1. Beyond Standard Adjuvant Therapy for Colon Cancer: Role of Nonstandard Interventions Jeffrey Meyerhardt, MD, MPH Dana-Farber Cancer Institute Boston, MA

2. Disclosures NIH Funding: Prior K07 and current R01 (co PI) related to research on diet/lifestyle in colon cancer survivors

3. Diet/Lifestyle in Cancer Patients: Why Study It? 1, 2 and 3 Patients ask 4Diet / lifestyle modify risk of developing cancer - seems like it may impact growth/progression of cancer 5 ~80,000 patients / year with stage II or III colorectal cancer in the US ~24,000 will recur Further strategies are needed to help these patients

4. Colorectal Cancer: Risk Factors Overview Decrease RiskIncrease RiskUncertain Impact ScreeningFamily historyStatins ExerciseIBDFiber Calcium/Vit DDiabetesGlycemic index AspirinObesityFruits/Vegetables Post-menopausal estrogen Red meat Western diet Folic Acid Alcohol Smoking

5. 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

6. Colorectal Cancer: CALGB 89803 NCI-sponsored adjuvant therapy trial for stage III colon cancer Patients enroll on adjuvant therapy trial 0 2 4 6 8 10 12 14 16 chemotherapy Complete questionnaire every 3 month f/u

7. Physical Activity and Colorectal Cancer Outcomes

8. 89803 and Exercise: Disease-Free Survival in Stage III Colon Cancer Survivors Meyerhardt, J. A. et al. J Clin Oncol; 24:3535-3541 2006 Regular Physical Activity (met-hours per week) Hazard Ratio Recurrence or Death

9. 89803 and Exercise: Overall Survival in Stage III Colon Cancer Survivors Meyerhardt, J. A. et al. J Clin Oncol; 24:3535-3541 2006 Regular Physical Activity (met-hours per week) Hazard Ratio Death any cause

10. 89803 and Exercise: Disease Free Survival Meyerhardt, J. A. et al. J Clin Oncol; 24:3535-3541 2006

11. 89803 and Exercise: Stratification Meyerhardt, J. A. et al. J Clin Oncol; 24:3535-3541 2006

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

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

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

15. NHS and Change in Physical Activity Meyerhardt, J. A. et al. J Clin Oncol; 24:3527-3534 2006

16. Diet and Colorectal Cancer Outcomes

17. Dietary Patterns Dietary patterns reflect more the real world complexity of diet – interactions and synergy of dietary components Dietary patterns can be derived from factor analysis – create food categories and then dataset drives pattern

18. Dietary Patterns Western and prudent pattern diets predictive of heart disease, diabetes 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

19. CALGB 89803: DFS By Dietary Pattern 11 1.1 1 0.7 1.3 0 0.5 1 1.5 2 2.5 3 3.5 4 12345 Quintiles of Dietary Pattern Hazard Ratio for Cancer Recurrence or Death Prudent diet 1.2 2 2.2 3.9 Western diet P, trend < 0.001 Meyerhardt, J. et al. JAMA 2007298(7):754-764.

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

21. Obesity and Colorectal Cancer Outcomes

22. Obesity and Colon Cancer Outcomes Mixed results on the impact of body mass index and colon cancer outcomes Most studies limited to single measurement at time of diagnosis / time of initiation of chemotherapy Literature limited to body mass index - ? if best measure

23. NSABP and Body Mass Index Dignam, J. J. et al. J. Natl. Cancer Inst. 2006 98:1647-1654 Disease-free and overall survival by body mass index (BMI) category in 4288 patients from National Surgical Adjuvant Breast and Bowel Project randomized clinical trials for Dukes B and C colon cancer

24. 89803 and Body Mass Index Meyerhardt J Clin Oncol. 2008 Sep 1;26(25):4109-15.

25. Change in Body Mass Index in US

26. 89803 and Change in Weight Meyerhardt J Clin Oncol. 2008 Sep 1;26(25):4109-15. Adjusted Hazard ratio (95% CI) > 5 kg weight loss1.39 (0.69 – 2.79) 2.1 – 5 kg weight loss1.15 (0.54 – 2.44) +/- 2 kg changeReferent 2 – 4.9 kg weight gain1.11 (0.66 – 2.06) > 5 kg weight gain1.19 (0.73 – 1.94) P trend = 0.13 P trend = 0.90

27. Aspirin and Colorectal Cancer Outcomes

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

29. Vitamin D and Colorectal Cancer Outcomes

30. Plasma Vitamin D and Survival in Colorectal Cancer Patients: NHS 1 0.89 0.83 0.49 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 <22.822.8-27.127.2-33.1>33.1 Quintiles of plasma Vitamin D ng/mL Hazard Ratio for Death (0.28-0.86) P, trend = 0.01 Ng, J Clin Oncol. 2008 Jun 20;26(18):2984-91.

31. Conclusions Colorectal cancer has the most consistent data for certain modifiable factors impacting risk of developing disease Increasing evidence that some of these factors may impact outcomes of patients with disease

32. What to recommend These data are observational but certainly warrant further study Physical activity has the most consistent data and reasonable to recommend to patients Diet – healthy diet has implications beyond colon cancer recurrence. Limited on best recommendation so far for colon cancer survivors Currently planning cooperative group trial to include celecoxib