Skip to main content
NCBI home page
Journal of Clinical Oncology logoLink to Journal of Clinical Oncology
. 2019 Oct 17;38(1):29–42. doi: 10.1200/JCO.19.01661

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

Kirsten K Ness 1,✉, Juan C Plana 2, Vijaya M Joshi 3, Russell V Luepker 4, Jean B Durand 5, Daniel M Green 1, Robyn E Partin 1, Aimee K Santucci 1, Rebecca M Howell 5, Deo Kumar Srivastava 1, Melissa M Hudson 1, Leslie L Robison 1, Gregory T Armstrong 1
PMCID: PMC7051850  PMID: 31622133

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.

INTRODUCTION

Improvement in therapy for childhood cancer has resulted in 5-year survival that exceeds 80%.1 However, treatment exposures increase risk for late effects,2,3 including well-established dose-response associations among anthracycline chemotherapy, chest-directed radiation, and risk of cardiomyopathy and cardiac-specific mortality.4 Risk is potentially compounded by other factors, such as depression and social isolation.5 As a result, survivors may be at risk for exercise intolerance at a relatively young age.6,7 This is important because exercise capacity is a global measure of function,8 predictive of future cardiovascular health9 and longevity.10 The association between exercise intolerance and mortality has not been evaluated in childhood cancer survivors, to our knowledge.

Exercise capacity reflects integration of cardiovascular, autonomic, pulmonary, muscular, and neurosensory function; therefore, it is also important to identify contributions of either overt or asymptomatic organ system dysfunctions to exercise intolerance, defined as the inability to perform as expected on a measure of exercise capacity. In addition, associations between intermediate markers of disease, such as abnormal global longitudinal strain (GLS), ejection fraction (EF), or diastolic function and exercise intolerance, may identify persons at high risk for heart failure (Fig 1).

FIG 1.

FIG 1.

Open in a new tab

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.

The aims of this study were to describe (1) differences in exercise capacity values and proportions of those with exercise intolerance between survivors exposed and unexposed to cardiotoxic therapy, and control subjects; (2) associations between exercise intolerance and mortality in survivors; and (3) associations among treatment exposures, organ system functions, lifestyle, and exercise intolerance among survivors.

METHODS

Participants

Participants were recruited from the St Jude Lifetime Cohort Study (SJLIFE).3,11 Persons eligible for this study were ≥ 18 years of age at evaluation, treated for childhood cancer at St Jude Children’s Research Hospital (SJCRH) from 1962 through 2007, ≥ 10 years postdiagnosis, and had no congenital heart disease history. Pregnant women were excluded.

To assure adequate power for comparison of key treatment exposures, survivors were stratified before recruitment by exposure (ie, chest-directed radiation; chest-directed radiation and anthracyclines; anthracyclines at doses of 1 to 199, 200 to 349, or ≥ 350 mg/m2; or neither chest-directed radiation nor anthracyclines), randomized within stratum, and approached for participation to avoid healthy participation bias. The sample was representative of the overall SJLIFE cohort. A comparison group (ie, control subjects) was recruited from among friends and family members of patients currently at SJCRH or non–first-degree relatives of SJLIFE participants. Eligibility criteria for control subjects were identical to those for survivors, except control subjects had no childhood cancer history. Study documents were approved by the SJCRH institutional review board. Participants provided written, informed consent before enrollment.

Diagnosis, Treatment, Lifestyle

Diagnosis and treatment information was abstracted from medical records. Total anthracycline dose (calculated in milligrams per square meter) was the sum of doxorubicin, daunorubicin, epirubicin, idarubicin, and mitoxantrone in doxorubicin-equivalent doses.12 Total alkylating-agent dose was estimated in cyclophosphamide equivalents (CED; also calculated in milligrams per square meter).13 Radiotherapy records were centrally reviewed. Exposures to the chest and brain were categorized as yes if at least part of the organ was in the treatment field; maximum total dose (maxTD) was determined by summing total prescribed dose from all overlapping treatment fields.14 Demographic and lifestyle variables were obtained from questionnaires, with smoking characterized in pack-years, moderate or vigorous physical activity as reporting < 150 or ≥ 150 minutes per week on the National Health and Nutrition Examination Survey Physical Activity Questionnaire,15 and diet quality as the score (out of 100) on the Healthy Eating Index, which maps dietary intake to 13 components reflecting the Dietary Guidelines for Americans 2015-2020.16 The average score on the index for the US population is 59.17

