Impact of Exercise on Psychological Burden in Adult Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study

Emily S Tonorezos; Jennifer S Ford; Linwei Wang; Kirsten K Ness; Yutaka Yasui; Wendy Leisenring; Charles A Sklar; Leslie L Robison; Kevin C Oeffinger; Paul C Nathan; Gregory T Armstrong; Kevin Krull; Lee W Jones

doi:10.1002/cncr.32173

. Author manuscript; available in PMC: 2020 Sep 1.

Published in final edited form as: Cancer. 2019 May 8;125(17):3059–3067. doi: 10.1002/cncr.32173

Impact of Exercise on Psychological Burden in Adult Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study

Emily S Tonorezos ^1,², Jennifer S Ford ³, Linwei Wang ⁴, Kirsten K Ness ⁵, Yutaka Yasui ⁵, Wendy Leisenring ⁶, Charles A Sklar ¹, Leslie L Robison ⁵, Kevin C Oeffinger ⁷, Paul C Nathan ⁸, Gregory T Armstrong ⁵, Kevin Krull ^5,^*, Lee W Jones ^1,^2,^*

¹Memorial Sloan Kettering, New York, NY

²Weill Cornell Medical College, New York, NY

³Hunter College, City University of New York, New York, NY

⁴BC Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada

⁵St. Jude Children’s Research Hospital, Memphis, TN

⁶Fred Hutchinson Cancer Research Center, Seattle, WA

⁷Duke University, Durham, NC

⁸The Hospital for Sick Children, Toronto, Canada

^✉

Correspondence: Emily Tonorezos, MD MPH; Memorial Sloan Kettering Cancer Center, 485 Lexington Ave, 2^nd Floor; New York, NY 10017; Tonoreze@mskcc.org; Tel 646-888-8080; Fax 929-321-1518

Denotes equal contribution

Authors Contributions:

Tonorezos, Emily S. – conceptualization, investigation, methodology, writing - original draft, and writing - review and editing.

Ford, Jennifer S. – conceptualization, investigation, methodology, writing - original draft, and writing - review and editing

Wang, Linwei – formal analysis, investigation, methodology, validation, writing – review and editing

Ness, Kirsten K. – conceptualization, investigation, methodology, and writing - review and editing.

Yasui, Yutaka – conceptualization, data curation, formal analysis, investigation, methodology, validation, writing – review and editing

Leisenring, Wendy – conceptualization, data curation, formal analysis, investigation, methodology, validation, writing – review and editing

Sklar, Charles A. – conceptualization, data curation,investigation, methodology, writing - review and editing

Robison, Leslie L. – conceptualization, data curation, funding acquisition, supervision, visualization, investigation, methodology, writing - review and editing

Oeffinger, Kevin C. – conceptualization, data curation, supervision, visualization, investigation, methodology, writing - review and editing

Nathan, Paul C, – conceptualization, data curation, supervision, visualization, investigation, methodology, writing - review and editing

Armstrong, Gregory T. – conceptualization, data curation, funding acquisition, project administration, resources, supervision, visualization, investigation, methodology, writing - review and editing

Krull, Kevin – conceptualization, data curation, investigation, methodology, project administration, resources, supervision, visualization, investigation, methodology, writing - review and editing

Jones, Lee W. – conceptualization, data curation, investigation, methodology, project administration, resources, supervision, visualization, investigation, methodology, writing - original draft, writing - review and editing

PMCID: PMC6690787 NIHMSID: NIHMS1023766 PMID: 31067357

Abstract

Background:

Childhood cancer survivors are at risk for adverse psychological outcomes. Whether exercise can attenuate this risk is unknown.

Methods:

6,199 CCSS participants (median[range] age 34.3 years[22.0-54.0] and median[range] age at diagnosis 10.0 years[0-21.0]) completed a questionnaire assessing vigorous exercise and medical/psychological conditions. Outcomes were evaluated a median[range] of 7.8[0.1-10.0] years later and were defined as: symptom level above 90^th percentile of population norms for depression, anxiety, or somatization on the Brief Symptom Inventory-18; cancer-related pain; cognitive impairment using a validated self-report neurocognitive questionnaire; or poor health-related quality of life (HRQOL). Log-binomial regression estimated associations between exercise [metabolic equivalent-hrs^.wk⁻¹(MET-hrs^.wk⁻¹)] and outcomes adjusting for cancer diagnosis, treatment, demographics, and baseline conditions.

Results:

The prevalence of depression at follow-up was 11.4%(95%CI:10.6-12.3%), anxiety 7.4%(95%CI:6.7-8.2%) and somatization 13.9%(95%CI:13.0-14.9). Vigorous exercise was associated with lower prevalence of depression and somatization. The adjusted prevalence ratio (PR) for depression was 0.87(95%CI:0.72-1.05) for 3 to 6 MET-hrs^.wk⁻¹, 0.76(95%CI:0.62-0.94) for 9 to 12 MET-hrs^.wk⁻¹, and 0.74(95%CI:0.58-0.95) for 15 to 21 MET-hrs^.wk⁻¹. Compared to 0 MET-hrs^.wk⁻¹, 15 to 21 MET-hrs^.wk⁻¹ was associated with an adjusted PR of 0.79 (95% CI: 0.62-1.00) for somatization. Vigorous exercise was also associated with less impairment in physical functioning, general health, and vitality (p_trends<0.001), emotional role limitations (p_trend=0.02) and mental health (p_trend=0.02) domains, as well as higher cognitive function in domains of task completion, organization, and working memory (p’s<0.05) but not cancer pain.

Conclusion:

Vigorous exercise is associated with less psychological burden and cognitive impairment in childhood cancer survivors.

