A Review of Cardiorespiratory Fitness in Adolescent and Young Adult Survivors of Childhood Cancer: Factors that Affect its Decline and Opportunities for Intervention

Abstract

Childhood cancer incidence and survivorship rates are increasing, leading to a growing population of survivors that are at risk for competing causes of death, most notably cardiovascular disease (CVD). Cardiorespiratory fitness (CRF), a key modifiable CVD risk factor, is lower than expected among childhood survivors 5–20 years post-diagnosis. This review discusses the studies that demonstrate lower CRF in survivors of childhood cancer and the potential mechanisms and factors contributing to lower CRF in this population. Both exercise interventions and strategies to improve CRF are considered. The review advocates for more robust clinical research and exercise interventions to improve CRF with the goal of reducing comorbidities and competing CVD risk among childhood cancer survivors into adolescence and young adulthood.

The incidence of childhood cancers has been increasing since 1975. However, treatment advances during this time have also led to increased survivorship, with 5-year survival rates at approximately 80%.^1–3 With a growing number of childhood cancer survivors, there is an increasing need to reduce the risk of comorbidities and competing causes of death in this population, such as cardiovascular disease (CVD). CVD mortality has been shown to be elevated among survivors of childhood cancer, with a recent analysis demonstrating a sevenfold higher risk for CVD mortality among survivors of childhood cancer compared with age-, year-, and sex-matched members of the general population.⁴ Multiple factors contribute to the increased risk of CVD among adolescent and young adult (AYA) survivors of childhood cancer.⁵ One key modifiable factor associated with increased CVD risk in youth is low cardiorespiratory fitness (CRF).⁶ CRF, as measured by maximal cardiopulmonary exercise testing (VO_2max), assesses overall efficiency of oxygen transport from the environment to the working muscles. Importantly, deficiencies in CRF can point to abnormal cardiac function, as well as impairments in other vital organs.^7,8 In the general population, low CRF is also associated with increased risk of overall mortality, as well as death from CVD and cancer.⁹ In young adults, CRF has been shown to predict development of diabetes, hypertension, and metabolic syndrome over 15 years of follow-up, placing young adults at long-term risk for CVD.¹⁰

The current review presents studies that have assessed CRF in the childhood cancer survivor population. The potential mechanisms and factors contributing to lower CRF are discussed. Moreover, interventions aimed at increasing physical activity and subsequent CRF in this population are considered, as well as unique strategies required to succeed in motivating children and young adults. Finally, the review advocates for widespread early introduction of physical activity interventions and CRF measurement among childhood cancer patients and survivors.

Methods

This study synthesizes previous publications on fitness in survivors of childhood cancer, with a particular focus on strategies for intervention specific to AYA survivors. A literature search for peer-reviewed studies measuring CRF in survivors of childhood cancer was performed through the MEDLINE databases. Search terms included “fitness,” “cardiorespiratory fitness,” “aerobic capacity,” “childhood cancer,” “adolescent cancer,” and “young adult cancer.” Boolean operators were used to combine the search terms. There were no restrictions on publication date or status. Observational studies were included, as well as clinical trials of the effects of exercise interventions on CRF. Studies were included if they assessed CRF via maximal cardiopulmonary exercise testing to obtain VO_2max measurements. VO_2max is a product of central (cardiac output; stroke volume × heart rate) and peripheral (systemic a-vO₂ difference; e.g., oxygen extraction from blood) components, and assesses clinical or subclinical deficits in oxygen transport.¹¹ Studies that used submaximal exercise tests or other proxies of fitness that did not directly measure VO_2max were excluded—six-minute walk test (n = 2),^12,13 Duke Activity Status Index (n = 1),¹⁴ 4 × 10 m shuttle run (n = 1)¹³—due to a lack of sensitivity to detect clinical or subclinical O₂ deficits to inform CVD prognosis, as well as the higher measurement error between and across subjects.^15,16 Citations identified through the database search were screened for inclusion by the abstract, and then full text papers were examined for final inclusion.

CRF in Childhood Cancer Survivors

CRF in AYAs is most widely studied among those with a history of acute lymphoblastic lymphoma (ALL) 15–25 years post-diagnosis (Table 1). Jarvela et al. assessed CRF after a median time of 15.9 years post-diagnosis. Mean CRF in survivors was 14% lower than in controls (VO_2max difference: −5.7 mL/kg/min; 95% confidence Interval [CI]: −9.4 to −1.9; p = 0.01).¹⁷ Christiansen et al. assessed CRF in adult survivors of childhood ALL with a median follow-up time of 23.4 years post-diagnosis, finding that only 53% of survivors attained predicted CRF values based on age and sex.¹⁸ In a separate study in the childhood ALL survivor population, with a median of 21.9 years of follow-up, Ness et al. compared CRF in survivors treated with or without cranial radiation with age- and sex-matched peers, finding significant impairments in both groups of survivors, compared with age-, sex-, and race-matched peers.¹⁹ Tonorezos et al. assessed CRF in adult survivors of childhood ALL, with the majority of cases more than 15 years post-diagnosis. Compared with age-, sex-, and race-matched controls, survivors had lower CRF (VO_2max survivors: 30.7 mL/kg/min) than controls (VO_2max controls: 39.9 mL/kg/min, p < 0.0001).²⁰ Finally, in a systematic review and meta-analysis published in 2005, it was found that survivors of childhood ALL had reduced CRF compared with controls, specifically a VO_2max difference of −5.97 mL/kg/min (CI: −12.35 to 0.41) in survivors compared with healthy controls.²¹ Taken together, these data show that AYA survivors of ALL have lower CRF than the general population at up to 25 years of follow-up.

