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The 2007 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) guidelines encourage cancer survivors to follow its cancer prevention recommendations. We evaluated whether adherence to the WCRF/AICR guidelines for cancer prevention was associated with lower mortality among older female cancer survivors.
From 2004–2009, 2,017 participants in the Iowa Women’s Health Study who had a confirmed cancer diagnosis (1986–2002) and completed the 2004 follow-up questionnaire were followed. Adherence scores for the WCRF/AICR guidelines for body weight, physical activity, and diet were computed assigning one, 0.5 or 0 points to each of eight recommendations depending on the degree of adherence. All-cause (n=461), cancer-specific (n=184), and cardiovascular disease (CVD)-specific mortality (n=145) were compared by the total adherence score and by adherence scores for each of the three components of the recommendations.
Women with the highest (6–8) vs. lowest (0–4) adherence score had lower all-cause mortality (HR=0.67, 95%CI=0.50–0.94). Meeting the physical activity recommendation was associated with lower all-cause (ptrend<0.0001), cancer-specific (ptrend=0.04), and CVD-specific mortality (ptrend=0.03). Adherence to dietary recommendations was associated with lower all-cause mortality (ptrend<0.05), whereas adherence to the body weight recommendation was associated with higher all-cause mortality (ptrend=0.009).
Adherence to the WCRF/AICR guidelines was associated with lower all-cause mortality among older female cancer survivors. Adherence to the physical activity recommendation had the strongest association with lower all-cause and disease-specific mortality.
Older cancer survivors may decrease their risk of death by leading a healthy lifestyle after a cancer diagnosis.
As a consequence of early detection, improvements in cancer treatment, and an aging population, the number of older cancer survivors is growing. Currently 68% of people diagnosed with cancer survive at least 5 years and 60% of the nearly 12 million cancer survivors are ages 65 years or older in the United States (1, 2). Aging and status as cancer survivor may increase older cancer survivors’ risk of recurrent and subsequent cancer (3) and other age-related chronic health conditions (4, 5), such as cardiovascular disease (CVD) (6, 7), diabetes (8) and osteoporosis (9). Thus, cancer survivorship in older adults is a growing area of investigation.
Health behaviors, such as maintaining ideal body weight, staying physically active and eating a healthy diet, have well-described associations with decreased risk for developing primary cancer (10–16). According to the American Cancer Society (ACS), approximately one-third of the cancer deaths in the United States are attributable to poor nutrition, physical inactivity, and excess body weight (2). Based on systematic reviews of the existing evidence, cancer prevention guidelines for weight control, physical activity, and diet have been published by the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR), the ACS, and others (16, 17). However, in 2007, the WCRF/AICR Expert Review Panels were unable to establish guidelines specific to cancer survivors due to lack of evidence, and simply encouraged cancer survivors to follow their cancer prevention recommendations. Recently, additional studies evaluating the health effects of these behaviors among cancer survivors have accumulated (18–22). In 2012, based on the new scientific evidence, the ACS updated their nutrition and physical activity guidelines for cancer survivors (23). However, most of the completed randomized control trials (RCT) evaluating health behaviors in cancer survivors have been restricted to short-term trials, targeted only a single health behavior, and were conducted with a relatively small number of survivors with a specific cancer. Whether multiple healthy lifestyle modifications, including maintaining an ideal body weight, staying physically active, and eating a healthy diet, also benefit cancer survivors’ health outcomes remains to be answered.
Here, we evaluated whether adherence to the 2007 WCRF/AICR body weight, physical activity, and dietary guidelines, combined or individually, is associated with lower all-cause, cancer-specific and CVD-specific mortality among older female cancer survivors in the Iowa Women’s Health Study (IWHS). To our knowledge, the effect of multiple health behaviors on survival after cancer diagnosis has not been evaluated in a prospective cohort study. The IWHS is an ongoing large prospective cohort study that has followed postmenopausal women for over 26 years. The prospective study design and large sample size allowed us to collect health behaviors both pre- and post-cancer diagnosis from over 2,000 women who had survived incident cancer during the follow-up period.