Keywords: Physical Activity, Late-Effects, Survivorship, Depression, Psychosocial

Precis:

In this report from the Childhood Cancer Survivor Study (CCSS), vigorous exercise was associated with a lower risk of subsequent depression and somatization; even small amounts of vigorous exercise appeared to be beneficial.

INTRODUCTION

The number of childhood cancer survivors living in the United States currently exceeds 420,000.¹ This number is expected to increase over the next two decades due to sustained improvements in treatment and supportive care.² At the same time, significant medical and psychological morbidity due to late effects of therapy has been well-documented.^{3, 4} Depression,^{5, 6} anxiety,^{7, 8} somatization,⁹ fatigue,¹⁰ poor health-related quality of life (HRQOL),¹¹ suicidal ideation,¹² impaired cognitive function,¹³ and reduced psychological well-being¹⁴ are frequent among childhood cancer survivors. Of importance, these symptoms do not occur in isolation, but rather in clusters.^{15, 16} Therefore, treatment strategies able to mitigate multiple symptoms simultaneously may have significant benefit for childhood cancer survivors.¹⁷

Exercise is a pleiotropic therapy shown to improve a broad array of psychological symptoms in patients without cancer.^18–20 In adults with or at risk for psychological disorders, regular exercise is consistently associated with fewer depressive or anxious symptoms^21–25 and less sleep disruption.^{26, 27} Randomized trials demonstrate that structured exercise training lessens anxiety and depressive symptoms, and improves short-term mood, cognition, and overall HRQOL in persons with or at risk for these problems.^28–32 In the pediatric oncology setting, a limited number of studies have demonstrated that exercise can benefit fatigue and overall quality of life.³³ Yet, the potential benefit of exercise to mitigate depression, anxiety, or somatization, or to have a more durable impact on these symptoms among adult survivors of childhood cancer survivors is unknown.

Therefore, we investigated the association between vigorous exercise and subsequent psychological symptoms, HRQOL, cancer pain, and cognitive impairment among adult survivors of childhood cancer in the Childhood Cancer Survivor Study (CCSS). In order to capture clinically significant psychological outcomes in a rigorous manner, we used population norms to define cases of depression, anxiety, or somatization.^{34, 35}

METHODS

Patients and Study Overview

The CCSS is a retrospective cohort with longitudinal follow-up of survivors of childhood cancer treated at 26 institutions in the United States and Canada between 1970 and 1986. Eligibility criteria include diagnosis of cancer at < 21 years and survival at least five years from diagnosis.^{34, 35} Participants or a designated proxy completed detailed a baseline questionnaire including medical history, chronic health conditions, education, smoking status, alcohol use, education, height, weight, exercise behavior and psychological symptoms (described in detail below). Other examined covariates, primarily derived from medical record review, include: age at diagnosis, gender, race, cancer diagnosis, alkylating agent exposure expressed as cyclophosphamide equivalent dose,³⁶ anthracycline exposure in doxorubicin equivalent dose,³⁷ and radiation therapy to the chest, brain or head. The CCSS protocol was reviewed and approved by the human subjects committee at each participating institution, and informed consent was obtained before study participation.

Exercise Assessment

Vigorous exercise was ascertained in the baseline questionnaire using the item “on how many of the past seven days did you exercise or do sports for at least 20 minutes that made you sweat or breathe hard (e.g., dancing, jogging, basketball, etc.)”, as in prior studies.³⁸ Total vigorous exercise was calculated as follows: frequency of sessions/week multiplied by session duration, weighted by the standardized classification of the energy expenditure associated with vigorous exercise in metabolic equivalents (9 METs) and expressed as MET-hours per week (hrs.wk-1);³⁹ 20 minutes of vigorous exercise a week (approximately 3 minutes per day) is equivalent to 3 MET-hrs.wk-1. Levels of total vigorous exercise were defined as 0, 3 to 6, 9 to 12, and 15 to 21 MET-hrs.wk-1.³⁸ The proportion of participants meeting national guidelines for vigorous exercise for adult cancer survivors, equivalent to ≥ 9 MET-hrs.wk-1 was calculated.^{40, 41}

Endpoints

Psychological outcomes were ascertained in a follow-up questionnaire completed a median of 7.8 years later (range, 0.1 −10.4). The primary endpoints were psychological symptoms (depression, anxiety, or somatization), cancer pain, domains of HRQOL, and neurocognitive dysfunction.

Depression, Anxiety, and Somatization were assessed using the BSI-18. The BSI-18 consists of 18 five-point Likert scale items (0=“not at all,” to 4=“extremely”) evaluating the degree to which particular symptoms distressed or bothered the patient over the past seven days. Depression, anxiety, and somatization were each assessed by 6 items for a total of 18 items. Scores were compared to population norms to generate T-scores with a mean of 50 and standard deviation of 10. The prevalence of clinically significant symptoms was defined as a T-score≥63, as per scoring standards ⁴² Analyses that included cases of depression, anxiety, or somatization as outcomes excluded participants with BSI completed by proxy.

Cancer Pain was assessed by the single item “Do you currently have pain as a result of your cancer or similar illness, or its treatment?” Participants who reported no pain or a small amount of pain were compared to those who reported medium, a lot, or very bad excruciating pain, as previously described.⁴³

Cognition was assessed using the CCSS-Neurocognitive Questionnaire (CCSS-NCQ), a tool developed and validated for the CCSS, ⁴⁴ consisting of 25 items assessing four domains of cognition: task efficiency (encompassing attention and processing speed), emotional regulation, organization, and memory. Impaired performance was defined as a score falling ≥90^th percentile based on sibling age and sex-adjusted norms, as in prior CCSS analyses.^{44, 45}

HRQOL was assessed with the Medical Outcomes Study 36-Item Short-Form (SF-36).¹⁵ The SF-36 includes questions about general health, well-being and quality of life in the previous four weeks and yields eight scaled scores: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health. Summary scales scores are also available for a physical composite and a mental composite. Scaled scores were generated as t-scores with mean of 50 and standard deviation of 10, and t-scores< 40 were considered impaired.

