Jeffrey A. Meyerhardt, MD, MPH Associate Professor of Medicine, Harvard Medical School Active Medical Staff, Medical Oncology, Dana-Farber Cancer Institute - speaker for Tuesday Call-on Congress 2012

1. Diet / Lifestyle and
Colorectal Cancer
Jeffrey Meyerhardt, MD, MPH
Dana-Farber Cancer Institute
Boston, MA

2. American Cancer Society
Guidelines on Nutrition and Physical Activity
for Cancer Prevention
• Recommendations for Individuals
– Achieve and maintain a healthy weight throughout life
– Adopt a physically active lifestyle
– Consume a healthy diet, with an emphasis on plant foods
• Choose foods and beverages in amounts that help achieve and
maintain a healthy weight.
• Limit consumption of processed meats and red meats.
• Eat at least 2.5 cups of vegetables and fruits each day.
• Choose whole grains instead of refined grain products.
– If you drink alcoholic beverages, limit consumption.
Kushi et al Ca: Can J Clin 2012

3. American Cancer Society
Guidelines on Nutrition and Physical Activity
for Cancer Prevention
• Recommendations for Community Action
– Increase access to affordable, healthy foods in
communities, worksites, and schools, and decrease
access to and marketing of foods and beverages of
low nutritional value, particularly to youth.
– Provide safe, enjoyable, and accessible
environments for physical activity in schools and
worksites, and for transportation and recreation in
communities.
Kushi et al Ca: Can J Clin 2012

4. American Cancer Society
Guidelines on Nutrition and Physical Activity
for Cancer Prevention – CRC
• Best advice to reduce the risk of colon cancer is to…
– Increase intensity and duration of physical activity
– Limit intake of red and processed meat
– Consume recommended levels of calcium
– Ensure sufficient vitamin D status
– Eat more vegetables and fruits
– Avoid obesity and central weight gain
– Avoid excess alcohol consumption
• In addition, it is very important to follow the ACS
guidelines for regular colorectal screening, as
identifying and removing precursor polyps in the colon
can prevent colorectal cancer.
Kushi et al Ca: Can J Clin 2012

5. Proportion of Colon Cancer
Preventable in Middle-Aged Men: HPFS
• Body mass index 25 kg/m2
• Physical activity 15 MET-hours/week
• Daily folate containing multivitamin
• Alcohol < 15 g/day
• Non-smoker
• Red meat 2 servings/week
3.1% of all men
Eliminate 71% of all colorectal cancer
(95% CI, 33-92%)
Platz Cancer Cause Contr 2000

6. What about Cancer
Patients/Survivors?

7. In 2001, an expert panel convened by the
American Cancer Society concluded
“…Properly conducted studies of the effect of
nutrition and physical activity on the
prognosis of cancer survivors are urgently
needed, and should be a high priority for all
academic and research funding agencies.”

8. Doc, what should I eat?
Should I exercise?
What else can I do?

9. Colorectal Cancer: Diet and Lifestyle
Impact on Cancer Patients
• Many studies on diet / lifestyle and risk
of DEVELOPING colorectal cancer
• Few studies show whether these factors
affect patients with colorectal cancer
– Disease recurrence
– Survival
– Tolerance to chemotherapy

10. Quick Epidemiology Lesion
Relative risks / Hazard Ratios
• Probability of an event (eg disease) in people exposed to
something compared to those not exposed
• Relative risk of 2 means that there is double the risk of a
disease due to some exposure compared to no exposure
• Relative risk of 0.5 means that there is ½ the risk of a
disease due to some exposures compared to no exposure

11. Quick Epidemiology Lesion
• HOWEVER, the baseline risk is important
– If baseline risk is 1/1000, then a relative risk of 2
is double but still ~1/500 only (0.2%)
– If baseline risk is 1/10, then a relative risk of 2 is
~ 1/5 (20%)

12. Cautions on Relative Risk
• Relative Risks are relative to another group
• Hazard ratios are like relative risk but also
account for time
• Marathon running vegetarians get colorectal
cancer
• Not all obese, meat and potato only couch
potatoes get colorectal cancer

13. Disclaimer / Audience Promise
• Everything from today’s talk relates to data
from large groups of individuals
• None should be translated as direct
recommendations to individual people
• Any changes that you are considering
MUST be discussed with your own doctor

14. Physical Activity and
Colorectal Cancer Outcomes

15. Colorectal Cancer:
CALGB 89803
• NCI-sponsored adjuvant therapy trial for stage III colon cancer
• Patients randomized to 2 different chemotherapy regimens
• 1264 patients enrolled between 1999 and 2001
Complete Complete
questionnaire questionnaire
Patients
enroll on 0 2 4 6 8 10 12 14 16
adjuvant
therapy
chemotherapy every 3 month f/u
trial
Saltz, L. B. et al. J Clin Oncol; 25:3456-3461 2007

