Vigorous physical activity and mental health – Associations suggest a link among childhood cancer survivors

Precis:

Vigorous physical activity among childhood cancer survivors is associated with superior psychological health and cognition. A simultaneous call for more research, while at the same time promoting healthful lifestyles is indicated.

Cancer and its treatment often negatively influence the psychological well-being of survivors of childhood cancers for years or even decades after diagnosis. Commonly occurring cancer-related symptoms include depression, anxiety, pain, fatigue, and cognitive impairment; these symptoms tend to cluster and culminate in poorer overall health-related quality of life (HRQOL). Exercise is an effective non-pharmacologic approach to mitigate cancer-related symptoms.¹ The American Cancer Society nutrition and physical activity guidelines recommend at least 150 minutes of moderate physical activity per week.² Yet, the majority of survivors of childhood cancers fail to meet these guidelines.³

Much of the evidence on exercise comes from studies among adult female breast cancer survivors. Recently, Dieli-Conwright and collegues⁴ conducted a randomized controlled trial (RCT) of a progressive exercise intervention, consisting of aerobic exercise and resistance training 3 times a week over a period of 16 weeks, among 100 adult female breast cancer survivors. At post-intervention, compared to the controls, the exercise group reported significant improvements in HRQOL (between group difference: 14.7; 95% Confidence Interval: 18.2 – 9.7; p < 0.001), fatigue (p < 0.001), and depression (p < 0.001), which were maintained at 3-month follow-up. To evaluate the impact of the LIVESTRONG at the YMCA exercise program among adult cancer survivors of various cancer types, Irwin and colleagues⁵ enrolled 186 male and female survivors. The intervention consisted of a twice weekly 90-minute exercise program of aerobic exercise and resistance training led by a YMCA trainer over the period of 12 weeks. The exercise program improved HRQOL (between group difference: 4.1; 95% Confidence Interval: 0.5 – 7.7; p < 0.03). However, among childhood cancer survivors, exercise intervention studies are sparse.

An ongoing RCT among 150 childhood cancer survivors (aged ≥ 16 years and diagnosed at least 5 years prior to the study), i.e., the SURfit study,⁶ is currently testing whether a 12-month partially-supervised exercise intervention can improve cardiovascular disease risk factors, bone health, body composition, physical activity, fitness, fatigue, mental health, and overall HRQOL. The intervention consists of at least 2.5 hours per week of vigorous physical activity, including 30 minutes of strength training and 2 hours of aerobic exercise. In addition, participants are requested to reduce screen time by 25%. Motivational tools include individual “personal coach” phone calls (conducted by a physiotherapist), a web-based daily activity diary, and pedometer. Data are collected a baseline, 3, 6, and 12 months. Proposed study completion for this RCT [NCT02730767] is March 2019.

In this issue of Cancer, Tonorezos and colleagues⁷ focus on the relationship between vigorous exercise and psychological well-being among 6,199 adult survivors of childhood cancer within the Childhood Cancer Survivor Study (CCSS) who currently have a median age of 34.3 years. They report that adult childhood cancer survivors who attest to engaging in higher levels of vigorous physical activity (≥ 9 MET hours per week) experience fewer symptoms of depression (Prevalence Ratio [PR]: 0.80; 95% Confidence Interval: 0.68 – 0.94; p = 0.009) and somatization (PR: 0.83; 95% Confidence Interval: 0.72 – 0.94; p = 0.001), fewer cognitive impairments in task completion (PR: 0.79; 95% Confidence Interval: 0.71 – 0.88; p < 0.001), and lower incidence of poor HRQOL in the domains of physical functioning (PR: 0.77; 95% Confidence Interval: 0.66 – 0.89; p < 0.001), general health (PR: 0.85; 95% Confidence Interval: 0.77 – 0.92; p < 0.001), and vitality (PR: 0.82; 95% Confidence Interval: 0.75 – 0.87; p < 0.001). These findings are similar to an earlier report by co-author, Krull et al.⁸ that appeared in the European Journal of Cancer roughly eight years ago and reported similar associations between overall levels of moderate to vigorous physical activity and neurocognitive impairment among 6,440 survivors in the CCSS sample. Thus, it appears that many of these associations remain significant and are stable over time.

The current study has several strengths. Data were collected prospectively using validated measures among a large sample of adult childhood cancer survivors enrolled in the CCSS.⁹ Moreover, a diverse representation of cancer diagnoses and treatment and extended follow-up (mean of 7.8 years) were noted. However, there are limitations. As with any observational study, one cannot infer causality. This is particularly important with respect to physical activity where the underlying issue is, “what came first?” Was depression the reason for inactivity or inactivity the reason for depression? Thus, the title of this paper over-reaches since it describes associations - not “impact.” That being said, observational studies, like that of Tonorezos et al.,⁷ are sentinel to developing an understanding of factors that may ultimately lend themselves to interventions that can improve care and treatment.

