Review Article

The role of body mass index, physical activity, and diet in colorectal cancer recurrence and survival: a review of the literature14
Alina Vrieling and Ellen Kampman
ABSTRACT The role of dietary and other lifestyle factors in colorectal cancer recurrence and survival is largely unknown. We conducted a review to summarize the evidence from epidemiologic studies that examined the association of body mass index (BMI), physical activity, and nutrition with colorectal cancer recurrence and survival. We searched MEDLINE and EMBASE for relevant epidemiologic studies published up to March 2010 by using MeSH terms and related key words. We identied 36 articles that were based on 31 independent studies on BMI (n 21), physical activity (n 6), or nutrition (n 12) in relation to colorectal cancer recurrence and survival. Studies were generally based on follow-up of cases in existing patient series, case-control or cohort studies, or chemotherapy trials. BMI, physical activity, and nutrition mostly referred to the time at or before diagnosis. Only 10 studies assessed BMI (n 1), physical activity (n 4), or nutrition (n 5) after diagnosis. There may be an association between higher BMI and body fatness before or at the time of diagnosis and a higher all-cause mortality or colorectal cancerspecic mortality or recurrence, although results may differ by sex, tumor location, and molecular subtype. There may be a relation between higher leisure-time physical activity after diagnosis and a lower all-cause or colorectal cancerspecic mortality. For dietary factors, statistically signicant associations were only shown for single foods, nutrients, and dietary patterns in single studies. In conclusion, only a paucity of data is available on the effect of dietary and other lifestyle factors on colorectal cancer recurrence and survival. Thus far, no clear conclusions can be drawn. Future studies are warranted, particularly on postdiagnosis BMI and diet. Am J Clin Nutr 2010;92:47190.

INTRODUCTION

Colorectal cancer is the third most common cancer worldwide (1). The number of patients who survive colorectal cancer is increasing, partly because of earlier detection and more-effective treatment methods. The age-adjusted 5-y relative survival rate over the period 19881999 increased from 48% to 54% in Europe (2), and a period analysis over 2000 to 2002 showed an age-adjusted 5-y relative survival rate of 56% for Europe and 66% for the United States (3). Worldwide, colon and rectum cancers accounted for 1 million new cases in 2002, and an estimated 2.8 million persons diagnosed with colorectal cancer were alive 5 y of diagnosis (1).

After diagnosis, individuals with colorectal cancer remain at an increased risk of colorectal cancer recurrence, secondary cancer, other chronic diseases, and cancer death. Their clinical outcome is dependent on several tumor characteristics, such as tumor stage, grade, lymph node involvement, and metastases (4). Also, differences in methods of treatment inuence the cancer prognosis. However, there is still a large variability in the clinical outcome of individuals with morphologic identical colorectal cancers who receive comparable therapeutic strategies. This variability may be due to differences in nutritional or other lifestyle factors. Dietary and lifestyle factors in relation to colorectal cancer incidence have been extensively investigated. The second World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) expert report (5) showed that higher body fatness, abdominal fatness, adult attained height, red meat and processed-meat intake, and lower physical activity are associated with a higher colorectal cancer risk. Higher alcohol intake is associated with a higher colorectal cancer risk in men, and probably also in women. Higher dietary ber, garlic, milk, and calcium intakes are probably associated with a lower colorectal cancer risk. Further, there is limited suggestive evidence for a protective effect of nonstarchy vegetables, fruit, sh, and foods that contain folate, vitamin D, or selenium. In contrast, higher intake of cheese and foods containing iron, animal fats, or sugars may lower colorectal cancer risk. Compared with the vast amount of literature with respect to colorectal cancer incidence, there is only a paucity of data about the effect of dietary and lifestyle factors on colorectal cancer recurrence and survival. This information is important because many individuals who have been diagnosed with colorectal cancer are motivated and have been shown to adjust their dietary and physical activity patterns (68). This review will summarize the evidence for the role of body mass index (BMI; in kg/m2), physical activity, and diet before, at the time of, and after co1 From the Division of Human Nutrition, Wageningen University, World Cancer Research Fund Project Group, Wageningen, Netherlands. 2 Supported by the World Cancer Research Fund. 3 Current address for AV: Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany. 4 Address correspondence to E Kampman, Division of Human Nutrition, Wageningen University, PO Box 8129, 6700 EV, Wageningen, Netherlands. E-mail: ellen.kampman@wur.nl. Received November 30, 2009. Accepted for publication June 24, 2010. First published online July 14, 2010; doi: 10.3945/ajcn.2009.29005.

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Am J Clin Nutr 2010;92:47190. Printed in USA. 2010 American Society for Nutrition

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VRIELING AND KAMPMAN

lorectal cancer diagnosis in colorectal cancer recurrence and survival.

METHODS

A search in the MEDLINE (www.ncbi.nlm.nih.gov/pubmed) and EMBASE (www.embase.com) databases was conducted up to March 2010 by using a combination of MeSH terms (colorectal neoplasms, recurrence, disease-free survival, mortality, motor activity, body weight, BMI, waist circumference, waist-hip ratio, body fat distribution, diet, diet therapy, food and beverages, and nutritional sciences) and related key words in titles or abstracts. Retrieved references were checked independently by the 2 investigators, and discordances were discussed and resolved. Relevant articles were obtained and included in the review if they reported on epidemiologic studies in colorectal cancer survivors with respect to BMI, physical activity, or diet in relation to allcause mortality, colorectal cancerspecic mortality, or colorectal cancer recurrence. Reference lists of relevant articles were checked to identify any additional epidemiologic studies. Only articles written in the English language were included. Studies were excluded from this review if they solely investigated associations of BMI, physical activity, or diet with intermediate endpoints of disease or with tumor characteristics and not with allcause mortality, colorectal cancerspecic mortality, or colorectal cancer recurrence. Weight loss and underweight were not taken into consideration because these factors are more likely to be of a disease-related cause than a lifestyle-related cause of disease outcome. Information extracted from each study included the rst author, year, country, sample (size and key characteristics), followup time, variable of interest, assessment method, outcome, contrast, risk estimates with 95% CIs, and factors that were adjusted for in the analysis. Because of the relatively small number of relevant studies and the large heterogeneity in type of exposure, timing of exposure assessment, and disease outcomes, a formal meta-analysis could not be conducted. The studies on BMI, physical activity, or diet in relation to all-cause mortality, colorectal cancerspecic mortality, or colorectal cancer recurrence were described separately according to the time period these factors were assessed [ie, before diagnosis (prediagnosis), at diagnosis, or after diagnosis (postdiagnosis)].
RESULTS

FIGURE 1. Overview of the number of retrieved relevant studies on BMI, physical activity (PA), and diet in relation to colorectal all-cause mortality, cancer-specic mortality, or recurrence by time of exposure assessment.

measured BMI (11, 12, 1921, 24, 25), and 4 studies obtained BMI from medical records (23, 26, 27, 29, 31). One study did not provide any information about BMI assessment (30). Some studies additionally reported on measured body weight (12, 17), waist circumference (12), percentage body fat (12), and visceral and subcutaneous fat areas (24, 30). BMI before cancer diagnosis Prediagnosis BMI and all-cause or cancer-specic mortality was investigated by 6 studies that were based on existing casecontrol (9, 10) or cohort studies (1116) that were originally designed to investigate dietary and lifestyle factors in relation to cancer incidence. Except for one study (11), all other studies were adjusted for the tumor stage. In 3 studies, including 410 colon cancer cases (9), 1882 colorectal cancer cases (11), and 526 colorectal cancer cases (12), no association of higher BMI with all-cause mortality (9, 11, 12) or colorectal cancerspecic mortality (12) was observed. Higher body fat, weight, and waist circumference were associated with a higher colorectal cancer specic mortality but not with all-cause mortality (12). One study in 633 colorectal cancer cases reported a higher risk of colon cancer-specic mortality [hazard ratio (HR): 2.1: 95% CI: 1.1, 3.8] and all-cause mortality (HR: 1.5: 95% CI: 1.0, 2.1) in obese compared with normal weight postmenopausal women (10). The risk of rectal cancer-specic mortality was not increased, and no association in overweight women was shown (10). Two studies in 647 colon cancer cases (1315) and 546 colorectal cancer cases (16), respectively, showed that the association between prediagnosis BMI and cancer-specic or allcause mortality may depend on molecular characteristics of the tumor. Higher BMI was associated with higher all-cause mortality in individuals with tumors positive for fatty acid synthase expression (13), p27 (cyclin-dependent kinase inhibitor 1B) expression (14), p21 (cyclin-dependent kinase inhibitor 1A) expression (15), or stathmin or oncoprotein-18 expression (16). The association between higher BMI and higher cancer-specic mortality only reached statistical signicance for individuals with tumors positive for p21 expression (15) and stathmin or oncoprotein-18 expression (16).

