In this webinar, we talk about the risks associated with colorectal cancer – including everything from diet, lifestyle, age, family history and more. We review the risks of recurrence for colorectal cancer survivors. Join us to learn how to reduce your risk of colorectal cancer! Presented by Harvey Murff, M.D, M.P.H. is an Associate Professor of Medicine in the Division of General Internal Medicine and Public Health at Vanderbilt University

1. Colorectal Cancer
Risk & Risk Reduction
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2. • Speaker: Dr. Harvey Murff
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Today’s Webinar:

3. Resources:

4. Disclaimer
:
The information and services provided by Fight Colorectal
Cancer are for general informational purposes only. The
information and services are not intended to be substitutes
for professional medical advice, diagnoses or treatment.
If you are ill, or suspect that you are ill, see a doctor
immediately. In an emergency, call 911 or go to the nearest
emergency room.
Fight Colorectal Cancer never recommends or endorses any
specific physicians, products or treatments for any condition.

5. Speaker:
Harvey Murff, M.D, M.P.H. is an Associate Professor of
Medicine in the Division of General Internal Medicine and Public
Health at Vanderbilt University. Dr. Murff completed an Internal
Medicine residency at Mount Sinai Medical Center in New York
City and a fellowship in General Internal Medicine at the
Brigham and Women’s Hospital in Boston, MA.
He obtained a Masters in Public Health at the Harvard School of
Public Health. His research interests includes colorectal cancer
screening and health disparities, chemoprevention of colorectal
cancer, and the impact of genetic factors and dietary intake of
polyunsaturated fatty acids on inflammation and cancer risk.
Dr. Murff has received support for his research from the
National Institutes of Health and the Department of Veterans
Affairs. Dr. Murff is a practicing General Internist at the
Tennessee Valley Healthcare System, Nashville Veterans Affairs
Hospital.

6. Primary and Secondary Prevention of
Colorectal Cancer
Harvey J Murff, MD. MPH
Associate Professor
Division of General Internal Medicine
01/27/2017

7. Fast Stats: Colorectal Cancer
CA: A Cancer Journal for Clinicians
Volume 66, Issue 1, pages 7-30, 7 JAN 2016 DOI: 10.3322/caac.21332
http://onlinelibrary.wiley.com/doi/10.3322/caac.21332/full#caac21332-fig-0001

8. Trends in Incidence CRC Rates
CA: A Cancer Journal for Clinicians
Volume 66, Issue 1, pages 7-30, 7 JAN 2016 DOI: 10.3322/caac.21332
http://onlinelibrary.wiley.com/doi/10.3322/caac.21332/full#caac21332-fig-0003

9. How Risk is Presented
• Absolute
– Chance of developing the disease over a
certain period of time
• More relevant to the individual (i.e. 1 in a 100)
• Relative
– How much higher or lower the risk is in
individuals with a certain risk factor compared
to those without the risk factor
• To interpret relative risk it is important to know the
how common is the condition
– For something uncommon a big relative risk may not
impact the number of new cases much

10. 2
10,000
1
10,000
= RR = 2
0.01% to 0.02%,
absolute number of
new cases = 1
1% to 2%, absolute
number of new
cases = 100
RR = 2=
200
10,000
10,000
100

11. Risks of Developing CRC
• Adenoma
– Prevalence 20-53% in individuals ≥ 50
– 3.4-7.6% have advanced histopathology
– 0.2 – 0.6% adenocarcinoma
• CRC
– Risks are higher with family history
• 1 first-degree relative (parent/sibling) 2-fold increase
• 2 or more relatives 4-fold increases depending on age at onset
Birth to 49 50 to 59 60 to 69 ≥ 70 Birth to
Death
Male 0.3 (1 in 300) 0.7 (1 in 149) 1.2 (1 in 82) 3.7 (1 in 27) 4.7 (1 in 21)
Female 0.3 (1 in 318) 0.5 (1 in 195) 0.9 (1 in 117) 3.4 (1 in 30) 4.4 (1 in 23)

12. Prevention
• Primary
– Prevents a cancer from ever occurring
• Secondary
– Reduce the impact of cancer detecting and
treating at an early stage or preventing
recurrence