In studying the results of Tonorezos et al.,⁷ with the end goal of developing an intervention, we are first confronted with the intensity of physical activity that is being explored (i.e., vigorous physical activity, such as aerobic exercise, jogging, and jumping rope). While exercise of this intensity is less likely to be inaccurately reported and misclassified, further studies are needed that can investigate less intensive levels that ultimately may yield important benefits as well. Blair et al.¹⁰ found that interventions that increase light physical activity render significant improvements among older cancer survivors. Parallel studies among younger populations with cancer also are needed. In addition, the use of more sensitive self-report measures and objective means to capture physical activity are needed to address this gap.

Given that cognition was a key factor assessed by Tonorezos et al.,⁷ there also is a need for future studies to use rigorous neuropsychological measures. In the current study, cognition was assessed via the original CCSS Neurocognitive Questionnaire (CCSS-NCQ), a self-report instrument developed for the CCSS, which was revised and re-validated post data collection.¹¹ Self-reported cognitive impairment refers to the degree of cognitive difficulty that individuals perceive in their daily lives and their satisfaction with their cognitive functioning. However, gold standards for assessing cognitive impairment are performance-based, rather than self-report, and assess the cognitive domains of attention, processing speed, executive function, memory, and language. The NIH Toolbox Cognition Battery offers a brief, easily accessible computerized battery, with built-in automated scoring that is validated for use in individuals from 3 to 85 years of age.¹² This battery, which has been utilized in cognitive studies among cancer survivors,^13,14 provides a “common currency” among researchers for comparisons across a wide range of studies and populations. The strength of future observational studies, as well as interventions could be improved through the use of these standardized performance-based measures.

The suggestions above point to future studies that may take several years to accomplish; however, there is one gap that could be addressed almost immediately by additional statistical analyses by Dr. Tonorezos and her colleagues. Indeed, the authors carefully controlled for several potentially confounding variables (i.e., age at follow-up, age at diagnosis, sex, race, smoking, education, cancer diagnosis, cancer treatment, baseline anxiety, depression, somatization or cancer pain, and baseline or interim severe, disabling, or life-threatening chronic health conditions); however, Body Mass Index (BMI) was not included in the listed covariates. This is concerning given that psychological well-being may be influenced by BMI. For example, in a secondary analysis of the Exercise and Nutrition to Enhance Recovery and Good Health for You (ENERGY) trial (a two-arm, single-blinded randomized controlled trial among 692 overweight or obese breast cancer survivors), Kenzik and colleagues¹⁵ found that BMI was directly associated with vitality and that during the intervention there was an indirect effect of BMI on vitality through physical activity. Additionally, Huang and collegues¹⁶ examined the association between BMI and cancer-related cognitive changes among 1,286 breast cancer survivors. Participants completed a neuropsychological test battery at 18 and 36 months post-diagnosis. Findings revealed a negative association between BMI and attention (p < 0.001) and delayed memory (p = 0.04). Among healthy adults, a concordance of studies have found a strong relationship between obesity and depression. A recent meta-analysis of nine studies (N = 171,701) found that individuals with obesity were significantly more likely to report depression compared to those who were eutrophic (PR: 1.32; 95% Confidence Interval: 1.26 – 1.38; p < 0.001).¹⁷ Perhaps, the most salient need for control of BMI comes from the previous analysis on the CCSS cohort which found that “survivors who fell into the obese BMI category were less likely to report meeting physical activity guidelines (Relative Risk = 0.80, 95% Confidence Interval: 0.74 – 0.87),” and “those who fell in the underweight category were also less likely to report meeting such guidelines (Relative Risk = 0.74, 95% Confidence Interval = 0.76 – 0.94).⁸ Therefore, there is ample rationale that supports the inclusion of BMI as a covariate in the analysis performed by Tonorezos et al.⁷ and we are hopeful that they will provide an addendum to their report which chronicles their findings.

In summary, we applaud the report of Tonorezos and colleagues and their work on exercise and psychological well-being among adult childhood cancer survivors. This work clearly adds to the growing body of literature among adult childhood cancer survivors. While future studies are needed, especially those that employ more sensitive and objective means to capture physical activity and cognition, and that also take into account key covariates, these findings underscore the National Comprehensive Cancer Network guidelines that endorse interventions that enhance healthy living practices in this vulnerable population.¹⁸