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.

FIG 1.

Conceptual model demonstrating the hypothesized association between cancer treatment modalities (chemotherapy, radiation, surgery), host characteristics (age, sex, race), organ system impairments (cardiovascular, pulmonary, musculoskeletal, neurosensory, autonomic), lifestyle (smoking, physical activity, diet), exercise intolerance (performing at a level less than expected for age, sex, and body size [study peak oxygen uptake < 85% predicted]), and mortality.

FIG 2.

Means and 95% CIs for (A) peak oxygen uptake (Vo₂peak), (B) global longitudinal strain (GLS; higher number is worse), (C) ejection fraction (EF), (D) heart rate reserve percentage, (E) percent predicted forced expiratory volume in 1 second (FEV₁), (F) isokinetic quadriceps strength (300°/s) z score, and (G) modified total neuropathy score (MTNS) from multivariable linear regression among exposed survivors. Control values with 95% CI (shaded) are shown on each panel. Means adjusted for age, sex, pack-years of smoking, and other treatment exposures are shown. CED, cyclophophamide equivalent dose; RT, radiotherapy.