Revised Abstract

The impact of dietary patterns on cancer The impact of dietary patterns on cancer recurrence and survival in patients with stage III recurrence and survival in patients with stage III

colon cancer: findings from CALGB 89803colon cancer: findings from CALGB 89803

Jeffrey A. MeyerhardtJeffrey A. Meyerhardt11, Donna Niedzwiecki, Donna Niedzwiecki22, Donna Hollis, Donna Hollis22, , Leonard B. SaltzLeonard B. Saltz33, Walter Willett, Walter Willett44, Robert J. Mayer, Robert J. Mayer11, Charles , Charles S. FuchsS. Fuchs11

11Dana-Farber Cancer Institute, Boston, MA; Dana-Farber Cancer Institute, Boston, MA; 22CALGB Statistical CALGB Statistical

Center, Durham, NC; Center, Durham, NC; 33Memorial Sloan-Kettering Cancer Memorial Sloan-Kettering Cancer Center, New York, NY; Center, New York, NY; 4 4 Harvard School of Public Health, Harvard School of Public Health, Boston, MABoston, MA

Revised AbstractContext: Dietary factors have been associated with the risk of developing colon cancer, however, the influence of diet on patients with established disease is unknown.

Objective: Determine influence of dietary patterns on cancer recurrences & mortality of colon cancer survivors. Design, Setting, Patients: We conducted a prospective observational study of 1,009 patients with stage III colon cancer enrolled in a randomized adjuvant chemotherapy trial. Patients reported on dietary intake using a semi-quantitative food frequency questionnaire during and 6 months after adjuvant chemotherapy. We identified two major dietary patterns, prudent and Western, by factor analysis. The prudent pattern was characterized by high fruit and vegetable, poultry and fish intakes; the Western pattern was characterized by high meat, fat, refined grains and dessert intakes. Patients were followed for cancer recurrence or death. Results: A higher intake of a Western pattern diet after cancer diagnosis was associated with a significantly increased risk of colon cancer recurrence or death (disease-free survival). Compared with patients in the lowest quintile of Western pattern diet, those in the highest quintile experienced an adjusted hazard ratio for recurrence or death of 3.91 (95% confidence interval [CI], 2.21 – 6.89; P for trend<0.0001), Western pattern diet was associated with a similar detriment in recurrence-free survival (adjusted P for trend<0.0001) and overall survival (adjusted P for trend<0.0001). The reduction in disease-free survival with a Western pattern diet was not significantly modified by gender, age, nodal stage, body mass index, physical activity level, baseline performance status, or treatment arm. In contrast, the prudent pattern diet was not significantly related to cancer recurrence or mortality. Conclusion: Higher intake of a Western pattern diet may increase the risk of recurrence and mortality among patients with stage III colon cancer patients treated with surgery and adjuvant chemotherapy. Further studies are needed to delineate which components of such a diet are most influential.

Background

• Patients diagnosed with cancer are highly motivated to seek information about diet, physical activity, dietary supplement use, and nutritional complementary therapies.1-4

• Epidemiologic and scientific research indicates that diet and other lifestyle factors have a significant influence on the risk of developing colon cancer. 5,6

• The influence of diet on colon cancer recurrences is unknown

• Factor analysis has been used to examine overall dietary patterns, beyond individual foods and nutrients, and the risk of several cancers.7-8

• Specific dietary patterns have been associated with the development of colorectal cancer in case-control and cohort studies.9-15

MethodsWe prospectively studied dietary patterns among 1,009 patients with stage III colon cancer enrolled in a randomized trial of post-operative adjuvant chemotherapy (CALGB 89803), which compared bolus 5-fluorouracil and leucovorin (5-FU/LV) to bolus irinotecan, 5-FU, and leucovorin (IFL) (Saltz et al. Proc ASCO 2004). Patients in these analyses completed semi-quantitative food frequency questionnaires (SFFQ) in the middle of their adjuvant chemotherapy (Q1) and approximately 6 months after the completion of adjuvant therapy (Q2). The questionnaire included 131 food items, vitamin and mineral supplements, and open‑ended sections for other supplements and foods not specifically listed. To identify dietary patterns, we applied factor analysis to data from the SFFQ in each cohort. Food items on the questionnaires were grouped into 39 predefined food groups

Patients who completed the first SFFQ were included in these analyses. Only patients who did not experience recurrence or die before Q1 were included in these analyses. To avoid biases due to declining health immediately before recurrence or death, we also excluded from analyses patients who experienced either event within 90 days following the dietary assessment. We updated dietary exposures based on the results of the second SFFQ (Q2) using cumulative averaging, but weighted proportional to times between Q1 and Q2 and then Q2 and disease-free survival time.