Statistical Analysis

Demographic, disease, and treatment characteristics were summarized for four exercise levels (in MET-hrs^.wk⁻¹) and compared using Chi-square tests for categorical measures and analysis of variance (ANOVA) for continuous measures.⁴⁶ Log-binomial regression was used to assess the association between the vigorous exercise levels or meeting national guidelines (i.e., < 9 versus ≥ 9 MET-hrs^.wk⁻¹) and prevalence of subsequent clinically significant psychological symptoms. Multivariable log-binomial models were adjusted for the following potential confounders: age at follow-up, age at diagnosis, sex, race, smoking, education, cancer diagnosis, cancer treatment variables (alkylating agents, anthracyclines, chest radiation, brain or head radiation), baseline anxiety, depression, somatization or cancer pain, and baseline or interim severe, disabling, or life-threatening chronic health conditions.⁴⁷ In models for the relationship between exercise and cognition, education was excluded as a covariate, as cognitive impairment precedes and impacts educational attainment in this population. The “COPY method” was used for the convergence issue of the models.⁴⁸ Results are reported as prevalence ratios (PRs) with the corresponding large-sample approximate 95% confidence intervals (CIs) and p-values. Statistical analyses were conducted using SAS (SAS Institute, Inc., Cary, NC). All statistical inferences were two-sided.

RESULTS

A total of 14,358 survivors completed the baseline CCSS questionnaire. Of these, 6,199 were included in our analysis. The most common reasons for exclusion were being under the age of 18 years at the time of the baseline questionnaire (n=3,352) or not completing both a baseline and follow-up questionnaire (n=3,192); other reasons for exclusion are displayed in Supplemental Figure 1. When we compared those in the final sample (N=6199) to survivors who completed a baseline questionnaire including exercise data but did not complete the follow-up questionnaire (N=2499), those with follow-up were more likely to be female, of higher educational levels, of white non-Hispanic race/ethnicity (p’s < 0.01), and to be vigorously exercising at 3 to 12 MET hours/week (p<0.01). Chronic medical conditions as well as cancer diagnosis and treatment variables did not differ between these two groups. Approximately half the participants in the final sample were male (n=3176; 51.2%) and the most common cancer diagnosis was leukemia (n=1857; 30.0%) followed by Hodgkin lymphoma (n=1001; 16.1%) (Table 1).

Table 1.

Demographic and treatment characteristics of 6199 adult survivors of childhood cancer by levels of vigorous exercise (total MET-hours week⁻¹).