16. Sample Question: Physical Activity

17. Colorectal Cancer:
CALGB 89803

18. 89803 and Exercise: Disease-Free Survival
in Stage III Colon Cancer Survivors
1.2
Hazard Ratio Recurrence or Death
1
1
0.8 0.87 0.9
0.6
0.4 0.51 0.55
0.2
0
<3 3-8.9 9-17.9 18.26.9 >27
Regular Physical Activity (met-hours per week)
Meyerhardt, J. A. et al. J Clin Oncol; 24:3535-3541 2006

19. How do you get these METs?
Leisure-Time Activity MET-Hours
Normal pace walking (2 to 2.9 mph) 3
Brisk pace walking (3 to 3.9 mph) 4
Very brisk pace walking (4+ mph) 4.5
Jogging (slower than 10 min/mile) 7
Running (faster than 10 min/mile) 12
Bicycling 7
Tennis, squash, racquetball 7
Lap swimming 7
Calisthenic, ski/stair machine, other aerobic exercise 6
Yoga, stretching, toning, lower intensity exercise 4
Other vigorous activities (lawn mowing) 6

20. Physical Activity Consistent Across Groups
Meyerhardt, J. A. et al. J Clin Oncol; 24:3535-3541 2006

21. NHS and Post-diagnosis Physical Activity
Meyerhardt, J. A. et al. J Clin Oncol; 24:3527-3534 2006

22. NHS and Post-diagnosis Physical Activity
Meyerhardt, J. A. et al. J Clin Oncol; 24:3527-3534 2006

23. NHS and Pre-diagnosis Physical Activity
Meyerhardt, J. A. et al. J Clin Oncol; 24:3527-3534 2006

24. CHALLENGE: Colon Health and Life-Long
Exercise Change trial
High risk Stage II or stage III colon cancer - completed adjuvant chemotherapy within 2-6 months
REGISTRATION
Baseline Testing
STRATIFICATION
Disease stage high risk III; centre; BMI ≤ 27.5 vs. > 27.5;
ECOG PS 0 vs. 1
RANDOMIZATION
ARM 1 ARM 2
Physical Activity Program + General Good Health General Health Education Materials
Education Material (Intervention Arm) (Control Arm)
Assessment of disease-free survival every 6 months
for first 3 years and annually from years 4-10
Courneya Curr Oncol.2008 Dec;15(6):271-8.

25. CHALLENGE: Colon Health and Life-Long
Exercise Change trial – Intervention Arm
Content Baseline to 6 mo. 6-12mo. 12-36 mo.
Behavior support 12 mandatory face-to-face sessions 12 Mandatory sessions held Mandatory monthly
sessions held biweekly biweekly, with option for face- sessions, with option for
to-face or telephone delivery face-to-face or telephone
delivery
Supervised physical 12 Mandatory sessions combined 12 sessions recommended; Monthly sessions
activity sessions with the mandatory behavior can be combined with the recommended; can be
support sessions biweekly behavior support combined with the monthly
sessions for those who behavior support sessions
12 Additional supervised physical choose face-to-face sessions for those who choose face-
activity sessions on alternate to-face sessions
weeks strongly recommended
Physical activity Gradually increase recreational Individualized (based on Individualized (based on
goal physical activity by 10 metabolic phase I results) to a phase II results) to a
equivalent tast (MET)- hours maximum increase of 20 maximum total of 27 MET-
weekly over baseline (to 10-19 MET-hours weekly (to a total hours weekly
MET-hours weekly) of 20-27 MET-hours weekly)
Courneya Curr Oncol. 2008 Dec;15(6):271-8.

26. Diet and Colorectal
Cancer Outcomes

27. Dietary Patterns
• Western and prudent pattern diets predictive of heart
disease, diabetes, colorectal cancer
• Prudent pattern: high intakes of
vegetables, fruit, legumes, whole grains, fish, and
poultry
• Western pattern: high intakes of red meat, processed
meat, refined grains, sweets and dessert, French
fries, and high-fat dairy products

28. Dietary Patterns in Colon Cancer Patients
Hazard Ratio for Cancer Recurrence or Death
4
3.9
3.5 P, trend < 0.001
3
2.5 Western diet
2
2.2
2
1.5 1.2
1.3
1 1 1.1 1
0.5 Prudent diet 0.7
0
1 2 3 4 5
Quintiles of Dietary Pattern
Meyerhardt, J. et al. JAMA 2007298(7):754-764.

