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Published in final edited form as: Cancer. 2014 Dec 19;121(10):1540–1547. doi: 10.1002/cncr.29211

Frailty in Childhood Cancer Survivors

Kirsten K Ness 1, Gregory T Armstrong 1, Mondira Kundu 2, Carmen L Wilson 1, Tamara Tchkonia 3, James L Kirkland 3
PMCID: PMC4424063  NIHMSID: NIHMS652619  PMID: 25529481

Abstract

Young adult childhood cancer survivors are at increased risk for frailty, a physiologic phenotype typically found among older adults. This phenotype is associated with new onset chronic health conditions and mortality among both older adults and among childhood cancer survivors. Mounting evidence suggests that poor fitness, muscular weakness and cognitive decline are common among adults treated for childhood malignancies, and that risk factors for these outcomes are not limited to those treated with cranial radiation. Although the pathobiology of this phenotype is not known, early cellular senescence, sterile inflammation and mitochondrial dysfunction in response to initial cancer or treatment related insults are hypothesized to play a role. Interventions to prevent or remediate frailty among childhood cancer survivors have not been tested. Pharmaceutical, nutriceutical and lifestyle interventions show some promise.

Keywords: Childhood cancer survivor, frailty, aging, fitness, weakness, senescence, inflammation, mitochondrial dysfunction

One of the greatest medical success stories over the past five decades is the improvement in survival among children newly diagnosed with a malignancy. Five-year survival rates now exceed 80 percent(%).1 Current estimates indicate that there are over 420,000 survivors of childhood cancer living in the United States.2 However, cure does not come without cost. Adults treated for childhood cancer are at increased risk for chronic health conditions,3-6 frequent hospitalization,7-9 and early mortality.10-13 The prevalence of chronic diseases among childhood cancer survivors increases with age; rates among survivors in their twenties are similar to rates among siblings in their fifties.3 Elevated rates of other outcomes typically associated with aging, like minimal cognitive dysfunction,14, 15 reduced muscle strength16-18 and poor exercise tolerance19, 20 are also reported among childhood cancer survivors and appear decades earlier than expected.21 This suggests that some survivors of childhood cancer have a physiological phenotype consistent with that found among older adults, frailty. This construct likely precedes or accompanies the development of clinically significant chronic disease that eventually results in reduced function, hospitalization and death.

Articles included in this review specific to childhood cancer survivors were identified in the PubMed and Web of Science database for clinical trials, observational studies, case series, and reviews, using the search strategy (“survivors” OR “survivor”) AND (“aging” OR “frailty”) AND (“childhood”) AND (“neoplasms” OR “cancer”) and were limited to those written in English. Included manuscripts were selected after reviewing the abstracts for relevance. The search was augmented with selected publications from reference lists of studies retrieved from databases.

Frailty

Frailty is a state of reduced physiologic reserve that increases susceptibility to chronic disease and disability.22 With typical aging, the innate or attained physiologic capacity of body systems declines over time. Initial changes in neuromuscular control, mechanical performance and energy metabolism are subtle and are not associated with noticeable loss of function during daily life. Unfortunately, sub-optimal lifestyle choices like inactivity, smoking and a high fat, high sugar content diet add to subtle age related changes, resulting in gradual loss of physiologic capacity. This trajectory of declining function is accelerated with exposure to acute insults (illness, injuries, major life events), particularly insults that damage organ systems and or result in periods of prolonged bed rest or inactivity. Frailty occurs when either there is not enough physiologic reserve to overcome organ system damage, or when access to interventions that promote recovery is limited (Figure 1).23, 24 In typical aging, declining physiologic reserve is clinically silent, detectable only with specific measures of functional, behavioral or biological performance or if acute illness or other stress unmasks decreased reserve.25

Figure 1.

Figure 1

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Frailty and function.91 The dashed line above the shading represents the cut-point between function and frailty. The dashed line with arrow represents decline in physiologic reserve with typical aging. The solid line with arrow represents potential decline in physiologic reserve among childhood cancer survivors whose acute insult occurs early in life. The solid line with arrow pointing directly down represents the potential impact of lifestyle on the trajectory of physiologic capacity; the additional arrows pointing upward potential recovery from loss of function based on access to intervention.