Exercise Intolerance

Maximal cardiopulmonary exercise testing (CPET) was performed on a treadmill using a modified Bruce protocol,18 or with a leg or arm ergometer ramping protocol (109 participants had amputation or balance impairments that prohibited walking on the treadmill). Exercise intolerance was defined as relative peak oxygen uptake (Vo2peak measured in milliliters per kilogram per minute) < 85% of predicted,19,20 and low cardiorespiratory fitness as maximal aerobic capacity < 7.9 metabolic equivalents (METs; 1 MET is the amount of oxygen consumed at rest: 3.5 mL/kg/min).9 A continuous 12-lead ECG and breath-by-breath gas analysis (Ultima CardiO2; MGC Diagnostics, St Paul, MN) were used to evaluate safety and Vo2peak. Resting heart rate (HR), respirations, and blood pressure (BP) were measured after 5 minutes of quiet sitting before CPET. Participants exercised until perceived maximal exertion. CPET was terminated for safety before maximal exertion for signs of ischemia (> 2 mm ST depression), frequent arrhythmias (bigeminy and trigeminy), hypertensive BP response (> 250/115 mm Hg), symptoms (eg, angina, shortness of breath, wheezing), or failure of HR to increase with increased exercise intensity. Immediately at test termination, participants were asked for peak rating of perceived exertion.21 After 1 minute of easy walking or cycling recovery, participants sat in a chair for 5 minutes. BP and HR were measured during the test, at peak exercise, and 2 and 5 minutes into recovery.

Mortality

Mortality was determined from a National Death Index search beginning December 31, 2017, and continuous annual follow-up (through February 21, 2019) from the SJCRH Cancer Registry. Cause of death was identified using International Classification of Diseases (Ninth and Tenth Revisions codes from the National Death Index) or direct assessment of death certificates, medical records, or next-of-kin interviews.

Cardiac Imaging

Systolic and diastolic function by three-dimensional echocardiography with Doppler were measured according to American Society of Echocardiography guidelines (abnormal left ventricular ejection fraction [EF] < 53%)22 on a Vivid 7 machine (GE Medical Systems, Milwaukee, WI). Global longitudinal peak systolic strain was obtained from speckle tracking using three apical views with commercially available software (EchoPAC PC, version 10.0; GE Medical Systems). Abnormal strain was defined as > 1.5 standard deviations (SDs) above sex-, age-, and vendor-specific means.23 A core laboratory at Baylor College of Medicine centrally evaluated all echocardiograms in a blinded manner. Diastolic dysfunction was defined as the presence of three or more of the following: (1) septal early diastolic myocardial relaxation (e′) < 7 cm/s and/or lateral e′ < 10 cm/s; (2) average E/e′ ratio > 14; (3) left atrial volume index > 34 mL/m2; and (4) peak tricuspid velocity > 2.8 m/s.24

Autonomic Response

Chronotropic incompetence25 or blunted BP responses26 were considered present among those who achieved < 80% of age- and sex-predicted HR reserve (≤ 62% if taking β blockers or calcium channel blockers)27 or whose systolic BP rise was < 20 mm Hg during CPET.

Pulmonary Function

Prebronchodilator spirometry was used to determine forced expiratory volume in 1 second (FEV1).28 FEV1 < 80% predicted for race and sex was considered impaired.29

Muscle Strength

Isokinetic quadriceps strength was evaluated while sitting (Biodex System 4; Biodex Medical Systems, Shirley, NY)30 from 15 maximal knee extensions with each leg at 300°/s.31 Peak torque for body weight (measured as newton-meter per kilogram) was converted to age- and sex-specific z scores (based on control values).

Neurosensory Integrity

Peripheral sensorimotor function was evaluated with the modified total neuropathy scale (MTNS).32 Participants were queried about sensory and motor symptoms and tested for pin sensation, vibration, distal strength, and deep tendon reflexes. Scores ≥ 5 (of 24) were considered to indicate impairment.32

Statistical Analyses

Descriptive statistics characterized the study population and were compared with t tests or χ2 statistics. Mean values are reported with SDs. After examining data for normality, multivariable linear regression, adjusted for age, sex, and mode of exercise testing, was used to compare CPET results between groups.19 Kaplan-Meier methodology estimated the crude association, and propensity score methods with stabilized inverse probability weights (based on age, sex, race, GLS > 1.5, and FEV1 < 80%) estimated adjusted association between exercise tolerance and mortality.33 Multivariable linear regression, adjusted for age, sex, mode of exercise testing, and pack-years of smoking, was used to evaluate associations among treatment, exercise tolerance, and organ system function. Treatment variables associated with exercise intolerance or organ system function in bivariate models (P < .10) were tested in final models. Age, sex, mode of exercise testing, and pack-years of smoking were retained in all models. Multivariable logistic regression was used to evaluate associations among organ system impairment, smoking, physical activity, diet, age, sex, race/ethnicity, and exercise intolerance. Variables associated with exercise intolerance (P < .10) in bivariate analyses were included in final models. SAS, version 9.4 (SAS Institute, Cary, NC), was used for analysis.