Table 1.

Studies Assessing CRF Among Survivors of Childhood Cancer

Study	Population characteristics	Median time post-diagnosis	Fitness level
Jarvela, J Cancer Surv, 2010¹⁷	• Childhood ALL • Age range 16–30 years • n = 21	15.9 years	14% lower than controls
Christiansen, Pediatr Blood Cancer, 2015¹⁸	• Childhood ALL • Median age 28.6 years (range 18.6–46.5) years • n = 138	23.4 years	47% failed to attain age-/sex-predicted values
Ness, Blood, 2015¹⁹	• Childhood ALL • Median age 28.6 years (range 18.4–44.6 years) • n = 365	21.9 years	20% lower than controls
Tonorezos, Pediatr Blood Cancer, 2013²⁰	• Childhood ALL • Median age 23.5 years (range 18–37 years) • n = 115	N/A Range 4 to >15 years	23% lower than controls
Van Brussel, Leukemia, 2005²¹	• Childhood ALL • Age range 7–19 years • n = 102	N/A Systematic review	13% lower than controls
De Caro, Pediatr Blood Cancer, 2011²²	• Childhood hematologic malignancies • Mean age 13.5 years • n = 55	6.2 years	9% lower than controls
De Caro, Arch Dis Child, 2006²³	• Anthracycline exposed • Age range 7–21 years • n = 84	6.4 years	13% lower than controls (Boys <13 years old, no other significant differences)
Miller, Pediatr Blood Cancer, 2013²⁴	• All-site childhood cancer • Mean age 22 years (range 8–40 years) • n = 72	13.4 years	Males: 8% lower than controls Females: 15% lower than control
Wolfe, J Pediatr Hematol Oncol, 2012²⁵	• Childhood brain tumor • Mean age 14.41 years • n = 13	N/A >2 years	35% lower than sex-/age-expected levels

ALL, acute lymphoblastic lymphoma; CRF, cardiorespiratory fitness.

Data on CRF in survivors of other childhood cancers are less robust, with most studies encompassing survivors with mixed cancer histories (Table 1). Among childhood cancer survivors exposed to anthracyclines, younger than 18 years old, and at least 1 year post-treatment, De Caro et al. found that CRF was significantly lower in survivors compared with controls (VO_2max: 41.4 ± 7.7 mL/kg/min vs. 45.7 ± 4.3 mL/kg/min, p = 0.05), respectively.²² Conversely, in a separate study of childhood cancer survivors younger than 21 years old, De Caro et al. found that only male survivors younger than 13 years of age had reduced CRF compared with age- and sex-matched controls.²³ Miller et al. assessed CRF among childhood cancer survivors at least 4 years post-diagnosis with a median follow-up time of 13.4 years. Compared with sibling controls, CRF was lower in both males (VO_2max: 28.53 mL/kg/min in survivors vs. 30.90 mL/kg/min in controls, p = 0.08) and females (VO_2max: 19.81 mL/kg/min in survivors vs. 23.40 mL/kg/min in controls, p = 0.03).²⁴ One known study assessed CRF in adolescent survivors of childhood brain tumors, aged 11–18 years at the time of testing, and compared the results to previously published data that assessed CRF in children with other chronic diseases. Wolfe et al. found that survivors had significantly lower CRF (VO_2max: 31.8 ± 7.2 mL/kg/min) than healthy controls (VO_2max: 49.3 ± 7.9 mL/kg/min) and children with pulmonary disease (VO_2max: 42.5 ± 6.8 mL/kg/min), and equivalent CRF to children with chronic heart disease (VO_2max: 33.7 ± 8.9 mL/kg/min).²⁵ Taken together, studies consistently point to reduced CRF in AYA survivors of childhood cancer. However, further studies are needed to assess whether CRF declines by cancer type and by time from diagnosis.

Factors that Contribute to CRF Decline in Childhood Cancer Survivors

Cardiac limitations

Survivors of childhood cancer are more likely than cancer-free siblings to have CVD, particularly congestive heart failure (HR: 5.9; CI: 3.4–9.6), myocardial infarction (HR: 5.0; CI: 2.3–10.4), valvular abnormalities (HR: 4.8; CI: 3.0–7.6), or pericardial disease (HR: 6.3; CI: 3.3–11.9), up to 30 years post-diagnosis.²⁶ Cardiac diseases among survivors of childhood cancer are well studied, and can contribute to reduced CRF, particularly through impairments in systolic and diastolic dysfunction, as well as heart rate response that can limit cardiac performance during exercise.²⁷ Ylanen et al. assessed left ventricular ejection fraction (LVEF) using cardiac magnetic resonance imaging in adolescent-aged, long-term survivors of childhood cancer that had been exposed to anthracyclines at 8 years of follow-up. Abnormal LV systolic function (<45%) was present in 18% (11/62) of survivors.²⁸ Similarly, among young adult survivors of childhood cancer, Christiansen et al. found that survivors treated with anthracyclines had significant impairments in diastolic function compared with controls after 20.4 years of follow-up.²⁹ Importantly, prior work has shown that impaired diastolic dysfunction leads specifically to impaired exercise capacity in ALL survivors previously exposed to anthracyclines.¹⁸ Finally, autonomic dysfunction has been demonstrated in patients treated for childhood and young adult cancers.³⁰ In a recent study of survivors of young adult Hodgkin lymphoma, Groarke et al. found that thoracic radiation therapy was associated with autonomic dysfunction, particularly elevated resting heart rate and abnormal heart rate recovery, and this resulted in impaired exercise tolerance and increased risk of all-cause mortality.³¹