13. How Medical Evidence is Generated

14. How Medical Evidence is Generated
Can Still Be “Bad”
Evidence

15. Why a Study Might Be Wrong
• Bias
– Systematic error in the design or conduct of a study
• participant selection or exposure outcome assessment
• Confounding
– Factor associated with both the disease and the risk
factor that is not on the causal pathway
• Chance
– False positive or false negative studies
Szklo et al Epidemiology Beyond the Basics 2nd edi 2007

16. Bias
• Selection
– Study only selects
cases from the
hospital
• Recall
– Asks cases about prior
exposures to food that
might be suspected to
be related to disease
Confounding
• Lung cancer
Matches
Lung Cancer

17. Bias
• Selection
– Study only selects
cases from the
hospital
• Recall
– Asks cases about prior
exposures to food that
might be suspected to
be related to disease
Confounding
• Lung cancer
Matches
Lung CancerSmoking

18. Observational Studies
• Case-control
– Starts with the disease
• Cohort study
– Starts with the exposure
• Big problems with bias
– Recall bias and case-control studies
• Big problem with confounding
– Lifestyle factors often cluster together
• (health lifestyle)
• Compares lowest to highest

19. Randomized Controlled Trials
• Randomization
– Evenly distributes confounders
• If the study is big enough
• Double-blind, placebo control
• “hard” outcomes
– Reduces bias
• Not all randomize trials follow these
designs and so they too can be misleading

20. Where are the RCT’s
• Lifestyle and behavioral interventions hard
to do in a RCT
• Contamination and cross-over
• Interventions with weaker effects need HUGE
sample sizes
• Choice of outcomes matter
• Surrogates do not always reflect the outcome of
interest
• CRC can take 20 years to develop
• Very expensive

21. Primary Prevention
• Screening
• Diet
• Physical Activity
• Body Weight
• Alcohol Use
• Smoking
• Medications

22. Screening
• Benefits of screening
– RCT show reduction in incidence and
mortality
– Removes pre-cancerous lesions
– Screening believed to be responsible for
almost 53% of reduced CRC mortality

23. Types of Screening
Inadomi JM. N Engl J Med 2017;376:149-156.
Inadomi JM. N Engl J Med 2017;376:149-156.

24. Limits of Screening
• Colonoscopy
• Sedation, serous AE < 0.6%, expensive
• CT colonography
• Radiation exposure, extra-colonic lesions
• Flexible sigmoidoscopy
• Only visualizes lower-third, combined with annual FOBT
• Guaiac-based FOBT
• Limited sensitivity, annual testing
• FIT
• Variation in positive tests, more expensive that FOBT
• Stool DNA
• More costly than FIT or FOBT
Strum WB. N Engl J Med 2016;374:1065-1075.

25. Lifestyle
• Why lifestyle changes
– Pros
• Similar changes impact multiple conditions
– Cons
• Data for some exposures weak
• Hard to do

26. Diet
• Fiber
• Fruits and Vegetables
• Red Meat/Processed Meat
• Fish
• Vitamins and Minerals

27. Fiber
• Where does the data come from?
– Observational studies
• 25 studies 10 g/day reduced CRC by 10%
– 10 slices of whole grain bread/day 3-4 cups wheat bran
cereal
– Randomized trials (adenomas)
• 2 studies results null
• Why the differences?
• Type of fiber (fiber from grains versus
fruit/vegetable/legume fiber)
• Outcome differences?
• Size of study or confounders?