29. CALGB 89803: Dietary Pattern
Meyerhardt, J. et al. JAMA 2007;298:2263-a.

30. Weight and Colorectal
Cancer Outcomes

31. Body Mass Index in Colon Cancer
Dignam, J. J. et al. J. Natl. Cancer Inst. 2006 98:1647-1654

32. Author Years N Outcome Hazard Ratio (95% CI) or P value
(compared to normal weight)
Tartter 1976-1979 279 Recur Rate P = 0.003 for above median weight
Meyerhardt 1988-1992 3759 DFS 1.11 (0.94-1.30) BMI > 30 kg/m2
OS 1.11 (0.96-1.29) BMI > 30 kg/m
Meyerhardt 1990-1992 1792 DFS 1.10 (0.91-1.32) BMI > 30 kg/m2
rectal
OS 1.09 (0.90-1.33) BMI > 30 kg/m2
Local Recur 1.31 (0.91-1.88) BMI > 30 kg/m2
Dignam 1989-1994 4288 DFS 1.06 (0.93-1.21) BMI 30-34.9 kg/m2
1.27 (1.05-1.53) BMI > 35 kg/m2
Meyerhardt 1999-2001 1053 DFS 1.00 (0.72-1.40) BMI 30-34.9 kg/m2
1.24 (0.84-1.83) BMI > 35 kg/m2
OS 0.90 (0.61-1.34) BMI 30-34.9 kg/m2
0.87 (0.54-1.42) BMI > 35 kg/m2
Hines 1981-2001 496 OS 0.77 (0.61-0.97) BMI > 25 all stages
0.92 (0.65-1.30) stage I-II
0.92 (0.59-1.45) stage III
0.58 (0.37-0.90) stage IV

33. Body Mass Index in Colon Cancer
Patients over Past Decade
< 21 21-24.9 25-29.9 30-34.9 > 35
INT-0089 14 % 34 % 34 % 13 % 5%
(1988-92)
89803 8% 26 % 36 % 20 % 10 %
(1999-2001)
% change in a - 43% - 24% + 6% + 54% + 100%
decade

34. Other Factors and Colorectal
Cancer Outcomes

35. Aspirin Use in Colon Cancer Patients
Chan, A. T. et al. JAMA 2009;302:649-658.

36. Aspirin Use and Cancer Recurrence in Stage III
Colon Cancer: Findings from CALGB 89803
Hazard Ratio for Cancer Recurrence (95%
CI)
Consistent aspirin use 0.45
(0.21-0.97)
Celecoxib or Rofecoxib use 0.56
(0.21-1.54)
Fuchs ASCO 2005

37. CALGB/SWOG 80702 for Stage III Colon Cancer
Celecoxib versus Placebo
N = 2,500 Arm A Arm B
12 FOLFOX 12 FOLFOX
+ +
Placebo daily Celecoxib
6 versus 12 400 mg daily
treatments
FOLFOX Arm C Arm D
6 FOLFOX 6 FOLFOX
+ +
Placebo daily Celecoxib
400 mg daily
Celecoxib starts concurrently with FOLFOX and continue for 3 years

38. Plasma Vitamin D and Survival in
Colorectal Cancer Patients
1 1
0.9 0.89
0.83
Hazard Ratio for Death
0.8
0.7
0.6
0.5
0.49
0.4 P, trend = 0.01
0.3
0.2
0.1
0
<22.8 22.8-27.1 27.2-33.1 >33.1
Quintiles of plasma Vitamin D ng/mL
Ng et al J Clin Oncol. 2008 Jun 20;26(18):2984-91

39. Predicted Vitamin D Level* & Survival in
Colorectal Cancer Patients: NHS/HPFS (N=1017)
CRC Specific Mortality Overall Mortality
* Based on race, geography, exercise, BMI,
dietary vitamin D, supplement vitamin D Ng et al Br J Cancer. 2009 101: 916-23.

40. Conclusions
• Colorectal cancer is a common disease
• Ways to prevent colorectal cancer
– Diet and lifestyle
– Get screening
• Colorectal cancer patients
– Need to do standard therapies – surgery, chemo if
recommended, radiation for certain rectal cancers
– Discuss with oncologist other things to complement standard
therapy
– However, changing behavior is not easy

41. Where Do We Go From Here?
• Are observational data enough?
• Survivorship raises issues of addressing other
diseases down the road
• Better biomarkers to study effects – decrease sample
size?
• Single exposure v multiple exposure intervention

42. Where Do We Go From Here?
• All of these studies required collaborative
efforts and funding
– Cooperative group system
– Large prospective cohort studies
• Intervention trials
– Expensive
– Need participation from providers and patients