	MET hours week⁻¹
Characteristics	All Patients	0	3 to 6	9 to 12	15 to 21	P-value
	No. (%)
Participants	6199 (100)	2170 (35.0)	1699 (27.4)	1457 (23.5)	873 (14.1)
Age at diagnosis, years						0.072
Median	10.0	10.3	9.8	9.8	9.7
Range	0.0 - 21.0	0.0 - 21.0	0.0 - 21.0	0.0 - 21.0	0.0 - 20.9
Age at questionnaire, years						<0.001
Mean	34.0	34.0	33.0	33.0	33.0
Range	22.0 - 54.0	23.0 - 53.0	23.0 - 53.0	23.0 - 54.0	22.0 - 53.0
Sex of patient						<0.001
Male	3176 (51.2)	1003 (46.2)	843 (49.6)	776 (53.3)	554 (63.5)
Race/ethnicity						0.243
Non-Hispanic White	5541 (89.4)	1933 (89.1)	1529 (90.0)	1313 (90.1)	766 (87.7)
BMI, kg/m²						0.029
Mean	26.4	26.6	26.4	26.3	25.9
Range	10.4-73.2	10.4 - 73.2	13.6 - 58.6	13.8 - 59.8	12.4 - 59.4
Smoking						<0.001
Current	972 (15.7)	384 (17.7)	270 (15.9)	180 (12.4)	138 (15.8)
Former	1039 (16.8)	365 (16.8)	266 (15.7)	249 (17.1)	159 (18.2)
Never	4185 (67.5)	1420 (65.5)	1161 (68.4)	1028 (70.6)	576 (66.0)
Highest education						<0.001
Lower than or high school	1139 (18.4)	523 (24.1)	253 (14.9)	203 (13.9)	160 (18.3)
Diagnosis						0.236
Leukemia	1857 (30.0)	600 (27.6)	531 (31.3)	459 (31.5)	267 (30.6)
CNS	766 (12.4)	289 (13.3)	194 (11.4)	165 (11.3)	118 (13.5)
Hodgkin lymphoma	1001 (16.1)	353 (16.3)	264 (15.5)	233 (16.0)	151 (17.3)
Non Hodgkin lymphoma	576 (9.3)	197 (9.1)	164 (9.7)	131 (9.0)	84 (9.6)
Kidney (Wilms)	438 (7.1)	151 (7.0)	133 (7.8)	96 (6.6)	58 (6.6)
Neuroblastoma	249 (4.0)	85 (3.9)	70 (4.1)	61 (4.2)	33 (3.8)
Soft tissue sarcoma	628 (10.1)	221 (10.2)	168 (9.9)	157 (10.8)	82 (9.4)
Bone cancer	684 (11.0)	274 (12.6)	175 (10.3)	155 (10.6)	80 (9.2)
Chemotherapy
Any chemotherapy	4376 (78.0)	1484 (77.0)	1233 (79.3)	1048 (78.3)	611 (77.6)	0.417
Alkylating dose (CED), mg/m²						0.804
None	2747 (53.3)	948 (54.0)	770 (53.4)	652 (52.9)	377 (52.3)
>0-<4000	482 (9.4)	158 (9.0)	146 (10.1)	110 (8.9)	68 (9.4)
4000-8000	587 (11.4)	200 (11.4)	170 (11.8)	130 (10.6)	87 (12.1)
≥8000	1334 (25.9)	450 (25.6)	355 (24.6)	340 (27.6)	189 (26.2)
Anthracycline dose, mg/m²						0.256
None	3470 (64.5)	1218 (65.8)	951 (63.7)	815 (63.4)	486 (64.5)
>0-<250	685 (12.7)	217 (11.7)	194 (13.0)	162 (12.6)	112 (14.9)
≥250	1226 (22.8)	416 (22.5)	347 (23.3)	308 (24.0)	155 (20.6)
Radiation therapy
Any radiation therapy	4032 (68.1)	1413 (68.8)	1119 (68.4)	945 (67.7)	555 (66.7)	0.563
Chest	1571 (28.5)	570 (29.8)	427 (27.9)	344 (26.5)	230 (29.8)	0.184
Chest direct dose						0.027
None	1650 (51.4)	545 (49.0)	461 (52.0)	398 (53.9)	246 (51.9)
<20 Gy	226 (7.0)	76 (6.8)	65 (7.3)	54 (7.3)	31 (6.5)
20-<30 Gy	398 (12.4)	134 (12.0)	97 (10.9)	89 (12.0)	78 (16.5)
30-<40 Gy	510 (15.9)	202 (18.1)	144 (16.3)	97 (13.1)	67 (14.1)
40-<50 Gy	363 (11.3)	131 (11.8)	96 (10.8)	86 (11.6)	50 (10.5)
≥50 Gy	65 (2.0)	25 (2.2)	23 (2.6)	15 (2.0)	2 (0.4)
Brain or head	2048 (37.1)	724 (37.9)	549 (35.9)	498 (38.4)	277 (35.8)	0.412
All head direct dose						0.099
None	1650 (44.7)	545 (43.0)	461 (45.8)	398 (44.5)	246 (47.2)
<20 Gy	39 (1.1)	10 (0.8)	9 (0.9)	12 (1.3)	8 (1.5)
20-<30 Gy	1191 (32.3)	398 (31.4)	341 (33.9)	296 (33.1)	156 (29.9)
30-<40 Gy	114 (3.1)	33 (2.6)	35 (3.5)	28 (3.1)	18 (3.5)
40-<50 Gy	143 (3.9)	62 (4.9)	31 (3.1)	30 (3.4)	20 (3.8)
≥50 Gy	551 (14.9)	219 (17.3)	129 (12.8)	130 (14.5)	73 (14.0)
CV risk factors
Diabetes mellitus	191 (3.1)	71 (3.3)	60 (3.5)	39 (2.7)	21 (2.4)	0.314
Hypertension	669 (10.8)	301 (13.9)	176 (10.4)	127 (8.7)	65 (7.4)	<0.001
Dyslipidemia	427 (6.9)	183 (8.4)	100 (5.9)	101 (6.9)	43 (4.9)	0.001
Obesity	1318 (21.3)	496 (22.9)	384 (22.6)	288 (19.8)	150 (17.2)	0.001
Any major chronic conditions at baseline	592 (9.5)	236 (10.9)	147 (8.7)	125 (8.6)	84 (9.6)	0.055
Psychological conditions at baseline	1328 (21.4)	490 (22.7)	352 (20.8)	294 (20.3)	192 (22.2)	0.290

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Abbreviations: BMI, body mass index; CED: cyclophosphamide equivalent dose;³⁶ CV, cardiovascular; MET, metabolic equivalent.

Psychological conditions at baseline includes: depression, anxiety, somatization, or cancer pain

Over a third of survivors reported no vigorous exercise (n=2170; 35%) and more than half (n=3689; 59%) did not meet national exercise guidelines for vigorous activity. Exercising survivors were younger, had a lower prevalence of cardiovascular risk factors and were more likely to be male. There was no association between psychological symptoms or major chronic health conditions and exercise at baseline (p’s>0.05; Table 1). During a median of 7.8 years (range, 0.1–10.4 years) follow-up, the prevalence of depression was 11.4% (95% CI:10.6%−12.3%), anxiety 7.4% (95% CI: 6.7%−8.2%) and somatization 13.9% (95% CI: 13.0%−14.9%).

Exercise and Psychological Symptoms

Vigorous exercise was associated with lower prevalence of depression (p_trend=0.003), and somatization (p_trend=0.005; Figure 1), but not anxiety (p_trend=0.75). Compared to 0 MET-hrs^.wk⁻¹, 15 to 21 MET-hrs^.wk⁻¹ was associated with an adjusted PR of 0.74 (95% CI: 0.58–0.95); p_trend =0.004) for depression, and 0.79 (95% CI: 0.62–1.00; p_trend =0.003) for somatization. Among those survivors adherent to national guidelines for vigorous activity (≥ 9 MET-hrs^.wk⁻¹ ), compared to those who did not meet guidelines (Supplement Table 1), the adjusted PR for cases of depression was 0.80 (95%CI: 0.68–0.94; p=0.009) and adjusted PR for cases of somatization was 0.83 (95% CI: 0.72–0.94; p=0.001).