Methods

Factor analysis (principal component) was conducted using the factor procedure in SAS software. Factor analysis aggregates correlated variables. We retained two factors and labeled these two factors as the "prudent" and "Western" patterns. The prudent pattern was characterized by high intakes of fruits, vegetables, whole grains, legumes, poultry, and fish and the Western pattern was characterized by refined grains, processed and red meats, desserts, high-fat dairy products, and french fries. These 2 factors are not correlated (correlation coefficient = 0.02). Factor scores were divided into quintiles for analyses.

We computed Cox proportional hazards for recurrence-free (RFS), disease-free (DFS) and overall survival (OS). Time intervals were measured from completion of the 1st questionnaire to recurrence or death, excluding events within the first 90 days to minimize potential bias from decreased activity due to underlying disease. Median follow-up after the 1st questionnaire was 5.3 years.

We used time-varying covariates to adjust for total calories, physical activity and body mass index with updating from Q2. Other covariates (including age at study entry, gender, number of positive lymph nodes, baseline performance status, presence of bowel perforation or obstruction at time of surgery, smoking history, treatment arm, and weight change between Q1 and Q2) were also entered into the model as fixed covariates. We tested for linear trends across quintiles of dietary pattern by assigning each participant the median value for the quintile and modeling this value as a continuous variable.

Derivation of Cohort SizeFigure 1: Derivation of Cohort Size

CALGB 89803 Total

Enrollment N = 1264

Did not complete Q1: Enrolled prior to diet/lifestyle amendment to protocol N = 87 Had cancer recurrence, died or was removed from protocol treatment prior to Q1 (midway through adjuvant therapy) N = 59 Did not complete questionnaire 1 for other reasons N = 23

Completed questionnaire 1 N = 1095 (98%)

Completed Q1 and were then excluded: Had cancer recurrence or died within 90 days after completion of Q1 N = 30

Calories exclusion* (outside realistic bounds) for Q1 N = 31 Left more than 70 food items blank on Q1 N = 7

Completed questionnaire 2 N = 981 (92%)

Did not complete questionnaire 2

N = 86

NOTE: To be evaluable for these analyses, patients only had to

complete questionnaire 1. However, if they did go on to

complete questionnaire 2 and had calorie exclusion or more than 70

items blank, they were not included in the analyses.

Final Sample Size for Dietary Pattern Study

N = 1009

Reason Inevaluable for Analyses N = 255)

Compliance with Dietary Questionnaire

Completed Q2 and were then excluded: Calories exclusion * (outside realistic bounds) for Q2 N = 15

Left more than 70 food items blank with Q2 N = 3

Q1 = questionnaire 1 (midway through adjuvant therapy); Q2 = questionnaire 2 (6 months after completion of adjuvant therapy) * Calorie exclusion: Less than 600 calories or greater than 4,200 calories per day for men and less than 500 calories or greater than 3,500 calories per day for women.

Pearson correlation coefficients for the relationship between food intake and factors representing dietary patterns

Food grouping Prudent WesternVegetables † 0.72 ---Leafy vegetables 0.71 ---Yellow vegetables 0.67 ---Cruciferous vegetables 0.65 ---Legumes 0.56 ---Fruit 0.55 -- Light salad dressing 0.48 ---Tomatoes 0.46 0.36 Garlic 0.39 --- Fish 0.46 --- Poultry 0.37 --- Fruit Juice 0.35 --- Whole grains 0.32 -- Low fat mayonnaise 0.31 -- Wine 0.19 --- Tea 0.16 --- Diet beverages --- -- High-fat dairy --- 0.67 Low-fat dairy --- 0.64

Food grouping Prudent WesternRefined grains --- 0.60Condiments --- 0.51Red meat --- 0.53Sweets and desserts --- 0.53Margarine --- 0.50Processed meat --- 0.45Potatoes 0.17 0.45Regular mayonnaise --- 0.35Butter --- 0.33French fries -0.16 0.37Eggs --- 0.30Snacks ‡ --- 0.36Nuts --- 0.30Coffee --- 0.29Sugar beverages - 0.15 0.29Beer --- 0.22Cream soup or chowder 0.16 0.25Pizza --- 0.26Regular salad dressing 0.19 0.19Liquor --- ---

* values < 0.15 are not shown (---). † Vegetables other than yellow, cruciferous, or leafy-green vegetables. ‡ Potato, corn chips, crackers, or popcorn.