The initial search retrieved 2801 articles. We identied a total of 36 relevant articles that were based on 31 independent epidemiologic studies in colorectal cancer survivors that reported on BMI, physical activity, or dietary factors in relation to all-cause mortality, colorectal cancerspecic mortality, or colorectal cancer recurrence (Figure 1). These studies are discussed in more detail in this review.
BMI

The association between BMI and recurrence or survival of colorectal cancer has been investigated in 21 observational studies described in 24 articles (932) (Table 1). Six studies evaluated BMI before diagnosis (916), 14 studies investigated BMI at diagnosis (1731), and one study focused on BMI during and after chemotherapy (32). Nine studies investigated selfreported BMI (9, 10, 1318, 22, 28, 32), 7 studies evaluated

TABLE 1 Epidemiologic studies of BMI (in kg/m2) and colorectal cancer recurrence or survival1 Follow-up time Diagnosis: 19761981 Median: 83 mo (range: 1125 mo) Self-reported BMI 5 y (study 1) or 2 y (study 2) before diagnosis All-cause mortality BMI, Q4 vs Q1 (cutoffs: NA) 0.99 (0.90, 1.08) Variable of interest Outcome Contrast RR (95% CI) Adjustment Age, sex, stage, and year of diagnosis

First author, year, country

Sample (size and key characteristics)

BMI before diagnosis Slattery, 1989, United States (9)

Doria-Rose, 2006, United States (10)

Diagnosis: 19881991 Mean: 9.4 y (range: 0.914.7 y)

CC-specic mortality

2.1 (1.1, 3.8) 1.5 (0.9, 2.5)

Age, stage, PMH use, and smoking

Self-reported BMI 5 y before interview, which was conducted a median of 13 mo (range: 428 mo) after diagnosis RC-specic mortality All-cause mortality

Park, 2006, Korea (11)

410 CC cases (M, F), aged 4079 y, identied through the Utah Cancer Registry and part of 2 case-control studies 206 deaths 633 CRC cases (F, post), aged 3874 y, identied through the Wisconsin Cancer Reporting System and part of a casecontrol study 280 deaths and 147 CRC deaths 1882 CRC patients (M) diagnosed within the NHICS 555 deaths and 524 CRC deaths Diagnosis: 19962002 FU ended in 2004 (median: 3.8 y) Measured BMI at baseline All-cause mortality Obesity (BMI 30) and overweight (BMI of 25.029.9) vs normal weight (BMI of 20.024.9) Obesity Overweight Obesity Overweight BMI 25 vs ,23 0.6 (0.2, 1.6) 1.0 (0.5, 2.1) 1.5 (1.0, 2.1) 1.2 (0.9, 1.6) 1.00 (0.81, 1.24)

LIFESTYLE FACTORS IN COLORECTAL CANCER SURVIVAL

Haydon, 2006, Australia (12)

Diagnosis: 19902002 Median: 5.5 y

CRC-specic mortality

Body fat per 10% Body weight per 10 kg Waist circumference per 10 cm BMI per 5 kg/m2 All-cause mortality CC-specic mortality BMI 27.5 vs ,27.5 BMI 27.5 vs ,27.5 All-cause mortality BMI 27.5 vs ,27.5 BMI 27.5 vs ,27.5

Measured percentage body fat, body weight, waist circumference, and BMI at baseline (19901994)

1.33 (1.04, 1.71) 1.15 (1.02, 1.29) 1.20 (1.05, 1.37) 1.15 (0.98, 1.35) NS for for for for 2.94 (0.48, 18.0) FASN12 0.91 (0.63, 1.30) FASN2 4.10 (1.14, 14.8) FASN12 0.86 (0.65, 1.14) FASN2 Pint 0.019

Age, alcohol consumption, fasting serum glucose concentration, cholesterol concentration, physical activity, food preference, blood pressure, and other comorbidities Age, sex, and tumor stage

Ogino, 2009, United States (13)

526 CRC patients (M, F; stages IIV), aged 4279 y, diagnosed within the MCCS cohort study 208 deaths and 181 CRC deaths 647 CC patients (M, F; stages IIV) diagnosed within the NHS and HPFS cohort studies 279 deaths and 160 CC deaths Diagnosis: 1976/1986 2002 FU up to June 2006 Self-reported BMI from biennial questionnaire immediately preceding CC diagnosis

Age, year of diagnosis, sex, tumor location, stage, tumor grade, K-ras, BRAF, p53, MSI, and CIMP

(Continued)

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TABLE 1 (Continued )

First author, year, country Follow-up time Diagnosis: 1976/1986 2002 FU up to June 2006 BMI 30 vs ,30 for for for All-cause mortality BMI 30 vs ,30 BMI 30 vs ,30 Self-reported BMI from biennial questionnaire immediately preceding CC diagnosis CC-specic mortality BMI 30 vs ,30 2.25 (0.84, 6.01) p27-nuclear1 1.24 (0.72, 2.14) p27-altered 3.07 (1.49, 6.32) p27-nuclear1 1.08 (0.71, 1.65) p27-altered Pint 0.013 for for for for for Variable of interest Outcome Contrast RR (95% CI)

Sample (size and key characteristics)

Adjustment

Ogino, 2009, United States (14)

630 CC patients (M, F; stages IIV) diagnosed within the NHS and HPFS cohort studies 272 deaths and 160 CC deaths

Ogino, 2009, United States (15) BMI 30 vs ,30 All-cause mortality BMI 30 vs ,30 BMI 30 vs ,30

647 CC patients (M, F; stages IIV) diagnosed within the NHS and HPFS cohort studies 279 deaths and 162 CC deaths

Diagnosis: 1976/1986 2002 FU up to June 2006

Self-reported BMI from biennial questionnaire immediately preceding CC diagnosis

CC-specic mortality

BMI 30 vs ,30

Age, year of diagnosis, sex, family history CRC, tumor location, stage, grade, K-ras, BRAF, PIK3CA, p53, cyclin D1, b-catenin, COX-2, FASN, LINE-1 methylation, MSI, and CIMP Age, year of diagnosis, sex, family history CRC, tumor location, stage, grade, K-ras, BRAF, PIK3CA, p53, cyclin D1, LINE-1 methylation, MSI, and CIMP for

Ogino, 2009, United States (16) FU up to June 2006

Diagnosis: 1976/1986 2002

CRC-specic mortality

BMI 30 vs ,30 BMI 30 vs ,30

VRIELING AND KAMPMAN

546 CRC patients (M, F; stages IIV) diagnosed within the NHS and HPFS cohort studies All-cause mortality

Self-reported BMI from biennial questionnaire immediately preceding CC diagnosis

5.85 (2.28, 15.0) p211 1.05 (0.60, 1.83) p212 3.40 (1.65, 6.98) p211 0.94 (0.62, 1.43) p212 Pint 0.002 2.36 (1.18, 4.69) STMN11 0.51 (0.24, 1.07) STMN12 Pint 0.005 BMI 30 vs ,30 BMI 30 vs ,30

for

236 deaths and 149 CRC deaths

1.93 (1.13, 3.32) for STMN11 0.71 (0.40, 1.28) for STMN12 Recurrence .1, P 0.015 for M P 0.085 for F

Age, year of diagnosis, sex, family history CRC, tumor location, stage, grade, K-ras, BRAF, PIK3CA, p53, p21, p27, cyclin D1, b-catenin, COX2, FASN, LINE-1 methylation, MSI, and CIMP

BMI at diagnosis Tartter, 1984, United States (17) Diagnosis 19761979 5-y recurrence-free rate

Self-reported preoperative weight and BMI

279 CC patients (M, F; Dukes stage B2, C1, C2) consecutively diagnosed and undergoing curative resection 65% disease-free at 5 y

Weight greater than the median vs less than the median (cutoffs: NA) BMI greater than the median vs less than the median (cutoffs: NA)

P 0.646 for M .1, P 0.009 for F

(Continued)

TABLE 1 (Continued )

First author, year, country Follow-up time Diagnosis: 19851987 5- or 10-y survival Self-reported BMI at time of interview; 3 mo of diagnosis All-cause mortality BMI NS (data not shown) Variable of interest Outcome Contrast RR (95% CI) Adjustment

Sample (size and key characteristics)

Dray, 2003, France (18)

Age, sex, tumor stage, tumor location, and interaction terms

Meyerhardt, 2003, United States (19) Recurrence

148 CRC patients (M, F; Dukes stage AD), aged 3079 y, identied in the Cote dOr area and part of a case-control study 46 and 70 deaths at 5 and 10 y, respectively 3759 CC patients (M, F; stages II and III) treated within a randomized adjuvant chemotherapy trial (INT-0089) 1600 deaths and 1289 CC recurrences Inclusion: 19881992 Median: 9.4 y (max: 12.7 y) Measured BMI at day 1 of chemotherapy All-cause mortality Obesity (BMI 30) vs normal weight (BMI of 21.024.9) All-cause mortality Recurrence 1.34 (1.07, 1.67) for F, Pint 0.02 NS for M 1.24 (0.98, 1.59) for F, Pint 0.06 2.58 (1.23, 5.42) for F ,50 y NS for M NS for M and F NS for M and F