Pulmonary limitations

Pulmonary limitations, including impairments in ventilator and gas exchange can also contribute to reduced CRF.²⁷ Pulmonary limitations are common in survivors of childhood cancer, as therapies used to treat childhood cancer, including radiation, chemotherapy, surgery, and hematopoietic stem-cell transplant, pose the risk of pulmonary toxicity.^32,33 For example, Armenian et al. assessed long-term pulmonary function in childhood cancer survivors with a median age at examination of 32.3 years (range 14.6–58.9 years) and after a median of 17.1 years since diagnosis. Compared with healthy controls, survivors had higher odds of restrictive deficits (OR: 6.5; CI: 1.5–28.4) and diffusion abnormalities (OR: 5.2; CI: 1.8–15.5). Predictors of pulmonary limitations included being younger than 16 years of age at diagnosis, exposure to more than 20 Gy chest radiation, and female sex.³⁴ Among AYA survivors of childhood cancer who had received bleomycin, De et al. found at least one pulmonary function abnormality, including obstructive lung disease, and impairments in lung capacity, expiratory volume, expiratory flow, and residual volume, in 52.5% of survivors after a median follow-up time of 3.9 years after diagnosis.³⁵ Similarly, after a median of 18 years of follow-up among childhood cancer survivors treated with bleomycin, Mulder et al. found pulmonary function impairments in 44% of survivors.³⁶ Huang et al. assessed pulmonary outcomes among young adult and adult survivors of childhood central nervous system malignancies. After a median follow-up time of 18.5 years, survivors had higher rates of fibrosis (relative risk [RR]: 2.0; CI: 1.0–3.5), chronic cough (RR: 1.6; CI: 1.2–2.1), chest wall abnormalities (RR: 19.0; CI: 4.2–85.7), and need for supplemental oxygen (RR: 2.5; CI: 1.9–3.3) compared with sibling controls.³⁷ Finally, using a comprehensive systematic clinical assessment, Hudson et al. found that the prevalence of adverse outcomes by organ system among adult survivors of childhood cancer was highest for the pulmonary system, with abnormal pulmonary function found in 65.2% of survivors after a median time from diagnosis of 25 years.³⁸

Vascular limitations

Impairments to the vascular system, specifically impairments in vascular stiffness and endothelial dysfunction, have also been reported among survivors of childhood cancer. Krystal et al. assessed arterial stiffness, as measured by pulse wave velocity, in AYA childhood cancer survivors after a mean of 7 years post-therapy. Compared with controls, survivors had significantly higher parameters of arterial stiffness (pulse wave velocity 6.37 ± 0.89 m/sec vs. 5.76 ± 0.88 m/sec, p = 0.012), and 70% of survivors had elevated arterial stiffness parameters compared with established normal values.³⁹ Several studies have found increased arterial stiffness and signs of endothelial dysfunction among survivors of childhood cancer exposed to anthracyclines at up to 10.2 years of follow-up.^40–43 For example, among adolescents, Jenei et al. found that both survivors of childhood cancer treated with anthracyclines (6.45 ± 3.25) and survivors treated with chemotherapy only (4.12 ± 2.32, p = 0.03) had significantly higher aortic stiffness index compared with healthy controls (2.08 ± 0.06).⁴⁰ Jarvela et al. assessed endothelial function among AYA long-term survivors of childhood ALL, finding that compared with healthy controls, survivors had impaired endothelial function, as measured by flow-mediated dilation response.⁴⁴ Similarly, Dengel et al. found that young adult survivors of childhood ALL, treated with or without cranial radiation, were at risk for impaired endothelial function, as measured by flow-mediated dilation response.⁴⁵ Importantly, among AYA survivors, arterial stiffness and other signs of endothelial dysfunction have been shown to be negatively associated with CRF.^46,47

Musculoskeletal limitations

Musculoskeletal impairments are known to impact CRF through limitations in movement and physical activity performance, as well as influencing skeletal muscle oxidative capacity.⁴⁸ Musculoskeletal problems that affect movement ability can limit physical activity participation and thus contribute to reductions in CRF. Specifically, in the Childhood Cancer Survivorship Study (CCSS) cohort, it was found that more than 10% of survivors experienced musculoskeletal problems, including osteoporosis, joint replacement, amputation, short stature, osteonecrosis, and loss of lean muscle mass and strength, all impairments that can limit physical activity participation.⁴⁹ Often overlooked is the effect of certain treatments on changes to pathways responsible for regulating skeletal muscle glycolysis and fatty acid oxidation, as well as impaired muscular relaxation and maximal twitch force, all important contributors to CRF.²⁷ Though data on muscular changes among survivors of childhood cancer are sparse, Scheede-Bergdahl et al. have reviewed potential mechanisms of chemotherapy-induced skeletal muscle dysfunction in survivors of childhood ALL, noting impairments in muscle satellite cells, motor neurons, and muscle mitochondrial function that all contribute to reduced mobility and oxidative function.⁵⁰

Exercise Training Interventions to Improve CRF in Childhood Cancer Patients and Survivors

Exercise training is a method proven to improve CRF in many different patient populations, including survivors of adult cancers and patients with cardiovascular diseases,^51–53 as well as adolescents with other chronic conditions.^54,55 Exercise training works to improve CRF through multiple mechanisms impacted by cancer treatment: notably, to increase cardiac function and lung diffusion capacity, to augment oxygen transport and utilization in working muscles, and to improve endothelial function, which is critical to meeting blood-flow demand of working muscles.²⁷