The IWHS is a prospective cohort study to investigate the association of dietary and other factors with risk of cancer and other chronic diseases (24). In 1986, a self-administered questionnaire was mailed to 99,826 women aged 55–69 who were identified from the Iowa Department of Transportation list of licensed drivers. Of these women, 41,836 women (42%) responded to the questionnaire collecting information on demographics, anthropometry, medical and family history, lifestyle factors, and usual dietary intake. Five follow-up questionnaires were administered to the remaining cohort participants by mail in 1987, 1989, 1992, 1997, and 2004. Incident cancers are identified by annual linkage with the State Health Registry of Iowa, a member of the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) program. For each primary cancer, detailed information including age at diagnosis, type and stage of cancer, first course of therapy, and subsequent cancer diagnosis is obtained. The annual migration rate from Iowa among the IWHS participants is <1%, resulting in a nearly complete follow-up of incident cancers (25). The IWHS was approved for human subject research by the Institutional Review Board of the University of Minnesota. The return of the questionnaires was considered as a subject’s consent to participate in the study.
Cancer survivors were selected from cohort participants who were alive and completed the latest follow-up questionnaire in 2004. The IWHS cancer survivors who completed the 2004 questionnaire were younger, more educated, less obese, less likely to be smokers, healthier as measured by a perception of overall health, more physically active, and reported fewer comorbid conditions at cohort baseline, compared to survivors who died before or did not respond to the 2004 follow-up (26). Women were excluded from this analysis if they reported a previous cancer diagnosis at cohort baseline (n=1,511), reported a cancer on the 2004 questionnaire that was not identified via the annual linkage with the State Health Registry (n=82), and/or their 2004 questionnaire was completed by proxy (n=3). Women diagnosed with cancer within 2 years prior to the 2004 follow-up were also not eligible for the current study because these short-term cancer survivors were more likely to be receiving cancer treatment that could have resulted in a modification to their lifestyle from long-term cancer survivors when they completed the questionnaire. In addition, cancer survivors who reported implausible dietary intake (left >30 items blank or reported energy intake estimates <600 or >5,000 kcal/day) in the 2004 food frequency questionnaire (FFQ) (n=198) or who did not report weight, height, or physical activity in the 2004 questionnaire (n=74) were excluded. We also excluded 63 survivors whose body mass index (BMI) was in the underweight category (<18.5) on the grounds that being underweight can be a result of many health conditions, including advanced or recurrent cancers as well as other age-related chronic diseases among older cancer survivors. As a result, 2,017 cancer survivors who were diagnosed with incident invasive cancer (except non-melanoma skin cancers) between 1986 and 2002 were followed for mortality from the 2004 survey through the end of 2009.
Demographics, medical history, anthropometry, and lifestyle factors including physical activity and dietary intake, were reassessed in the 2004 follow-up questionnaire. BMI was calculated (kilograms per square meter) using self-reported height and weight. Survivors were categorized into three physical activity levels; “high” if they reported ≥2 times/week vigorous (e.g., jogging, racket sports, swimming, aerobics, strenuous sports) or ≥5 times/week moderate activities (e.g., bowling, golf, light sports, or physical exercise, gardening, taking long walks), “moderate” if they reported 2–4 times/week moderate or once/week vigorous and moderate activities, or otherwise “low” (27). Usual intake frequency of 127 food items was assessed using the Harvard FFQ (28, 29), which has been validated in the IWHS population (30). Usual intake of food groups (e.g. total and red meat intakes) was computed based on a serving size for each food item. The 2004 questionnaire also included a single question asking whether a woman was currently undergoing cancer treatment. The total comorbidity count included self-reported presence of comorbid conditions that could affect mortality assessed in the baseline and any follow-up. These comorbid conditions included Parkinson’s disease, rheumatoid arthritis, diabetes, hip fractures, hypertension, heart attack, heart disease, and stroke.
