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Whole Grain Intake and Survival Among Scandinavian Colorectal Cancer Patients a
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Guri Skeie , Tonje Braaten , Anja Olsen , Cecilie Kyrø , Anne Tjønneland , Lena Maria c
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Nilsson , Rikard Landberg & Eiliv Lund
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Department of Community Medicine , University of Tromsø , Tromsø , Norway
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Danish Cancer Society Research Center , Copenhagen , Denmark
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Department of Public Health and Clinical Medicine, Nutritional Research , Umeå University , Umeå , Sweden d
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Department of Food Science, BioCenter , Swedish University of Agricultural Sciences , Uppsala , Sweden Published online: 25 Nov 2013.
To cite this article: Guri Skeie , Tonje Braaten , Anja Olsen , Cecilie Kyrø , Anne Tjønneland , Lena Maria Nilsson , Rikard Landberg & Eiliv Lund (2014) Whole Grain Intake and Survival Among Scandinavian Colorectal Cancer Patients, Nutrition and Cancer, 66:1, 6-13, DOI: 10.1080/01635581.2014.847472 To link to this article: http://dx.doi.org/10.1080/01635581.2014.847472
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Nutrition and Cancer, 66(1), 6–13 C 2014, Taylor & Francis Group, LLC Copyright ISSN: 0163-5581 print / 1532-7914 online DOI: 10.1080/01635581.2014.847472
Whole Grain Intake and Survival Among Scandinavian Colorectal Cancer Patients Guri Skeie and Tonje Braaten Department of Community Medicine, University of Tromsø, Tromsø, Norway
Anja Olsen, Cecilie Kyrø, and Anne Tjønneland Danish Cancer Society Research Center, Copenhagen, Denmark
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Lena Maria Nilsson Department of Public Health and Clinical Medicine, Nutritional Research, Ume˚a University, Ume˚a, Sweden
Rikard Landberg Department of Food Science, BioCenter, Swedish University of Agricultural Sciences, Uppsala, Sweden
Eiliv Lund Department of Community Medicine, University of Tromsø, Tromsø, Norway
to industrialized countries could be attributed to the high dietary fiber consumption (1). Whole-grain (WHG) cereals contain beneficial components beyond dietary fiber (e.g., vitamins, minerals, lignans, beta-glucan, inulin, phytochemicals, phytosterols, phytin, and sphingolipids), and these components might also contribute to the beneficial effects of WHG in products, alone or in interaction with dietary fiber and other components (2). The continuous update project by the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) included WHG in their latest report but did not grade the evidence. However, in their systematic review and meta-analysis of prospective studies, they found a reduced risk of CRC when increasing the WHG intake (3). Some studies from the United States and Norway on WHG and mortality have found an inverse association with all-cause mortality (4–7), but 1 study found no association with total mortality, only cardiovascular deaths (8). A study of the healthy Nordic food index found that WHG rye bread consumption was the single component of the index that was most consistently associated with reduced mortality (9). Studies from Norway and the United States that have analyzed cancer mortality per se found no association with WHG consumption in comprehensively adjusted analyses (6,7). An ecological analysis from the Seven Countries Study found that higher fiber intake was associated with lower CRC mortality (10), and a more recent paper from the European Prospective Investigation into Cancer and Nutrition (EPIC) study found reduced mortality from smoking related cancers (including CRC) in persons with higher intakes
To our knowledge, no studies of associations between intake of whole grain (WHG) and survival of colorectal cancer have been published, despite evidence that dietary fiber, and to some extent WHG, are associated with lower risk of colorectal cancer. Scandinavia is an area where the WHG consumption traditionally is high. We performed a case-only (N = 1119) study in the Scandinavian HELGA cohort of pre-diagnosis WHG intake (total WHG, WHG wheat, WHG rye, and WHG oats) and survival of colorectal cancer. Cox regression analyses were used to study the associations, both in categorical and continuous models, stratified by location (proximal, distal, rectum) and country. No evidence of an association was found, neither for total WHG intake (hazard ratio = 1.32, 95% confidence interval: 0.88–1.97 lowest vs. highest tertile, adjusted for age at diagnosis, metastasis status, smoking, folate, margarine, and energy), nor for specific grains. Prediagnosis consumption of WHG does not seem to improve survival of colorectal cancer in subjects diagnosed within this prospective population-based Scandinavian cohort.
INTRODUCTION The relationship between cereal food consumption and colorectal cancer (CRC) has occupied scientists ever since Burkitt suggested that lower CRC rates in African countries compared
Submitted 3 February 2013; accepted in final form 12 August 2013. Address correspondence to Guri Skeie, Department of Community Medicine, University of Tromsø, N-9037, Tromsø, Norway. Phone: 004777646594. Fax: 0047 77 64 48 31. E-mail: [email protected]
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WHOLE GRAIN AND SURVIVAL OF COLORECTAL CANCER
of dietary fiber, particularly from cereals and vegetables (11). To our knowledge, no studies published have investigated prognosis or survival of CRC patients according to WHG consumption, and there is in general a paucity of papers on dietary factors and CRC recurrence and survival (12). However, a study from Utah found lower survival for colon cancer patients consuming higher amounts of dietary fiber (13), whereas a French study found no association between dietary fiber intake and CRC survival (14). In the Scandinavian countries, the consumption of WHG has traditionally been high, and although wheat is the dominant source in Norway, rye is an important source of WHG in Sweden and Denmark (15). Compared to the CRC mortality rates in Europe (17.35 per 100,000 for men and 10.51 for women), the mortality rate for women is higher in all three countries, whereas for men it is higher in Denmark (20.30), lower in Sweden (13.67), and level in Norway (17.05) (16). We have previously shown that intake of WHG products is associated with lower CRC incidence in the Scandinavian population-based HELGA cohort (17). The aim of this study was to describe the association between pre-diagnosis intake of total WHG, WHG wheat, WHG rye, and WHG oats, and survival among participants from the HELGA cohort diagnosed with CRC. MATERIAL AND METHODS The HELGA Cohort The HELGA cohort consists of 119,913 participants from 3 prospective Scandinavian cohorts: The Norwegian Women and Cancer study (NOWAC) (18), The Northern Sweden Health and Disease Study (19), and the Danish Diet, Cancer and Health Study (20). These cohorts are also members of the EPIC study (21). Participants were recruited from the general population using the unique personal registration numbers. In Norway, the participants were selected at random among women born 1943–1957 from the entire country. In Sweden, the participants were inhabitants from the V¨asterbotten County. All persons aged 40, 50, and 60 years were invited for screening. In Denmark, inhabitants born in Denmark, free from cancer and aged 50–64 yr from Copenhagen and Aarhus and the surrounding areas were invited. Data collection took part in 1992–1996 (Sweden), 1993–1997 (Denmark), and 1998–1999 (Norway). The local medical ethics review boards and other relevant authorities in the 3 countries approved of the studies, and the participants provided informed consent. Exposure and Adjustment Variables Dietary intake was measured before diagnosis by validated country-specific semiquantitative food frequency questionnaires (FFQ) (22–24). WHG was defined according to the AACC International (25): “Whole grains shall consist of the intact, ground, cracked or flaked caryopsis, whose principal anatomical components—the starchy endosperm, germ and bran—are present in the same relative proportions as they exist
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in the intact caryopsis.” Grains included in the definition used in the present study consist of the following (all belonging to the Poaceae family): wheat, rye, oats, barley, rice, millet, corn/maize (dried), triticale and sorghum/durra, but specific estimates are only given for the first 3. The WHG contents were obtained through published values, labeling information, recipes, official reports (26), and contacts with producers. Both information about total WHG content, and content from wheat, rye, oats, and other WHG sources were collected. For specific WHG foods included in the FFQs, values were used directly, for composite foods, or where unspecific questions were asked, WHG values were weighted based on frequency of consumption in a detailed single 24-h dietary recall in a subset of the study population (15,27). The WHG content was expressed as the WHG contents of the unprepared ingredients divided by the weight of the prepared product. For food-based analyses we created a variable for WHG products. This is the sum of food groups that either contained only WHG products (WHG bread) or >75% of the products included in the category contained WHG (crispbread and breakfast cereals). The more detailed information about crispbread and breakfast cereals was obtained from the aforementioned 24-h dietary recalls (15). The participants also filled in questionnaires regarding lifestyle factors such as smoking, education, and use of menopausal hormone therapy. Weight and height were measured in Sweden and Denmark, and self-reported in Norway. Information about physical activity was not comparable between the countries.