Age, race, baseline performance status, bowel obstruction, bowel perforation, Duke stage, presence of peritoneal implants, predominant macroscopic pathologic feature, and completion chemotherapy NS for M and F 1.61 (1.00, 2.59) for M, P for trend 0.11 NS for F NS for M and F NS for M and F NS for M and F 1.66 (1.07, 2.56) for M NS for F

Meyerhardt, 2004, United States (20)

Inclusion: 19901992 Median: 9.9 y (max: 11.8 y)

Measured BMI at day 1 of chemotherapy

All-cause mortality Local recurrence

Overweight (BMI of 27.529.9 and 25.0 27.49) vs normal weight Obesity (BMI 30) vs normal weight (BMI of 2024.9)

LIFESTYLE FACTORS IN COLORECTAL CANCER SURVIVAL

1688 RC patients (M, F; stages II and III) treated within a randomized adjuvant chemotherapy and radiotherapy trial (INT-0114) Deaths and RC recurrences: NA Recurrence Recurrence or death Local recurrence Inclusion: 19891994 Median: 11.2 y Measured BMI at day 1 of chemotherapy CC-specic mortality All-cause mortality Recurrence Recurrence or death

Age, race, baseline performance status, bowel obstruction, extent of bowel-wall invasion, no. of positive lymph nodes, and operation type

Dignam, 2006, United States (21)

1.36 (1.06, 1.73) 1.28 (1.04, 1.57) 1.38 (1.10, 1.73) 1.27 (1.05, 1.53) NS NS

4288 CC patients (M, F; Dukes stage B and C) treated within 2 randomized adjuvant chemotherapy trials (NSABP C-04 and C-05) 1697 deaths, 1159 CC deaths, and 1286 CC recurrences or secondary primary tumors

Overweight (BMI of 27 29.9) and overweight (BMI of 2526.9) vs normal weight Severe obesity (BMI 35) vs normal weight (BMI of 18.524.9) Obesity (BMI of 30.034.9) Overweight (BMI of 25.029.9)

Age, sex, race, performance status, number of positive lymph nodes, presence of bowel obstruction, and treatment

475
(Continued)

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TABLE 1 (Continued )

First author, year, country Follow-up time Diagnosis: 19941996 79 y 1.01 (0.94, 1.08) for familial CRC 0.96 (0.93, 0.99) for sporadic CRC Self-reported BMI at diagnosis All-cause mortality BMI per 1-kg/m2 increase BMI per 1-kg/m2 increase Variable of interest Outcome Contrast RR (95% CI) Adjustment Age, sex, treatment with surgery, radiation, and chemotherapy

Sample (size and key characteristics)

Zell, 2007, United States (22)

Moghimi-Dehkordi, 2008, Iran (23)

141 familial (at least one rst- degree relative) and 358 sporadic CRC patients (M, F); part of the UCI 199 deaths and 95 CRC deaths (of 106 recorded deaths) 1127 CRC patients (M, F; stage IIV; average age at diagnosis: 54 y), registered in a cancer registry 21% deaths of 1127 patients with survival info (237 patients) Included: 2002 January 2007 Median: 7.9 y BMI at diagnosis from medical records All-cause mortality Overweight (BMI of 2529.9) and obesity (BMI .30) vs normal weight (BMI of 18.624.9) 1.41 (P 0.65) 1.80 (P 0.15) Surgery: 19982001 .1 y All-cause mortality Recurrence or death Preoperative BMI from database; visceral obesity before surgery All-cause mortality Recurrence or death .1.00 (P 0.210) .1.00 (P 0.064) .1.00 (P 0.241) 1.98 (1.02, 3.87)

VRIELING AND KAMPMAN

Moon, 2008, Korea (24)

161 CRC patients (M, F; average age: 66 y) selected from a surgical database Deaths: NA

Family history of cancer, rst treatment, tumor grade, tumor size, extent of wall penetration, regional lymph node metastasis, distant metastasis, and pathologic stage Not clearly stated (age, sex, tumor size, and lymph node metastasis)

Tian, 2008, China (25)

Diagnosis: January June 2006 1-y survival

Measured BMI 20 d after surgery

All-cause mortality

Overweight (BMI 25) vs normal weight (BMI ,25) Ratio of visceral fat area and subcutaneous fat area greater than the median vs less than the median (cutoff values: NA) BMI .25 vs 1825

1.27 (0.08, 19.4)

Age, sex, and tumor stage

Asghari-Jafarabadi, 2009, Iran (26) Included: 2002October 2007 Mean: 9.3 y (CC) and 11.3 y (RC)

BMI at diagnosis from medical records

All-cause mortality

39 CRC patients (M, F; stages IIV) who underwent surgery in 4 provincial-level hospitals in Fuzhou, China 14 deaths 1219 CRC patients (M, F; stages IIV; average age at diagnosis: 54 y), registered in a cancer registry Deaths: NA

Overweight (BMI of 2529.9) and obesity (BMI .30) vs normal weight (BMI of 18.624.9)

239 CC: 0.32 (0.14, 0.71 (0.25, 291 RC: 0.40 (0.16, 0.76 (0.16,

0.73) 2.03) 0.97) 3.57)

CC: sex, alcohol, inammatory bowel disease, tumor stage, grade, and size RC: personal history of cancer, treatment, and tumor stage (Continued)

TABLE 1 (Continued )

First author, year, country Follow-up time Surgery: 19812002 FU up to 2008 (minimum: 5 y) BMI at day of surgery from medical records All-cause mortality Overweight/obese (BMI 25) vs normal weight (,18.5) 0.77 (0.61, 0.97) NS for stages IIII only 0.58 (0.37, 0.90) for stage IV Variable of interest Outcome Contrast RR (95% CI)

Sample (size and key characteristics)

Adjustment Age, race, comorbidity, tumor stage, grade, and bowel obstruction

Hines, 2009, United States (27)

You, 2009, Taiwan (28)

Included: 19952002 Median: 74.5 mo (range: 32.9136.8 mo) Recurrence or death

Self-reported BMI at day of admission

Local recurrence

Obesity (BMI 30) and overweight (BMI of 2529.9) vs underweight (BMI ,18.5)

4.71 (1.01, 21.9) 3.24 (0.78, 13.4) for lower RC NS for upper RC NS for lower and upper RC

Age, sex, resection margin, tumor size, grade, and stage

Ballian, 2010, United States (29)

496 CC patients (M, F; stages IIV; average age: 67 y) who underwent surgery at the University of Alabama at Birmingham Hospital 333 deaths 1873 RC patients (M, F; stages IIV) registered in the Colorectal Section Tumor Registry, Chang-Gung Memorial Hospital, consecutively undergoing resection 230 RC patients (M, F; stages IIII) who underwent protectomy 44 recurrences; deaths: NA Surgery: 19972009 Median: 23 mo (range: 0158 mo) BMI at day of surgery Recurrence All-cause mortality BMI 30 vs ,30 P 0.49 P 0.63

LIFESTYLE FACTORS IN COLORECTAL CANCER SURVIVAL

Guiu, 2010, France (30)

Included: 20022008 Median: 24 mo (range: 370) and 30 mo (range: 484), respectively

Visceral fat area, subcutaneous fat area, and BMI before chemotherapy initiation

All-cause mortality

Visceral fat area greater than or equal to the median vs less than the median Subcutaneous fat area greater than or equal to the median vs less than the median BMI 23.6 vs ,23.6

2.88 (1.13, 7.32) (bevacizumabbased), NS (chemotherapy alone) NS (bevacizumabbased, chemotherapy alone) NS (bevacizumabbased, chemotherapy alone)

80 CRC patients who received bevacizumab-based chemotherapeutic treatment and 40 CRC patients who received chemotherapy alone (M, F; metastatic CRC) 58 and 18 deaths, respectively

Age, sex, tumor stage at diagnosis, tumor stage after resection, postoperative complications, margin status, tumor grade, and preoperative chemoradiotherapy Performance status, visceral fat area, and subcutaneous fat area

(Continued)

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TABLE 1 (Continued )

First author, year, country Follow-up time Surgery: 20022006 BMI from medical records All-cause mortality Overweight (BMI 25) vs normal weight (BMI ,25) NS Variable of interest Outcome Contrast RR (95% CI)

Sample (size and key characteristics)

Adjustment No adjustment

Pathak, 2010, United Kingdom (31)

73 CRC patients with liver metastases (M, F; median age: 65 y) who underwent hepatectomy in the Aintree University Hospital Deaths: NA Inclusion: 19992001 Median: 5.3 y Recurrence or death 1.24 (0.84, 1.83) 1.00 (0.72, 1.40) 0.81 (0.59, 1.11) NS NS NS