Baseline Characteristics by Quintile of Western Pattern Diet 1 2 3 4 5 p value

Number of Patients 201 202 202 202 202

Physical activity (median MET-hours/week) at Q2 8 6.5 7.8 8.4 7.5 0.97

Male (%) 36 51 51 66 77 <0.0001

Median Age (yrs) 59 59 62 60 62 0.77

Median body mass index (kg/m2) at Q1 26.4 28 27 27.5 27.5 0.12

Median Weight change (kg) 2.3 2.3 3.2 2.7 3.2 0.09

Baseline performance status (%) 0.85PS 0 75 77 73 77 76PS 1-2 25 23 27 23 24

Invasion through bowel wall (T stage) 0.27T1-2 12 19 15 13 13T3-4 88 81 85 87 87

Number of positive lymph nodes (%) 0.241-3 (N1) 68 67 63 68 594+ (N2) 32 33 37 32 41

Treatment arm (%) 0.255-FU/LV 57 51 48 47 50IFL 43 49 52 53 50

Smoking Status (%) <0.0001Current 4 4 9 11 13Past 38 51 44 47 51Never 58 45 47 42 36

MET = metabolic equivalent tasks; CEA = carcinoembryonic antigen; 5-FU = 5-fluorouracil; LV = leucovorin; IFL = irinotecan, 5-FU, lecovorin

Western Pattern

Baseline Characteristics by Quintile of Prudent Pattern Diet

1 2 3 4 5 p value

Number of Patients 201 202 202 202 202

Physical activity (median MET-hours/week) at Q2 3.8 6.8 7.7 10.7 11.6 <0.0001

Male (%) 64 56 57 57 46 0.008

Median Age (yrs) 57 62 61 63 60 0.1

Median body mass index (kg/m2) at Q1 27.5 27.7 26.8 27.7 27.3 0.41

Median Weight change (kg) 2.7 3.4 2.3 2.7 2.3 0.16

Baseline performance status (%) 0.17PS 0 71 76 81 78 73PS 1-2 29 24 19 22 27

Invasion through bowel wall (T stage) 0.41T1-2 11 15 14 14 18T3-4 89 85 86 86 82

Number of positive lymph nodes (%) 0.391-3 (N1) 63 63 62 69 684+ (N2) 37 37 38 31 32

Treatment arm (%) 0.695-FU/LV 53 51 51 46 52IFL 47 49 49 54 48

Smoking Status (%) 0.0004Current 16 10 7 4 4Past 45 48 48 49 42Never 39 42 45 47 54

MET = metabolic equivalent tasks; CEA = carcinoembryonic antigen; 5-FU = 5-fluorouracil; LV = leucovorin; IFL = irinotecan, 5-FU, lecovorin

Prudent Pattern

Impact of Western pattern diet on colon cancer recurrence and mortality

1 2 3 4 5 p value

Cancer recurrence or death-any cause (Disease Free Survival)# of events / # at Risk 71/201 57/202 73/202 68/202 83/202

Multivariate adjusted hazard ratio Ref 1.2 2.03 2.16 3.91 <0.0001(0.76-1.89) (1.30-3.16) (1.32-3.52) (2.21-6.89)

Cancer recurrence (Recurrence-Free Survival)# of events / # at Risk 68/201 51/202 68/202 61/202 76/202


Overall mortality# of events / # at Risk 57/201 35/202 51/202 53/202 55/202


Quintile of Western Pattern Diet

* Adjusted for gender, age, depth of invasion through bowel wall (T1-2 v T3-4), number of positive lymph nodes (1-3 v 4 or more), presence of clinical at time of surgery, presence of bowel obstruction at time of surgery, baseline performance status (0 v 1-2), treatment arm, weight change between 1st and

Impact of Prudent pattern diet on colon cancer recurrence and mortality

1 2 3 4 5 p trend

Cancer recurrence or death-any cause (Disease Free Survival)