Study Population In the cohort, 581 men and 672 women were prospectively diagnosed with CRC as their first primary cancer; out of these 830 were Danes, 214 Norwegians, and 209 Swedes. Information about cancer incidence and vital status was obtained from national cancer registries, patient registries and cause of death registries, and was complete until December 31, 2007 (Denmark) and December 31, 2008 (Norway and Sweden). Censoring for total deaths was done on the same date, whereas specific causes of death were complete until December 31, 2006 (Denmark) and December 31, 2007 (Norway and Sweden). CRC was defined as cancers coded C18, C19, or C20 according to the International Statistical Classification of Diseases, Injuries and Causes of Death, version 10 (ICD-10). Proximal (right) colon tumors included those located in the cecum, appendix, ascending colon, hepatic flexure, transverse colon, and splenic flexure (C18.0–18.5); distal (left) colon tumors included the descending and sigmoid colon (C18.6–18.7). Rectal cancers included both cancers in the rectosigmoid junction (C19) and in rectum (C20). Information about cancer stage was collected with different specification in the 3 countries, and merged into localized cancer, metastatic cancer, including regional metastases, and
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G. SKEIE ET AL.
missing or unknown metastasis status. Treatment information was not available. Analyses were stratified on location, and nonspecific colon cancers and cancers of the overlapping lesion were excluded (C18.8–18.9, n = 49). The analyses focused on adenocarcinomas and carcinomas, and cases with missing, nonspecific, and other morphology were excluded (n = 51). Eleven persons were diagnosed upon death and did not contribute follow-up time. Two persons were excluded because of implausible energy intakes [lower than 2.5 megajoules (MJ)—both genders, or higher than 18 MJ (women) or 21 MJ (men)], and 2 persons because of implausible WHG intakes (higher than 160 g/day). Nineteen persons were excluded because of missing information on smoking. Finally, 529 men and 590 women, among them 756 Danes, 178 Norwegians, and 185 Swedes were included in the analyses. There were 316 proximal colon cancers, 332 distal colon cancers, and 471 rectal cancers. The majority of the participants had distant or regional metastases (n = 836), but some had localized disease (n = 187), or unknown metastasis status (n = 96). In the Norwegian cohort, repeated measurements of diet were available, and these were used to analyze dietary change related to CRC diagnosis. The dietary change cohort comprise not only the Norwegian HELGA subcohort but a larger sample from the NOWAC study and is described in detail in (28). Briefly, the first wave of data collection took place in 1996–1999 (n = 67,932), and the second in 2002–2005 (n = 50,800), including 80.5% of the eligible participants. After exclusions, 130 women who were diagnosed with CRC between questionnaires, and 43,154 cancer-free women were included in the analyses. Dietary fiber content has been calculated, but WHG content has not been determined for this cohort. Causes of Death Causes of death were coded according to ICD-10, and deaths were analyzed as total deaths (n = 390). Eighty-six percent of the deaths had specified causes (n = 334). Among them, 309 (91%) were due to cancer, 295 (88%) due to CRC. Statistical Analyses Age-adjusted baseline characteristics were computed as least square means in general linear models, with dummy variables for the strata variable (country). Categorical variables were also included as dummy variables. Country, tumor location, and metastasis status were not age-adjusted. Several variables were tested to check confounding effects— variables identified as probably or convincingly associated with CRC incidence in the continuous update project of WCRF/AICR (dietary fiber, dairy products/milk/calcium, red meat, processed meat, alcohol, body mass index, and height) (29); factors identified in a review of dietary factors and CRC survival (vitamin D and folate) (12); and variables from our earlier article identifying factors associated with WHG use (smoking, length of
education, vegetables, fruit, fish, tea, coffee, margarine, white bread, and cakes and biscuits) (30). Because of a lack of linearity, these variables were modeled as tertiles, except from smoking (never, former, and current), and level of education (none/primary school, technical/professional school, secondary school, and longer education). For the adjustment factors, sexand country-specific tertiles were created, because of the skewed distribution across countries for some of them. For total WHG and total WHG products, sex-specific cohort wide tertiles were created, however, the intake distribution for specific grains differed by country, so for WHG wheat, rye, and oats, country- and sex-specific tertiles were created. The Cox proportional hazards model was used to calculate hazard ratios for mortality, with corresponding 95% confidence intervals. Results are presented separately for men and women, as inspections of survival plots revealed diverging curves for sex. All analyses were stratified by country and location (distal colon, proximal colon, and rectum). Assumptions of the Cox proportional hazards model were tested by inspection of plots and inclusions of time-dependent covariates in the models. The interaction between time and total WHG consumption was significant for men, and for women there was a significant association between tumor location and time. Therefore, the analyses were run both with the total dataset, and with a dataset restricted to seven years of follow-up, where interaction was not an issue. Time since diagnosis was used as the primary time variable. All models were adjusted for age at diagnosis and metastasis status (metastatic, unknown, localized). Models for WHG wheat, WHG rye, and WHG oats were mutually adjusted for the other grain types. In addition, multivariate adjusted models taking also smoking (never, former, current), intake of folate (in tertiles), and margarine (in tertiles) into consideration, and models additionally adjusted for energy intake (in tertiles) are presented. Both continuous (per 20 g extra WHG per day, per 10 g extra of specific grains per day, per 50 g extra of WHG products) and categorical analyses with WHG intake in tertiles as the independent variable were run. For the categorical analyses, tertile medians were used to test for trend. Survival plots were computed for each location. For these plots, the follow-up was restricted to 7 yr after diagnosis. Sensitivity analyses were done excluding participants dying the first year after the diagnosis. The dietary change analyses were done as described in Ref. 28. Mean dietary change was calculated as values from the second measurement minus values form the first measurement. Models were adjusted for energy in tertiles, baseline food or nutrients (continuous), categories of baseline body mass index, baseline type of questionnaire, and age at study entry (continuous). Baseline mean values, mean change values, and standard errors of the changes were obtained in analyses of variance using a general linear model where all variables were adjusted for each other. The significance level was set to P < 0.01 (28). CRC survivors were ranked on time since diagnosis to obtain
WHOLE GRAIN AND SURVIVAL OF COLORECTAL CANCER
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2 groups of equal size to compare dietary change according to time since diagnosis. All analyses were done in SAS (version 9.2 and 9.3). The level of significance was set to 0.05.
RESULTS In general, the high WHG consumers were thinner, smoked less, and were slightly older at diagnosis compared to low consumers (Table 1). Fewer women in the highest WHG tertile had never used menopausal hormone treatments. High WHG users tended to eat less red meat, consume more dairy products, and eat more of foods typically spread on sandwiches or accompanying them, and they had a higher folate and energy intake. There was more than a threefold difference in mean intake of total WHG between the highest and lowest tertiles. Also for WHG products was there an approximately threefold difference between the mean intake in the highest and lowest tertiles, and the distribution for the specific grains varied widely as well. Most cancers were colon cancers, but in the two upper tertiles of WHG intake for men, approximately 50% of the cancers were rectal cancers. Roughly 75% of the cancers were metastatic (including regional metastases), and 10–20% were localized. For men the 1-yr survival rate was lowest in the highest WHG tertile (80.9% vs. 87.5% in the lowest tertile), whereas for women, the 1-yr survival rate was highest in the highest WHG tertile (90.4% vs. 85.9% in the lowest tertile). Slightly more persontime seemed to have been accumulated in the highest WHG tertiles. In Table 2, the risk of death is given according to prediagnosis total WHG consumption, consumption of specific grains, and of WHG products. Neither the categorical nor the continuous analyses showed any association between total WHG consumption on survival. A lower risk in crude continuous and categorical analyses of WHG oats consumption in women was not supported in adjusted analyses. Analyses restricted to 7 yr of follow-up gave essentially the same results (results not shown). When those who died the first year after diagnosis were excluded, the results were still essentially the same, except a higher risk of death was found for women in the second tertile of WHG oats consumption, also in fully adjusted analyses (HR = 1.58, 95% CI: 1.01–2.48; results not shown). Figure 1 shows survival plots for men and women, for each location separately, with follow-up restricted to 7 yr. These plots do not show any clear associations between WHG consumption and CRC survival. Short-term survivors answered the follow-up questionnaire less than 2.2 yr after they got their diagnosis, whereas long-term survivors were between 2.2 and 6.9 yr after diagnosis when answering the follow-up questionnaire. The intake of dark bread decreased significantly in both short-term survivors, long-term survivors, and cancer-free women, but did not differ between groups (Table 3). Likewise, the intake of total bread and crispbread decreased, but there were no significant differences be-
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tween the groups. Similarly, there was no difference in dietary fiber change.