BMI after diagnosis Meyerhardt, 2008, United States (32)

VRIELING AND KAMPMAN

1053 CRC patients (M, F; stage III) treated within a postoperative adjuvant chemotherapy trial (CALGB 89803) 261 deaths, 369 recurrences and deaths, and 338 recurrences All-cause mortality Recurrence

Self-reported BMI midway through and 6 mo after completion of adjuvant chemotherapy (14 and 4 mo after surgical resection, respectively); weight change

Class II to III obesity (BMI 35) or class I obesity (BMI of 30 34.9) or overweight (BMI of 2529.9) vs normal weight (BMI of 2124.9) 5 kg weight gain vs 62 kg weight gain

Age, sex, depth of invasion through bowel wall, no. of positive lymph nodes, clinical perforation at time of surgery, bowel obstruction at time of surgery, baseline performance status, treatment group, time between rst and second questionnaire, timevarying BMI, smoking status at second questionnaire, and physical activity

1 RR, relative risk; CC, colon cancer; Q, quartile; NA, not available; CRC, colorectal cancer; post, postmenopausal; PMH, postmenopausal hormone; NHICS, National Health Insurance Corporation Study; FU, follow-up; MCCS, Melbourne Collaborative Cohort Study; NHS, Nurses Health Study; HPFS, Health Professionals Follow-Up Study; FASN, fatty acid synthase; 1, positive; 2, negative; K-ras, Kirsten rat sarcoma viral oncogene homolog; BRAF, v-raf murine sarcoma viral oncogene homolog B1; MSI, microsatellite instability; CIMP, CpG island methylator phenotype; PIK3CA, phosphoinositide-3-kinase, catalytic, alpha polypeptide; COX-2, cyclooxygenase-2; LINE-1, long interspersed nucleotide element-1; STMN1, stathmin 1; max, maximum; RC, rectal cancer; NSABP, National Surgical Adjuvant Breast and Bowel Project; UCI, University of California Irvine CRC gene-environment study; CALGB, Cancer and Leukemia Group B; Pint, P for interaction. 2 Only adjusted for stage because of 7 total deaths.

LIFESTYLE FACTORS IN COLORECTAL CANCER SURVIVAL

479

BMI at cancer diagnosis Fourteen studies investigated BMI at the time of colorectal cancer diagnosis (1731). The rst study on BMI in relation to colon cancer recurrence was published in 1984 and conducted in 279 consecutively diagnosed colon cancer patients who were undergoing curative resection (17). This study showed a higher risk of recurrence in women but not in men above compared with below the median BMI and did not adjust for any other relevant factors. One study that was based on an existing casecontrol study that included 148 colorectal cancer patients showed no relation between BMI at diagnosis and 5 or 10 y of survival (18). In a study initially set up as a case-case study, higher BMI was associated with lower all-cause mortality in 358 sporadic colorectal cancer cases but not in 141 familial colorectal cancer cases (22). One study conducted in Iran was reported twice (23, 26) and rst showed analyses for colorectal cancer patients combined (23) and later showed analyses for colon and rectal cancer cases, separately (26). Although the follow-up time for the colon and rectal cancer cases was somewhat longer than for the colorectal cancer cases combined, the number of colon and rectal cases included in the analyses was lower than the number of colorectal cancer cases, partly because of differential adjustment for confounding factors. Overweight and obesity were nonstatistically signicantly associated with higher all-cause mortality in colorectal cancer cases combined (23). All-cause mortality was signicantly lower in overweight and nonsignicantly lower in obese colon and rectal cancer cases separately compared with normal weight colon and rectal cancer cases (26). In 39 colorectal cancer (25) and 230 rectal cancer patients (29), overweight (25) and obesity (29) were not associated with all-cause mortality (25, 29) or recurrence (29). No association for overweight was shown in 73 colorectal cancer patients with liver metastases (31), whereas in another study in stage IV colon cancer patients, a protective effect on all-cause mortality was shown (27). In a small study in 161 colorectal cancer patients, a high compared with low ratio of visceral fat and subcutaneous fat area was associated with a higher risk of recurrence or all-cause mortality (HR: 1.98; 95% CI: 1.02, 3.87), whereas no association for overweight was shown (24). A recent study in 80 colorectal cancer patients who received a bevacizumab-based chemotherapeutic treatment conrmed that a visceral fat area above the median compared with below the median was associated with a higher risk of allcause mortality (HR: 2.88; 95% CI: 1.13, 7.32) (30). No associations with the subcutaneous fat area and BMI were observed, and none of these 3 factors were associated with all-cause mortality in 40 colorectal cancer patients who received chemotherapy alone (30). A study in 1873 rectal cancer patients reported a higher risk of local recurrence in obese compared with underweight patients with lower rectal cancer (HR: 4.71: 95% CI: 1.01, 21.9) but not in patients with upper rectal cancer (28). No association of obesity with recurrence and death was observed for both patient groups (28). Three large adjuvant chemotherapy trials investigated BMI measured at day 1 of chemotherapy (1921) in relation to cancer recurrence and survival in 3759 (19) and 4288 (21) patients with colon cancer and 1688 patients with rectal cancer (20). Analyses were extensively adjusted for several prognostic variables, including the tumor stage, bowel obstruction at the time of surgery,

and functional and physical performance status. In one study, obese women (BMI 30) were at a higher risk of all-cause mortality (HR: 1.34; 95% CI: 1.07, 1.67) and at a nonsignicantly higher risk of colon cancer recurrence (HR: 1.24; 95% CI: 0.98, 1.59) compared with normal weight women, particularly those ,50 y of age (HR: 2.58; 95% CI 1.23, 5.42 for colon cancer recurrence) (19). No such associations were observed in men (19). In the other study, only severe obesity (BMI 35) compared with normal weight was associated with a higher risk of recurrence (HR: 1.38; 95% CI: 1.10, 1.73), colon cancer-specic mortality (HR: 1.36; 95% CI: 1.06, 1.73), and all-cause mortality (HR: 1.28; 95% CI: 1.04, 1.57), and similar results were obtained for men and women (21). In patients with rectal cancer, obese men (BMI 30) were at higher risk of local rectal cancer recurrence compared with normal weight men (HR: 1.61; 95% CI: 1.00, 2.59) (20). The risk of all-cause mortality was not increased, and no signicant associations were observed in women. Local rectal cancer recurrence was also higher in overweight men (BMI of 2526.9: HR: 1.66; 95% CI: 1.07, 2.56). Further, no signicant associations with overweight were shown in these studies. BMI after cancer diagnosis Only one study investigated BMI during chemotherapy and weight change from the time of chemotherapy through 6 mo after completion of chemotherapy (32). This study was conducted in 1053 patients with colon cancer. Obese (BMI of 3034.9) or severely obese (BMI 35) subjects compared with normal weight subjects at the time of chemotherapy were not at higher risk of recurrence and/or all-cause mortality. Also, weight gain from the time of chemotherapy through 6 mo after chemotherapy was not associated with recurrence and/or death. Physical activity The association between physical activity and recurrence or survival of colorectal cancer was investigated in 6 studies (12, 18, 3336) (Table 2). In 4 of these studies, previously validated physical activity questionnaires were used, and leisure-time physical activity was assessed in metabolic equivalent task (MET)hours per week (3336). One study recorded physical activity as low (totally sedentary lifestyle), moderate, or high (recreational or occupational activity that required strenuous physical activity), but no further details were given (18). In the other study, 3 questions were asked about the frequency per week of vigorous exercise, less vigorous exercise, and walking (12). There were no results of randomized clinical trials on physical activity and recurrence or survival of colorectal cancer. Physical activity before cancer diagnosis In 526 colorectal cancer patients who were identied within a cohort study, nonoccupational physical activity was assessed before diagnosis (12). Exercisers were shown to be at lower risk of colorectal cancerspecic mortality than were nonexercisers (HR: 0.73; 95% CI: 0.54, 1.00). In another study in 573 female colorectal cancer patients, colorectal cancerspecic and allcause mortality did not differ for women in the highest quartile compared with the lowest quartile of leisure-time physical activity that was assessed a median of 6 mo before diagnosis (33).

