Prospective study of dietary changes in cancer survivors for five years including pre- and post- diagnosis compared with those in cancer-free participants

The number of long-term survivors after a cancer diagnosis is increasing. Few investigations have compared survivors’ diets to their original pre-diagnosis dietary pattern or with the patterns of cancer-free controls. We examined the dietary changes in survivors for five years (i.e. before to after diagnosis) in cancer survivors, comparing them with cancer-free controls in a prospective cohort study in Japan. Using 1995–1998 for the baseline and 2000–2003 for the follow-up survey, a validated food frequency questionnaire was administered to 33,643 men and 39,549 women aged 45–74 years. During the follow-up period, 886 men and 646 women had developed cancer. Participants that had not been diagnosed with cancer served as controls. There was a greater decrease in the calorie intake (median change: − 168 kcal/d [Interquartile range: − 640, 278]) in male cancer survivors compared to controls (− 33 kcal/d [− 453, 380], P < .001). On comparison with cancer-free controls, multiple linear regression analysis revealed a significantly larger reduction in energy-adjusted ethanol intake for male cancer survivors (β =  − 0.36). There was no difference in changes in fruit and vegetable or red meat intake and no other significant differences in dietary changes between survivors and controls for either gender. This suggests that most dietary changes in survivors after cancer diagnosis are not systematically different from those that occur in people without a cancer diagnosis.

Statistical analysis. Individual changes in dietary intake were calculated by subtracting intake values at baseline from those at follow-up based on the respective FFQ. The Wilcoxon signed-rank test was used to determine the significance of any change of intake between baseline and follow-up survey. Changes among cancer survivors were compared with those among cancer-free the controls. The Mann-Whitney U-test was used to compare controls and survivors for all cancers, and the Kruskal-Wallis test was used for controls and survivors for specific cancer types. Because this comparison of controls and survivors for specific cancer types was conducted by univariate analysis, multiple comparisons were not performed. Statistical significance was considered at the P < 0.01 level in this analysis because of the large number of participants. For these univariate analyses, Bonferroni correction (with statistical significance considered at the P < 0.0005 level for both genders) was further made because of the number of exposures. Only those items for which significant differences were found in these univariate analyses were considered in further multivariate analysis. Relative changes in energy-adjusted intake (/1000 kcal by the density method), expressed as the ratio of the follow-up intake value to the baseline intake value as the dependent variable, were calculated using linear regression analysis with the existence of a cancer diagnosis as the independent variable. Those with zero intake in the baseline survey only were excluded, because it was impossible to calculate from each item as follows: for men, ethanol (n = 1473, 3.0% of survivors, 4.4% of controls); rice (n = 261, 0.3% of survivors, 0.8% of controls); and milk and dairy products (n = 1117, 4.3% of survivors, 3.3% of controls) were excluded. For women, rice (n = 344, 0.6% of survivors, 0.9% of controls) and vegetables (n = 102, 0.2% of survivors, 0.3% of controls) were excluded. These relative changes were calculated by the following formula: (energy-adjusted intakes by follow-up survey − those by baseline survey)/energy-adjusted intakes by baseline survey.
Ethics statement. Enrolled individuals were informed of the objectives and contents including follow-up, of the study. Informed consent was obtained from each participant implicitly when they completed the questionnaires of the JPHC Study. The study was approved by the Institutional Review Boards of the National Cancer Center in Tokyo, Japan (approval number: 2001-021), and all procedures in this study were performed in accordance with the relevant ethical guidelines regulations in Japan. Detailed information on the study was mailed to each participant and is published on the study website (http:// epi. ncc. go. jp/ jphc).

Results
We confirmed 1,532 cases of newly diagnosed cancer (886 cases among men and 646 cases among women) among the 73,192 participants by December 31, 2002. By site, these were 226 cases of colorectal, 244 cases of gastric, and 416 cases of other cancers among men, and 134 cases of colorectal, 91 cases of gastric, 158 cases of breast, and 263 cases of other cancers among women. Mean duration between diagnosis and follow-up dietary measurement was 2.1 years for the survivors.
Characteristics of participants. The baseline characteristics of participants are shown in Table 1. With the exception of breast cancer patients, survivors were older than the cancer-free control participants among both men and women. The distribution by BMI category was similar in controls and survivors other than for gastric cancer in men (relatively low proportion of overweight) and for breast cancer (relatively high proportion of obesity) in women. There were more former smokers among survivors than controls, while nonsmokers were Comparison of changes in crude intakes. Crude intakes of energy, nutrients, and food groups estimated by FFQs and those changes over five years are shown in Table 2 for men and Table 3 for women, respectively. Changes in nutrient intakes as a result of changes in food habits are shown in Supplemental tables S1 and S2. At baseline, intake levels in survivors were similar to those in the cancer-free controls among both men and women. Most nutrients and food groups examined showed significant changes between baseline and follow-up surveys for both cancer-free controls and survivors of all cancers among both sexes. Most nutrients or food groups showed no statistically significant difference in the change in intake between cancer-free controls and survivors for either gender. In men, total energy intake decreased in both survivors and controls over five years, with a significantly greater decrement in survivors (    www.nature.com/scientificreports/ with significantly smaller changes in survivors than controls (P < 0.001). The results for grains were similar to those for rice, which accounts for the major part of grain intake. Milk and dairy product or coffee intake did not materially change between the baseline and follow-up surveys in survivors of all cancers and controls, although these did show statistical significance (P < 0.01 for both). In further Bonferroni correction, the statistical significance of milk and dairy products or coffee was lost, whereas the results for total energy, ethanol and rice were not changed. Additionally, the reduction in energy intake among male survivors was larger for short- , but not to a significant extent (P = 0.69). Additionally, after adjustment for age and other factors, the relative changes in energy intake among women also showed no difference between cancer survivors and cancer-free participants (1% [95% confidence intervals (CI): − 2 to 4]). Rice intake was decreased in female survivors (− 3.