A level of adherence to the eight recommendations in the 2007 WCRF/AICR guidelines for cancer prevention was determined for each cancer survivor using the scoring pattern outlined in Table 1. Participants received 0 points for each indicator if they did not meet the recommendation, 0.5 points for partial recommendation adherence, or 1 point for complete recommendation adherence. The recommendation to limit nutrient dense foods was excluded as an indicator because data on calorie intake by food grams was not available. The recommendation against dietary supplement use for cancer prevention was also excluded, because we were unable to ascertain the reason for supplement use, such as nutrient repletion vs. general health promotion. In addition, the breastfeeding recommendation was not applicable for this older study population and thus was excluded from our scoring. Scores for the eight indicators (one each for body weight and physical activity, and six for dietary recommendations) were summed as the WCRF/AICR recommendation adherence score (range 0–8). We further separated the adherence score into the three components of the WCRF/AICR guidelines – body weight (0–1), physical activity (0–1) and diet (0–6). A score for adherence to the WCRF/AICR guidelines prior to cancer diagnosis was also computed using data collected at cohort baseline in 1986.
Vital status of the cohort participants is updated annually via linkage with the State Health Registry of Iowa, supplemented with the National Death Index (National Center for Health Statistics). A total of 461 deaths were identified from 2004 through 2009 among the cancer survivors included in this study. For each death, the date and cause of death were obtained. The two most common causes of death were cancer (n=184) and CVD (n=145). Person-years of follow-up time for each cancer survivor was computed from January 1, 2004 through the date of death, the date on which the participant moved out of Iowa, or December 31, 2009, whichever occurred first.
Demographic and lifestyle characteristics of the cancer survivors and characteristics of their cancers were compared by quartiles of the WCRF/AICR adherence score using a Student t-test and a chi-square test for continuous and categorical variables, respectively. Age-adjusted risk of all-cause mortality was compared by demographic and lifestyle factors and cancer characteristics using Cox proportional hazards regression to determine confounders. Multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) for all-cause, cancer-specific, and CVD-specific mortality across the WCRF/AICR adherence score quartiles were computed using Cox proportional hazards regression. Covariates in the final analytic models included confounders that were statistically significantly associated with both adherence score quartiles and all-cause mortality (total number of comorbid conditions, current smoking (yes/no), perceived general health (excellent/good or fair/poor), and cancer type) as well as risk factors for death (i.e., factors which were statistically significantly associated with all-cause mortality including age at the 2004 survey, cancer stage (localized, regional, or distant), current cancer treatment at the time of the 2004 survey (yes/no), surgery and chemotherapy as a first course of cancer therapy (yes/no), and subsequent cancer before 2004 (yes/no)). Person-years from cancer diagnosis through the end of 2003 were also included as a covariate because survivors’ behavior and mortality might be affected by time since diagnosis. In addition, we adjusted the analysis for adherence to the recommendations prior to cancer diagnosis based on the data from the 1986 baseline questionnaire in order to isolate the effect of post-diagnosis recommendation adherence on mortality outcomes. We further evaluated whether the associations between WCRF/AICR recommendation adherence and all-cause or disease-specific mortality differed by cancer type, i.e., breast, colorectal, gynecologic (cervical, endometrial, ovarian, and other female genital organ cancers), and other cancers.
To evaluate the effect of each component of the WCRF/AICR guidelines (body weight, physical activity, and diet) on mortality independent of the effects of the other two components, all-cause and disease-specific mortality were also compared by adherence to each component of the guidelines while adjusting for adherence to the other components of the guidelines. We created a series of spline curves describing the multivariable-adjusted hazard ratio for the association between BMI and three mortality outcomes to evaluate inflection points for the risk. Statistical significance was defined as p<0.05.