480

TABLE 2 Epidemiologic studies of physical activity and colorectal cancer recurrence or survival1 Follow-up time Variable of interest Outcome Contrast RR (95% CI) Adjustment

First author, year, country

Sample (size and key characteristics)

Physical activity before diagnosis Haydon, 2006, Australia (12) Diagnosis: 19902002 Median: 5.5 y Self-reported nonoccupational physical activity at baseline (median: 5.3 y before diagnosis) CRC-specic mortality Exercisers vs nonexercisers 0.73 (0.54, 1.00)

Age, sex, and tumor stage

Meyerhardt, 2006, United States (33)

526 CRC patients (M, F; stages IIV; aged 2775 y) diagnosed within the MCCS cohort 208 deaths and 181 CRC deaths 573 CRC patients (F; stages IIII) diagnosed within the NHS 132 deaths and 80 CRC deaths Inclusion: 19862002 Median: 9.6 y Self-reported leisuretime physical activity (median: 6 mo before diagnosis) CRC-specic mortality All-cause mortality Total MET-h activity prediagnosis, 18 vs ,3/wk 0.86 (0.44, 1.67) 0.95 (0.57, 1.59)

VRIELING AND KAMPMAN

Meyerhardt, 2009, United States (36)

661 CRC patients (M; stages IIII) diagnosed within the HPFS 258 deaths and 88 CRC deaths

Diagnosis: 19862004 Median: 8.6 y Self-reported leisuretime physical activity (6 mo before diagnosis)

CRC-specic mortality All-cause mortality

Total MET-h activity prediagnosis

P for trend 0.65 P for trend 0.26

Age at diagnosis, year of diagnosis, BMI, stage of disease, tumor-differentiation grade, location of primary tumor, chemotherapy, time from diagnosis to physical activity measurement, change in BMI before and after diagnosis, and smoking status Age at diagnosis, year of diagnosis, BMI, stage of disease, tumordifferentiation grade, location of primary tumor, time from diagnosis to physical activity measurement, change in BMI before and after diagnosis, and smoking status

Physical activity at time of diagnosis Dray, 2003, France (18) Diagnosis 19851987 5- or 10-y survival

148 CRC patients (M, F; Dukes stage AD; aged 3079 y) identied in the Cote dOr area and part of a case-control study 46 and 70 deaths 5 and 10 y, respectively

Physical activity at time of interview, 3 mo of diagnosis

All-cause mortality

Physical activity

NS (data not shown)

Age, sex, stage, and tumor location

(Continued)

TABLE 2 (Continued )

First author, year, country Follow-up time Variable of interest Outcome Contrast RR (95% CI)

Sample (size and key characteristics)

Adjustment

Physical activity after diagnosis Meyerhardt, 2006, United States (33) Inclusion: 19862002 Median: 9.6 y 0.48 (0.24, 0.97) 1.32 (0.74, 2.34) Similar results Self-reported leisuretime physical activity (median: 6 mo before diagnosis and 14 y postdiagnosis) and change in physical activity All-cause mortality CRC-specic mortality Total MET-h activity postdiagnosis, 18 vs ,3/wk Increase in physical activity vs no change Decrease in physical activity vs no change 0.39 (0.18, 0.82)

573 CRC patients (F; stages IIII) diagnosed within the NHS 132 deaths and 80 CRC deaths

LIFESTYLE FACTORS IN COLORECTAL CANCER SURVIVAL

Meyerhardt, 2006, United States (34)

832 CC patients (M, F; stage III) treated within a postoperative adjuvant chemotherapy trial (CALGB 89803) 84 deaths and 159 CC recurrences

Inclusion: 19992001 Median: 3.8 y

Self-reported physical activity 6 mo after completion of chemotherapy

All-cause mortality Recurrence Recurrence or death

Total MET-h activity postdiagnosis, 27 vs ,3/wk

0.37 (0.16, 0.82) 0.60 (0.36, 1.01) 0.55 (0.33, 0.91)

Age at diagnosis, year of diagnosis, BMI, stage of disease, tumor-differentiation grade, location of primary tumor, chemotherapy, time from diagnosis to physical activity measurement, change in BMI before and after diagnosis, and smoking status Age, sex, depth of invasion through bowel wall, no. of positive lymph nodes, clinical perforation at time of surgery, bowel obstruction at time of surgery, baseline CEA, tumordifferentiation grade, baseline performance status, treatment arm, weight change between rst and second questionnaire, BMI at time of second questionnaire, time between study entry and completion of second questionnaire (Continued)

481

482

TABLE 2 (Continued )

First author, year, country Follow-up time Diagnosis: 1976/1986 2002 FU: 1986 to June 2006 Self-reported leisuretime physical activity 14 y (median: 17 mo) postdiagnosis CC-specic mortality Total MET-h activity postdiagnosis, 18 vs ,18/wk Variable of interest Outcome Contrast

Sample (size and key characteristics)

RR (95% CI) 0.64 (0.33, 1.23) 0.32 (0.12, 0.85) for p271

Adjustment Age, sex, stage, year of diagnosis, histology grade, BMI, and time of physical activity assessment No interaction by FASN, K-ras, p53, p21, PIK3CA

Meyerhardt, 2009, United States (35)

484 CC patients (M, F; stages IIII) diagnosed within the NHS and HPFS 152 deaths and 50 CC deaths All-cause mortality

VRIELING AND KAMPMAN

Meyerhardt, 2009, United States (36)

661 CRC patients (M; stages IIII) diagnosed within the HPFS 258 deaths and 88 CRC deaths

Diagnosis: 19862004 Median: 8.6 y

Self-reported leisuretime physical activity 6 mo to 4 y (median: 15 mo) postdiagnosis

CRC-specic mortality All-cause mortality

Total MET-h activity postdiagnosis, 18 vs ,18/wk Total MET-h activity postdiagnosis, 27 vs ,3/wk

1.40 (0.41, 4.72) for p272 Pint 0.03 0.60 (0.41, 0.86) Pint 0.37 for p271 vs p272 0.47 (0.24, 0.92) 0.59 (0.41, 0.86)

Age at diagnosis, year of diagnosis, BMI, stage of disease, tumor-differentiation grade, location of primary tumor, time from diagnosis to physical activity measurement, change in BMI before and after diagnosis, and smoking status

1 RR, relative risk; CRC, colorectal cancer; MCCS, Melbourne Collaborative Cohort Study; NHS, Nurses Health Study; MET-h, metabolic equivalent task-hours; CC, colon cancer; CALGB, Cancer and Leukemia Group B; CEA, carcinoembryonic antigen; HPFS, Health Professionals Follow-Up Study; FU, follow-up; 1, positive; 2, negative; FASN, fatty acid synthase; K-ras, Kirsten rat sarcoma viral oncogene homolog; PIK3CA, phosphoinositide-3-kinase, catalytic, alpha polypeptide; Pint, P for interaction; MET-h, metabolic equivalent task hours.

LIFESTYLE FACTORS IN COLORECTAL CANCER SURVIVAL

483

Similarly, in 661 male colorectal cancer patients, no signicant trend in colorectal cancerspecic and all-cause mortality was detected with increasing exercise (36). Physical activity at time of cancer diagnosis In a study in 148 colorectal cancer patients, physical activity assessed at 3 mo of diagnosis was not related to the 5- or 10-y survival of colorectal cancer (18). Physical activity after cancer diagnosis In the study in 573 female colorectal cancer patients (33), cases in the highest quartile for leisure-time physical activity that was assessed 14 y after diagnosis were at lower risk of colorectal cancerspecic mortality than were cases in the lowest quartile (HR: 0.39; 95% CI: 0.18, 0.82). Similar results were obtained in the 661 male colorectal cancer survivors (HR: 0.47; 95% CI: 0.24, 0.92) (36). Risk estimates for all-cause mortality were comparable with those for colorectal cancer specic mortality for both studies. Furthermore, female colorectal cancer patients who increased their physical-activity level after diagnosis were at lower risk of colorectal cancer specic mortality (HR: 0.48; 95% CI: 0.24, 0.97) and all-cause mortality than were patients that did not change their physicalactivity level (33). A randomized adjuvant chemotherapy trial in 832 colon cancer patients showed a lower risk of colon cancer recurrence or death for patients in the highest quintile of physical activity 6 mo after chemotherapy than for patients in the lowest quintile (HR: 0.55; 95% CI: 0.33, 0.91) (34). Another study in 484 colon cancer patients showed a nonsignicantly lower risk of colon cancer-specic mortality (HR: 0.64: 95% CI: 0.33, 1.23) and a lower risk of all-cause mortality (HR: 0.60: 95% CI: 0.41, 0.86) for cases with a leisure-time physical activity of 18 MET-h/wk than cases who engaged in ,18 MET-h/wk of exercise after diagnosis (35). This study also investigated whether this protective association was dependent on molecular characteristics of the tumor. The postdiagnosis leisure-time physical activity of 18 MET-h/wk compared with ,18 MET-h/wk decreased the risk of colon cancer-specic mortality for tumors with p27 nuclear expression (HR: 0.32; 95% CI: 0.12, 0.85) but not for tumors with a loss of p27. Physical activity did not differentially affect the all-cause mortality of p27-positive and p27-negative tumors. No modifying effect of fatty acid synthase, Kirsten rat sarcoma viral oncogene homolog; p53; p21; and phospoinositide-3kinase, catalytic, alpha polypeptide on the association between exercise and colon cancer-specic or all-cause mortality was observed. Dietary factors The association between dietary factors and the recurrence or survival of colorectal cancer has been investigated in 12 observational studies described in 14 articles (9, 11, 18, 22, 25, 26, 3744) (Table 3). Seven of these studies examined dietary factors that referred to the time before cancer diagnosis (9, 11, 18, 22, 26, 3740), and 5 studies investigated postdiagnosis dietary factors (25, 4144). Eight studies examined habitual diet assessed by a questionnaire (9, 11, 18, 22, 25, 26, 37, 38, 41). These studies used food-frequency questionnaires (9, 22, 25, 37,