# of events / # at Risk 79/201 79/202 71/202 53/202 70/202

Multivariate adjusted hazard ratio Ref 1.13 0.96 0.7 1.26 0.79(0.71-1.67) (0.63-1.46) (0.44-1.11) (0.80-1.97)

Cancer recurrence (Recurrence-Free Survival)

# of events / # at Risk 73/201 68/202 67/202 52/202 64/202

Multivariate adjusted hazard ratio Ref 1.05 0.96 0.76 1.2 0.76(0.70 -1.60) (0.62-1.49) (0.47-1.22) (0.75-1.94)

Overall mortality

# of events / # at Risk 63/202 58/202 44/202 34/202 52/202

Multivariate adjusted hazard ratio Ref 1.14 0.75 0.59 1.14 0.75(0.73-1.78) (0.44-1.29) (0.33-1.65) (0.81-2.45)

Quintile of Prudent Pattern Diet

* Adjusted for gender, age, depth of invasion through bowel wall (T1-2 v T3-4), number of positive lymph nodes (1-3 v 4 or more), presence of clinical at time of surgery, presence of bowel obstruction at time of surgery, baseline performance status (0 v 1-2), treatment arm, weight change between 1st and questionnaire, time-varying body mass index, time-varying physical activity level and time-varying total calories.

Subgroup analyses by quintile of Western pattern diet n 1 2 3 4 5 p trend p for intxn

Age 0.59<61 (median age) 516 Ref 1.47 2.34 1.72 3.3 <0.0001

(0.74-2.91) (1.21-4.52) (0.83-3.57) (1.45-7.54)> 61 (median age) 493 Ref 1.08 1.67 3.03 5.14 0.008

(0.56-2.07) (0.89-3.14) (1.50-6.14) (2.28-11.60)

BMI 0.69< 25 (under/normal weight) 331 Ref 0.84 1.21 1.69 2.87 0.01

(0.36-1.99) (0.56-2.63) (0.71-4.05) (1.04-7.91)> 25 (overweight / obese) 678 Ref 1.37 2.43 2.42 4.1 <0.0001

(0.78-2.40) (1.39-4.25) (1.32-4.45) (2.02-8.29)

Gender 0.66Male 568 Ref 1.2 2.29 2.49 4.46 <0.0001

(0.63-2.30) (1.23-4.25) (1.30-4.75) (2.13-3.35)Female 441 Ref 1.34 1.86 1.7 4.39 0.005

(0.69-2.62) (0.94-3.69) (0.75-3.87) (1.68-11.42)

Physical Activity 0.55Lower 2 quintiles 657 Ref 1.09 2.21 2.59 5.01 <0.0001

(0.61-1.95) (1.25-3.91) (1.34-5.01) (2.40-10.5)Higher 3 quintiles 260 Ref 1.26 1.59 1.53 2.28 0.08

(0.58-2.71) (0.78-3.27) (0.71-3.28) (0.93-5.61)

Treatment arm 0.65-FU/LV 511 Ref 0.93 1.59 2.16 5.23 <0.0001

(0.49-1.74) (0.87-2.93) (1.15-4.21) (2.33-11.75)IFL 498 Ref 1.75 2.78 2.35 3.37 0.004

(0.87-3.69) (1.39-5.59) (1.09-5.07) (1.61-8.68)* Adjusted for gender, age, depth of invasion through bowel wall (T1-2 v T3-4), number of positive lymph nodes (1-3 v 4 or more), presence of clinical

perforation at time of surgery, presence of bowel obstruction at time of surgery, baseline performance status (0 v 1-2), treatment arm, weight change

between 1st and 2nd questionnaire, time-varying body mass index, time-varying physical activity level and time-varying total calories.

• In a cohort of patients with stage III colon cancer treated with surgery and adjuvant chemotherapy surviving without cancer recurrence 3 months after the completion of a FFQ, increasing consumption of a Western pattern diet after diagnosis was associated with an increased risk of cancer recurrence or death.

• Compared to patients in the lowest level, those in the highest level of Western pattern intake experienced a tripling in risk of recurrence or death.

• In contrast, prudent pattern diet did not influence the outcome after curative resection of stage III colon cancer.

• These data suggest that a diet characterized by higher intakes of red and processed meats, sweets and desserts, french fries, and refined grains increases the risk of cancer recurrence and decreases survival.

• Further analyses are underway to better delineate specific nutrients or food groupings that may be most influential.

Conclusions

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Revised Abstract