DISCUSSION This study is the first study to present survival of CRC patients by prediagnosis intake of total WHG and different types of WHGs. No significant associations were found for total WHG, for WHG wheat, WHG rye, or WHG oats separately, or for WHG products in multivariate adjusted analyses. A significant inverse trend for WHG oats and mortality was found in women in crude analyses, but this association disappeared in multivariate adjusted analyses. On the other hand, an increased risk among women in the second tertile of WHG oats consumption in the analyses when deaths the first year after diagnosis were excluded persisted with adjustment. However, few questions about oats products were asked in the original questionnaires, and the estimates for this grain are rather unstable. We therefore suggest caution in interpreting these results. A range of positive health effects of WHG has been suggested by observational studies lately (2), including associations with cancer incidence (3), and total mortality (4–7). Only 2 studies provided specific estimates for cancer death, both found significantly decreased mortality with higher WHG intake in crude analyses, but with multivariate adjustments, the results were no longer significant (6,7). Two recent large studies on dietary fiber intake (particularly cereal fiber) and mortality found lower rates both for all-cause mortality and cancer mortality (31), or smoking-related cancer mortality (including CRC as a smokingrelated cancer) with higher fiber intakes (11). All these studies have been conducted in general population groups, not on cancer patients. Also, there are differences in amounts and types of WHG/cereal fiber-rich foods consumed. The NIH-AARP study and the EPIC study had more deaths than our study and the WHG studies and were therefore better powered to find possible differences (11,31). On the other hand, studies of CRC patients and dietary fiber have suggested no association (14) or detrimental associations with high intakes (13). In addition, a recent study of colon cancer Stage III patients found significant associations between higher dietary glycemic load and total carbohydrate intake and increased risk of recurrence and mortality (32). The strengths of this study included the detailed information about WHG intakes, including information on specific grains, the wide WHG consumption distribution, and the prospective design. The limitations were the availability of only one measurement of diet. Dietary measurements were conducted before diagnosis; this prevents recall bias but might not be representative if the participants changed their diet after diagnosis. Analyses from the NOWAC study have showed that women decrease their consumption of bread and cereal products after CRC diagnosis; however, the decrease was similar to the decrease seen in cancer-free women (28). In the current article, we repeated these analyses but divided the CRC survivors by time since
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TABLE 1 Prediagnosis diet and lifestyle factors, and disease characteristics of the colorectal cancer cases in the HELGA cohort, adjusted for age at diagnosis and country Men (n = 529)
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Tertile of whole grain consumption (total whole grain range, g/day) Prediagnosis factors Body mass index (kg/m2) Smoking status (%) Never Former Current Highest education attained (%) Primary school/none Secondary school Technical school University/higher education Use of hormones for menopause (%) Current Former Never Intake of red meat (g/day) Intake of processed meat (g/day) Intake of dairy products (g/day) Intake of margarine (g/day) Energy intake (kcal/day) Dietary fiber (g/day) Folate (ug/day) Whole grain (g/day) Total From wheat From rye From oats Whole grain products (g/day) Country of origin (%)1 Denmark Sweden Norway Diagnosis characteristics Age at diagnosis (years) Tumor location (%)1 Proximal colon Distal colon Rectum Metastasis status (%)1 Metastatic Unknown Localized 1-yr survival rate (%) Person-yr accumulated from diagnosis to censoring 1
Women (n = 590)
1 (4.7–35.1)
2 (35.2–56.8)
3 (56.9–133.9)
1 (0.3–33.1)
2 (33.2–54.0)
3 (54.1–144.5)
27.1
26.6
25.8
26.0
26.1
24.9
22.8 41.8 35.4
27.5 36.6 35.9
26.8 39.6 33.6
36.1 24.4 39.5
41.3 26.8 31.9
46.2 29.2 24.6
37.5 8.3 29.6 24.6
33.1 8.6 35.7 22.6
33.3 11.6 32.8 22.3
34.1 12.8 41.5 11.6
41.0 15.2 39.5 4.3
35.6 18.4 35.4 10.6
26.2 10.4 63.4 41.2 28.3 348 16.5 1766 22.2 261
26.2 12.9 60.9 38.2 29.1 409 17.5 2042 28.3 305
81.9 37.0 320 20.5 2165 18.5 270
82.3 36.3 373 26.9 2347 23.2 297
77.7 43.7 441 29.4 2632 30.3 342
23.3 12.8 63.9 43.3 25.1 267 12.9 1539 16.1 217
23.7 3.5 17.6 0.9 79.4
44.9 4.7 32.3 5.9 135.6
77.4 7.7 49.8 17.5 195.9
22.0 10.7 10.6 0 65.7
42.3 12.4 23.9 5.0 119.6
74.1 26.1 31.7 14.6 195.0
92.0 8.0
88.1 11.9
63.1 36.9
81.1 11.2 7.7
50.3 15.2 34.5
35.0 16.8 48.2
64.8
64.3
65.1
61.6
61.7
62.5
26.1 30.1 43.8
19.8 31.1 49.1
26.7 23.3 50.0
30.1 25.5 44.4
35.0 35.5 29.5
30.5 32.0 37.5
73.9 6.2 19.9 87.5 631
74.6 9.0 16.4 88.8 666
69.9 12.5 17.6 80.9 669
77.0 3.6 19.4 85.9 756
78.7 10.1 11.2 86.2 807
73.6 10.2 16.2 90.4 840
Not adjusted.