38, 41) or a qualitative and quantitative dietary questionnaire (18) or obtained information about alcohol intake from a baseline questionnaire (11) or hospital-document information (26). Four studies evaluated blood concentrations of vitamins (39, 40, 4244). As also reported by the second WCRF/AICR expert report (5), only 5 small intervention studies conducted in 100 randomly assigned colorectal cancer patients investigated the effects of diet and supplements with respect to all-cause mortality, and no signicant results were shown. A more recent avonoid intervention in 29 colorectal cancer patients did not show any effect on cancer recurrence either (45). The null results can be largely explained by small numbers and low trial quality, and are not further discussed in this review. Dietary factors before cancer diagnosis Six studies investigated prediagnosis diet and were initially set up as case-control (9, 18), case-case (22, 37), or cohort (11, 38) studies to examine the association between dietary factors and colorectal cancer incidence or were based on cancer-registry data (26). Studies included 148 to 1882 colorectal cancer cases. Diet was assessed after a cancer diagnosis by a questionnaire that referred to habitual diet before the diagnosis (9, 18, 22, 26, 37) or interview (11, 38). In all but one (11) studies, associations were adjusted for the tumor stage at the diagnosis, and associations in one study (22) were additionally adjusted for the cancer treatment. In 2 of the 3 studies, high compared with low energy intake before diagnosis was associated with a lower risk of allcause death at 2 (9) and 5 y (18) of survival, but no association was shown after longer follow-up. In the other study, prediagnosis energy intake was not associated with overall survival after 79 y of follow-up (22). Higher dietary ber intake was associated with a higher risk of all-cause mortality in one study (9) but not in the other 2 studies (18, 22). In the case-case study, higher meat consumption was associated with a higher risk of all-cause mortality in familial but not sporadic colorectal cancer cases (37). Further, regular compared with infrequent wine consumption was associated with a lower risk of all-cause mortality in cases with a family history of colorectal cancer only (22). No association was shown for total alcohol consumption with all-cause mortality in 2 studies in colorectal (11) and colon (26) cancer cases, respectively. Whole-year daily use of cod liver oil or daily use of other dietary supplements compared with nonuse was also not associated with all-cause mortality in colorectal cancer cases (38). In a cohort study that included 304 colorectal cancer cases, plasma concentrations of 25-hydroxyvitamin D3 [25(OH)D] (39) or folate (40) were evaluated. Plasma concentrations were assessed a median of 6 y before the colorectal cancer diagnosis and were related to colorectal cancerspecic and all-cause mortality. Both analyses were adjusted for the stage of disease, and in the analysis on folate, a limited adjustment for the use of chemotherapy was possible. Colorectal cancerspecic mortality was nonsignicantly lower for subjects in the highest quartile than in the lowest quartile of plasma 25(OH)D concentrations (HR: 0.61; 95% CI: 0.31, 1.19) and was signicantly lower for the highest quintile than for the lowest quintile of plasma folate concentrations (HR: 0.42; 95% CI: 0.20, 0.88). Results were similar for all-cause mortality.

484

TABLE 3 Epidemiologic studies of diet, blood concentrations of vitamins, and colorectal cancer recurrence or survival1 Follow-up time All-cause mortality Energy 0.60 (0.37, 0.98) (particularly for those dying ,2 y of diagnosis) NS NS NS NS NS NS NS NS 0.18 (0.07, 0.44) NS Carbohydrate Fat Protein Foods, micronutrients All-cause mortality Alcohol, 124.2 vs 0 g/wk Similar Similar Similar NS 0.92 (0.72, 1.19) Diagnosis: 19761981 Median: 83 mo (range: 1125 mo) FFQ ,6 mo after diagnosis Referring to the 5 y (study 1) or 2 y (study 2) before diagnosis Q4 vs Q1 (cutoffs: NA) Dietary assessment method Outcome Contrast RR (95% CI) Adjustments Age, sex, stage, year of diagnosis, religion, and crude ber

First author, year, country

Sample (size and key characteristics)

Diet before diagnosis Slattery, 1989, United States (9)

410 CC cases (M, F; aged 4079 y) identied through the Utah Cancer Registry and part of 2 case-control studies 206 deaths

VRIELING AND KAMPMAN

Dray, 2003, France (18)

Diagnosis: 19851987 5- or 10-y survival

Qualitative and quantitative dietary questionnaire ,3 mo after diagnosis Referring to the year before diagnosis

All-cause mortality after 5 y All-cause mortality between 5 and 10 y

Crude ber Fat (total, percentage kcal) Fat types Protein (total, percentage kcal) Cholesterol Calcium Vitamin A Vitamin C Energy, high vs moderate and low

Age, sex, stage, tumor location, and interaction terms

Park, 2006, Korea (11)

148 CRC patients (M, F; Dukes stage AD; aged 3079 y) identied in the Cote dOr area and part of a case-control study 46 and 70 deaths 5 and 10 y, respectively 1882 CRC patients (M) diagnosed within the NHICS 555 deaths and 524 CRC deaths Diagnosis: 19962002 FU to end of 2004 (median: 3.8 y) Self-administered baseline questionnaire including alcohol use

Zell, 2007, United States (37)

Diagnosis: 19941996 79 y

144 familial (at least one rst-degree relative) and 367 sporadic CRC patients (M, F) part of the UCI 203 deaths

FFQ less than a median of 2 y after diagnosis Referring to the year before diagnosis

All-cause mortality

2.24 (1.25, 4.03) for familial CRC 1.01 (0.67, 1.51) for sporadic CRC

Meat: 10.827.4 (Q4) vs 010.7 (Q1Q3) servings/wk Meat: 12.661.5 (Q4) vs 05.3 (Q1Q3) servings/wk

Age, BMI, fasting serum glucose concentration, cholesterol concentration, physical activity, food preference, blood pressure, and other comorbidities Age, sex, and stage

(Continued)

TABLE 3 (Continued )

First author, year, country Follow-up time Diagnosis: 19941996 79 y FFQ less than a median of 2 y after diagnosis Referring to the year before diagnosis All-cause mortality Wine, 13 glasses/mo vs ,1 glass/mo Outcome Contrast RR (95% CI)

Sample (size and key characteristics)

Dietary assessment method

Adjustments Age, sex, stage, SES, BMI, beer, liquor, treatment with surgery, radiation, and chemotherapy

Zell, 2007, United States (22)

141 familial (at least one rst-degree relative) and 358 sporadic CRC patients (M, F) part of the UCI 199 deaths and 95 CRC deaths (of 106 recorded deaths) Included 2002 to October 2007 Mean: 9.3 y (CC) and 11.3 y (RC) Hospital document information All-cause mortality Beer Liquor Energy Fiber Calcium Fruit and vegetables Alcohol past or current vs never used

Asghari-Jafarabadi, 2009, Iran (26)

0.50 (0.25, 0.99) for familial CRC; 0.89 (0.59, 1.33) for sporadic CRC NS NS NS NS NS NS 239 CC: 1.84 (0.89, 3.81)

Sex, BMI, inammatory bowel disease and tumor stage, grade, and size

Skeie, 2009, Norway (38)

Diagnosis 1996/1999 2007 FU up to end 2007

1219 CRC patients (M, F; stages IIV; average age: 54 y) at diagnosis registered in a cancer registry Deaths: NA 399 CRC patients (F; 65% regional metastases; average age: 61 y) diagnosed within the Norwegian Women and Cancer cohort study 143 deaths FFQ at baseline (1996 1999) Referring to the year before interview All-cause mortality

0.82 (0.48, 1.41)

Age at diagnosis, smoking, stage 1.19 (0.84, 1.69)

Whole year daily users vs nonusers of cod liver oil Daily users vs nonusers of other dietary supplements

LIFESTYLE FACTORS IN COLORECTAL CANCER SURVIVAL

Blood concentrations before diagnosis Ng, 2008, United States (39) Diagnosis 19892002 FU up to 2005 Median: 78 mo (range: 36162 mo) Plasma 25(OH)D concentrations assessed a median of 6.0 y (range: 2.1 10.7 y) before diagnosis

304 CRC patients (M, F; stages IIV) diagnosed within the NHS and HPFS cohort studies 123 deaths and 96 CRC deaths

CRC-specic mortality All-cause mortality

Plasma 25(OH)D, Q4 vs Q1

0.61 (0.31, 1.19) 0.52 (0.29, 0.94)