RESULTS

Among 1,369 eligible survivors, 67 declined, 24 completed a survey only, 18 were lost to follow-up, and 1,260 (92.0%) enrolled in this study (Data Supplement), with all testing completed during the same week for each participant between April 1, 2012, and June 21, 2016. Participants and nonparticipants did not differ by age (36.4 ± 9.2 v 37.1 ± 9.5 years; P = .45), sex (51.1% v 52.3% male; P = .81), race/ethnicity (84.1% v 82.6% non-Hispanic white; P = .67), or cancer diagnosis (P = .38). CPET was completed by 1,041 participants (83%). Among the 219 who did not complete CPET, 14 had orthopedic restrictions, 24 had cognitive and/or physical disabilities (eg, hemiplegia), five had renal dysfunction, and 14 had fasting glucose levels ≥ 300 mg/dL, prohibiting testing. The remaining 162 (74%) had recently diagnosed cardiac (n = 48 heart failure, 10 heart block, 10 arrhythmias, 10 recent myocardial infarction or bypass surgery) or pulmonary (n = 11) disease, or baseline laboratory values or symptoms (n = 10 elevated brain natriuretic peptide or troponin, 25 uncontrolled hypertension, 22 significant dyspnea, 16 ECG abnormalities) contraindicating CPET.18 Those unable to complete CPET were older (40.8 ± 9.5 v 35.5 ± 8.9 years; P < .001) and more likely than those who completed CPET to be male (58.9% v 48.3%; P = .005), nonwhite (24.2% v 14.8%; P < .001), survivors of lymphoma or osteosarcoma (44.3 v 27.15; P < .001), and treated with chest radiation. Anthracycline exposure was similar between those who completed CPET and those who did not (51.6% v 50.6%; P = .79).

The characteristics of those who completed CPET are shown in Table 1. Survivors exposed to anthracyclines and/or chest radiation were slightly older at diagnosis and more likely to have been treated for lymphoma or bone tumors than those unexposed to anthracyclines and/or chest radiation. Survivors, exposed and unexposed, had lower lean mass and lower scores on the Healthy Eating Index and were less likely to have a college degree, health insurance, or be married than control subjects.

TABLE 1.

Characteristics of Childhood Cancer Survivors Exposed and Not Exposed to Anthracyclines and/or Chest-Directed Radiotherapy and Community Control Subjects

graphic file with name JCO.19.01661t1.jpg

Open in a new tab

On average, survivors had evidence of exercise intolerance, with lower mean Vo2peak than control subjects (exposed to cardiotoxic therapy: 25.74 ± 8.63 mL/kg/min; P < .001; unexposed: 26.82 ± 8.36 mL/kg/min; control subjects: 32.69 ± 7.75 mL/kg/min P for all < .001; Table 2). Low cardiorespiratory fitness (maximal aerobic capacity < 7.9 METS) was present among 59.6% (95% CI, 57.8% to 61.4%) of exposed survivors, 39.5% (95% CI, 37.1% to 41.9%) of unexposed survivors, and 30.3% (95% CI, 27.8% to 32.8%) of control subjects. Exercise intolerance (Vo2peak < 85% predicted) was present among 63.8% (95% CI, 62.0% to 65.8%) of exposed, 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. Despite consistent effort across groups, indicated by similar ratings of perceived exertion and robust respiratory exchange ratios, survivors had evidence of potential cardiac, pulmonary, and peripheral contributions to exercise intolerance (Data Supplement), with lower mean oxygen pulse (ie, oxygen uptake per heart beat at rest), higher mean minute volume (ie, volume of gas inhaled or exhaled per minute), lower breathing reserve percentages (ie, the difference between maximal voluntary ventilation and maximum ventilation during the CPET), and less robust HR and BP exercise responses, compared with control subjects.

TABLE 2.

Cardiopulmonary Exercise Testing Data of Childhood Cancer Survivors and Control Subjects

graphic file with name JCO.19.01661t2.jpg

Open in a new tab

After median follow-up of 4.0 (interquartile range, 1.9-4.8) years, there were 24 survivor deaths, 21 (3.3%) among those with and three (0.7%; log-rank P = .007) among those without exercise intolerance (Data Supplement). Causes included second malignant neoplasms (n = 12), cardiac conditions (n = 5), liver failure (n = 2), infection (n = 1), and external causes (n = 4). The unadjusted and adjusted (ie, age, sex, race, GLS > 1.5 SD and FEV1 < 80% predicted) hazard ratios for all-cause mortality were 4.48 (95% CI, 1.33 to 15.00) and 3.93 (95% CI, 1.09 to 14.14), respectively, among those with, compared with those without, exercise intolerance.