Several studies have assessed the effect of exercise training on CRF, measured by VO_2max, in survivors of childhood cancer, particularly among survivors of childhood ALL (Table 2). San Juan et al. performed an 8-week supervised exercise program in children who had undergone bone marrow transplantation for leukemia within the previous 12 months. The same program, which consisted of three 90–120 minute weekly sessions of aerobic and resistance training, was performed in healthy controls, with patients showing significantly greater improvements in CRF from baseline to 8 weeks than controls.⁵⁶ In a different study, San Juan et al. assessed an in-hospital exercise intervention among children undergoing maintenance treatment for ALL. The exercise program consisted of three 30-minute sessions per week of supervised moderate to vigorous aerobic exercise plus resistance training. Significant increases in CRF were found from baseline to post–16 weeks of training (VO_2max: 24.3 ± 5.9 mL/kg/min vs. 30.2 ± 6.2 mL/kg/min, p < 0.05).⁵⁷ In a study of AYA survivors of childhood ALL, Jarvela et al. assessed the effect of a home-based exercise program that included instructions in muscular strength training and encouragement to perform a strength exercise program three to four times per week, as well as an aerobic exercise of choice for at least three sessions of 30 minutes each per week. From baseline to 16 weeks, CRF increased significantly (VO_2max: 35.2 mL/kg/min vs. 37.1 mL/kg/min, p = 0.01).⁵⁸ In contrast, Takken et al. found no difference in CRF after 12 weeks of supervised and home-based moderate intensity aerobic and resistance training among child and adolescent survivors of childhood ALL.⁵⁹ Data are scarce on interventions to improve CRF in non-ALL populations. Smith et al. performed an exercise training intervention among adult survivors of childhood sarcomas with subclinical cardiomyopathy who had been treated with anthracyclines. The intervention consisted of home-based moderate intensity aerobic training for 20–45 minutes three to five times per week plus resistance training two to three days per week. After 12 weeks of training, CRF improved by 10.6%.⁶⁰

Table 2.

Exercise Interventions to Improve CRF in Childhood Cancer Survivors

Study	Population characteristics	Intervention features	Outcome
San Juan, Int J Sports Med, 2008⁵⁶	• Childhood leukemia • Bone marrow transplant within past 12 months • n = 8 • Mean age 10.9 years (range 8–16 years)	• 8 weeks • Supervised, in hospital • 90–120 minutes/session • 3 sessions/week • 30 minutes moderate/vigorous aerobic exercise • Sports games • Strength training	↑ VO_2max by 20%
San Juan, Med Sci Sports Exerc, 2007⁵⁷	• Childhood ALL • Maintenance treatment • n = 7 • Age range 4–7 years	• 16 weeks • Supervised, in hospital • 90–120 minutes/session • 3 sessions/week • Moderate/vigorous 30 minutes aerobic exercise • Sports games • Strength training	↑ VO_2max by 24%
Jarvela, Pediatr Blood Cancer, 2012⁵⁸	• Childhood ALL • Long-term survivors • n = 17 • Age range 16–30 years	• 16 weeks • Unsupervised, home based • 3–4 sessions/week • 30 minutes moderate aerobic exercise • Strength training	↑ VO_2max by 5%
Takken, Psychooncology, 2009⁵⁹	• Childhood ALL • >6 months post-treatment • n = 9 • Mean age 9.3 years (range 6–14 years)	• 12 weeks • Two 45-minute sessions/week supervised at local physiotherapy • 2 sessions/week unsupervised, home based • Moderate/vigorous aerobic exercise • Strength training	No improvement in VO_2max
Smith, Pediatr Blood Cancer, 2013⁶⁰	• Childhood sarcoma • Treated with anthracyclines • Signs of subclinical cardiomyopathy • Long-term survivors • n = 5 • Mean age 38 years (range 33–40 years)	• 12 weeks • Unsupervised, home based • 3–5 sessions/week • 20–45 minutes moderate aerobic exercise • Strength training	↑ VO_2max by 11%

Barriers to Exercise and Intervention Preferences of Childhood Cancer Survivors

The evidence presented above shows that interventions can be an effective way to mitigate loss of CRF among childhood cancer patients and survivors. However, outside of the intervention setting, survivors are more likely to decrease their physical activity levels and fail to meet physical activity recommendations. In separate studies, Gotte et al. and Fuemmeler et al. assessed physical activity levels in childhood and adolescent cancer patients during treatment, finding that compared with pre-diagnosis levels, minutes per week spent on physical activity decreased, and that compared with healthy controls, patients performed significantly less moderate to vigorous physical activity, respectively.^61,62 Similarly, Murnane et al. studied AYA cancer survivors, aged 15–25 years, in Australia, finding a significant reduction in the average minutes of physical activity during treatment (difference 173 minutes; CI: 134–212 minutes; p < 0.001) and after treatment (difference 71 minutes; CI: 33–109 minutes; p < 0.001) compared with pretreatment levels.⁶³