Age at diagnosis, season of blood draw, sex, cancer stage, grade of tumor differentiation, location of primary tumor, year of diagnosis, BMI at diagnosis, and postdiagnosis physical activity (Continued)

485

486

TABLE 3 (Continued )

First author, year, country Follow-up time Diagnosis: 19892002 FU to 2005 Median: 78 mo (range: 36162 mo) Plasma folate concentrations assessed a median of 6.0 y (range 2.110.7 y) before diagnosis CRC-specic mortality All-cause mortality Plasma folate, Q5 vs Q1 0.42 (0.20, 0.88) 0.46 (0.24, 0.88) Outcome Contrast RR (95% CI)

Sample (size and key characteristics)

Dietary assessment method

Adjustments

Wolpin, 2008, United States (40)

301 CRC patients (M, F; stages IIV) diagnosed within the NHS and HPFS cohort studies 122 deaths and 95 CRC deaths

Diet after diagnosis Meyerhardt, 2007, United States (41) Inclusion: 19992001 Median: 5.3 y All-cause mortality Recurrence Recurrence or death

2.32 (1.36, 3.96) 2.85 (1.75, 4.63) 3.25 (2.04, 5.19)

VRIELING AND KAMPMAN

1009 patients (M, F; stage III) treated within a postoperative adjuvant chemotherapy trial (CALGB 89803) 251 deaths, 223 CC deaths, and 324 CC recurrences

FFQ midway through adjuvant therapy and 6 mo after completion of adjuvant therapy (4 and 14 mo after surgical resection, respectively) Referring to the past 3 mo

Western dietary pattern (high consumption of meat, fat, rened grains, and desserts), Q4 vs Q1 Prudent dietary pattern (high consumption of fruit and vegetables, poultry, and sh)

NS

Tian, 2008, China (25)

39 CRC patients (M, F; stages IIV) who underwent surgery in 4 provincial-level hospitals in Fuzhou, China 14 deaths

Diagnosis: January to June 2006 1-y survival

FFQ during 20 d after surgery Referring to the last week

All-cause mortality

Low vs high energy Low vs high protein

1.97 (0.21, 18.1) 1.56 (0.19, 12.8)

Age at diagnosis, stage of disease, histologic differentiation, receipt of chemotherapy, tumor location, time period of diagnosis, BMI, physical activity, smoking status, aspirin use, alcohol consumption, total vitamin D intake, and PMH use (including male sex) Age, sex, depth of invasion through bowel wall, no. of positive lymph nodes, clinical perforation at time of surgery, bowel obstruction at time of surgery, baseline performance status, treatment group, weight change between rst and second questionnaire, and time-varying BMI, physical activity, and total calories Age, sex, and tumor stage

(Continued)

TABLE 3 (Continued )

First author, year, country Follow-up time Outcome Contrast RR (95% CI)

Sample (size and key characteristics)

Dietary assessment method

Adjustments

Blood concentrations after diagnosis Leung, 2008, United Kingdom (42) Diagnosis 20002006 Median: 26 mo in survivors (min 12 mo) Serum concentrations of antioxidant vitamins before potentially curative resection or chemotherapy and/or supportive care CRC-specic mortality, in patients with unresectable liver metastases

53 patients with primary operable CRC and 53 patients with unresectable liver metastases (M, F) 10 and 42 deaths and 5 and 41 CRC deaths Inclusion 20012004 All-cause mortality

5.61 (2.43, 12.91)

Modied Glasgow Prognostic Score, a-tocopherol, a-carotene

Bystro m, 2009, Sweden (43)

Serum concentrations of cobalamin and folate before chemotherapy

Greater than the median vs less than the median Retinol a-Tocopherol Lutein Lycopene a-Carotene b-Carotene Cobalamin ,300 pmol/ L vs .300 pmol/L Folate NS

NS NS NS NS NS NS ,1.00 (P 0.002)

No adjustment

LIFESTYLE FACTORS IN COLORECTAL CANCER SURVIVAL

Ng, 2009, United States (44)

93 CRC patients (M, F; aged 4276 y) with unresectable metastases within a postoperative adjuvant chemotherapy trial (Nordic VI study) Deaths: NS 1017 CRC patients (M, F; stages IIV) diagnosed within the NHS and HPFS cohort studies 283 deaths and 119 CC deaths Diagnosis: 19862004 FU up to 2006 (median: 116 mo; range 41 238 mo) Predicted plasma 25(OH)D concentrations 14 y postdiagnosis CRC-specic mortality All-cause mortality

Postdiagnosis predicted 25(OH)D, Q5 vs Q1

0.50 (0.26, 0.95) 0.62 (0.42, 0.93)

Age at diagnosis, sex, cancer stage, grade of tumor differentiation, location of primary tumor, and year of diagnosis

RR, relative risk; CC, colon cancer; FFQ, food-frequency questionnaire; Q, quartile; NA, not available; NHICS, National Health Insurance Corporation Study; FU, follow-up; CRC, colorectal cancer; UCI, University of California Irvine CRC gene-environment study; SES, socioeconomic status; RC, rectal cancer; 25(OH)D, 25-hydroxyvitamin D3; HPFS, Health Professionals Follow-Up Study; NHS, Nurses Health Study; PMH, postmenopausal hormone (PMH); CALGB, Cancer and Leukemia Group B.

487

488
Dietary factors after cancer diagnosis

VRIELING AND KAMPMAN

Postdiagnosis diet in relation to colorectal cancer recurrence and survival was reported by 2 studies (25, 41). One study was a large postoperative adjuvant chemotherapy trial in 1009 stageIII colorectal cancer patients, and diet was assessed midway through therapy and 6 mo after completion of therapy. Analyses were extensively adjusted for several prognostic factors, including the tumor stage, clinical perforation, and bowel obstruction at the time of surgery. Subjects in the highest quartile compared with subjects in the lowest quartile of a Western dietary pattern, characterized by high intakes of meat, fat, rened grains, and dessert had a higher risk of all-cause mortality (HR: 2.32; 95% CI: 1.36, 3.96), recurrence (HR: 2.85; 95% CI: 1.75, 4.63), and recurrence and/or death (HR: 3.25; 95% CI: 2.04, 5.19). No associations for a prudent dietary pattern, which was characterized by high intakes of fruit and vegetables, poultry, and sh, were observed. The other study was a very small study in 39 colorectal cancer patients, and no association was observed for low compared with high energy or protein intake during the week 3 after diagnosis with 1 y of survival (25). One study investigated plasma concentrations of antioxidants before potentially curative resection or chemotherapy and/or supportive care (42). This study included 53 patients with primary operable colorectal cancer and 53 patients with unresectable liver metastases. Patients with unresectable liver metastases with plasma retinol concentrations above the median were shown to have a lower colorectal cancerspecic mortality than patients whose plasma retinol concentrations were below the median. No associations were observed for a-tocopherol, lutein, lycopene, a-carotene, and b-carotene plasma concentrations, and no associations were reported for patients with primary operable colorectal cancer. In another study in 93 colorectal cancer patients with unresectable metastases, patients with serum cobalamin concentrations below the median had a lower risk of all-cause mortality than did patients with serum cobalamin concentrations above the median (43). Folate concentrations were not associated with all-cause mortality in this study. One large cohort study, including 1017 colorectal cancer cases, observed a lower risk with higher predicted 25(OH)D concentrations for colorectal cancerspecic mortality (HR: 0.50; 95% CI: 0.26, 0.95) and all-cause mortality (HR: 0.62; 95% CI: 0.42, 0.93) (44).
DISCUSSION