Distributions for Vo2peak, GLS, EF, HR reserve, FEV1, quadriceps-strength z score, and MTNS score are reported in Figure 2 by treatment exposures. After accounting for age, sex, and smoking pack-years, > 350 mg/m2 of anthracyclines, > 30 Gy of chest radiation, > 20 Gy of cranial radiation, and carboplatin were associated with lower Vo2peak (Fig 2A). Exposure to > 350 mg/m2 anthracyclines and chest radiation was associated with higher GLS and lower EF (Fig 2B and 2C). Chest radiation maxTD > 30 Gy and carboplatin > 4,000 mg/m2 were associated with achieving < 80% of HR reserve during exercise (Fig 2D). Chest radiation maxTD > 30 Gy was associated with lower mean FEV1, with alkylating agents (CED > 8,000 mg/m2) potentiating the effects of chest radiation (Fig 2E). Cranial radiation > 20 Gy was associated with less quadriceps strength (Fig 2F), and cisplatin was associated with a lower MTNS score (Fig 2G).

FIG 2.

FIG 2.

Open in a new tab

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.

Associations between organ system impairment and exercise intolerance among survivors exposed to cardiotoxic agents are reported in Table 3. EF < 53% was not associated with exercise intolerance, whereas GLS > 1.5 SD above predicted age and sex increased the odds of exercise intolerance (1.71; 95% CI, 1.11 to 2.63). This association persisted when analysis was limited to survivors exposed to cardiotoxic therapy who had EF ≥ 53% (odds ratio, 1.57; 95% CI, 1.00 to 2.55). Those with chronotropic incompetence, FEV1 < 80% predicted, reporting nonwhite race, with < 150 min/wk of moderate or vigorous physical activity, less quadriceps strength, and poorer diet quality had the highest odds of exercise intolerance. Models that included survivors not exposed to cardiotoxic therapy produced similar results (Table 4). Diastolic dysfunction, occurring in 25.7% of exposed survivors and 15.1% of unexposed survivors, was not associated with exercise intolerance, so it was excluded from final models.

TABLE 3.

Association of Exercise Intolerance With Organ System Impairment, Lifestyle and Demographics Among Exposed Survivors

graphic file with name JCO.19.01661t3.jpg

Open in a new tab

TABLE 4.

Relative Odds of Exercise Intolerance by Organ System Impairment, Lifestyle, and Demographics Among All Survivors

graphic file with name JCO.19.01661t4.jpg

Open in a new tab

DISCUSSION

This comprehensive evaluation of adult survivors of childhood cancer without previously diagnosed cardiomyopathy demonstrates substantial prevalence of exercise intolerance and an association between exercise intolerance and all-cause mortality. Previously identified risk factors for mortality in this population include recurrent or second neoplasms, cardiovascular and pulmonary diseases, and self-reported inactivity.34,35 To our knowledge, this is the largest study to date that includes a survivor population with a wide variety of treatment exposures and that used maximal rather than submaximal CPET to characterize exercise intolerance. Identification of exercise intolerance among childhood cancer survivors is not unexpected, given previous reports in smaller, diagnosis-specific cohorts.6,36-40 However, it is striking that mean Vo2peak among survivors, whose median age was 35 years, was similar to values in a meta-analysis of Vo2peak among persons in their seventies and eighties,41 and that exercise intolerance increased hazard of death by nearly four-fold. To put this in context, in the general population, METs at peak exercise < 7.9, slightly higher than the means in our study, are associated with 40% to 70% increased risk of all-cause, and 47% to 56% increased risk of cardiovascular disease mortality.9 Our results also identify associations among treatment exposures, cardiac, autonomic, pulmonary, and muscular health, and exercise intolerance.

Additional findings in this study are that abnormal GLS, but not EF, was associated with, and that cardiac autonomic dysfunction contributed to, exercise intolerance. Because GLS is predictive of subsequent EF reductions in patients with adult-onset malignancies who are receiving anthracycline-based chemotherapy, recently published guidelines from ASCO on prevention and monitoring of cardiac dysfunction recommend the use of echocardiography-derived strain in individuals with clinical signs and symptoms of cardiac dysfunction.42 Our findings potentially expand use of strain to identify early cardiac dysfunction in childhood cancer survivors with exercise intolerance who have normal EF. The finding that cardiac autonomic dysfunction is associated with exercise intolerance suggests that inability of survivors to increase HR and BP in response to exercise, particularly if exposed to chest radiation, a risk factor for conduction abnormalities,43 may explain difficulties these patients have engaging in physical activity.25,44 Additional research is needed to understand mechanisms of autonomic injury, so interventions can be developed to manage this impairment.