Regarding cognition, fewer impairments in task completion (p_trend<0.001), organization (p_trend=0.038), and working memory (p_trend=0.003) were observed (Figure 1) among exercising survivors, compared to those who were not exercising vigorously. Among those meeting national exercise guidelines for vigorous activity, task completion was less likely to be impaired (PR 0.79; 95%CI: 0.71–0.88; p_trend<0.001), compared to those not meeting guidelines, although differences were not observed for the other domains of cognitive function (Supplement Table 1). Vigorous exercise was not associated with less cancer pain (Figure 1).

In reference to HRQOL, vigorous exercise was associated with less impairment in physical functioning, general health, and vitality (p_trends<0.001), as well as emotional role limitations (p_trend=0.02) and mental health (p_trend=0.02) domains (Figure 2). Compared to no vigorous exercise, those meeting national exercise guidelines (≥ 9 MET-hrs^.wk⁻¹) had a lower adjusted prevalence of poor HRQOL in domains of physical functioning (PR 0.77; 95% CI:0.66–0.89; p<0.001), general health (PR 0.85; 95%CI: 077–0.92; p<0;001), and vitality (PR 0.82; 95% CI:0.75–0.87; p<0.001) (Figure 2).

Figure 2. — Prevalence Ratios (PR) of domains of health-related quality of life according to levels of vigorous exercise (total MET-hrs wk⁻¹) among 6,199 survivors of childhood cancer.

DISCUSSION

The principal finding from this large cohort of childhood cancer survivors is that vigorous exercise is associated with a lower risk of depression, somatization, or cognitive impairment. Survivors meeting national exercise guidelines for vigorous activity had an approximately 20% lower risk of depression or somatization, compared to those who did not meet guidelines. To our knowledge, our study is the first to observe this relationship among adult survivors of childhood cancer with a range of diagnoses and treatment exposures, thereby adding to the growing body of evidence for the widespread benefit of exercise and importance for the rapidly growing population of childhood cancer survivors.

In this cohort, over 70% of survivors had at least one of the following: psychological symptoms, cognitive impairment, cancer pain, or poor health-related quality of life. Yet, our results suggest that even small amounts of vigorous exercise may ameliorate these outcomes. Our study significantly extends prior work in exercise-oncology research by investigating the impact of exercise on psychological outcomes classified according to standard definitions and population-based cutoffs to define clinically significant psychological and cognitive symptoms, as well as cancer pain and quality of life. In addition, our analysis captured clinically significant outcomes up to 10 years after exercise assessment. Prior studies in non-cancer adult populations consistently demonstrate that regular exercise is associated with short-term improvements in mood and risk of new onset major depression or cognitive impairment, but demonstrating an impact on longer-term predefined outcomes is a major strength of this investigation.^24,49–52

Exercise may ameliorate treatment or stress-related chronic inflammation,^{53, 54} oxidative stress,^{55, 56} impaired neurotransmission,^{57, 58} or cytokine and hormonal derangements.⁵⁹ Cognitive impairment is a common late effect in childhood and adult cancer survivors widely attributed to certain systemic therapies as well as cranial radiation therapy,⁶⁰ through a variety of mechanisms including impaired neurogenesis.^{61, 62} Intriguingly, in a murine model of whole-body radiation, exercise blunted an anticipated decline in memory via increases in hippocampal plasticity;⁶² other investigations suggest that cardiorespiratory fitness may directly impact brain function, or that the psychological benefit of exercise may be via improved sleep duration or quality.^{9, 63–65}

It is important to note the clinical and research implications of these findings. In the CCSS, all participants are five years or more from the completion of therapy at baseline assessment. Therefore, quantification of vigorous exercise and psychological symptoms or cognitive impairment occurred well after treatment was over. For clinicians caring for adult survivors of childhood cancer, our results imply that exercise assessment and recommendation after treatment represents an opportunity to improve future emotional and cognitive health. Whether an exercise intervention will prove beneficial for these survivors will require further study. Nonetheless, asking childhood cancer survivors about exercise behavior and discussing suggested benefits of engaging in vigorous physical activity is a reasonable extension of this work.

Our study has important limitations. Although the multivariable analyses adjusted for potentially confounding variables including baseline emotional symptoms, it was not possible to delineate whether the association between exercise and lower risk of depression or somatization represents a direct benefit of exercise. In addition, exercise was assessed by a self-administered questionnaire; some misclassification of exposure as well as residual confounding could have occurred. Our exercise measure only assessed vigorous-intensity exercise. Thus, it is possible that respondents re-classified or ‘up-graded’ participation in lower intensity exercise to vigorous-intensity exercise. Notably, these forms of misclassification are likely to bias towards the null and so do not explain our findings suggesting a cognitive and emotional benefit. Statistical modeling did not adjust for multiple testing, as all outcomes were designated a priori based on prior evidence suggesting a potential benefit from vigorous exercise. The possibility that exercising survivors were more likely to use psychoactive medications, such as antidepressants, and therefore less likely to report symptoms such as depression, should be considered. Prior work in CCSS, however, suggests that use of psychoactive medications is associated with worsened neurocognitive outcomes.^{66, 67}Therefore, use of psychoactive medications among exercising survivors is unlikely to explain our findings. Finally, all psychological symptoms were self-reported; thus, some misclassification is possible, although outcomes were designated by predefined thresholds and population norms.⁴²

In conclusion, our results demonstrate that exercise is associated with better emotional, cognitive, and quality of life outcomes, independent of chronic medical conditions, in childhood cancer survivors. These findings suggest that vigorous exercise could have a significant benefit on the long-term health and wellbeing of this population.