The decreases in physical activity demonstrated during treatment have been shown to persist long into survivorship. Jarvela et al. assessed physical activity levels in AYA (aged 16–30 years) survivors of childhood ALL after a median of 15.9 years post-diagnosis, finding that 30% of male survivors and 36.4% of female survivors reported less than 1 hour of moderate walking per week.¹⁷ In a separate study of young adult survivors of childhood ALL (mean age 29 years), Florin et al. examined physical activity levels after a mean of 23.1 years of follow-up. Compared with the general population, survivors were less likely to meet the Centers for Disease Control and Prevention (CDC) physical activity guidelines (OR: 1.44; CI: 1.32–1.57) and were more likely to be inactive (OR: 1.74; CI: 1.56–1.94).⁶⁴ Similarly, in a study of Korean children and adolescents aged 9–16 years who had completed treatment for cancer at least 6 months previously, Chung et al. found that physical activity decreased from pre-diagnosis to survivorship, and 92.2% of survivors did not meet recommended physical activity levels.⁶⁵ Finally, in a Swiss study of young adult and adult survivors of childhood cancer, Rueegg et al. found that only 52% of survivors met physical activity guidelines after a mean of 19.5 years post-diagnosis.⁶⁶

AYAs are a population with unique motivations and barriers to exercise adherence that must be taken into consideration when promoting a physically active lifestyle. Gotte et al. assessed motivations and barriers for physical activity in childhood cancer patients undergoing treatment. Barriers to exercise included: (1) physical aspects (fatigue, pain, dizziness, nausea); (2) psychological aspects (moodiness, low motivation); and (3) organizational constraints (lack of time, lack of space in hospital, lack of peers to exercise with, lack of sports equipment available). Motivations to exercise included desire to maintain or increase strength and CRF, fear of losing self-reliance due to weakness, feelings of normalcy, and positive side effects of exercise on mood, sleep, and quality of life.⁶⁷ Arroyave et al. examined perceived barriers to improving exercise behaviors among AYA childhood cancer survivors, finding that the main barriers were fatigue, lack of time, and not belonging to a gym.⁶⁸ In a study of adolescent survivors of childhood cancer, Chung et al. found that fatigue, decreased strength and endurance following treatment, and concern about academic performance prevented survivors from participating in regular physical activity.⁶⁵ Gilliam et al. found that higher levels of family and peer support, greater family income, male sex, and higher self-efficacy were associated with higher levels of physical activity among childhood cancer survivors aged 8–16 years.⁶⁹ In a group of adolescent cancer survivors, Wright et al. found that lack of time was the biggest barrier to exercise, while social support motivated survivors to participate in physical activity.⁷⁰ In the CCSS cohort, Ness et al. found that survivors most at risk for an inactive lifestyle included females, black race, older age, those with depression, smokers, underweight or obese status, as well as those treated with cranial radiation or amputation.⁷¹ Finally, Van Dijk-Lokkart et al. assessed barriers to participation in physical activity interventions among childhood cancer patients on treatment or less than 1 year post-treatment, finding that parents most frequently limited participation due to beliefs that it would be too time-consuming or too demanding. Children chose not to participate due to time constraints and current involvement with other sources of physical activity.⁷² These barriers are not unique to cancer survivors, but are seen in healthy AYA survivors as well.⁷³

Badr et al. assessed the intervention preferences of AYA survivors of childhood cancer, reporting that 87% were interested in exercise interventions. Overall, survivors preferred mail or computer-based interventions, with younger survivors preferring camp-based programs.⁷⁴ In a similar study, Rabin et al. found that young adult cancer survivors prefer interventions that are convenient and take into account their busy lifestyle, and interventions that provide social support. Preferences included delivering the intervention over an online forum, such as a message board or blog that would allow connections with other young survivors as well as behavioral counselors. Many, however, also expressed that face-to-face group meetings would be beneficial initially before transitioning to online communication.⁷⁵ Moreover, among AYA cancer survivors, Murnane et al. found that 85% of those assessed would like to receive exercise information at some point after their cancer, with the majority preferring home-based exercise training or group programs at a local gym.⁶³ Unique interventions that have proven successful in increasing physical activity among childhood cancer survivors include adventure-based training, Facebook delivered education, and an exercise program incorporating the theory of planned behavior motivational training.^76–78

Conclusion

Survivorship rates among childhood cancers are increasing. However, survivors are at increased risk for CVD late effects. CRF, an important marker of CVD risk, is markedly reduced among childhood cancer survivors into young adulthood, as evidenced in the current review (Table 1). While exercise training is a known strategy to improve CRF (Table 2), few studies have objectively measured and tracked CRF in this subset of survivors. Importantly, CRF can be attained non-invasively by cardiopulmonary exercise testing (CPET). A discussion of CPET in the clinical oncology setting, as well as the importance of objectively measuring CRF, has been published elsewhere.^16,79 Accurate and reproducible assessment of CRF is key for future exercise research in this area of childhood cancer survivorship: (1) to pinpoint high-risk cancer subtypes, as well as tracking CRF longitudinally to focus on the most vulnerable patients; (2) to determine biological mechanisms for loss of CRF; and (3) to assess the impact of exercise training on CRF and subsequent long-term cancer and cardiovascular outcomes in childhood cancer survivors. In the clinic setting, CRF assessment allows for individualized training goals based on % VO_2max attained during testing, as well as helping to identify previously unrecognized impairments (i.e., cardiac, pulmonary). This is particularly important in childhood cancer survivors who have different treatment exposures and characteristics (i.e., age, prior exercise history, cancer stage) that can potentially impact CRF. Lastly, childhood cancer survivors have unique barriers to exercise and physical activity in the survivorship setting, as discussed in the current review. Strategies for long-term adherence to an active lifestyle to maintain higher levels of CRF are needed, especially among AYAs. Given that survivors of childhood cancer have a long lifespan ahead, strategies to motivate sustained physical activity are desperately needed to promote cardiovascular health.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

References

Bleyer

, O'Leary

, Barr

, Ries

LAG

(Eds). Cancer epidemiology in older adolescents and young adults 15 to 29 years of age, including SEER incidence and survival: 1975–2000. NIH Pub. No. 06–5767. Bethesda, MD: National Cancer Institute; 2006.