Comparison in relative changes in energy-adjusted intakes. Relative changes in nutrient and food
group intakes for cancer survivors compared with those for cancer-free controls are shown in Table 4 for men and women. Energy-adjusted intake was used because the energy intake was decreased for both cancer survivors and controls in both genders. We analyzed the nutrients and the food groups that showed statistically significant differences in the prior comparison by crude intake: ethanol, grains, rice, milk and dairy products in men; and grains, rice and vegetable in women. Compared to controls, a significant decrement (β = − 0.36, [95% CI: − 0.53 to − 0.20]), especially in gastric cancer survivors (β = − 0.45, [95% CI: − 0.76 to − 0.14]), was observed in ethanol intake among men. Among women, changes in intake between baseline and follow-up did not differ between cancer survivors and controls in the fully-adjusted models.

Discussion
This study investigated dietary changes in cancer survivors compared to cancer-free controls by gender based on a large-scale prospective cohort study in Japan. Although there was a marked decrease in the energy and ethanol intake in male survivors, the changes in many elements of a comprehensive range of nutrients and food groups were similar to those of controls, indicating that most dietary changes according to cancer diagnosis and subsequent survival were not significant.
A greater reduction in total energy intake in survivors was observed among men only. A previous study that included male survivors 11 reported decreased energy intake, consistent with our results, although that study did not compare changes with those in cancer-free controls. In the case of females, a prospective study reported no difference in the reduction of energy intake over 6 years between survivors and controls 17 . These results suggest that changes in total energy intake over time for female survivors may not be particularly differ from changes in those without a cancer diagnosis.
We found that ethanol intake was decreased in male cancer survivors. Previous studies examining changes in ethanol intake are limited. Consistent with our findings, a study 11 examining men and women combined found that intake was decreased in survivors, although there was no comparison with cancer-free controls, while another study 17 in females showed no change among survivors and no difference compared with controls, again consistent with our findings. For women, the proportion of those who did not drink was > 60% of respondents for both questionnaires, so it is possible that alcohol-related intake changes could not be detected. Alcohol is considered to be a risk for several types of cancer 6 , and avoidance of alcohol is recommended to prevent new primary tumors in survivors 5 .
Among major site-specific cancer survivors, alcohol intake reduction in men with gastric cancer was the most prominent change from pre-diagnosis to subsequent survival in men. However, given that this study could not use information on cancer stage or treatment, it cannot be ruled out that the decrease may be attributable to gastric cancer-specific treatments rather than a change to a healthier lifestyle.
A slightly larger but insignificant increment was observed in vegetable, but not fruit, intakes for cancer survivors, especially for breast cancer survivors, than for cancer-free controls over five years among women only. Previous studies of breast cancer patients in Europe, which compared dietary changes prospectively with those for controls 17,18 , reported a slightly larger increment of intakes of both fruit and vegetables in survivors than in cancer-free participants (18.1 g and 13.6 g for the differences in changes of fruit and vegetable intake, respectively 17 Table 4. Relative changes a in energy-adjusted nutrient and food group intakes in cancer survivors compared with controls for male (n = 33,643) and female (n = 39,549). β: Difference in the intake changes compared with cancer-free controls, CI: 95% confidence intervals. a Changes are expressed as the ratio to the baseline intake according to following formula: (follow-up survey intake − baseline survey intake)/baseline survey intake; intakes were energy − adjusted by the density method. b The unit of intake is g/day.  18 ), contrary to our findings. This difference in findings might be owing to the small number of breast cancer survivors (158 cases) caused by the relatively low incidence of this cancer in Japan 2 , although the reported difference in increments was at most 13 g or 3.3% between survivors and cancer-free controls 17,18 . Also, no differences were observed in the reductions in red meat intake between cancer survivors and controls in either gender. A previous study in women reported no difference in red meat intake reduction 17 , similar to our results. These results also suggest that dietary changes in intakes among survivors may not be attributed to a cancer diagnosis. There are some limitations to this study. First, the period from diagnosis to the follow-up dietary survey was uneven. The mean interval was 2.1 years. One report noted that dietary changes were largest immediately after the cancer diagnosis (during the treatment/recovery period), after which intakes gradually returned to levels before diagnosis 31 . Thus, due to the short observation period, the results may have overestimated dietary changes as shown in separate calculations by observation period for energy and ethanol intake among men. In addition, survivors would have included severe cancers, which also would have led to an overestimation of changes. Second, rice, a traditional Japanese staple food, is generally consumed in a refined form. Although this study did not examine the consumption of whole grains, it is unlikely that many Japanese people consume unrefined brown rice frequently 32 , albeit that further research on this question is warranted.
Evidence to date on the diet of cancer survivors in relation to prognosis includes studies that use the diet prior to diagnosis as exposure [33][34][35][36][37] . Our findings of few and small changes from before the diagnosis in several nutrients and food groups in survivors indicate that cancer diagnosis and subsequent early survival do not cause drastic dietary changes. These findings may aid in the evaluation of the contribution of pre-diagnosis diets and may create future research opportunities on dietary habits in association with prognosis.
In conclusion, the dietary changes over five years, including before and after cancer diagnosis, in cancer survivors were small compared with changes among cancer-free controls in a prospective large-scale populationbased cohort study. These findings suggest that most dietary changes in cancer survivors are not systematically different from those that occur in people without a cancer diagnosis.