Supplementary Material

Supp TableS1

NIHMS1023766-supplement-Supp_TableS1.docx^{(19.5KB, docx)}

Supp figS1

NIHMS1023766-supplement-Supp_figS1.png^{(180.1KB, png)}

Acknowledgments

Funding / Support: National Cancer Institute (CA55727, CA21765) and American Lebanese-Syrian Associated Charities (CCSS). AKTIV Against Cancer and Kavli Trust (LWJ).

Footnotes

Conflicts of Interest: None

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7.Bagur J, Massoubre C, Casagranda L, Faure-Conter C, Trombert-Paviot B, Berger C. Psychiatric disorders in 130 survivors of childhood cancer: Preliminary results of a semi-standardized interview. Pediatr Blood Cancer. 2015;62: 847–853. [DOI] [PubMed] [Google Scholar]
8.Kunin-Batson AS, Lu X, Balsamo L, et al. Prevalence and predictors of anxiety and depression after completion of chemotherapy for childhood acute lymphoblastic leukemia: A prospective longitudinal study. Cancer. 2016;122: 1608–1617. [DOI] [PMC free article] [PubMed] [Google Scholar]
9.Brinkman TM, Zhu L, Zeltzer LK, et al. Longitudinal patterns of psychological distress in adult survivors of childhood cancer. Br J Cancer. 2013;109: 1373–1381. [DOI] [PMC free article] [PubMed] [Google Scholar]
10.Yi J, Kim MA, Tian T. Perceived long-term and physical health problems after cancer: adolescent and young adult survivors of childhood cancer in Korea. Eur J Oncol Nurs. 2014;18: 145–150. [DOI] [PubMed] [Google Scholar]
11.Zeltzer LK, Lu Q, Leisenring W, et al. Psychosocial outcomes and health-related quality of life in adult childhood cancer survivors: a report from the childhood cancer survivor study. Cancer Epidemiol Biomarkers Prev. 2008;17: 435–446. [DOI] [PubMed] [Google Scholar]
12.Brinkman TM, Liptak CC, Delaney BL, Chordas CA, Muriel AC, Manley PE. Suicide ideation in pediatric and adult survivors of childhood brain tumors. J Neurooncol. 2013;113: 425–432. [DOI] [PubMed] [Google Scholar]
13.Cheung YT, Brinkman TM, Li C, et al. Chronic health conditions and neurocognitive function in aging survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. JNCI: Journal of the National Cancer Institute. 2017;110: 411–419. [DOI] [PMC free article] [PubMed] [Google Scholar]
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17.Castellino SM, Ullrich NJ, Whelen MJ, Lange BJ. Developing interventions for cancer-related cognitive dysfunction in childhood cancer survivors. J Natl Cancer Inst. 2014;106. [DOI] [PMC free article] [PubMed] [Google Scholar]
18.Ren H, Collins V, Clarke SJ, et al. Epigenetic changes in response to tai chi practice: a pilot investigation of DNA methylation marks. Evid Based Complement Alternat Med. 2012;2012: 841810. [DOI] [PMC free article] [PubMed] [Google Scholar]
19.Santa Mina D, Guglietti CL, de Jesus DR, et al. The acute effects of exercise on cortical excitation and psychosocial outcomes in men treated for prostate cancer: a randomized controlled trial. Front Aging Neurosci. 2014;6: 332. [DOI] [PMC free article] [PubMed] [Google Scholar]
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[R1] 1.Robison LL, Hudson MM. Survivors of childhood and adolescent cancer: life-long risks and responsibilities. Nat Rev Cancer. 2014;14: 61–70. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R2] 2.Armstrong GT, Chen Y, Yasui Y, et al. Reduction in late mortality among 5-year survivors of childhood cancer. New England Journal of Medicine. 2016;374: 833–842. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R3] 3.Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med. 2006;355: 1572–1582. [DOI] [PubMed] [Google Scholar]

[R4] 4.Hudson MM, Ness KK, Gurney JG, et al. Clinical ascertainment of health outcomes among adults treated for childhood cancer. Jama. 2013;309: 2371–2381. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R5] 5.Deyell RJ, Lorenzi M, Ma S, et al. Antidepressant use among survivors of childhood, adolescent and young adult cancer: a report of the Childhood, Adolescent and Young Adult Cancer Survivor (CAYACS) Research Program. Pediatr Blood Cancer. 2013;60: 816–822. [DOI] [PubMed] [Google Scholar]

[R6] 6.Johannsdottir IM, Karlstad O, Loge JH, Fossa SD, Kiserud C, Skurtveit S. Prescriptions of Antidepressants to Survivors of Cancer in Childhood, Adolescence, and Young Adulthood: A Population-Based Study. J Adolesc Young Adult Oncol. 2016. [DOI] [PubMed] [Google Scholar]

[R7] 7.Bagur J, Massoubre C, Casagranda L, Faure-Conter C, Trombert-Paviot B, Berger C. Psychiatric disorders in 130 survivors of childhood cancer: Preliminary results of a semi-standardized interview. Pediatr Blood Cancer. 2015;62: 847–853. [DOI] [PubMed] [Google Scholar]

