Colorectal Cancer Risk & Risk Reduction

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• Speaker: Dr. Harvey Murff

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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.

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.

Primary and Secondary Prevention of Colorectal Cancer

Harvey J Murff, MD. MPHAssociate Professor

Division of General Internal Medicine01/27/2017

Fast Stats: Colorectal Cancer

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

Trends in Incidence CRC Rates

CA: A Cancer Journal for CliniciansVolume 66, Issue 1, pages 7-30, 7 JAN 2016 DOI: 10.3322/caac.21332http://onlinelibrary.wiley.com/doi/10.3322/caac.21332/full#caac21332-fig-0003

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

2

10,000

1

10,000

= RR = 20.01% to 0.02%,

absolute number of new cases = 1

1% to 2%, absolute number of new

cases = 100RR = 2=200

10,000

10,000

100

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)

Prevention• Primary

– Prevents a cancer from ever occurring• Secondary

– Reduce the impact of cancer detecting and treating at an early stage or preventing recurrence

How Medical Evidence is Generated

How Medical Evidence is Generated

Can Still Be “Bad” Evidence

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

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

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

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

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

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

Primary Prevention

• Screening• Diet• Physical Activity• Body Weight• Alcohol Use• Smoking • Medications

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

Types of Screening

Inadomi JM. N Engl J Med 2017;376:149-156.

Inadomi JM. N Engl J Med 2017;376:149-156.

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.

Lifestyle

• Why lifestyle changes– Pros

• Similar changes impact multiple conditions– Cons

• Data for some exposures weak• Hard to do

Diet

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

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?

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

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

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)

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

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

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

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

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

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

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

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

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

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

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 years10% 225 84 139 284 23 333 58815% 267 86 121 260 28 395 64420% 286 92 122 248 21 605 834Aged 60 to 69 years10% 159 66 112 314 31 -20 18015% 186 80 104 298 24 96 30920% 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

CVD RiskNonfatal

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 years10% 148 137 139 209 35 219 62115% 150 143 135 200 34 334 71620% 152 144 132 184 29 463 833Aged 60 to 69 years10% 101 116 105 230 32 -12 28415% 110 129 93 216 34 17 32420% 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

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

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/processedASA/NSAIDS

ColonoscopyCRC Mortality

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

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)

Surveillance-Polyps

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

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

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

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