Beyond Standard Adjuvant Therapy for Colon Cancer: Role of

Nonstandard Interventions

Jeffrey Meyerhardt, MD, MPH

Dana-Farber Cancer Institute

Boston, MA

Disclosures

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

Diet/Lifestyle in Cancer Patients: Why Study It?

1, 2 and 3 Patients ask

4 Diet / 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

Colorectal Cancer: Risk Factors Overview

Decrease Risk Increase Risk Uncertain Impact

Screening Family history Statins

Exercise IBD Fiber

Calcium/Vit D Diabetes Glycemic index

Aspirin Obesity Fruits/Vegetables

Post-menopausal

estrogen

Red meat

Western diet

Folic Acid

Alcohol

Smoking

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

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

Complete questionnaire

every 3 month f/u

Physical Activity and Colorectal Cancer Outcomes

89803 and Exercise: Disease-Free Survivalin Stage III Colon Cancer Survivors

Meyerhardt, J. A. et al. J Clin Oncol; 24:3535-3541 2006

1

0.87 0.9

0.51 0.55

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<3 3-8.9 9-17.9 18.26.9 >27

Regular Physical Activity (met-hours per week)

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89803 and Exercise: Overall Survival in Stage III Colon Cancer Survivors

Meyerhardt, J. A. et al. J Clin Oncol; 24:3535-3541 2006

1

0.85

0.71 0.71

0.37

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<3 3-8.9 9-17.9 18.26.9 >27

Regular Physical Activity (met-hours per week)

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89803 and Exercise: Disease Free Survival

Meyerhardt, J. A. et al. J Clin Oncol; 24:3535-3541 2006

89803 and Exercise: Stratification

Meyerhardt, J. A. et al. J Clin Oncol; 24:3535-3541 2006

NHS and Post-diagnosis Physical Activity

Meyerhardt, J. A. et al. J Clin Oncol; 24:3527-3534 2006

NHS and Post-diagnosis Physical Activity

Meyerhardt, J. A. et al. J Clin Oncol; 24:3527-3534 2006

NHS and Pre-diagnosis Physical Activity

Meyerhardt, J. A. et al. J Clin Oncol; 24:3527-3534 2006

NHS and Change in Physical Activity

Meyerhardt, J. A. et al. J Clin Oncol; 24:3527-3534 2006

Diet and Colorectal Cancer Outcomes

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

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

CALGB 89803: DFS By Dietary Pattern

11 1.1 10.7

1.3

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0.5

1

1.5

2

2.5

3

3.5

4

1 2 3 4 5Quintiles of Dietary PatternH

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Prudent diet

1.2

22.2

3.9

Western diet

P, trend < 0.001P, trend < 0.001

Meyerhardt, J. et al. JAMA 2007298(7):754-764.

CALGB 89803: Dietary Pattern

Meyerhardt, J. et al. JAMA 2007;298:2263-a.

Obesity and Colorectal Cancer Outcomes

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

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

89803 and Body Mass Index

Meyerhardt J Clin Oncol. 2008 Sep 1;26(25):4109-15.

Change in Body Mass Index in US

89803 and Change in Weight

Meyerhardt J Clin Oncol. 2008 Sep 1;26(25):4109-15.

Adjusted Hazard ratio (95% CI)

> 5 kg weight loss 1.39 (0.69 – 2.79)

2.1 – 5 kg weight loss 1.15 (0.54 – 2.44)

+/- 2 kg change Referent

2 – 4.9 kg weight gain 1.11 (0.66 – 2.06)

> 5 kg weight gain 1.19 (0.73 – 1.94)

Ptrend = 0.13

Ptrend = 0.90

Aspirin and Colorectal Cancer Outcomes

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

Vitamin D and Colorectal Cancer Outcomes

Plasma Vitamin D and Survival in Colorectal Cancer Patients: NHS

1

0.890.83

0.49

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

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<22.8 22.8-27.1 27.2-33.1 >33.1

Quintiles of plasma Vitamin D ng/mL

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(0.28-0.86)

P, trend = 0.01

Ng, J Clin Oncol. 2008 Jun 20;26(18):2984-91.

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

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