28. Fruits and Vegetables
• Where does the data come from?
– Observational studies (14 studies)
• Why might this be true?
• Fiber/antioxidants?
• What is the estimated effect size?
• 9% decreased relative risk
• Not considered statistically significant
• Maybe an effect with distal CRC

29. Red Meat/Processed Meat
• Where does the data come from?
– Observational studies and animal studies
– Most studies (2/3) have found a statistical association
(̴ 30 studies)
• WHO in 2015 – group 1 carcinogen
• Why might this be true?
• Polyaromatic hydrocarbons or nitrates?
• What is the estimated effect size?
• 18% increase relative risk (100’s for smoking)
• 2-3 strips of bacon daily for 10+ years = 1
additional CRC case

30. Fish
• Where does the data come from?
– Observational
• Diet reported (41 studies)
• Biomarker studies (5 studies)
– Clinical Trials
• Reduced number of adenomas by 22% (FAP)
• Clinical trials underway
• Why might this be true?
– Anti-inflammatory effect (like aspirin)
• What is the estimated effect size?
– 12% (diet studies) 40% (biomarker)

31. Vitamin and Minerals
• Folate
– Dark leafy greens, broccoli, asparagus
– Observational Studies
• May be beneficial in very early stages
– Clinical Trials (Adenomas)
• Null or might even increase risk
– Why the difference
• Preparation folate versus folic acid
• Timing early stages versus late stages
• Study designs

32. Vitamin and Minerals
• Vitamin B6 (pyridoxine)
– Tuna, salmon, chicken, beef, spinach, seeds,
nuts
– Observational Studies
• Effect size 10-20% reduction of CRC
• Magnesium
– Very limited data
– Single study in women found 40% reduction

33. Calcium and Dairy
• Where does the data come from?
– Observational studies (19 cohorts)
– Mixed overall 18% risk reduction with milk only (?)
– Clinical trials
• 3 RCT adenomas 20% reduction in risk
• 1 RCT cancers: null
• Why might this be true?
• Unclear mechanisms – binds bile acids
• Major concerns with RCT, contamination, dose,
short duration

34. Vitamin D
• Where does the data come from?
– Observational studies
• 50% reduced risk of CRC
– Clinical trials
• 1 RCT null but used low dose
• Ongoing higher dose studies
• Why might this be true?
• Unclear mechanisms, cell proliferation,
inflammation

35. Physical Activity
• Where does the data come from?
– Observational studies (>20)
• Why might this be true?
• Unknown mechanisms
• What is the estimated effect size?
• 27% decrease relative risk
• Least active to most active
Closest thing to a “wonder drug”
Premature Death
Heart Disease
Stroke
Diabetes
High blood pressure
Multiple cancers
Depression
Dementia

36. Body Weight
• Where does the data
come from?
– Observational studies
• Why might this be
true?
– Insulin/ Adipose associate
inflammation
• What is the estimated
effect size?
– 23-45% increase relative risk
– Possible dose response
• BMI
– Weight/height2
• Overweight
– ≥ 27.3♀ ≥ 27.8 ♂
• Average height ♀(5’4”)
– 159 lbs
• Average height ♂(5’10”)
– 194 lbs
• Obese
– ≥ 30
• Average height ♀(5’4”)
– 175 lbs
• Average height ♂(5’10”)
– 209 lbs

37. Alcohol use
• Where does the data come from?
– Observational studies
– > 60 studies
• Why might this be true?
• Unknown by believed to be related to folate
• What is the estimated effect size?
• 21% increase relative risk for moderate drinkers
– 2-3 drinks per day
• 52% increased relative risk for heavy drinkers
– ≥ 4 drinks per day

38. Tobacco use
• Where does the data come from?
– Observational studies
– > 100 studies
• Why might this be true?
• At least 43 known carcinogens in tobacco smoke
• What is the estimated effect size?
• 18% increase relative risk
• Also associated with increased colon polyp risk
– Serrated polyps

39. Medications-Aspirin/NSAIDs
• Where does the data come from?
• RCT (adenomas)
– 4 trials reduced recurrent adenomas by 17%
• RCT (cancer)
– 1 trial which was null
• Secondary analysis of RCT
– 4 trials 24% reduction in CRC mortality
• Observational studies
» 22% and 34% reduction of adenomas (ASA,
NSAIDS)
• Why the discrepancies
• Dose, duration of therapy

40. Aspirin Recommendations
• United States Preventive Services
• Adults aged 50-59 years
– Low-dose aspirin for prevention of
cardiovascular disease and colorectal cancer
who have a 10% or greater 10-year CVD risk,
are not at increased risk of bleeding, have a
life expectancy of at least 10 years and are
willing to rake aspirin for at least 10 years