This review shows that there is a paucity of published studies on BMI, physical activity, and dietary factors in relation to colorectal cancer recurrence and survival. Because of these small numbers and the large heterogeneity in the type of exposure, timing of exposure assessment, and disease outcomes investigated, summarizing the results and drawing rm conclusions is difcult. Higher BMI or body fatness before or at time of diagnosis may be associated with higher all-cause mortality, colorectal cancerspecic mortality, or recurrence, although results appeared to differ according to sex, tumor location, and the molecular subtype of the tumor. There is suggestive evidence that a higher postdiagnosis leisure-time physical activity is associated with lower all-cause and colorectal cancerspecic mortality. Further, dietary factors might be associated with all-

cause mortality, colorectal cancerspecic mortality, or recurrence, but signicant associations were only shown for single foods, nutrients, and dietary patterns in single studies. Different study designs have been used to investigate the association of BMI, dietary factors, and physical activity with colorectal cancer recurrence and survival. Studies were based on the follow-up of colorectal cancer patients who were either part of a patient series, existing case-control, case-case, and cohort studies, or randomized adjuvant chemotherapy trials. As previously discussed by Kushi et al (46), such cancer-survival studies are very cost-effective because already collected data can be used. However, a general limitation of these studies is that they are specically designed to examine the colorectal cancer risk rather than colorectal cancer recurrence and survival. In studies based on existing case-control studies, dietary and other lifestyle factors are assessed after diagnosis and generally refer to the time before or the time at diagnosis. These studies may be prone to recall bias, with the implication that cases may report differently depending on their health status, their ability to eat and to be physically active, and their beliefs about cancer causes. Further, prediagnosis exercise and diet may actually be reective of postdiagnosis exercise and diet. Selection bias may also have occurred because only survivors of colorectal cancer were included in these studies. The advantage of studies that are based on existing cohort studies conducted in healthy individuals is that they are not subject to recall bias. However, a limitation is that, for each individual, the cancer is diagnosed at a different time point during the follow-up time of the study. Thereby, the time between data collection and cancer diagnosis is not identical for all colorectal cancer survivors. Further, in existing cohort studies as well as in case-control studies, therapeutic data are mostly not collected, and the patient population is very heterogeneous and includes all stages of disease. In contrast, in studies based on randomized chemotherapy trials, treatment and follow-up care is standardized, and homogeneous disease stages are included. A prospective evaluation of dietary and other lifestyle factors and evaluation of changes in these factors that may occur after patients completed adjuvant chemotherapy and recovered from treatment effects are possible. Information on disease- and therapy-related factors is also available, although adjustment for these factors may not substantially change the crude-risk estimates (19, 20, 41). Disadvantages of therapeutic trials are that patients may differ from the population at large, and postdiagnosis physical activity and diet may be reective of prediagnosis physical activity and diet, which are not assessed. The ndings of an higher risk of all-cause mortality, colorectal cancerspecic mortality, or recurrence with higher BMI or body fatness before (10, 1216) or at the time of diagnosis (17, 1921, 24, 28, 30) and lower leisure-time physical activity after diagnosis (3336) are in agreement with the epidemiologic evidence on colorectal cancer development (5). The elevated risks for higher BMI are not likely to be due to the chemotherapy underdosing of obese patients (1921). Rather, as in colorectal cancer risk, the risks may be mediated by a higher insulin resistance and higher concentrations of insulin and insulin-like growth factor I, which promote cell proliferation and inhibit apoptosis (47, 48). Higher physical activity may lower colorectal cancer recurrence and mortality risk by similar, but opposed,

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mechanisms. For the dietary factors, only the association of higher prediagnosis plasma concentrations of 25(OH)D and folate with lower colorectal cancerspecic mortality (39, 40, 44) was in line with the suggestive protective effect of foods that contain vitamin D or folate on primary colorectal cancer risk (5). Although the recommendations on physical activity and nutrition are met by only a small proportion of colorectal cancer survivors (4952), the subjects appear to have a strong interest in making changes in dietary and other lifestyle factors after the diagnosis of cancer (68). To our knowledge, there is no substantial evidence that changes in diet or lifestyle after diagnosis affect colorectal cancer recurrence and survival. Thus, the important question that remains concerns what type of studies are needed to gain more insight in the role of dietary and other lifestyle factors in colorectal cancer recurrence and survival. First, in line with what is already being done for breast survivors (5356), it is of vital importance to set up new prospective cohort studies of colorectal cancer survivors. Considerations for the design of such studies have been discussed by Kushi et al (46). In brief, colorectal cancer cases should be rapidly ascertained so they can be enrolled soon after the diagnosis of cancer. Dietary and lifestyle factors should be assessed at critical points in time (eg, at the diagnosis and before, during, and after treatment of colorectal cancer). Colorectal cancer cases should be clearly dened with respect to the tumor location and tumor stage. Blood samples or tissue samples of the primary colorectal tumor should be collected and stored for further investigation of genetic factors and biomarkers. Data on cancer treatment, supplement use, and other potential prognostic factors should also be routinely collected. Studies should be able to stratify by sex and tumor location because these may be potential effect modiers. Further, it is important to assess markers of abdominal fatness, such as waist and hip circumference, in addition to body weight, on the basis of the positive associations shown in 2 previous colorectal cancersurvivor studies (12, 24). Second, on the basis of the outcomes of these cohort studies, randomized trials to investigate the causal relation between dietary and other lifestyle factors with colorectal cancer recurrence and survival should be initiated. Recently, 4 study protocols and one feasibility study of randomized trials were published that aim to investigate the effects of physical activity or a lifestyle intervention in colorectal cancer survivors (5761). Two of these studies address colorectal cancer recurrence or mortality (58, 59). The Colon Health and Life-Long Exercise Change trial is set up to establish the effect of a 3-y behavioral support program and supervised physical activity sessions on disease-free survival in 962 colon cancer survivors (58). LiveWell is a 3-mo personalized lifestyle program for colorectal survivors (59), and a feasibility study in 18 survivors showed that such a lifestyle intervention is feasible and should be personalized to suit abilities, provide feedback on personal goals, and encourage social support (59). In conclusion, a paucity of studies on the effect of dietary and other lifestyle factors in relation to colorectal cancer recurrence and survival is available, with large heterogeneity in the type of exposure, timing of exposure assessment, and disease outcomes. Although some studies suggest that higher BMI before or at the time of diagnosis and lower leisure-time physical activity after

diagnosis may be related to a higher risk of colorectal cancer specic recurrence and mortality, no rm conclusions can be drawn. New observational studies and randomized trials in colorectal cancer survivors are warranted. These studies should especially address the effect of BMI and diet after diagnosis. Until new evidence becomes available, colorectal cancer survivors are advised to follow the WCRF/AICR dietary recommendations for cancer prevention (5).
The authors responsibilities were as followsAV and EK: contributed to the conception and design of the manuscript, literature search, and interpretation of data; AV: wrote the manuscript; and EK: critically appraised the manuscript. Neither author had a conict of interest.

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LETTERS TO THE EDITOR

Erratum
n M, Casas R, Arranz S, Valderas-Martinez P, Portoles O, Chiva-Blanch G, Urpi-Sarda M, Llorach R, Rotches-Ribalta M, Guille Corella D, et al. Differential effects of polyphenols and alcohol of red wine on the expression of adhesion molecules and inammatory cytokines related to atherosclerosis: a randomized clinical trial. Am J Clin Nutr 2012;95:32634. An error was identied in the 24-h urinary excretion of total resveratrol metabolites, which was incorrect at baseline and after 3 interventions. The statistical analysis between interventions has now been updated. The aim of this measure was to provide intervention compliance through the calculation of the biomarker of wine consumption. This has been previously dened as the sum of 7 phase II metabolites of resveratrol specied in reference 31. These metabolites are as follows: trans- and cis-resveratrol-3-O-glucuronide, cis-resveratrol-4#-O-glucuronide, trans- and cis-resveratrol-4#-O-sulfate, and trans- and cisresveratrol-3-O-sulfate. On page 328, the rst sentence of the left-hand column of the Methods section should read as follows: Resveratrol conjugates derived from phase II metabolism were measured in 24-h urine samples by using the validated methodology described by Urpi-Sarda et al (30) quantitatively adapted due to the commercial and available standards. trans- and cis-Resveratrol-3-Oglucuronide (98% purity each), cis-resveratrol-4#-O-glucuronide (96% purity), and trans-resveratrol-3-O-sulfate (98% purity) were purchased from Toronto Research Chemicals Inc. trans- and cis-Resveratrol-4#-O-sulfate and cis-resveratrol-3-O-sulfate were quantied using the trans-resveratrol-3-O-sulfate calibration curve. Incorrect values were given on page 329 in the right-hand column of the Results section. The second sentence of the rst paragraph should read as follows: After consumption of RW and DRW, 24-h urinary excretion of total resveratrol metabolites increased in relation to baseline amounts from 0.94 lmol (95% CI: 0.43, 1.46 lmol) to 6.04 lmol (95% CI: 4.76, 7.31 lmol) and 6.28 lmol (95% CI: 5.10, 7.46 lmol), respectively (P , 0.001, both). Resveratrol metabolite concentrations were not statistically different after DRW and RW interventions (P 1.00) and were statistically higher after RW and DRW interventions than after gin consumption [0.51 lmol (95% CI: 0.08, 0.94 lmol); P , 0.001]. After the gin intervention, the concentration of resveratrol metabolites did not change signicantly compared with that at baseline (P 1.00). Total resveratrol metabolites have been used only as a measure of compliance in this report and were not used in any of the calculations, did not affect the results or discussion of the article, and therefore have no implications for the main results or their interpretation.
doi: 10.3945/ajcn.112.038810.

Erratum
Vrieling A, Kampman E. The role of body mass index, physical activity, and diet in colorectal cancer recurrence and survival: a review of the literature. Am J Clin Nutr 2010;92:47190. The DOI was published incorrectly in the September 2010 issue of The American Journal of Clinical Nutrition as 10.3945/ ajcn.2010.29005. The correct DOI is as follows: 10.3945/ajcn.2009.29005.
doi: 10.3945/ajcn.112.039115.