Table 2 shows characteristics of cancer survivors and their cancers for all survivors and by levels of adherence to the WCRF/AICR guidelines. At the time of the 2004 follow-up survey, the average age of the IWHS cancer survivors was 78.9 y (standard deviation (SD)=3.9 y; range=72–88 y) (Table 2). The average time since cancer diagnosis was 8.6 years (SD=4.8 years). A total comorbidity count ranged from zero to 11 with a median of two. The three most common cancer types among the study subjects were breast (n=938), colorectal (n=380), and gynecologic cancers (n=262). Compared to survivors of breast or gynecologic cancers, more colon cancer survivors reported excellent or good general health while more survivors of “other cancers” reported fair or poor perceived general health. Among the 215 women who reported current treatment for cancer in the 2004 survey, 62% were survivors for 2-<5 years. Among the 244 women who had experienced more than one primary cancer, 51% had survived their first cancer for at least 10 years (data not shown). Survivors who had higher education level, smaller number of comorbid conditions, were less likely to be smokers, and perceived excellent or good general health reported higher adherence to the WVRF/AICR guidelines (ptrend<0.01 for all). The distributions of age and marital status were not different by levels of recommendation adherence. Cancer characteristics, except for cancer type, did not differ by levels of recommendation adherence; more colorectal cancer survivors reported greater adherence to the guidelines while more gynecologic cancer survivors reported poorer adherence. Survivors who reported current cancer treatment in the 2004 questionnaire were more likely to have poorer adherence to the guidelines (ptrend=0.08).
The mean follow-up time from 2004 through 2009 was 5.4 years. Survivors who reported older age, a greater number of comorbid conditions, current smoking, and fair or poor perceived general health condition were at higher risk of death compared to survivors without these factors (data not shown). While risk of death did not differ among survivors of the three common cancers (breast, colorectal and gynecologic), survivors of cancers other than these three common cancers were at higher risk of death (HR=1.47, 95%CI=1.18–1.83 vs. breast cancer survivors, data not shown).
Survivors who reported greater adherence to the WCRF/AICR guidelines were at lower risk of death (ptrend=0.003) (Table 3). Compared with survivors who scored four or less out of eight for recommendation adherence, survivors who scored six or above were at 33% lower risk of death. Interactions between adherence to the guidelines and cancer type on the mortality outcomes were not statistically significant. When stratified by cancer type, lower risk of death was observed among survivors of breast cancers (ptrend=0.01), but not among survivors of colorectal and gynecologic cancers. Albeit not statistically significant, survivors of other cancers who scored six or above out of eight for recommendation adherence were at lower risk for dying compared to those who scored four or less (HR=0.55, 95% CI=0.30–1.01). Similarly, although the trend was weaker, women who reported greater adherence to the guidelines were at lower risk for dying from cancer among survivors of breast cancer and cancer other than the three common cancers. The level of recommendation adherence was not associated with risk of CVD-specific mortality overall or by cancer type. None of the observed associations changed by further adjusting for pre-diagnosis WCRF/AICR recommendation adherence (data not shown). Adherence to the physical activity recommendation was associated with the body weight and dietary recommendations (p<0.0001), while adherence to the dietary recommendations was not associated with the body weight recommendation. For any of the three mortality outcomes, survivors who adhered to the physical activity recommendation were at decreased risk (26–40% reduction) compared to those who did not adhere, regardless of adjustment for BMI and adherence to the dietary recommendations (Table 4). Risk of death from any cause, cancer, or CVD among survivors with complete vs. no adherence to the physical activity recommendation were 38%, 28%, and 40% lower, respectively. Survivors who met more dietary recommendations were at lower risk of all-cause mortality only (ptrend<0.05). In contrast, survivors who met the recommendation to maintain a normal body weight had 34% higher risk of death compared to those who did not. The spline curves show that the risk peaked at normal range BMI (21 to 24) for all three mortality outcomes and constantly decreased up to 35% at BMI above 24 (Figure 1). Further adjustment for survivors’ pre-diagnosis adherence to each of three components of the guidelines did not change the observed associations between adherence to the physical activity or body weight recommendation and mortality outcomes (data not shown). The inverse association between adherence to the dietary recommendations and risk of all-cause mortality was attenuated and no longer statistically significant by additional adjustment for pre-diagnosis adherence to the dietary recommendations (ptrend=0.10).