StatBite: Trends in U.S. childhood cancer survival (1975–2004). J Natl Cancer Inst. 2009; 101(13):909.

Ward

, DeSantis

, Robbins

, et al. Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin. 2014; 64(2):83–103.

Armstrong

, Liu

, Yasui

, et al. Late mortality among 5-year survivors of childhood cancer: a summary from the Childhood Cancer Survivor Study. J Clin Oncol. 2009; 27(14):2328–38.

Berkman

, Lakoski

. Treatment, behavioral, and psychosocial components of cardiovascular disease risk among survivors of childhood and young adult cancer. J Am Heart Assoc., 2015; 4(4).

Lobelo

, Pate

, Dowda

, et al. Cardiorespiratory fitness and clustered cardiovascular disease risk in U.S. adolescents. J Adolesc Health. 2010; 47(4):352–9.

Wasserman

, Hansen

, Sue

, et al. (Eds). Principles of exercise testing and interpretation. Philadelphia, PA: Lippincott Williams & Wilkins; 2012.

Weisman

, Zeballos

. An integrated approach to the interpretation of cardiopulmonary exercise testing. Clin Chest Med. 1994; 15(2):421–45.

Kampert

, Blair

, Barlow

, Kohl

3rd . Physical activity, physical fitness, and all-cause and cancer mortality: a prospective study of men and women. Ann Epidemiol. 1996; 6(5):452–7.

10.

Carnethon

, Gidding

, Nehgme

, et al. Cardiorespiratory fitness in young adulthood and the development of cardiovascular disease risk factors. JAMA. 2003; 290(23):3092–100.

11.

Mitchell

, Saltin

. The oxygen transport system and maximal oxygen uptake. In: Tipton

(Ed.). Exercise physiology. New York: Springer; 2003: pp. 255–91.

12.

Slater

, Steinberger

, Ross

, et al. Physical activity, fitness, and cardiometabolic risk factors in adult survivors of childhood cancer with a history of hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2015; 21(7):1278–83.

13.

Hoffman

, Mulrooney

, Steinberger

, et al. Deficits in physical function among young childhood cancer survivors. J Clin Oncol. 2013; 31(22):2799–805.

14.

Ness

, Morris

, Nolan

, et al. Physical performance limitations among adult survivors of childhood brain tumors. Cancer. 2010; 116(12):3034–44.

15.

Balady

, Arena

, Sietsema

, et al. Clinician's guide to cardiopulmonary exercise testing in adults: a scientific statement from the American Heart Association. Circulation. 2010; 122(2):191–225.

16.

Jones

, Eves

, Haykowsky

, et al. Cardiorespiratory exercise testing in clinical oncology research: systematic review and practice recommendations. Lancet Oncol. 2008; 9(8):757–65.

17.

Jarvela

, Niinikoski

, Lahteenmaki

, et al. Physical activity and fitness in adolescent and young adult long-term survivors of childhood acute lymphoblastic leukaemia. J Cancer Surviv. 2010; 4(4):339–45.

18.

Christiansen

, Kanellopoulos

, Lund

, et al. Impaired exercise capacity and left ventricular function in long-term adult survivors of childhood acute lymphoblastic leukemia. Pediatr Blood Cancer. 2015; 62(8):1437–43.

19.

Ness

, DeLany

, Kaste

, et al. Energy balance and fitness in adult survivors of childhood acute lymphoblastic leukemia. Blood. 2015; 125(22):3411–19.

20.

Tonorezos

, Snell

, Moskowitz

, et al. Reduced cardiorespiratory fitness in adult survivors of childhood acute lymphoblastic leukemia. Pediatr Blood Cancer. 2013; 60(8):1358–64.

21.

van Brussel

, Takken

, Lucia

, et al. Is physical fitness decreased in survivors of childhood leukemia? A systematic review. Leukemia. 2005; 19(1):13–17.

22.

De Caro

, Smeraldi

, Trocchio

, et al. Subclinical cardiac dysfunction and exercise performance in childhood cancer survivors. Pediatr Blood Cancer. 2011; 56(1):122–6.

23.

De Caro

, Fioredda

, Calevo

, et al. Exercise capacity in apparently healthy survivors of cancer. Arch Dis Child. 2006; 91(1):47–51.

24.

Miller

, Lopez-Mitnik

, Somarriba

, et al. Exercise capacity in long-term survivors of pediatric cancer: an analysis from the Cardiac Risk Factors in Childhood Cancer Survivors Study. Pediatr Blood Cancer. 2013; 60(4):663–8.

25.

Wolfe

, Hunter

, Madan-Swain

, et al. Cardiorespiratory fitness in survivors of pediatric posterior fossa tumor. J Pediatr Hematol Oncol. 2012; 34(6):e222–7.

26.

Mulrooney

, Yeazel

, Kawashima

, et al. Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort. BMJ. 2009; 339:b4606.

27.

Lakoski

, Eves

, Douglas

, Jones

. Exercise rehabilitation in patients with cancer. Nat Rev Clin Oncol. 2012; 9(5):288–96.

28.