Our data indicating an association between less-than-recommended levels of physical activity and exercise intolerance indicate a potential intervention target, given that numerous publications report childhood cancer survivors are inactive.44,45 However, adopting an active lifestyle requires motivation and self-discipline.46,47 Although difficult for anyone, adopting an active lifestyle may be more difficult for survivors,48 who, even when clinically asymptomatic, have evidence of organ system impairment. Our comprehensive clinical testing supports this hypothesis and, to our knowledge, is first to identify contributions of not only impaired cardiac function but also pulmonary, autonomic, and muscle function to exercise intolerance in this population. Although these associations are potentially bidirectional, organ system impairments are relevant targets for screening and medical management. Exercise prescription by trained specialists, tailored to accommodate specific impairments (eg, teaching individuals taking β blockers to monitor perceived rate of exertion rather than HR response to exercise, or prescribing upper-body cardiac conditioning rather than walking for those whose motor neuropathy results in frequent tripping) may be necessary for survivors who report difficulty engaging in physical activity. Our data suggest asymptomatic childhood cancer survivors previously exposed to chest radiation, cranial radiation, anthracyclines, alkylating agents, or platinum should be screened for organ system impairments before exercise and activity interventions are recommended or implemented.

Results should be interpreted in the context of limitations. First, although participation rates in this study were high, and participants did not differ from nonparticipants by age, race, or sex, not all eligible survivors enrolled. If those with exercise intolerance were more or less likely to participate, our analysis may over- or underestimate the prevalence or severity of this outcome. Second, the racial distribution differed between survivors and control subjects. Although we adjusted for race in the analyses, residual confounding is possible and may have influenced estimates. Third, survivors who could not complete CPET were excluded from analysis; therefore, it is likely we underestimated the prevalence of exercise intolerance. Fourth, analyses of associations between organ system impairment and exercise intolerance were cross-sectional, making it difficult to assign a temporal component to this relation. For example, acutely, children with cancer experience sarcopenia and muscle weakness, which, along with malaise and fatigue, likely contribute to situational inactivity and acute exercise intolerance. Additional research is needed to determine when and if these muscular impairments resolve, and if they are related to inactivity and persistent exercise intolerance among survivors. Finally, participants were all treated for childhood cancer at one institution. Although treatment exposures are similar to those among children treated in North America,3,11,49,50 results may not be generalizable to all survivors.

To conclude, exercise intolerance in childhood cancer survivors, who, at a median age of 35 years, have Vo2peak values like those expected among persons in their seventies and eighties, is an independent predictor of all-cause mortality. In addition, echocardiography-determined GLS may be a better indicator of exercise intolerance than EF and should be considered when screening asymptomatic survivors. Finally, beyond treatment-related cardiac dysfunction, pulmonary and muscular impairments independently increase risk for exercise intolerance and are detectable in asymptomatic survivors. These impairments need to be addressed when recommending physical activity or prescribing exercise.

ACKNOWLEDGMENT

We thank Tracie Gatewood for assisting with manuscript preparation.

Appendix

TABLE A1.

Mean (SD) Values for Additional Measures From Cardiopulmonary Exercise Testing Among Childhood Cancer Survivors and Control Subjects

graphic file with name JCO.19.01661ta1.jpg

Open in a new tab

Footnotes

Listen to the podcast by Dr Campbell at http://ascopubs.org/journal/jco/podcasts

Supported by a grant to St Jude Children’s Research Hospital provided by the National Cancer Institute (Grant No. U01 CA195547, M.M.H.; and R01 CA157838, G.T.A.); Cancer Center Support Grant No. P30 CA21765; and the American Lebanese-Syrian Associated Charities (K.K.N.).