[R8] 8.Kunin-Batson AS, Lu X, Balsamo L, et al. Prevalence and predictors of anxiety and depression after completion of chemotherapy for childhood acute lymphoblastic leukemia: A prospective longitudinal study. Cancer. 2016;122: 1608–1617. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R9] 9.Brinkman TM, Zhu L, Zeltzer LK, et al. Longitudinal patterns of psychological distress in adult survivors of childhood cancer. Br J Cancer. 2013;109: 1373–1381. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R10] 10.Yi J, Kim MA, Tian T. Perceived long-term and physical health problems after cancer: adolescent and young adult survivors of childhood cancer in Korea. Eur J Oncol Nurs. 2014;18: 145–150. [DOI] [PubMed] [Google Scholar]

[R11] 11.Zeltzer LK, Lu Q, Leisenring W, et al. Psychosocial outcomes and health-related quality of life in adult childhood cancer survivors: a report from the childhood cancer survivor study. Cancer Epidemiol Biomarkers Prev. 2008;17: 435–446. [DOI] [PubMed] [Google Scholar]

[R12] 12.Brinkman TM, Liptak CC, Delaney BL, Chordas CA, Muriel AC, Manley PE. Suicide ideation in pediatric and adult survivors of childhood brain tumors. J Neurooncol. 2013;113: 425–432. [DOI] [PubMed] [Google Scholar]

[R13] 13.Cheung YT, Brinkman TM, Li C, et al. Chronic health conditions and neurocognitive function in aging survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. JNCI: Journal of the National Cancer Institute. 2017;110: 411–419. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R14] 14.Li HC, Lopez V, Joyce Chung OK, Ho KY, Chiu SY. The impact of cancer on the physical, psychological and social well-being of childhood cancer survivors. Eur J Oncol Nurs. 2013;17: 214–219. [DOI] [PubMed] [Google Scholar]

[R15] 15.Garaigordobil M Predictor variables of happiness and its connection with risk and protective factors for health. Front Psychol. 2015;6: 1176. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R16] 16.Padmaja G, Vanlalhruaii C, Rana S, Nandinee D, Hariharan M. Care givers’ depression, anxiety, distress, and somatization as predictors of identical symptoms in cancer patients. J Cancer Res Ther. 2016;12: 53–57. [DOI] [PubMed] [Google Scholar]

[R17] 17.Castellino SM, Ullrich NJ, Whelen MJ, Lange BJ. Developing interventions for cancer-related cognitive dysfunction in childhood cancer survivors. J Natl Cancer Inst. 2014;106. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R18] 18.Ren H, Collins V, Clarke SJ, et al. Epigenetic changes in response to tai chi practice: a pilot investigation of DNA methylation marks. Evid Based Complement Alternat Med. 2012;2012: 841810. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R19] 19.Santa Mina D, Guglietti CL, de Jesus DR, et al. The acute effects of exercise on cortical excitation and psychosocial outcomes in men treated for prostate cancer: a randomized controlled trial. Front Aging Neurosci. 2014;6: 332. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R20] 20.Schuch FB, Deslandes AC, Stubbs B, Gosmann NP, Silva CT, Fleck MP. Neurobiological effects of exercise on major depressive disorder: A systematic review. Neurosci Biobehav Rev. 2016;61: 1–11. [DOI] [PubMed] [Google Scholar]

[R21] 21.Rebar A, Duncan M, Short C, Vandelanotte C. Differences in health-related quality of life between three clusters of physical activity, sitting time, depression, anxiety, and stress. BMC Public Health. 2014;14: 1088. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R22] 22.Balboa-Castillo T, Leon-Munoz L, Graciani A, Rodriguez-Artalejo F, Guallar-Castillon P. Longitudinal association of physical activity and sedentary behavior during leisure time with health-related quality of life in community-dwelling older adults. Health Qual Life Outcomes. 2011;9: 47 – 57. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R23] 23.Bize R, Johnson J, Plotnikoff R. Physical activity level and health-related quality of life in the general adult population: a systematic review. Prev Med. 2007;45: 401 – 415. [DOI] [PubMed] [Google Scholar]

[R24] 24.Goodwin RD. Association between physical activity and mental disorders among adults in the United States. Prev Med. 2003;36: 698–703. [DOI] [PubMed] [Google Scholar]

[R25] 25.De Moor MH, Beem AL, Stubbe JH, Boomsma DI, De Geus EJ. Regular exercise, anxiety, depression and personality: a population-based study. Prev Med. 2006;42: 273–279. [DOI] [PubMed] [Google Scholar]

[R26] 26.Quan SF, O’Connor GT, Quan JS, et al. Association of physical activity with sleep-disordered breathing. Sleep and Breathing. 2007;11: 149–157. [DOI] [PubMed] [Google Scholar]

[R27] 27.Peppard PE, Young T. Exercise and sleep-disordered breathing: an association independent of body habitus. Sleep. 2004;27: 480–484. [DOI] [PubMed] [Google Scholar]

[R28] 28.Cooney G, Dwan K, Greig C, et al. Exercise for depression. Cochrane Database Syst Rev. 2013;9: CD004366. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R29] 29.Yan S, Jin YZ, Oh YS, Choi YJ. Effect of exercise on depression in university students: a meta-analysis of randomized controlled trials. J Sports Med Phys Fitness. 2015. [PubMed] [Google Scholar]

[R30] 30.Branco JC, Jansen K, Sobrinho JT, et al. Physical benefits and reduction of depressive symptoms among the elderly: results from the Portuguese “National Walking Program”. Cien Saude Colet. 2015;20: 789–795. [DOI] [PubMed] [Google Scholar]

[R31] 31.Dall CH, Gustafsson F, Christensen SB, Dela F, Langberg H, Prescott E. Effect of moderate- versus high-intensity exercise on vascular function, biomarkers and quality of life in heart transplant recipients: A randomized, crossover trial. J Heart Lung Transplant. 2015. [DOI] [PubMed] [Google Scholar]