Ylanen

, Poutanen

, Savikurki-Heikkila

, et al. Cardiac magnetic resonance imaging in the evaluation of the late effects of anthracyclines among long-term survivors of childhood cancer. J Am Coll Cardiol. 2013; 61(14):1539–47.

29.

Christiansen

, Hamre

, Massey

, et al. Left ventricular function in long-term survivors of childhood lymphoma. Am J Cardiol. 2014; 114(3):483–90.

30.

Kamath

, Halton

, Harvey

, et al. Cardiac autonomic dysfunction in survivors of acute lymphoblastic leukemia in childhood. Int J Oncol. 1998; 12(3):635–40.

31.

Groarke

, Tanguturi

, Hainer

, et al. Abnormal exercise response in long-term survivors of Hodgkin lymphoma treated with thoracic irradiation: evidence of cardiac autonomic dysfunction and impact on outcomes. J Am Coll Cardiol. 2015; 65(6):573–83.

32.

Josephson

, Goldfarb

. Pulmonary complications of childhood cancers. Expert Rev Respir Med. 2014; 8(5):561–71.

33.

Huang

, Hudson

, Stokes

, et al. Pulmonary outcomes in survivors of childhood cancer: a systematic review. Chest. 2011; 140(4):881–901.

34.

Armenian

, Landier

, Francisco

, et al. Long-term pulmonary function in survivors of childhood cancer. J Clin Oncol. 2015; 33(14):1592–600.

35.

, Guryev

, LaRiviere

, et al. Pulmonary function abnormalities in childhood cancer survivors treated with bleomycin. Pediatr Blood Cancer. 2014; 61(9):1679–84.

36.

Mulder

, Thonissen

, van der Pal

, et al. Pulmonary function impairment measured by pulmonary function tests in long-term survivors of childhood cancer. Thorax. 2011; 66(12):1065–71.

37.

Huang

, Chen

, Dietz

, et al. Pulmonary outcomes in survivors of childhood central nervous system malignancies: a report from the Childhood Cancer Survivor Study. Pediatr Blood Cancer. 2014; 61(2):319–25.

38.

Hudson

, Ness

, Gurney

, et al. Clinical ascertainment of health outcomes among adults treated for childhood cancer. JAMA. 2013; 309(22):2371–81.

39.

Krystal

, Reppucci

, Mayr

, et al. Arterial stiffness in childhood cancer survivors. Pediatr Blood Cancer. 2015; 62(10):1832–7.

40.

Jenei

, Bardi

, Magyar

, et al. Anthracycline causes impaired vascular endothelial function and aortic stiffness in long term survivors of childhood cancer. Pathol Oncol Res. 2013; 19(3):375–83.

41.

Herceg-Cavrak

, Ahel

, Batinica

, et al. Increased arterial stiffness in children treated with anthracyclines for malignant disease. Coll Antropol. 2011; 35(2):389–95.

42.

Jang

, Choi

, Jeon

. Vascular endothelial dysfunction after anthracyclines treatment in children with acute lymphoblastic leukemia. Korean J Pediatr. 2013; 56(3):130–4.

43.

Chow

, Chin

, Dahl

, Rosenthal

. Anthracyclines cause endothelial injury in pediatric cancer patients: a pilot study. J Clin Oncol. 2006; 24(6):925–8.

44.

Jarvela

, Niinikoski

, Heinonen

, et al. Endothelial function in long-term survivors of childhood acute lymphoblastic leukemia: effects of a home-based exercise program. Pediatr Blood Cancer. 2013; 60(9):1546–51.

45.

Dengel

, Ness

, Glasser

, et al. Endothelial function in young adult survivors of childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2008; 30(1):20–5.

46.

Quan

, Blizzard

, Sharman

, et al. Resting heart rate and the association of physical fitness with carotid artery stiffness. Am J Hypertens. 2014; 27(1):65–71.

47.

Pahkala

, Laitinen

, Heinonen

, et al. Association of fitness with vascular intima-media thickness and elasticity in adolescence. Pediatrics. 2013; 132(1):e77–84.

48.

American Thoracic Society, American College of Chest Physicians. ATS/ACCP Statement on cardiopulmonary exercise testing. Am J Respir Crit Care Med. 2003; 167(2):211–77.

49.

Ness

, Hudson

, Ginsberg

, et al. Physical performance limitations in the Childhood Cancer Survivor Study cohort. J Clin Oncol. 2009; 27(14):2382–9.

50.

Scheede-Bergdahl

, Jagoe

. After the chemotherapy: potential mechanisms for chemotherapy-induced delayed skeletal muscle dysfunction in survivors of acute lymphoblastic leukaemia in childhood. Front Pharmacol. 2013; 4:49.

51.

May

, Van Weert

, Korstjens

, et al. Improved physical fitness of cancer survivors: a randomised controlled trial comparing physical training with physical and cognitive–behavioural training. Acta Oncol. 2008; 47(5):825–34.

52.

Stoller

, de Bruin

, Schindelholz

, et al. Efficacy of feedback-controlled robotics-assisted treadmill exercise to improve cardiovascular fitness early after stroke: a randomized controlled pilot trial. J Neurol Phys Ther. 2015; 39(3):156–65.

53.

Buys

, Avila

, Cornelissen

. Exercise training improves physical fitness in patients with pulmonary arterial hypertension: a systematic review and meta-analysis of controlled trials. BMC Pulm Med. 2015; 15:40.

54.