This is one of the first studies to report that overall health behaviors included in the evidence-based cancer prevention guidelines may be beneficial to improve survival after cancer diagnosis. We found that older female cancer survivors who met a greater number of WCRF/AICR guidelines for cancer prevention were at lower risk of all-cause mortality, possibly also cancer-specific mortality, but not CVD-specific mortality. Among the three components of the WCRF/AICR guidelines (body weight, physical activity, and diet), adherence to the physical activity recommendation was the strongest factor associated with lower risk of each mortality outcome. Adherence to the dietary recommendations was also associated with lower risk of all-cause mortality but not cancer-specific and CVD-specific mortality, whereas adherence to the body weight recommendation was associated with higher risk of all-cause mortality. Our results indicate that, despite pre-diagnosis health behaviors, leading a healthy lifestyle after a cancer diagnosis may be important for better survival among older cancer survivors.
There is a growing body of literature evaluating the effect of individual health behavior (e.g., physical activity, weight loss, and healthy diet) interventions on health outcomes among cancer survivors (31–34). Current evidence indicates that physical activity interventions improve fitness, strength, physical function, cardiopulmonary fitness, and cancer-related psychosocial status, whereas dietary interventions improve diet-quality and thus nutrition-related biomarkers and body weight among cancer survivors (35, 36). Physical activity and dietary interventions have also resulted in improved biomarkers associated with disease progression and overall survival, such as insulin levels and tumor proliferation rates (35). We found that survivors who engaged in moderate, rather than vigorous, physical activity were at somewhat lower risk for dying from cancer. These findings are consistent with a previous report that found moderate-intensity physical activity intervention reduced oxidative DNA damage, while high-intensity physical activity increased DNA damage among colorectal cancer survivors (37). Further research focusing on physical activity intensity among older survivors is needed to confirm these findings.
A healthy diet is thought to impact health outcomes via weight management, but the mechanisms are likely more complex. In our study, adherence to the dietary and body weight recommendations were not associated, and adjusting for adherence to the body weight recommendation did not change the association between adherence to the dietary recommendations and mortality outcomes (data not shown). On the other hand, adjusting for adherence to the physical activity recommendation weakened the associations between adherence to the dietary recommendations and all-cause or disease-specific mortality. In a previous RCT, increased intake of fruits and vegetables improved survival among breast cancer survivors, but their weight did not change (38).
Weight control has consistently been found to be a key factor in the prevention of many chronic diseases via changes in hormones, growth factors, immune system function, and inflammation (35, 36). Historically, cancer has been associated with cachexia due to the profound wasting coupled with anorexia that can occur, especially at the advanced stage. However, given that cancer is now often diagnosed at earlier stages, obesity (rather than underweight) is more likely to be an issue among cancer survivors. Increasing evidence indicates that being obese may increase risk of cancer recurrence and comorbidities such as CVD and diabetes, and worsen overall survival among cancer survivors (39–42). Suggested mechanisms of the association between body weight and cancer outcomes include alterations in circulating hormones, genomic instability, dysregulated growth signaling and cellular energetics, inhibition of apoptosis and immune surveillance, angiogenesis, insulin and insulin-like growth factor-1 signaling, and inflammatory modulation by adipokines (43)..
On the other hand, in our older cancer survivor population, women having normal body weight were at higher risk of death compared to those being obese. An “obesity paradox” – where the prognosis of overweight and obese individuals appears to be better than the prognosis of normal weight subjects – has been identified among older adults and individuals with chronic diseases such as CVD (44–49). Lower body weight in older cancer survivors is likely to reflect unintentional weight loss from cancer, side effects of cancer treatment, and other age-related chronic health conditions. While intentional weight loss may have beneficial health effects (50), unintentional weight loss may be a sign of deteriorating health status and malnutrition and may increase the risk of death (51–53). In the current study, we were unable to distinguish intentional and unintentional weight loss after cancer diagnosis, based on data collected in the 2004 follow-up survey. However, we excluded underweight cancer survivors (BMI < 18.5) who were most likely to have lost weight unintentionally as a result of cancer and other health conditions. Moderate weight gain may be beneficial for older cancer survivors.
