-peptide / insulin• circulating IGF-1 or IGF-1/BP-3• Acromegaly ( IGF, insulin)• Type 2 diabetes• Metabolic syndrome ( insulin)• BMI• waist circumference• physical activity• Western diet ( insulin)• Tallness ( IGF-1)
* based on meta-analyses
1.01.4
3.0
1.8
2.3
4.7
3.63.3
3.5
0.0
1.0
2.0
3.0
4.0
5.0O
dds
Ratio
Tertile 1 Tertile 2 Tertile 3
C-Peptide
Tertile 1 Tertile 1 Tertile 3IGF-1 / IGFBP-3:
Physicians’ Health StudyC
olon
Can
cer
Ma et al., 2004
In the Physicians’ Health Study,
80% of colon cancers
were attributed to being
above the low tertile of
C-peptide (insulin) and of IGF-1.
Meta-Analysis of Risk of CRC for an Increase for 1 Portion of Red Meat
Sandhu et al., CEBP 2001
Meta-Analysis of Risk of CRC for an Increase of 1 Portion of Processed Meat
Sandhu et al., CEBP 2001
Factors That Decrease Risk
• Physical activity• Calcium (1000 mg/day)*• Vitamin D• Multivitamins (folate, B6?)
• Aspirin*• Hormone replacement therapy*• Fiber ?
* Randomized trial evidence
• Most studies, including randomizedclinical trials of adenomas, indicatea benefit of calcium intake
• A recent pooled analysis of majorcohort studies found a non-linearinverse association
Cho et al., JNCI 2004
Nonparametric Regression Curve for the Relationship between Total Calcium Intake and Colorectal Cancer
Pooled Cohort Analysis
NCI, National Cancer Mortality Maps & Graphs
Plasma 25(OH) Vitamin D and Colorectal CancerNurses’ Health Study
0
0.25
0.5
0.75
1
1.25
1.5
1.75
13 20 24 28 35
Median (ng/mL)
Mul
tivar
iabl
e O
R
P trend = 0.02
Feskanich D. et al., CEBP 2004
Colorectal Cancer Risk(NHS, HPFS)
0.88
0.65
0.921.000.961.0
0.80 0.790.69
0.0
0.2
0.4
0.6
0.8
1.0
1.2
<250 250-399 400-499 600-799 >800
Total Folate Intake (mg/day)
Mu
ltiva
ria
te R
R
0-4 year lag (P=0.19)
12-16 year lag (P=0.01)
Lee JE et al., submitted
• Alcohol is an antagonist
of folate and vitamin B6
• Risk of CRC is particularly high
when alcohol is high and
folate is low
Inflammation is a risk factor for CRC
• inflammatory markers
• expression of COX-2
• aspirin / NSAIDs risk
RR and 95% CI of CRCaccording to Years of Aspirin Use
NHS
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
0 1-4 5-9 10-19 > 20
Years of Regular Use
Mu
ltiv
ari
ate
Re
lati
ve
Ris
k
Giovannucci et al., NEJM 1995
Adenoma Cancer <1 cm 1 cm Latency
Smoking > 35-40 yr Aspirin > 10 yr Folate/vitamin B6 > 10 yr Alcohol > 10 yr Calcium/vitamin D > 10 yr Physical inactivity 0 < 10 yr Central adiposity 0 < 10 yr IGF-1/insulin 0 < 10 yr Estrogens 0 < 10 yr
Summary of Results for Colon Cancer
increases risk decreases risk
smoking aspirin (–)
folate (–)
alcohol
vitamin D (–)
calcium (–)
physical activity (–)
body size
Western diet
insulin, IGF
estrogens (–)
SCHMTC: Normal cell to
cancer - environment
IncreasedCell
Growth
AdenomaI
CancerAdenoma
IIAdenoma
IIINormal
Cell
smoking aspirin (–)
folate (–)
alcohol
vitamin D (–)
calcium (–)
physical activity (–)
body size
Western diet
insulin, IGF
estrogens (–)
APCmutation
K-rasmutation
COX-2 over-expression MSI
p27 lossp53 mutation
IncreasedCell
Growth
AdenomaI
CancerAdenoma
IIAdenoma
IIINormal
Cell
Primary vs. Secondary
Prevention
Wei E.K., et al. Am J Epidemiol, 2009
Age-specific incidenceper 100,000 person-yearsof colon cancer determinedby:
smokingbody weightexerciseprocessed meat intakemultivitamin use
Nurses’ Health Study
NOTE: Does not account for alcohol, vitamin D, calcium, hormone use, aspirin/NSAIDs
0
50
100
150
200
250
30 35 40 45 50 55 60 65 70
Age
Inc
ide
nc
e
High risk - neverscreened
High risk - screenedfrom age 50-70
Moderate risk -never screened
Low risk - neverscreened