AUTHOR CONTRIBUTIONS

Conception and design: Kirsten K. Ness, Russell V. Luepker, Jean B. Durand, Deo Kumar Srivastava, Melissa M. Hudson, Leslie L. Robison, Gregory T. Armstrong

Financial support: Melissa M. Hudson, Leslie L. Robison, Gregory T. Armstrong

Administrative support: Melissa M. Hudson, Leslie L. Robison, Gregory T. Armstrong

Provision of study material or patients: Kirsten K. Ness, Daniel M. Green, Melissa M. Hudson, Leslie L. Robison, Gregory T. Armstrong

Collection and assembly of data: Kirsten K. Ness, Jean B. Durand, Robyn E. Partin, Aimee K. Santucci, Rebecca M. Howell, Melissa M. Hudson, Leslie L. Robison, Gregory T. Armstrong

Data analysis and interpretation: Kirsten K. Ness, Juan C. Plana, Vijaya M. Joshi, Jean B. Durand, Daniel M. Green, Robyn E. Partin, Deo Kumar Srivastava, Melissa M. Hudson, Gregory T. Armstrong

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/journal/jco/site/ifc.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Vijaya M. Joshi

Stock and Other Ownership Interests: Johnson & Johnson, Gilead Sciences

Jean-B. Durand

Consulting or Advisory Role: Novartis, GenomeSmart

Melissa M. Hudson

Consulting or Advisory Role: Oncology Research Information Exchange Network, Princess Máxima Center, SurvivorLink

No other potential conflicts of interest were reported.