Because frailty is distinguishable from, and often precedes symptomatic chronic disease and disability, detecting frailty in a vulnerable population, like childhood cancer survivors, is potentially useful. Identification of individuals at risk for future chronic disease and disability so they can be referred for early intervention is important.25 Additionally, changing the trajectory of physiologic decline is theoretically possible. Survivors who adopt a healthy lifestyle have the opportunity to prevent early manifestation of frailty. Frailty prevention requires a system that promotes cost effective screening, not only for serious diseases amenable to early detection and treatment, but also a system that incorporates screening and intervention for early deficits in neuromuscular control, muscle strength and energy metabolism.26

Models of Frailty

Investigators who study aging have used different approaches to characterize frailty. Fried and colleagues were one of the first groups to describe a specific “frailty” phenotype.24 Theyused five indicators of physiological reserve; individuals with two were considered “pre-frail” and those with three or more “frail.” The criteria were applied at baseline, four and seven year follow-ups in the Cardiovascular Health Study. This sample of 5,317 men and women 65 years of age or older were evaluated for: 1) Sarcopenia - unintentional weight loss of ten pounds or 5% of body mass or more in past year; 2) Decreased muscle strength - hand grip strength in the lowest 20th percentile for sex and body mass index; 3) Poor endurance - self-reported exhaustion (from two questions on the Center for Epidemiologic Studies Depression Scale); 4) Slowness - walking time per 15 feet in the lowest 20th percentile for gender and height; 5) Low activity - physical activity < 383 kilocalories per week for males, < 270 kilocalories per week for females. Overall, 7% were classified as “frail”, and 47% were classified as “pre-frail.” Incident frailty was 7% for years 0-3 and 7% for years 4-7. Adjusted hazard ratios for falls, disability, hospitalization and death at seven years ranged from 1.2-1.8 when persons with baseline frailty were compared to those with no frailty. This model was validated in the Women's Health and Aging Study,27, 28 and the Women's Health Initiative.29

Others have proposed different frailty phenotypes by applying fewer,30, 31 modifying,29 or adding measures to Fried criteria,32-34 by using clinician assessment to characterize fitness and health,35 or by counting known clinical comorbidities or deficits to define a frailty threshold.36, 37 There are basically two approaches. The first, like the Fried Index, employs physical measures with set cut-points, classifies persons with and without frailty at a baseline time point, and evaluates whether or not those who meet frailty criteria differ from those who do not meet frailty criteria on future adverse outcomes, like chronic disease, hospitalization and death. The second approach, characterized in the Canadian Study of Health and Aging,37 does not employ measures of physiologic reserve, but counts impairments and co-morbidities (up to 70 items) to create an index score representing increasing degrees of frailty. Each approach has strengths and weaknesses. The Fried Index is reproducible and coherent.38 However, its focus on physiologic measures has been criticized,39 as physiologic measures do not take into account cognition, mood or social items known to impact health.38 The model derived using data from the Canadian Study of Health and Aging has excellent mathematical properties, but is criticized because it is long and not easily applied in a general clinical setting. deSouto Barreto40 suggests that frailty should be operationalized locally so that definitions can take into account the unique characteristics of a given population.