diagnosis. The results did not differ by time since diagnosis, but since there were only 65 survivors in each group, the variability in the numbers was substantial. Therefore, it cannot be ruled out that a larger sample would have revealed some differences in change by time since diagnosis, and if the tendencies seen here are representative, decreases in bread and crispbread
consumption might be larger closer to diagnosis and treatment, and more comparable to general trends a few years after diagnosis. Analyzing prediagnosis diet reduces the potential for selection bias due to selective survival (33). Although ideally several dietary measurements before and at given intervals after diagnosis should have been included, it is not likely that
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WHOLE GRAIN AND SURVIVAL OF COLORECTAL CANCER
TABLE 2 Prediagnosis consumption of total whole grain (WHG), WHG wheat, WHG rye, and WHG oats, and risk of death in Scandinavian colorectal cancer patients (n = 1,119) Men (n = 529)
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Total WHG Colon and rectum (continuous, per 20 g) Total WHG tertiles 1 2 3 P for trend (linear) WHG wheat4 (continuous, per 10 g) WHG wheat tertiles4 1 2 3 P for trend (linear) WHG rye4 (continuous, per 10 g) WHG rye tertiles4 1 2 3 P for trend (linear) WHG oats4 (continuous, per 10 g) WHG oats tertiles4 1 2 3 P for trend (linear) WHG products (continuous, per 50 g) WHG products 1 2 3 P for trend (linear) 1
Deaths
Model 11 HR (95% CI)
Model 22 HR (95% CI)
Women (n = 590) Model 33 HR (95% CI)
Deaths
Model 11 HR (95% CI)
Model 22 HR (95% CI)
193
0.99 (0.88–1.12) 1.00 (0.88–1.14) 1.00 (0.88–1.14)
197
0.90 (0.79–1.03) 0.93 (0.81–1.08) 0.93 (0.81–1.07)
67 61 65
Ref Ref Ref 0.83 (0.58–1.18) 0.84 (0.58–1.20) 0.83 (0.58–1.20) 0.98 (0.68–1.41) 1.00 (0.67–1.48) 1.00 (0.67–1.48) ns ns ns
69 74 54
Ref Ref Ref 1.03 (0.72–1.46) 1.10 (0.77–1.57) 1.10 (0.77–1.58) 0.78 (0.53–1.15) 0.92 (0.60–1.40) 0.91 (0.60–1.39) ns ns ns
193
0.98 (0.72–1.35) 0.94 (0.67–1.31) 0.94 (0.67–1.31)
197
1.06 (0.92–1.21) 1.03 (0.89–1.19) 1.02 (0.89–1.18)
66 62 65
Ref Ref Ref 1.09 (0.76–1.58) 1.19 (0.81–1.76) 1.19 (0.81–1.76) 1.08 (0.74–1.60) 0.97 (0.64–1.49) 0.97 (0.64–1.49) ns ns ns
72 59 66
Ref Ref Ref 0.76 (0.53–1.10) 1.03 (0.70–1.52) 1.02 (0.69–1.51) 1.01 (0.69–1.48) 1.41 (0.76–2.63) 1.35 (0.72–2.53) ns ns ns
193
0.98 (0.90–1.06) 0.98 (0.90–1.07) 0.98 (0.90–1.07)
197
0.96 (0.85–1.08) 0.98 (0.87–1.11) 0.98 (0.87–1.11)
65 62 66
Ref Ref Ref 0.77 (0.54–1.11) 0.76 (0.51–1.11) 0.75 (0.51–1.11) 0.82 (0.58–1.17) 0.90 (0.60–1.36) 0.90 (0.60–1.36) ns ns ns
67 69 61
Ref Ref Ref 0.94 (0.66–1.33) 0.78 (0.51–1.17) 0.78 (0.51–1.18) 0.91 (0.63–1.32) 0.93 (0.60–1.45) 0.93 (0.60–1.46) ns ns ns
193
1.03 (0.90–1.17) 1.05 (0.91–1.20) 1.05 (0.91–1.20)
197
0.82 (0.70–0.97) 0.88 (0.75–1.04) 0.88 (0.75–1.04)
60 72 61
Ref Ref Ref 1.04 (0.73–1.48) 1.09 (0.75–1.58) 1.09 (0.75–1.58) 0.97 (0.65–1.45) 1.12 (0.73–1.70) 1.11 (0.72–1.70) ns ns ns
64 74 59
Ref Ref Ref 1.36 (0.95–1.93) 1.12 (0.80–1.58) 1.13 (0.80–1.59) 0.95 (0.63–1.42) 0.83 (0.55–1.26) 0.83 (0.55–1.26) 0.007 ns ns
193
1.00 (0.90–1.11) 1.00 (0.90–1.13) 1.01 (0.90–1.13)
197
0.96 (0.86–1.07) 0.98 (0.87–1.11) 0.97 (0.86–1.10)
67 59 67
Ref Ref Ref 0.95 (0.67–1.36) 0.96 (0.66–1.40) 0.96 (0.66–1.40) 1.03 (0.73–1.46) 1.05 (0.71–1.56) 1.06 (0.71–1.56) ns ns ns
62 72 63
Ref Ref Ref 1.19 (0.83–1.70) 1.27 (0.89–1.82) 1.26 (0.88–1.81) 1.02 (0.71–1.46) 1.11 (0.75–1.65) 1.10 (0.74–1.64) ns ns ns
Adjusted for age at diagnosis and metastasis, and stratified for country and location (proximal colon, distal colon, rectum). As model 1, but additionally adjusted for smoking, folate (in tertiles) and margarine (in tertiles). 3 Model 2 + adjustment for energy (in tertiles). 4 Models for specific grains were mutually adjusted for the other grains. 2
Model 33 HR (95% CI)
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FIG. 1. Survival of colorectal cancer by tertile of total whole grain intake for different locations, men and women. A: Proximal colon, men. B: Distal colon, men. C: Rectum, men. D: Proximal colon, women. E: Distal colon, women. F: Rectum, women. All analyses adjusted for metastasis status (metastasis, unknown, localized), smoking (never, former, current), country, sex-specific tertiles of folate, margarine, and energy.
the lack of dietary measurements after diagnosis is a major limitation. No treatment information was available, but it is unlikely that treatment should differ between WHG consumption groups. In conclusion, prediagnosis consumption of WHG, in total or from wheat, rye, or oats do not seem to improve survival of CRC patients diagnosed within a prospective population-based Scandinavian cohort.
ACKNOWLEDGMENTS We wish to thank Knut Hansen for assistance in data set preparation, and we also acknowledge Professor G¨oran Hallmans, Ume˚a University, for support and valuable advice. FUNDING This study was supported by NordForsk [Centre of Excellence programme HELGA (070015)] and The Danish
TABLE 3 Adjusted change in bread, cereals, and fiber intake (99% confidence interval) among short-term and long-term colorectal cancer survivors, compared with cancer-free women Short-term colorectal cancer survivors (n = 65)
Long-term colorectal cancer survivors (n = 65)
Cancer-free women (n = 43,154)
Food/food group/ nutrient (g/day)
Meana
SE
Meana
SE
Meana
SE
P value
Bread and crispbread Dark breadb Breakfast cereals Dietary fiber
−22.0 −36.4 0.9 −0.7
6.6 7.6 2.4 0.7
−11.4 −34.8 0.5 0.3
6.6 7.6 2.4 0.7
−14.6 −32.8 −0.9 −0.3
0.6 0.7 0.2 0.1
0.5 0.8 0.7 0.5
All analyses are adjusted for age (years at baseline), baseline type of questionnaire, baseline energy intake in tertiles, baseline body mass index groups (≤20, 20.1–25, >25), and baseline intake of the food (g/day) (28). a Differences in italics are significantly different from 0. b A question on medium dark breads was introduced in the follow-up questionnaires. Therefore, the decrease in dark bread is larger than the decrease in total bread and crispbread.
WHOLE GRAIN AND SURVIVAL OF COLORECTAL CANCER
Cancer Society. The Northern Sweden Health and Disease Study was supported by the Joint Committee of the Northern Sweden Health Care Region, V¨asterbotten County Council, The Swedish Research Council, The Swedish Council for Working Life and Social Research, and The Cancer Research Foundation in Northern Sweden. Some of the data in this article are from the Cancer Registry of Norway. The Cancer Registry of Norway is not responsible for the analysis or interpretation of the data presented.