[R32] 32.Carneiro LS, Fonseca AM, Vieira-Coelho MA, Mota MP, Vasconcelos-Raposo J. Effects of structured exercise and pharmacotherapy vs. pharmacotherapy for adults with depressive symptoms: A randomized clinical trial. J Psychiatr Res. 2015;71: 48–55. [DOI] [PubMed] [Google Scholar]

[R33] 33.Baumann FT, Bloch W, Beulertz J. Clinical exercise interventions in pediatric oncology: a systematic review. Pediatr Res. 2013;74: 366–374. [DOI] [PubMed] [Google Scholar]

[R34] 34.Robison LL, Mertens AC, Boice JD, et al. Study design and cohort characteristics of the Childhood Cancer Survivor Study: a multi-institutional collaborative project. Med Pediatr Oncol. 2002;38: 229–239. [DOI] [PubMed] [Google Scholar]

[R35] 35.Robison LL, Armstrong GT, Boice JD, et al. The Childhood Cancer Survivor Study: a National Cancer Institute–supported resource for outcome and intervention research. Journal of Clinical Oncology. 2009;27: 2308–2318. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R36] 36.Green DM, Nolan VG, Goodman PJ, et al. The cyclophosphamide equivalent dose as an approach for quantifying alkylating agent exposure: a report from the Childhood Cancer Survivor Study. Pediatr Blood Cancer. 2014;61: 53–67. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R37] 37.Feijen EA, Leisenring WM, Stratton KL, et al. Equivalence Ratio for Daunorubicin to Doxorubicin in Relation to Late Heart Failure in Survivors of Childhood Cancer. J Clin Oncol. 2015;33: 3774–3780. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R38] 38.Jones LW, Liu Q, Armstrong GT, et al. Exercise and risk of major cardiovascular events in adult survivors of childhood hodgkin lymphoma: a report from the childhood cancer survivor study. J Clin Oncol. 2014;32: 3643–3650. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R39] 39.Ainsworth BE, Haskell WL, Herrmann SD, et al. 2011 Compendium of Physical Activities: a second update of codes and MET values. Med Sci Sports Exerc. 2011;43: 1575–1581. [DOI] [PubMed] [Google Scholar]

[R40] 40.Rock CL, Doyle C, Demark-Wahnefried W, et al. Nutrition and physical activity guidelines for cancer survivors. CA Cancer J Clin. 2012;62: 243–274. [DOI] [PubMed] [Google Scholar]

[R41] 41.Schmitz KH, Courneya KS, Matthews C, et al. American College of Sports Medicine roundtable on exercise guidelines for cancer survivors. Med Sci Sports Exerc. 2010;42: 1409–1426. [DOI] [PubMed] [Google Scholar]

[R42] 42.Derogatis LR. Brief symptom inventory 18. Minneapolis, MN: NCS Pearson; 2000. [Google Scholar]

[R43] 43.Hudson MM, Mertens AC, Yasui Y, et al. Health status of adult long-term survivors of childhood cancer: A report from the childhood cancer survivor study. Jama. 2003;290: 1583–1592. [DOI] [PubMed] [Google Scholar]

[R44] 44.Krull KR, Gioia G, Ness KK, et al. Reliability and validity of the Childhood Cancer Survivor Study Neurocognitive Questionnaire. Cancer. 2008;113: 2188–2197. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R45] 45.Kadan-Lottick NS, Zeltzer LK, Liu Q, et al. Neurocognitive functioning in adult survivors of childhood non-central nervous system cancers. J Natl Cancer Inst. 2010;102: 881–893. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R46] 46.Gray R A class of K-sample tests for comparing the cumulative incidence of competing risk. Annual Statistics. 1988;16: 1141–1154. [Google Scholar]

[R47] 47.Armstrong GT, Oeffinger KC, Chen Y, et al. Modifiable risk factors and major cardiac events among adult survivors of childhood cancer. J Clin Oncol. 2013;31: 3673–3680. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R48] 48.Deddens J, Petersen M, Lei X. Estimation of prevalence ratio’s when proc genmod does not converge. . 28th Annual SAS Users Group International Conference, 2003. [Google Scholar]

[R49] 49.Ten Have M, de Graaf R, Monshouwer K. Physical exercise in adults and mental health status findings from the Netherlands mental health survey and incidence study (NEMESIS). J Psychosom Res. 2011;71: 342–348. [DOI] [PubMed] [Google Scholar]

[R50] 50.Hamer M, Stamatakis E, Steptoe A. Dose-response relationship between physical activity and mental health: the Scottish Health Survey. Br J Sports Med. 2009;43: 1111–1114. [DOI] [PubMed] [Google Scholar]

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PERMALINK

Impact of Exercise on Psychological Burden in Adult Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study

Emily S Tonorezos, MD MPH

Jennifer S Ford, PhD

Linwei Wang, MS

Kirsten K Ness, PT PhD

Yutaka Yasui, PhD

Wendy Leisenring, ScD

Charles A Sklar, MD

Leslie L Robison, PhD

Kevin C Oeffinger, MD

Paul C Nathan, MD MSc

Gregory T Armstrong, MD; MSCE

Kevin Krull, PhD

Lee W Jones, PhD

Abstract

Background:

Methods:

Results:

Conclusion:

Precis:

INTRODUCTION

METHODS

Patients and Study Overview

Exercise Assessment

Endpoints

Statistical Analysis

RESULTS

Table 1.

Exercise and Psychological Symptoms

Figure 1.

Figure 2.

DISCUSSION

Supplementary Material

Acknowledgments

Footnotes

REFERENCES

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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