Slaman

, Roebroeck

, van der Slot

, et al. Can a lifestyle intervention improve physical fitness in adolescents and young adults with spastic cerebral palsy? A randomized controlled trial. Arch Phys Med Rehabil. 2014; 95(9):1646–55.

55.

McCormack

, McCarthy

, Harrington

, et al. Effects of exercise and lifestyle modification on fitness, insulin resistance, skeletal muscle oxidative phosphorylation and intramyocellular lipid content in obese children and adolescents. Pediatr Obes. 2014; 9(4):281–91.

56.

San Juan

, Chamorro-Vina

, Moral

, et al. Benefits of intrahospital exercise training after pediatric bone marrow transplantation. Int J Sports Med. 2008; 29(5):439–46.

57.

San Juan

, Fleck

, Chamorro-Vina

, et al. Effects of an intrahospital exercise program intervention for children with leukemia. Med Sci Sports Exerc. 2007; 39(1):13–21.

58.

Jarvela

, Kemppainen

, Niinikoski

, et al. Effects of a home-based exercise program on metabolic risk factors and fitness in long-term survivors of childhood acute lymphoblastic leukemia. Pediatr Blood Cancer. 2012; 59(1):155–60.

59.

Takken

, van der Torre

, Zwerink

, et al. Development, feasibility and efficacy of a community-based exercise training program in pediatric cancer survivors. Psychooncology. 2009; 18(4):440–8.

60.

Smith

, Ness

, Joshi

, et al. Exercise training in childhood cancer survivors with subclinical cardiomyopathy who were treated with anthracyclines. Pediatr Blood Cancer. 2014; 61(5):942–5.

61.

Gotte

, Kesting

, Winter

, et al. Comparison of self-reported physical activity in children and adolescents before and during cancer treatment. Pediatr Blood Cancer. 2014; 61(6):1023–8.

62.

Fuemmeler

, Pendzich

, Clark

, et al. Diet, physical activity, and body composition changes during the first year of treatment for childhood acute leukemia and lymphoma. J Pediatr Hematol Oncol. 2013; 35(6):437–43.

63.

Murnane

, Gough

, Thompson

, et al. Adolescents and young adult cancer survivors: exercise habits, quality of life and physical activity preferences. Support Care Cancer. 2015; 23(2):501–10.

64.

Florin

, Fryer

, Miyoshi

, et al. Physical inactivity in adult survivors of childhood acute lymphoblastic leukemia: a report from the childhood cancer survivor study. Cancer Epidemiol Biomarkers Prev. 2007; 16(7):1356–63.

65.

Chung

, Li

, Chiu

, et al. The impact of cancer and its treatment on physical activity levels and behavior in Hong Kong Chinese childhood cancer survivors. Cancer Nurs. 2014; 37(3):E43–51.

66.

Rueegg

, von der Weid

, Rebholz

, et al. Daily physical activities and sports in adult survivors of childhood cancer and healthy controls: a population-based questionnaire survey. PLoS One. 2012; 7(4):e34930.

67.

Gotte

, Kesting

, Winter

, et al. Experience of barriers and motivations for physical activities and exercise during treatment of pediatric patients with cancer. Pediatr Blood Cancer. 2014; 61(9):1632–7.

68.

Arroyave

, Clipp

, Miller

, et al. Childhood cancer survivors' perceived barriers to improving exercise and dietary behaviors. Oncol Nurs Forum. 2008; 35(1):121–30.

69.

Gilliam

, Madan-Swain

, Whelan

, et al. Cognitive influences as mediators of family and peer support for pediatric cancer survivors' physical activity. Psychooncology. 2013; 22(6):1361–8.

70.

Wright

, Bryans

, Gray

, et al. Physical activity in adolescents following treatment for cancer: influencing factors. Leuk Res Treatment. 2013; 2013:592395.

71.

Ness

, Leisenring

, Huang

, et al. Predictors of inactive lifestyle among adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Cancer. 2009; 115(9):1984–94.

72.

van Dijk-Lokkart

, Braam

, Huisman

, et al. Factors influencing childhood cancer patients to participate in a combined physical and psychosocial intervention program: Quality of Life in Motion. Psychooncology. 2015; 24(4):465–71.

73.

Jodkowska

, Mazur

, Oblacinska

. Perceived barriers to physical activity among Polish adolescents. Przegl Epidemiol. 2015; 69(1):73–8, 169–73.

74.

Badr

, Chandra

, Paxton

, et al. Health-related quality of life, lifestyle behaviors, and intervention preferences of survivors of childhood cancer. J Cancer Surviv. 2013; 7(4):523–34.

75.

Rabin

, Simpson

, Morrow

, Pinto

. Intervention format and delivery preferences among young adult cancer survivors. Int J Behav Med. 2013; 20(2):304–10.

76.

, Chung

, Ho

, et al. Effectiveness of an integrated adventure-based training and health education program in promoting regular physical activity among childhood cancer survivors. Psychooncology. 2013; 22(11):2601–10.

77.

Valle

, Tate

, Mayer

, et al. A randomized trial of a Facebook-based physical activity intervention for young adult cancer survivors. J Cancer Surviv. 2013; 7(3):355–68.

78.

Keats

, Culos-Reed

. A community-based physical activity program for adolescents with cancer (project TREK): program feasibility and preliminary findings. J Pediatr Hematol Oncol. 2008; 30(4):272–80.

79.

Kaminsky

, Arena

, Beckie

, et al. The importance of cardiorespiratory fitness in the United States: the need for a national registry: a policy statement from the American Heart Association. Circulation. 2013; 127(5):652–62.