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16. Bosetti C, Levi F, Rosato V, Bertuccio P, Lucchini F, et al.: Recent trends in colorectal cancer mortality in Europe. Int J Cancer 129, 180–191, 2011. 17. Kyro C, Skeie G, Loft S, Landberg R, Christensen J, et al.: Intake of whole grains from different cereal and food sources and incidence of colorectal cancer in the Scandinavian HELGA cohort. Cancer Causes Control 24, 1363–1374, 2013. 18. Lund E, Dumeaux V, Braaten T, Hjartaker A, Engeset D, et al.: Cohort profile: The Norwegian Women and Cancer Study NOWAC Kvinner og kreft. Int J Epidemiol 37, 36–41, 2008. 19. Hallmans G, Agren A, Johansson G, Johansson A, Stegmayr B, et al.: Cardiovascular disease and diabetes in the Northern Sweden Health and Disease Study Cohort: evaluation of risk factors and their interactions. Scand J Public Health 31, 18–24, 2003. 20. Tjonneland A, Olsen A, Boll K, Stripp C, Christensen J, et al.: Study design, exposure variables, and socioeconomic determinants of participation in Diet, Cancer and Health: a population-based prospective cohort study of 57,053 men and women in Denmark. Scand J Public Health 35, 432–441, 2007. 21. Riboli E, Hunt KJ, Slimani N, Ferrari P, Norat T, et al.: European Prospective Investigation into Cancer and Nutrition (EPIC): study populations and data collection. Public Health Nutr 5, 1113–1124, 2002. 22. Hjartaker A, Andersen LF, and Lund E: Comparison of diet measures from a food-frequency questionnaire with measures from repeated 24-hour dietary recalls. The Norwegian Women and Cancer Study. Public Health Nutr 10, 1094–1103, 2007. 23. Johansson I, Hallmans G, Wikman Å, Biessy C, Riboli E, et al.: Validation and calibration of food-frequency questionnaire measurements in the Northern Sweden Health and Disease cohort. Public Health Nutr 5, 487–496, 2002. 24. Tjonneland A, Overvad K, Haraldsdottir J, Bang S, Ewertz M, et al.: Validation of a Semiquantitative Food Frequency Questionnaire Developed in Denmark. Int J Epidemiol 20, 906–912, 1991. 25. American Association of Cereal Chemists. Definition of whole grain: 1999. Retrieved from http://www.aaccnet.org/initiatives/definitions/ Pages/WholeGrain.aspx 26. DTU Food: The National Food Institute (Denmark): (2008). Wholegrain: Definition and scientific background for recommendations. Søborg, Denmark: Author. 27. Wirfalt E, McTaggart A, Pala V, Gullberg B, Frasca G, et al.: Food sources of carbohydrates in a European cohort of adults. Public Health Nutr 5, 1197–1215, 2002. 28. Skeie G, Hjartaker A, Braaten T, and Lund E: Dietary change among breast and colorectal cancer survivors and cancer-free women in the Norwegian Women and Cancer cohort study. Cancer Causes Control 20, 1955–1966, 2009. 29. World Cancer Research Fund/American Institute for Cancer Research: Colorectal cancer 2011 report. Food, Nutrition, Physical Activity, and the Prevention of Colorectal Cancer. Retrieved from http://www. dietandcancerreport.org/cancer resource center/downloads/cu/ColorectalCancer-2011-Report.pdf 30. Kyro C, Skeie G, Dragsted LO, Christensen J, Overvad K, et al.: Intake of whole grains in Scandinavia is associated with healthy lifestyle, socio-economic and dietary factors. Public Health Nutr 14, 1787–1795, 2011. 31. Park Y, Subar AF, Hollenbeck A, and Schatzkin A: Dietary fiber intake and mortality in the NIH-AARP Diet and Health Study. Arch Intern Med 171, 1061–1068, 2011. 32. Meyerhardt JA, Sato K, Niedzwiecki D, Ye C, Saltz LB, et al.: Dietary glycemic load and cancer recurrence and survival in patients with Stage III colon cancer: findings from CALGB 89803. J Natl Cancer Inst 104, 1702–1711, 2012. 33. Kushi LH, Kwan ML, Lee MM, and Ambrosone CB: Lifestyle factors and survival in women with breast cancer. J Nutr 137, 236S–242S, 2007.
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Whole Grain Intake and Survival Among Scandinavian Colorectal Cancer Patients a
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Guri Skeie , Tonje Braaten , Anja Olsen , Cecilie Kyrø , Anne Tjønneland , Lena Maria c
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Department of Food Science, BioCenter , Swedish University of Agricultural Sciences , Uppsala , Sweden Published online: 25 Nov 2013.
To cite this article: Guri Skeie , Tonje Braaten , Anja Olsen , Cecilie Kyrø , Anne Tjønneland , Lena Maria Nilsson , Rikard Landberg & Eiliv Lund (2014) Whole Grain Intake and Survival Among Scandinavian Colorectal Cancer Patients, Nutrition and Cancer, 66:1, 6-13, DOI: 10.1080/01635581.2014.847472 To link to this article: http://dx.doi.org/10.1080/01635581.2014.847472
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Nutrition and Cancer, 66(1), 6–13 C 2014, Taylor & Francis Group, LLC Copyright ISSN: 0163-5581 print / 1532-7914 online DOI: 10.1080/01635581.2014.847472
Whole Grain Intake and Survival Among Scandinavian Colorectal Cancer Patients Guri Skeie and Tonje Braaten Department of Community Medicine, University of Tromsø, Tromsø, Norway
Anja Olsen, Cecilie Kyrø, and Anne Tjønneland Danish Cancer Society Research Center, Copenhagen, Denmark
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Lena Maria Nilsson Department of Public Health and Clinical Medicine, Nutritional Research, Ume˚a University, Ume˚a, Sweden
Rikard Landberg Department of Food Science, BioCenter, Swedish University of Agricultural Sciences, Uppsala, Sweden
Eiliv Lund Department of Community Medicine, University of Tromsø, Tromsø, Norway
to industrialized countries could be attributed to the high dietary fiber consumption (1). Whole-grain (WHG) cereals contain beneficial components beyond dietary fiber (e.g., vitamins, minerals, lignans, beta-glucan, inulin, phytochemicals, phytosterols, phytin, and sphingolipids), and these components might also contribute to the beneficial effects of WHG in products, alone or in interaction with dietary fiber and other components (2). The continuous update project by the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) included WHG in their latest report but did not grade the evidence. However, in their systematic review and meta-analysis of prospective studies, they found a reduced risk of CRC when increasing the WHG intake (3). Some studies from the United States and Norway on WHG and mortality have found an inverse association with all-cause mortality (4–7), but 1 study found no association with total mortality, only cardiovascular deaths (8). A study of the healthy Nordic food index found that WHG rye bread consumption was the single component of the index that was most consistently associated with reduced mortality (9). Studies from Norway and the United States that have analyzed cancer mortality per se found no association with WHG consumption in comprehensively adjusted analyses (6,7). An ecological analysis from the Seven Countries Study found that higher fiber intake was associated with lower CRC mortality (10), and a more recent paper from the European Prospective Investigation into Cancer and Nutrition (EPIC) study found reduced mortality from smoking related cancers (including CRC) in persons with higher intakes
To our knowledge, no studies of associations between intake of whole grain (WHG) and survival of colorectal cancer have been published, despite evidence that dietary fiber, and to some extent WHG, are associated with lower risk of colorectal cancer. Scandinavia is an area where the WHG consumption traditionally is high. We performed a case-only (N = 1119) study in the Scandinavian HELGA cohort of pre-diagnosis WHG intake (total WHG, WHG wheat, WHG rye, and WHG oats) and survival of colorectal cancer. Cox regression analyses were used to study the associations, both in categorical and continuous models, stratified by location (proximal, distal, rectum) and country. No evidence of an association was found, neither for total WHG intake (hazard ratio = 1.32, 95% confidence interval: 0.88–1.97 lowest vs. highest tertile, adjusted for age at diagnosis, metastasis status, smoking, folate, margarine, and energy), nor for specific grains. Prediagnosis consumption of WHG does not seem to improve survival of colorectal cancer in subjects diagnosed within this prospective population-based Scandinavian cohort.
