Exercise Intolerance, Mortality, and Organ System Impairment in Adult Survivors of Childhood Cancer

Abstract

PURPOSE Exercise intolerance, associated with heart failure and death in general populations, is not well studied in survivors of childhood cancer. We examined prevalence of exercise intolerance in survivors exposed or not to cardiotoxic therapy, and associations among organ system function, exercise intolerance, and mortality. METHODS Participants consisted of 1,041 people who had survived cancer ≥ 10 years (and had or did not have exposure to anthracyclines and/or chest-directed radiation) and 285 control subjects. Exercise intolerance was defined as peak oxygen uptake < 85% predicted from maximal cardiopulmonary exercise testing; organ functions were ascertained with imaging or clinical testing. Multivariable regression of the data was performed to compare exercise capacity between survivors exposed or unexposed to cardiotoxic therapy and control subjects, and to evaluate associations between treatment and organ function, and organ function and exercise intolerance. Propensity score methods in time-to-event analyses evaluated associations between exercise intolerance and mortality. RESULTS Survivors (mean age ± standard deviation [SD], 35.6 ± 8.8 years) had lower mean (± SD) peak oxygen uptake (exposed: 25.74 ± 8.36 mL/kg/min; unexposed: 26.82 ± 8.36 mL/kg/min) than did control subjects (32.69 ± 7.75 mL/kg/min; P for all < .001). Exercise intolerance was present in 63.8% (95% CI, 62.0% to 65.8%) of exposed survivors, 55.7% (95% CI, 53.2% to 58.2%) of unexposed survivors, and 26.3% (95% CI, 24.0% to 28.3%) of control subjects, and was associated with mortality (hazard ratio, 3.9; 95% CI, 1.09 to 14.14). Global longitudinal strain (odds ratio [OR], 1.71; 95% CI, 1.11 to 2.63), chronotropic incompetence (OR, 3.58; 95% CI, 1.75 to 7.31); forced expiratory volume in 1 second < 80% (OR, 2.59; 95% CI, 1.65 to 4.09), and 1 SD decrease in quadriceps strength (OR, 1.49; 95% CI, 1.23 to 1.82) were associated with exercise intolerance. Ejection fraction < 53% was not associated with exercise intolerance. CONCLUSION Exercise intolerance is prevalent among childhood cancer survivors and associated with all-cause mortality. Treatment-related cardiac (detected by global longitudinal strain), autonomic, pulmonary, and muscular impairments increased risk. Survivors with impairments may require referral to trained specialists to learn to accommodate specific deficits when engaging in exercise.

Exercise cardiovascular magnetic resonance reveals reduced cardiac reserve in pediatric cancer survivors with impaired cardiopulmonary fitness

“…This is supported by findings from our study, in which there was no significant difference in resting LV FS, LVEF or GLS between our two study groups, nor did these measures correlate with peak VO 2 . The largest of these previous studies [35] demonstrated that impaired peak VO 2 was associated with reduced resting GLS, but not resting LVEF in 1041 long-term (> 10 years) pediatric cancer survivors, supporting the notion that exercise intolerance is a maker of cardiac dysfunction in cancer survivors. However, results from our study suggest that impairments in fitness and cardiac reserve may precede impairment in GLS.…”

“…However, our study is the first in pediatric cancer survivors to document this relationship with impaired peak VO 2 . A handful of cross-sectional studies have investigated cardiac impairment in long-term pediatric cancer survivors with normal or reduced peak VO 2 [29,30,35]. However results from these studies have been inconsistent, which may relate to the assessment of cardiac function in the resting state.…”

A randomized controlled trial of a structured exercise intervention after the completion of acute cancer treatment in adolescents and young adults

“…This often persists into longterm survivorship, and is associated with increased cardiovascular disease risk and late mortality. [5][6][7][8][9][10] Impaired fitness may also contribute to the well-documented worse physical functioning, poorer healthrelated quality of life (QOL), 11 and excessive fatigue experienced by AYA cancer survivors. 12 Despite 85% wanting exercise information, this need was unmet in 55% of AYA attending a quaternary cancer center.…”

“…27 VO 2peak is a strong predictor of cardiovascular and all-cause mortality in childhood and adult cancer survivors and is correlated with survival, risk of recurrence, QOL, fatigue, and functional independence. 5,27,28 The purpose of this current RCT was to determine whether a 10-week structured exercise intervention was associated with improved cardiorespiratory fitness, as measured by VO 2peak , when compared with controls in AYA patients who had recently completed acute systemic cancer treatment. AYA were defined as per the Australian definition of 15-25 years.…”

Effects of a physical activity program from diagnosis on cardiorespiratory fitness in children with cancer: a national non-randomized controlled trial

“…A prevalent and serious longterm consequence of childhood cancer treatment is impaired physical function with limited ability to perform daily tasks, impaired self-perception [4,5], and reduced capacity to fully participate in social activities, including school [6,7]. These disabilities are associated with poor health [8] and increased mortality [9].…”