REFERENCES

  • 1.Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2014. National Cancer Institutehttps://seer.cancer.gov/csr/1975_2014/
  • 2.Armstrong GT, Kawashima T, Leisenring W, et al. Aging and risk of severe, disabling, life-threatening, and fatal events in the childhood cancer survivor study. J Clin Oncol. 2014;32:1218–1227. doi: 10.1200/JCO.2013.51.1055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.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: 10.1001/jama.2013.6296. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Mulrooney DA, Armstrong GT, Huang S, et al. Cardiac outcomes in adult survivors of childhood cancer exposed to cardiotoxic therapy: A cross-sectional study. Ann Intern Med. 2016;164:93–101. doi: 10.7326/M15-0424. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Zahl T, Steinsbekk S, Wichstrøm L. Physical activity, sedentary behavior, and symptoms of major depression in middle childhood. Pediatrics. 2017;139:e20161711. doi: 10.1542/peds.2016-1711. [DOI] [PubMed] [Google Scholar]
  • 6.Ness KK, DeLany JP, Kaste SC, et al. Energy balance and fitness in adult survivors of childhood acute lymphoblastic leukemia. Blood. 2015;125:3411–3419. doi: 10.1182/blood-2015-01-621680. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.van Brussel M, Takken T, Lucia A, et al. Is physical fitness decreased in survivors of childhood leukemia? A systematic review. Leukemia. 2005;19:13–17. doi: 10.1038/sj.leu.2403547. [DOI] [PubMed] [Google Scholar]
  • 8.Morey MC, Pieper CF, Cornoni-Huntley J. Is there a threshold between peak oxygen uptake and self-reported physical functioning in older adults? Med Sci Sports Exerc. 1998;30:1223–1229. doi: 10.1097/00005768-199808000-00007. [DOI] [PubMed] [Google Scholar]
  • 9.Kodama S, Saito K, Tanaka S, et al. Cardiorespiratory fitness as a quantitative predictor of all-cause mortality and cardiovascular events in healthy men and women: A meta-analysis. JAMA. 2009;301:2024–2035. doi: 10.1001/jama.2009.681. [DOI] [PubMed] [Google Scholar]
  • 10.Ladenvall P, Persson CU, Mandalenakis Z, et al. Low aerobic capacity in middle-aged men associated with increased mortality rates during 45 years of follow-up. Eur J Prev Cardiol. 2016;23:1557–1564. doi: 10.1177/2047487316655466. [DOI] [PubMed] [Google Scholar]
  • 11.Ojha RP, Oancea SC, Ness KK, et al. Assessment of potential bias from non-participation in a dynamic clinical cohort of long-term childhood cancer survivors: Results from the St. Jude Lifetime Cohort Study. Pediatr Blood Cancer. 2013;60:856–864. doi: 10.1002/pbc.24348. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.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: 10.1200/JCO.2015.61.5187. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.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: 10.1002/pbc.24679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Stovall M, Weathers R, Kasper C, et al. Dose reconstruction for therapeutic and diagnostic radiation exposures: Use in epidemiological studies. Radiat Res. 2006;166:141–157. doi: 10.1667/RR3525.1. [DOI] [PubMed] [Google Scholar]
  • 15.US Department of Health and Human Services : National Health and Nutrition Examination Survey. 2007-2008 Data Documentation, Codebook, and Frequencies. Physical Activity (PAQ_E) 2009 https://wwwn.cdc.gov/Nchs/Nhanes/2007-2008/PAQ_E.htm#Component_Description
  • 16.U.S. Department of Health and Human Services : U.S. Department of Agriculture: Dietary Guidelines for Americans 2015-2020. 8th ed. http://health.gov/dietaryguidelines/2015/guidelines/
  • 17. doi: 10.1016/j.jand.2018.05.021. Krebs-Smith SM, Pannucci TE, Subar AF, et al: Update of the Healthy Eating Index: HEI-2015. J Acad Nutr Diet 118:1591-1602, 2018 [Erratum: J Acad Nutr Diet (epub ahead of print on August 20, 2019)] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Riebe D, Ehrman JK, Liguori G, et al. ACSM’s Guidelines for Exercise Testing and Prescription. 10th ed. Philadelphia, PA: Wolters Kluwer; 2018. [Google Scholar]
  • 19.Kaminsky LA, Arena R, Myers J. Reference standards for cardiorespiratory fitness measured with cardiopulmonary exercise testing: Data from the Fitness Registry and the Importance of Exercise National Database. Mayo Clin Proc. 2015;90:1515–1523. doi: 10.1016/j.mayocp.2015.07.026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Myers J, Kaminsky LA, Lima R, et al. A Reference Equation for Normal Standards for VO2 Max: Analysis from the Fitness Registry and the Importance of Exercise National Database (FRIEND Registry) Prog Cardiovasc Dis. 2017;60:21–29. doi: 10.1016/j.pcad.2017.03.002. [DOI] [PubMed] [Google Scholar]
  • 21.Borg GA.Borg’s Perceived Exertion and Pain Scales Champaign, IL: Human Kinetics; Champaign, IL: 1998. pp104 [Google Scholar]
  • 22. doi: 10.1093/ehjci/jev014. Lang RM, Badano LP, Mor-Avi V, et al: Recommendations for cardiac chamber quantification by echocardiography in adults: An update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 16:233-270, 2015 [Erratum: Eur Heart J Cardiovasc Imaging 2016;17:412] [DOI] [PubMed] [Google Scholar]
  • 23.Takigiku K, Takeuchi M, Izumi C, et al. Normal range of left ventricular 2-dimensional strain: Japanese Ultrasound Speckle Tracking of the Left Ventricle (JUSTICE) study. Circ J. 2012;76:2623–2632. doi: 10.1253/circj.cj-12-0264. [DOI] [PubMed] [Google Scholar]
  • 24.Nagueh SF, Smiseth OA, Appleton CP, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: An update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2016;29:277–314. doi: 10.1016/j.echo.2016.01.011. [DOI] [PubMed] [Google Scholar]
  • 25.Brubaker PH, Kitzman DW. Chronotropic incompetence: Causes, consequences, and management. Circulation. 2011;123:1010–1020. doi: 10.1161/CIRCULATIONAHA.110.940577. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Schultz MG, La Gerche A, Sharman JE. Blood pressure response to exercise and cardiovascular disease. Curr Hypertens Rep. 2017;19:89. doi: 10.1007/s11906-017-0787-1. [DOI] [PubMed] [Google Scholar]