INTRODUCTION The relationship between cereal food consumption and colorectal cancer (CRC) has occupied scientists ever since Burkitt suggested that lower CRC rates in African countries compared
Submitted 3 February 2013; accepted in final form 12 August 2013. Address correspondence to Guri Skeie, Department of Community Medicine, University of Tromsø, N-9037, Tromsø, Norway. Phone: 004777646594. Fax: 0047 77 64 48 31. E-mail: [email protected]
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WHOLE GRAIN AND SURVIVAL OF COLORECTAL CANCER
of dietary fiber, particularly from cereals and vegetables (11). To our knowledge, no studies published have investigated prognosis or survival of CRC patients according to WHG consumption, and there is in general a paucity of papers on dietary factors and CRC recurrence and survival (12). However, a study from Utah found lower survival for colon cancer patients consuming higher amounts of dietary fiber (13), whereas a French study found no association between dietary fiber intake and CRC survival (14). In the Scandinavian countries, the consumption of WHG has traditionally been high, and although wheat is the dominant source in Norway, rye is an important source of WHG in Sweden and Denmark (15). Compared to the CRC mortality rates in Europe (17.35 per 100,000 for men and 10.51 for women), the mortality rate for women is higher in all three countries, whereas for men it is higher in Denmark (20.30), lower in Sweden (13.67), and level in Norway (17.05) (16). We have previously shown that intake of WHG products is associated with lower CRC incidence in the Scandinavian population-based HELGA cohort (17). The aim of this study was to describe the association between pre-diagnosis intake of total WHG, WHG wheat, WHG rye, and WHG oats, and survival among participants from the HELGA cohort diagnosed with CRC. MATERIAL AND METHODS The HELGA Cohort The HELGA cohort consists of 119,913 participants from 3 prospective Scandinavian cohorts: The Norwegian Women and Cancer study (NOWAC) (18), The Northern Sweden Health and Disease Study (19), and the Danish Diet, Cancer and Health Study (20). These cohorts are also members of the EPIC study (21). Participants were recruited from the general population using the unique personal registration numbers. In Norway, the participants were selected at random among women born 1943–1957 from the entire country. In Sweden, the participants were inhabitants from the V¨asterbotten County. All persons aged 40, 50, and 60 years were invited for screening. In Denmark, inhabitants born in Denmark, free from cancer and aged 50–64 yr from Copenhagen and Aarhus and the surrounding areas were invited. Data collection took part in 1992–1996 (Sweden), 1993–1997 (Denmark), and 1998–1999 (Norway). The local medical ethics review boards and other relevant authorities in the 3 countries approved of the studies, and the participants provided informed consent. Exposure and Adjustment Variables Dietary intake was measured before diagnosis by validated country-specific semiquantitative food frequency questionnaires (FFQ) (22–24). WHG was defined according to the AACC International (25): “Whole grains shall consist of the intact, ground, cracked or flaked caryopsis, whose principal anatomical components—the starchy endosperm, germ and bran—are present in the same relative proportions as they exist
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in the intact caryopsis.” Grains included in the definition used in the present study consist of the following (all belonging to the Poaceae family): wheat, rye, oats, barley, rice, millet, corn/maize (dried), triticale and sorghum/durra, but specific estimates are only given for the first 3. The WHG contents were obtained through published values, labeling information, recipes, official reports (26), and contacts with producers. Both information about total WHG content, and content from wheat, rye, oats, and other WHG sources were collected. For specific WHG foods included in the FFQs, values were used directly, for composite foods, or where unspecific questions were asked, WHG values were weighted based on frequency of consumption in a detailed single 24-h dietary recall in a subset of the study population (15,27). The WHG content was expressed as the WHG contents of the unprepared ingredients divided by the weight of the prepared product. For food-based analyses we created a variable for WHG products. This is the sum of food groups that either contained only WHG products (WHG bread) or >75% of the products included in the category contained WHG (crispbread and breakfast cereals). The more detailed information about crispbread and breakfast cereals was obtained from the aforementioned 24-h dietary recalls (15). The participants also filled in questionnaires regarding lifestyle factors such as smoking, education, and use of menopausal hormone therapy. Weight and height were measured in Sweden and Denmark, and self-reported in Norway. Information about physical activity was not comparable between the countries.
Study Population In the cohort, 581 men and 672 women were prospectively diagnosed with CRC as their first primary cancer; out of these 830 were Danes, 214 Norwegians, and 209 Swedes. Information about cancer incidence and vital status was obtained from national cancer registries, patient registries and cause of death registries, and was complete until December 31, 2007 (Denmark) and December 31, 2008 (Norway and Sweden). Censoring for total deaths was done on the same date, whereas specific causes of death were complete until December 31, 2006 (Denmark) and December 31, 2007 (Norway and Sweden). CRC was defined as cancers coded C18, C19, or C20 according to the International Statistical Classification of Diseases, Injuries and Causes of Death, version 10 (ICD-10). Proximal (right) colon tumors included those located in the cecum, appendix, ascending colon, hepatic flexure, transverse colon, and splenic flexure (C18.0–18.5); distal (left) colon tumors included the descending and sigmoid colon (C18.6–18.7). Rectal cancers included both cancers in the rectosigmoid junction (C19) and in rectum (C20). Information about cancer stage was collected with different specification in the 3 countries, and merged into localized cancer, metastatic cancer, including regional metastases, and
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missing or unknown metastasis status. Treatment information was not available. Analyses were stratified on location, and nonspecific colon cancers and cancers of the overlapping lesion were excluded (C18.8–18.9, n = 49). The analyses focused on adenocarcinomas and carcinomas, and cases with missing, nonspecific, and other morphology were excluded (n = 51). Eleven persons were diagnosed upon death and did not contribute follow-up time. Two persons were excluded because of implausible energy intakes [lower than 2.5 megajoules (MJ)—both genders, or higher than 18 MJ (women) or 21 MJ (men)], and 2 persons because of implausible WHG intakes (higher than 160 g/day). Nineteen persons were excluded because of missing information on smoking. Finally, 529 men and 590 women, among them 756 Danes, 178 Norwegians, and 185 Swedes were included in the analyses. There were 316 proximal colon cancers, 332 distal colon cancers, and 471 rectal cancers. The majority of the participants had distant or regional metastases (n = 836), but some had localized disease (n = 187), or unknown metastasis status (n = 96). In the Norwegian cohort, repeated measurements of diet were available, and these were used to analyze dietary change related to CRC diagnosis. The dietary change cohort comprise not only the Norwegian HELGA subcohort but a larger sample from the NOWAC study and is described in detail in (28). Briefly, the first wave of data collection took place in 1996–1999 (n = 67,932), and the second in 2002–2005 (n = 50,800), including 80.5% of the eligible participants. After exclusions, 130 women who were diagnosed with CRC between questionnaires, and 43,154 cancer-free women were included in the analyses. Dietary fiber content has been calculated, but WHG content has not been determined for this cohort. Causes of Death Causes of death were coded according to ICD-10, and deaths were analyzed as total deaths (n = 390). Eighty-six percent of the deaths had specified causes (n = 334). Among them, 309 (91%) were due to cancer, 295 (88%) due to CRC. Statistical Analyses Age-adjusted baseline characteristics were computed as least square means in general linear models, with dummy variables for the strata variable (country). Categorical variables were also included as dummy variables. Country, tumor location, and metastasis status were not age-adjusted. Several variables were tested to check confounding effects— variables identified as probably or convincingly associated with CRC incidence in the continuous update project of WCRF/AICR (dietary fiber, dairy products/milk/calcium, red meat, processed meat, alcohol, body mass index, and height) (29); factors identified in a review of dietary factors and CRC survival (vitamin D and folate) (12); and variables from our earlier article identifying factors associated with WHG use (smoking, length of
education, vegetables, fruit, fish, tea, coffee, margarine, white bread, and cakes and biscuits) (30). Because of a lack of linearity, these variables were modeled as tertiles, except from smoking (never, former, and current), and level of education (none/primary school, technical/professional school, secondary school, and longer education). For the adjustment factors, sexand country-specific tertiles were created, because of the skewed distribution across countries for some of them. For total WHG and total WHG products, sex-specific cohort wide tertiles were created, however, the intake distribution for specific grains differed by country, so for WHG wheat, rye, and oats, country- and sex-specific tertiles were created. The Cox proportional hazards model was used to calculate hazard ratios for mortality, with corresponding 95% confidence intervals. Results are presented separately for men and women, as inspections of survival plots revealed diverging curves for sex. All analyses were stratified by country and location (distal colon, proximal colon, and rectum). Assumptions of the Cox proportional hazards model were tested by inspection of plots and inclusions of time-dependent covariates in the models. The interaction between time and total WHG consumption was significant for men, and for women there was a significant association between tumor location and time. Therefore, the analyses were run both with the total dataset, and with a dataset restricted to seven years of follow-up, where interaction was not an issue. Time since diagnosis was used as the primary time variable. All models were adjusted for age at diagnosis and metastasis status (metastatic, unknown, localized). Models for WHG wheat, WHG rye, and WHG oats were mutually adjusted for the other grain types. In addition, multivariate adjusted models taking also smoking (never, former, current), intake of folate (in tertiles), and margarine (in tertiles) into consideration, and models additionally adjusted for energy intake (in tertiles) are presented. Both continuous (per 20 g extra WHG per day, per 10 g extra of specific grains per day, per 50 g extra of WHG products) and categorical analyses with WHG intake in tertiles as the independent variable were run. For the categorical analyses, tertile medians were used to test for trend. Survival plots were computed for each location. For these plots, the follow-up was restricted to 7 yr after diagnosis. Sensitivity analyses were done excluding participants dying the first year after the diagnosis. The dietary change analyses were done as described in Ref. 28. Mean dietary change was calculated as values from the second measurement minus values form the first measurement. Models were adjusted for energy in tertiles, baseline food or nutrients (continuous), categories of baseline body mass index, baseline type of questionnaire, and age at study entry (continuous). Baseline mean values, mean change values, and standard errors of the changes were obtained in analyses of variance using a general linear model where all variables were adjusted for each other. The significance level was set to P < 0.01 (28). CRC survivors were ranked on time since diagnosis to obtain
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2 groups of equal size to compare dietary change according to time since diagnosis. All analyses were done in SAS (version 9.2 and 9.3). The level of significance was set to 0.05.