A cancer diagnosis may provide a “teachable moment” (a life event that is accompanied by self-reflection) (54) for cancer survivors to make positive changes in their health behaviors (55, 56). Making positive changes in multiple health behaviors may be most effective in prolonging life after cancer diagnosis. Healthier behaviors often coexist. In fact, adherence to the physical activity and dietary recommendations and current smoking status were associated each other in our study. However, evidence supporting the combined effect of multiple health behaviors on survival after a cancer diagnosis, as we provide here, is scarce. Following the WCRF/AICR guidelines for cancer prevention has been shown to be associated with lower risk for dying from, as well as developing, cancer in prospective studies of healthy individuals. In a previous IWHS analysis, cancer-free women who followed zero or one vs. six to nine of the 1997 WCRF/AICR recommendations were at a 35% higher risk for cancer incidence and a 43% higher risk for cancer-specific mortality (57). Similarly, each additional 2007 WCRF/AICR guideline recommendation met was associated with a 5% lower risk for developing cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) study (58). Concordance to the ACS cancer prevention guidelines, which are similar to the WCRF/AICR guidelines, has also been associated with lower risk of death from cancer, CVD, or any cause among cancer-free individuals in the Cancer Prevention Study-II Nutrition Cohort study (59). Here, for the first time, we report findings from a large population-based study supporting that adherence to evidence-based guidelines for cancer prevention may also be beneficial to improve survival among cancer survivors.
The prospective study design is an important strength of this study. Anthropometry and health behaviors were assessed before (at cohort baseline) and after (in the 2004 follow-up) cancer diagnosis. Therefore, we could measure participants’ adherence to all three components (body weight, physical activity, and diet) of the WCRF/AICR guidelines before and after cancer diagnosis. We were able to identify that pre- and post-diagnosis adherence to the recommendations were reasonably correlated (correlation coefficient (r)=0.43) in our older cancer survivor population, and further adjust analysis for pre-diagnosis adherence to the recommendations. Another strength is a large number of cohort participants. After the 18-years of follow-up, we could identify more than 2,000 survivors of multiple cancer types and almost 500 deaths among these cancer survivors during the subsequent 5-year follow-up. The analysis focused specifically on older cancer survivors, which is a rapidly expanding population that has been understudied. Data on factors that may affect the association between recommendation adherence and mortality, such as demographics, health behaviors, comorbidities as well as cancer characteristics were available for inclusion as covariates in the analysis. All analyses were adjusted for current smoking, which is a well-known risk factor for death (2). Residual confounding is likely to be minimal considering the extremely low prevalence (3%) of current smoking.
One limitation of our study is the reliance on death records to determine the cause of death. There were limited numbers of deaths attributed to cancer and CVD, which might have limited statistical power to detect associations of adherence to the WCRF/AICR recommendations and its interactions with cancer type on the risk of disease-specific mortality. In our scoring algorithm, the eight recommendations contribute equal weight to the total adherence score. Because the total adherence score consists of six dietary recommendations, the dietary component contributes more weight to the total adherence score than the body weight and physical activity components. To overcome this limitation, we evaluated the associations of adherence to each of the body weight, physical activity, and dietary recommendations and mortality individually. The current study included only women who had survived until the 2004 follow-up questionnaire and were able to complete the questionnaire, thus survival bias may be an issue. All study subjects were older women and the majority (99.6%) was white, which limits the generalizability of our findings to young and middle-aged adults, men, or ethnic minority groups. Potential residual confounding by measured and/or unmeasured cancer characteristics and comorbid conditions cannot be ruled out.
In summary, cancer survivors with greater overall adherence to the evidence-based cancer prevention guidelines for health behaviors, including maintaining an ideal body weight, staying physically active and eating a healthy diet, were at lower risk of death among older female cancer survivors. Our results support that the WCRF/AICR’s recommendation for cancer survivors to follow its cancer prevention guidelines. Staying physically active appears to be a key health behavior to prolong life after cancer diagnosis among older female cancer survivors. More research needs to be done to understand how diet and obesity influence health outcomes among cancer survivors.
Financial support: National Cancer Institute (R01 CA039742)
Conflicts of interest: None of the authors have a conflict of interest to declare.