  • 27.Khan MN, Pothier CE, Lauer MS. Chronotropic incompetence as a predictor of death among patients with normal electrograms taking beta blockers (metoprolol or atenolol) Am J Cardiol. 2005;96:1328–1333. doi: 10.1016/j.amjcard.2005.06.082. [DOI] [PubMed] [Google Scholar]
  • 28.Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J. 2005;26:319–338. doi: 10.1183/09031936.05.00034805. [DOI] [PubMed] [Google Scholar]
  • 29.Hudson MM, Ehrhardt MJ, Bhakta N, et al. Approach for classification and severity grading of long-term and late-onset health events among childhood cancer survivors in the St. Jude Lifetime Cohort. Cancer Epidemiol Biomarkers Prev. 2017;26:666–674. doi: 10.1158/1055-9965.EPI-16-0812. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Feiring DC, Ellenbecker TS, Derscheid GL. Test-retest reliability of the Biodex isokinetic dynamometer. J Orthop Sports Phys Ther. 1990;11:298–300. doi: 10.2519/jospt.1990.11.7.298. [DOI] [PubMed] [Google Scholar]
  • 31.Neder JA, Nery LE, Shinzato GT, et al. Reference values for concentric knee isokinetic strength and power in nonathletic men and women from 20 to 80 years old. J Orthop Sports Phys Ther. 1999;29:116–126. doi: 10.2519/jospt.1999.29.2.116. [DOI] [PubMed] [Google Scholar]
  • 32.Wampler MA, Miaskowski C, Hamel K, et al. The modified total neuropathy score: A clinically feasible and valid measure of taxane-induced peripheral neuropathy in women with breast cancer. J Support Oncol. 2006;4:W9–W16. [Google Scholar]
  • 33.Austin PC. The use of propensity score methods with survival or time-to-event outcomes: Reporting measures of effect similar to those used in randomized experiments. Stat Med. 2014;33:1242–1258. doi: 10.1002/sim.5984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Armstrong GT, Chen Y, Yasui Y, et al. Reduction in late mortality among 5-year survivors of childhood cancer. N Engl J Med. 2016;374:833–842. doi: 10.1056/NEJMoa1510795. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Scott JM, Li N, Liu Q, et al. Association of exercise with mortality in adult survivors of childhood cancer. JAMA Oncol. 2018;4:1352–1358. doi: 10.1001/jamaoncol.2018.2254. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Christiansen JR, Kanellopoulos A, Lund MB, et al. Impaired exercise capacity and left ventricular function in long-term adult survivors of childhood acute lymphoblastic leukemia. Pediatr Blood Cancer. 2015;62:1437–1443. doi: 10.1002/pbc.25492. [DOI] [PubMed] [Google Scholar]
  • 37.De Caro E, Smeraldi A, Trocchio G, et al. Subclinical cardiac dysfunction and exercise performance in childhood cancer survivors. Pediatr Blood Cancer. 2011;56:122–126. doi: 10.1002/pbc.22606. [DOI] [PubMed] [Google Scholar]
  • 38.Miller AM, Lopez-Mitnik G, Somarriba G, 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;60:663–668. doi: 10.1002/pbc.24410. [DOI] [PubMed] [Google Scholar]
  • 39.Tonorezos ES, Snell PG, Moskowitz CS, et al. Reduced cardiorespiratory fitness in adult survivors of childhood acute lymphoblastic leukemia. Pediatr Blood Cancer. 2013;60:1358–1364. doi: 10.1002/pbc.24492. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Wolfe KR, Hunter GR, Madan-Swain A, et al. Cardiorespiratory fitness in survivors of pediatric posterior fossa tumor. J Pediatr Hematol Oncol. 2012;34:e222–e227. doi: 10.1097/MPH.0b013e3182661996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Shvartz E, Reibold RC. Aerobic fitness norms for males and females aged 6 to 75 years: A review. Aviat Space Environ Med. 1990;61:3–11. [PubMed] [Google Scholar]
  • 42.Armenian SH, Lacchetti C, Barac A, et al. Prevention and monitoring of cardiac dysfunction in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2017;35:893–911. doi: 10.1200/JCO.2016.70.5400. [DOI] [PubMed] [Google Scholar]
  • 43.Adams MJ, Lipshultz SE, Schwartz C, et al. Radiation-associated cardiovascular disease: Manifestations and management. Semin Radiat Oncol. 2003;13:346–356. doi: 10.1016/S1053-4296(03)00026-2. [DOI] [PubMed] [Google Scholar]
  • 44.Ness KK, Leisenring WM, Huang S, et al. Predictors of inactive lifestyle among adult survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. Cancer. 2009;115:1984–1994. doi: 10.1002/cncr.24209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Wilson CL, Stratton K, Leisenring WL, et al. Decline in physical activity level in the Childhood Cancer Survivor Study cohort. Cancer Epidemiol Biomarkers Prev. 2014;23:1619–1627. doi: 10.1158/1055-9965.EPI-14-0213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Finnegan L, Wilkie DJ, Wilbur J, et al. Correlates of physical activity in young adult survivors of childhood cancers. Oncol Nurs Forum. 2007;34:E60–E69. doi: 10.1188/07.ONF.E60-E69. [DOI] [PubMed] [Google Scholar]
  • 47.Lachman ME, Lipsitz L, Lubben J, et al. When adults don’t exercise: Behavioral strategies to increase physical activity in sedentary middle-aged and older adults. Innov Aging. 2018;2:igy007. doi: 10.1093/geroni/igy007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Cox CL, Montgomery M, Oeffinger KC, et al. Promoting physical activity in childhood cancer survivors: Results from the Childhood Cancer Survivor Study. Cancer. 2009;115:642–654. doi: 10.1002/cncr.24043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Hudson MM, Ness KK, Nolan VG, et al. Prospective medical assessment of adults surviving childhood cancer: Study design, cohort characteristics, and feasibility of the St. Jude Lifetime Cohort study. Pediatr Blood Cancer. 2011;56:825–836. doi: 10.1002/pbc.22875. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Bhakta N, Liu Q, Ness KK, et al. The cumulative burden of surviving childhood cancer: An initial report from the St Jude Lifetime Cohort Study (SJLIFE) Lancet. 2017;390:2569–2582. doi: 10.1016/S0140-6736(17)31610-0. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Oncology are provided here courtesy of American Society of Clinical Oncology

RESOURCES