RESULTS In general, the high WHG consumers were thinner, smoked less, and were slightly older at diagnosis compared to low consumers (Table 1). Fewer women in the highest WHG tertile had never used menopausal hormone treatments. High WHG users tended to eat less red meat, consume more dairy products, and eat more of foods typically spread on sandwiches or accompanying them, and they had a higher folate and energy intake. There was more than a threefold difference in mean intake of total WHG between the highest and lowest tertiles. Also for WHG products was there an approximately threefold difference between the mean intake in the highest and lowest tertiles, and the distribution for the specific grains varied widely as well. Most cancers were colon cancers, but in the two upper tertiles of WHG intake for men, approximately 50% of the cancers were rectal cancers. Roughly 75% of the cancers were metastatic (including regional metastases), and 10–20% were localized. For men the 1-yr survival rate was lowest in the highest WHG tertile (80.9% vs. 87.5% in the lowest tertile), whereas for women, the 1-yr survival rate was highest in the highest WHG tertile (90.4% vs. 85.9% in the lowest tertile). Slightly more persontime seemed to have been accumulated in the highest WHG tertiles. In Table 2, the risk of death is given according to prediagnosis total WHG consumption, consumption of specific grains, and of WHG products. Neither the categorical nor the continuous analyses showed any association between total WHG consumption on survival. A lower risk in crude continuous and categorical analyses of WHG oats consumption in women was not supported in adjusted analyses. Analyses restricted to 7 yr of follow-up gave essentially the same results (results not shown). When those who died the first year after diagnosis were excluded, the results were still essentially the same, except a higher risk of death was found for women in the second tertile of WHG oats consumption, also in fully adjusted analyses (HR = 1.58, 95% CI: 1.01–2.48; results not shown). Figure 1 shows survival plots for men and women, for each location separately, with follow-up restricted to 7 yr. These plots do not show any clear associations between WHG consumption and CRC survival. Short-term survivors answered the follow-up questionnaire less than 2.2 yr after they got their diagnosis, whereas long-term survivors were between 2.2 and 6.9 yr after diagnosis when answering the follow-up questionnaire. The intake of dark bread decreased significantly in both short-term survivors, long-term survivors, and cancer-free women, but did not differ between groups (Table 3). Likewise, the intake of total bread and crispbread decreased, but there were no significant differences be-
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tween the groups. Similarly, there was no difference in dietary fiber change.
DISCUSSION This study is the first study to present survival of CRC patients by prediagnosis intake of total WHG and different types of WHGs. No significant associations were found for total WHG, for WHG wheat, WHG rye, or WHG oats separately, or for WHG products in multivariate adjusted analyses. A significant inverse trend for WHG oats and mortality was found in women in crude analyses, but this association disappeared in multivariate adjusted analyses. On the other hand, an increased risk among women in the second tertile of WHG oats consumption in the analyses when deaths the first year after diagnosis were excluded persisted with adjustment. However, few questions about oats products were asked in the original questionnaires, and the estimates for this grain are rather unstable. We therefore suggest caution in interpreting these results. A range of positive health effects of WHG has been suggested by observational studies lately (2), including associations with cancer incidence (3), and total mortality (4–7). Only 2 studies provided specific estimates for cancer death, both found significantly decreased mortality with higher WHG intake in crude analyses, but with multivariate adjustments, the results were no longer significant (6,7). Two recent large studies on dietary fiber intake (particularly cereal fiber) and mortality found lower rates both for all-cause mortality and cancer mortality (31), or smoking-related cancer mortality (including CRC as a smokingrelated cancer) with higher fiber intakes (11). All these studies have been conducted in general population groups, not on cancer patients. Also, there are differences in amounts and types of WHG/cereal fiber-rich foods consumed. The NIH-AARP study and the EPIC study had more deaths than our study and the WHG studies and were therefore better powered to find possible differences (11,31). On the other hand, studies of CRC patients and dietary fiber have suggested no association (14) or detrimental associations with high intakes (13). In addition, a recent study of colon cancer Stage III patients found significant associations between higher dietary glycemic load and total carbohydrate intake and increased risk of recurrence and mortality (32). The strengths of this study included the detailed information about WHG intakes, including information on specific grains, the wide WHG consumption distribution, and the prospective design. The limitations were the availability of only one measurement of diet. Dietary measurements were conducted before diagnosis; this prevents recall bias but might not be representative if the participants changed their diet after diagnosis. Analyses from the NOWAC study have showed that women decrease their consumption of bread and cereal products after CRC diagnosis; however, the decrease was similar to the decrease seen in cancer-free women (28). In the current article, we repeated these analyses but divided the CRC survivors by time since
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G. SKEIE ET AL.
TABLE 1 Prediagnosis diet and lifestyle factors, and disease characteristics of the colorectal cancer cases in the HELGA cohort, adjusted for age at diagnosis and country Men (n = 529)
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Tertile of whole grain consumption (total whole grain range, g/day) Prediagnosis factors Body mass index (kg/m2) Smoking status (%) Never Former Current Highest education attained (%) Primary school/none Secondary school Technical school University/higher education Use of hormones for menopause (%) Current Former Never Intake of red meat (g/day) Intake of processed meat (g/day) Intake of dairy products (g/day) Intake of margarine (g/day) Energy intake (kcal/day) Dietary fiber (g/day) Folate (ug/day) Whole grain (g/day) Total From wheat From rye From oats Whole grain products (g/day) Country of origin (%)1 Denmark Sweden Norway Diagnosis characteristics Age at diagnosis (years) Tumor location (%)1 Proximal colon Distal colon Rectum Metastasis status (%)1 Metastatic Unknown Localized 1-yr survival rate (%) Person-yr accumulated from diagnosis to censoring 1
Women (n = 590)
1 (4.7–35.1)
2 (35.2–56.8)
3 (56.9–133.9)
1 (0.3–33.1)
2 (33.2–54.0)
3 (54.1–144.5)
27.1
26.6
25.8
26.0
26.1
24.9
22.8 41.8 35.4
27.5 36.6 35.9
26.8 39.6 33.6
36.1 24.4 39.5
41.3 26.8 31.9
46.2 29.2 24.6
37.5 8.3 29.6 24.6
33.1 8.6 35.7 22.6
33.3 11.6 32.8 22.3
34.1 12.8 41.5 11.6
41.0 15.2 39.5 4.3
35.6 18.4 35.4 10.6
26.2 10.4 63.4 41.2 28.3 348 16.5 1766 22.2 261
26.2 12.9 60.9 38.2 29.1 409 17.5 2042 28.3 305
81.9 37.0 320 20.5 2165 18.5 270
82.3 36.3 373 26.9 2347 23.2 297
77.7 43.7 441 29.4 2632 30.3 342
23.3 12.8 63.9 43.3 25.1 267 12.9 1539 16.1 217
23.7 3.5 17.6 0.9 79.4
44.9 4.7 32.3 5.9 135.6
77.4 7.7 49.8 17.5 195.9
22.0 10.7 10.6 0 65.7
42.3 12.4 23.9 5.0 119.6
74.1 26.1 31.7 14.6 195.0
92.0 8.0
88.1 11.9
63.1 36.9
81.1 11.2 7.7
50.3 15.2 34.5
35.0 16.8 48.2
64.8
64.3
65.1
61.6
61.7
62.5
26.1 30.1 43.8
19.8 31.1 49.1
26.7 23.3 50.0
30.1 25.5 44.4
35.0 35.5 29.5
30.5 32.0 37.5
73.9 6.2 19.9 87.5 631
74.6 9.0 16.4 88.8 666
69.9 12.5 17.6 80.9 669
77.0 3.6 19.4 85.9 756
78.7 10.1 11.2 86.2 807
73.6 10.2 16.2 90.4 840
Not adjusted.