41. CVD Risk
Nonfatal MIs
Prevented
Nonfatal
Ischemic
Strokes
Prevented
CRC Cases
Prevented
Serious GI
Bleeding
Caused
Hemorrhagic
Strokes
Caused
Net Life-Years
Gained
QALYs Gained
Aged 50 to 59 years
10% 225 84 139 284 23 333 588
15% 267 86 121 260 28 395 644
20% 286 92 122 248 21 605 834
Aged 60 to 69 years
10% 159 66 112 314 31 -20 180
15% 186 80 104 298 24 96 309
20% 201 84 91 267 27 116 318
Table 1. Lifetime Events in 10,000 Men Taking Aspirin
Final Recommendation Statement: Aspirin Use to Prevent Cardiovascular Disease and Colorectal Cancer: Preventive Medication. U.S.
Preventive Services Task Force. November 2016.
https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/aspirin-to-prevent-cardiovascular-
disease-and-cancer

42. CVD Risk
Nonfatal
MIs
Prevented
Nonfatal
Ischemic
Strokes
Prevented
CRC Cases
Prevented
Serious GI
Bleeding
Caused
Hemorrhagic
Strokes
Caused
Net Life-Years
Gained
QALYs Gained
Aged 50 to 59 years
10% 148 137 139 209 35 219 621
15% 150 143 135 200 34 334 716
20% 152 144 132 184 29 463 833
Aged 60 to 69 years
10% 101 116 105 230 32 -12 284
15% 110 129 93 216 34 17 324
20% 111 130 97 217 33 48 360
Table 2. Lifetime Events in 10,000 Women Taking Aspirin*
Final Recommendation Statement: Aspirin Use to Prevent Cardiovascular Disease and Colorectal Cancer: Preventive Medication. U.S.
Preventive Services Task Force. November 2016.
https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/aspirin-to-prevent-cardiovascular-
disease-and-cancer

43. Hormone Replacement Therapy
• Where does the data come from?
– Clinical trials
– Women's Health Initiative
» Short term reduced CRC risk (44%)
» Long term HRT participants had more advanced
disease and higher mortality
» Increased risk of breast cancer, heart attacks, blood
clots, strokes

44. 10% 20% 30% 40% 50% 60%
Fiber
-20%-30%-40%-50%-60% -10%
Physical
Activity
Decrease CRC Risk Increase CRC Risk
Fish(D)
Vit D
Fruits and
Vegetables
B6Fish(b)
Calcium
(polyps)
Tobacco
Alcohol
(moderate)
Alcohol
(heavy)
Obesity
Red
meat/processed
ASA/NSAIDS
Colonoscopy
CRC Mortality

45. Surveillance after CRC
• Yearly colonoscopies until normal then
every 3-5 years
• Imaging and biomarkers
– Intensive surveillance appears to be
associated with a 20-25% reduced risk of
CRC mortality compared to less intense
• Still under considerable debate

46. Cancer Survivorship
• Diet
– Limited observational studies
• Western diet may increase recurrent (185%
relative risk increase) in Stage III
• Physical Activity
– Observational (6 studies)
• 43-61% reduced risk with high PA
• Obesity
– Observational
• Obesity associated with 38% worse disease-free
survival (Stage II and III)

47. Surveillance-Polyps
Strum WB. N Engl J Med 2016;374:1065-1075.

48. Secondary Prevention
• Lifestyle and Chemoprevention
– Physical Activity
• Increases survival with colorectal, breast, prostate
– Calcium supplementation
• prevents recurrence
– Antioxidants (beta-carotene, vitamin C, vitamin E )
• null
– Aspirin
• Prevents recurrences but dose and duration
unclear

49. Ongoing Studies and Novel
Therapies
• VITAL
– Vitamin D and Omega 3
• N = 25,874, 4-years
• seAFOod Trial
• N = 755, n-3 + ASA
• Metformin
– Reduced polyp formation
• Difluromethyornithin (DFMO) + sulindac
– 70% reduction of recurrent adenomas

50. Question & Answer:
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