diagnosis. The results did not differ by time since diagnosis, but since there were only 65 survivors in each group, the variability in the numbers was substantial. Therefore, it cannot be ruled out that a larger sample would have revealed some differences in change by time since diagnosis, and if the tendencies seen here are representative, decreases in bread and crispbread
consumption might be larger closer to diagnosis and treatment, and more comparable to general trends a few years after diagnosis. Analyzing prediagnosis diet reduces the potential for selection bias due to selective survival (33). Although ideally several dietary measurements before and at given intervals after diagnosis should have been included, it is not likely that
11
WHOLE GRAIN AND SURVIVAL OF COLORECTAL CANCER
TABLE 2 Prediagnosis consumption of total whole grain (WHG), WHG wheat, WHG rye, and WHG oats, and risk of death in Scandinavian colorectal cancer patients (n = 1,119) Men (n = 529)
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Total WHG Colon and rectum (continuous, per 20 g) Total WHG tertiles 1 2 3 P for trend (linear) WHG wheat4 (continuous, per 10 g) WHG wheat tertiles4 1 2 3 P for trend (linear) WHG rye4 (continuous, per 10 g) WHG rye tertiles4 1 2 3 P for trend (linear) WHG oats4 (continuous, per 10 g) WHG oats tertiles4 1 2 3 P for trend (linear) WHG products (continuous, per 50 g) WHG products 1 2 3 P for trend (linear) 1
Deaths
Model 11 HR (95% CI)
Model 22 HR (95% CI)
Women (n = 590) Model 33 HR (95% CI)
Deaths
Model 11 HR (95% CI)
Model 22 HR (95% CI)
193
0.99 (0.88–1.12) 1.00 (0.88–1.14) 1.00 (0.88–1.14)
197
0.90 (0.79–1.03) 0.93 (0.81–1.08) 0.93 (0.81–1.07)
67 61 65
Ref Ref Ref 0.83 (0.58–1.18) 0.84 (0.58–1.20) 0.83 (0.58–1.20) 0.98 (0.68–1.41) 1.00 (0.67–1.48) 1.00 (0.67–1.48) ns ns ns
69 74 54
Ref Ref Ref 1.03 (0.72–1.46) 1.10 (0.77–1.57) 1.10 (0.77–1.58) 0.78 (0.53–1.15) 0.92 (0.60–1.40) 0.91 (0.60–1.39) ns ns ns
193
0.98 (0.72–1.35) 0.94 (0.67–1.31) 0.94 (0.67–1.31)
197
1.06 (0.92–1.21) 1.03 (0.89–1.19) 1.02 (0.89–1.18)
66 62 65
Ref Ref Ref 1.09 (0.76–1.58) 1.19 (0.81–1.76) 1.19 (0.81–1.76) 1.08 (0.74–1.60) 0.97 (0.64–1.49) 0.97 (0.64–1.49) ns ns ns
72 59 66
Ref Ref Ref 0.76 (0.53–1.10) 1.03 (0.70–1.52) 1.02 (0.69–1.51) 1.01 (0.69–1.48) 1.41 (0.76–2.63) 1.35 (0.72–2.53) ns ns ns
193
0.98 (0.90–1.06) 0.98 (0.90–1.07) 0.98 (0.90–1.07)
197
0.96 (0.85–1.08) 0.98 (0.87–1.11) 0.98 (0.87–1.11)
65 62 66
Ref Ref Ref 0.77 (0.54–1.11) 0.76 (0.51–1.11) 0.75 (0.51–1.11) 0.82 (0.58–1.17) 0.90 (0.60–1.36) 0.90 (0.60–1.36) ns ns ns
67 69 61
Ref Ref Ref 0.94 (0.66–1.33) 0.78 (0.51–1.17) 0.78 (0.51–1.18) 0.91 (0.63–1.32) 0.93 (0.60–1.45) 0.93 (0.60–1.46) ns ns ns
193
1.03 (0.90–1.17) 1.05 (0.91–1.20) 1.05 (0.91–1.20)
197
0.82 (0.70–0.97) 0.88 (0.75–1.04) 0.88 (0.75–1.04)
60 72 61
Ref Ref Ref 1.04 (0.73–1.48) 1.09 (0.75–1.58) 1.09 (0.75–1.58) 0.97 (0.65–1.45) 1.12 (0.73–1.70) 1.11 (0.72–1.70) ns ns ns
64 74 59
Ref Ref Ref 1.36 (0.95–1.93) 1.12 (0.80–1.58) 1.13 (0.80–1.59) 0.95 (0.63–1.42) 0.83 (0.55–1.26) 0.83 (0.55–1.26) 0.007 ns ns
193
1.00 (0.90–1.11) 1.00 (0.90–1.13) 1.01 (0.90–1.13)
197
0.96 (0.86–1.07) 0.98 (0.87–1.11) 0.97 (0.86–1.10)
67 59 67
Ref Ref Ref 0.95 (0.67–1.36) 0.96 (0.66–1.40) 0.96 (0.66–1.40) 1.03 (0.73–1.46) 1.05 (0.71–1.56) 1.06 (0.71–1.56) ns ns ns
62 72 63
Ref Ref Ref 1.19 (0.83–1.70) 1.27 (0.89–1.82) 1.26 (0.88–1.81) 1.02 (0.71–1.46) 1.11 (0.75–1.65) 1.10 (0.74–1.64) ns ns ns
Adjusted for age at diagnosis and metastasis, and stratified for country and location (proximal colon, distal colon, rectum). As model 1, but additionally adjusted for smoking, folate (in tertiles) and margarine (in tertiles). 3 Model 2 + adjustment for energy (in tertiles). 4 Models for specific grains were mutually adjusted for the other grains. 2
Model 33 HR (95% CI)
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G. SKEIE ET AL.
FIG. 1. Survival of colorectal cancer by tertile of total whole grain intake for different locations, men and women. A: Proximal colon, men. B: Distal colon, men. C: Rectum, men. D: Proximal colon, women. E: Distal colon, women. F: Rectum, women. All analyses adjusted for metastasis status (metastasis, unknown, localized), smoking (never, former, current), country, sex-specific tertiles of folate, margarine, and energy.
the lack of dietary measurements after diagnosis is a major limitation. No treatment information was available, but it is unlikely that treatment should differ between WHG consumption groups. In conclusion, prediagnosis consumption of WHG, in total or from wheat, rye, or oats do not seem to improve survival of CRC patients diagnosed within a prospective population-based Scandinavian cohort.
ACKNOWLEDGMENTS We wish to thank Knut Hansen for assistance in data set preparation, and we also acknowledge Professor G¨oran Hallmans, Ume˚a University, for support and valuable advice. FUNDING This study was supported by NordForsk [Centre of Excellence programme HELGA (070015)] and The Danish
TABLE 3 Adjusted change in bread, cereals, and fiber intake (99% confidence interval) among short-term and long-term colorectal cancer survivors, compared with cancer-free women Short-term colorectal cancer survivors (n = 65)
Long-term colorectal cancer survivors (n = 65)
Cancer-free women (n = 43,154)
Food/food group/ nutrient (g/day)
Meana
SE
Meana
SE
Meana
SE
P value
Bread and crispbread Dark breadb Breakfast cereals Dietary fiber
−22.0 −36.4 0.9 −0.7
6.6 7.6 2.4 0.7
−11.4 −34.8 0.5 0.3
6.6 7.6 2.4 0.7
−14.6 −32.8 −0.9 −0.3
0.6 0.7 0.2 0.1
0.5 0.8 0.7 0.5
All analyses are adjusted for age (years at baseline), baseline type of questionnaire, baseline energy intake in tertiles, baseline body mass index groups (≤20, 20.1–25, >25), and baseline intake of the food (g/day) (28). a Differences in italics are significantly different from 0. b A question on medium dark breads was introduced in the follow-up questionnaires. Therefore, the decrease in dark bread is larger than the decrease in total bread and crispbread.
WHOLE GRAIN AND SURVIVAL OF COLORECTAL CANCER
Cancer Society. The Northern Sweden Health and Disease Study was supported by the Joint Committee of the Northern Sweden Health Care Region, V¨asterbotten County Council, The Swedish Research Council, The Swedish Council for Working Life and Social Research, and The Cancer Research Foundation in Northern Sweden. Some of the data in this article are from the Cancer Registry of Norway. The Cancer Registry of Norway is not responsible for the analysis or interpretation of the data presented.
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