Frailty among childhood cancer survivors

Pre-frailty and frailty were recently described, using the Fried criteria, among 1922 survivors of childhood cancer participating in the St. Jude Lifetime Cohort (SJLife) study.41 In this young adult cohort, with a mean age of 33.6 (standard deviation (SD) 8.1) years, pre-frailty and frailty were evident among 2.7 and 12.9% of males and 12.9 and 31.5% of females. These rates are similar to those reported in a meta-analysis of 44,894 persons ≥65 years of age ,42 where the prevalence of frailty was 9.9%. In SJLife, frailty increased with age, and was associated with new onset chronic health conditions (Relative risk (RR) 2.2, 95% Confidence interval (CI) 1.2-4.2) and mortality (Hazard ratio (HR) 2.6, 95% CI 1.2-6.2). Among male survivors, frailty was also associated with smoking and being underweight or obese. Although previous exposure to cranial radiation (CRT) increased risk for frailty, suggesting a role for hypothalamic pituitary axis dysfunction (growth hormone deficiency) in frail health, frailty was not limited to survivors exposed to CRT. Among survivors with no CRT exposure, no associations between specific chemotherapy agents or doses and frailty were identified, supporting the hypothesis that any exposure to cytotoxic agents may have a lasting impact on physiologic function across the lifespan.43

Findings from SJLife are supported by other published literature indicating that physical performance among young adult survivors of childhood cancer resembles that expected in older adults. For example, in a cohort of 78 adults (median age 22, range 18-58 years) treated for a brain tumor during childhood, both cardiopulmonary fitness and handgrip strength values were lower among survivors than among age-, sex-, race- and zip code-matched peers, but similar to values expected among persons in their sixties (Table 1).44 These impairments are evident in even younger cohorts. Wolfe et al45 reported lower than expected peak oxygen uptake during exercise (31.8 (SD 7.2) vs. 49.3 (SD 7.9) ml/kg/min) among twelve adolescent (mean age 14.41 (SD 1.86) years) survivors of posterior fossa tumors. Piscione et al46 documented strength deficits among 30% of another group (N=30, mean age 11.4 (SD 4.1)) of adolescent survivors of posterior fossa tumors.

Table 1.

Strength and fitness values among adult survivors of childhood brain tumors compared to age-, sex-, race-matched peers and to values among adults 60-70 years of age.

Outcome Brain tumor survivors Mean (SD) Comparison group Mean (SD) Healthy adults ages 60-69 years Mean (SD)
Hand grip strength, kg
    Females 24.7(9.2) 31.5(5.8) 23.5(5.2)92
    Males 39.0(12.2) 53.0(10.1) 39.0(8.2)92
Knee extension strength, N
    Females 246.6(95.5) 339.1(92.4) 270.3(81.6)93
    Males 304.7(116.4) 466.6(92.1) 381.8(80.8)93
Exercise tolerance, ml/kg/min
    Females 25.1(8.6) 31.1(5.1) 22.3(2.1)48
    Males 24.6(9.5) 33.2(3.4) 30.0(2.7)48
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Kg=kilograms; N=Newton; ml/kg/min=milliliters per kilogram per minute

Impairments in cardiopulmonary fitness and strength are not limited to brain tumor survivors. In a study of 415 adult (median age 35.6 (range 21.9-52.3 years) survivors of childhood acute lymphoblastic leukemia (ALL), 46.5% had reduced six minute walk distances and 30.1% had impaired quadriceps strength. In an even younger cohort of childhood ALL survivors, Tonorezos et al47 reported mean cardiopulmonary fitness values (N=115, median age 23.5, range 18-37 years) lower than peers (30.7±7.6 vs. 39.9±7.8 milliliters/kilogram/minute (ml/kg/min)), but similar to values predicted for persons aged 50 to 59 (29.7±2.7 ml/kg/min) years.48 In a cohort of 75 ALL survivors (30.2 (SD 7.1) years), mean quadriceps strength values were one SD less than expected when compared to population-norms.17 Again, these problems appear early in young survivors, among children still receiving cancer therapy, and among children with newly diagnosed ALL. van Brussel et al49 documented impaired cardiopulmonary fitness and quadriceps weakness among thirteen adolescent ALL survivors (mean age 15.5 years), Marchese et al50 found impaired mobility and quadriceps weakness among eight children with ALL after delayed intensification, and we reported impaired fitness and quadriceps weakness among 109 children with newly diagnosed ALL.51

Additional studies indicate that fitness and physical performance are impaired in survivors not exposed to central nervous system (CNS) therapies (i.e. CRT, intrathecal or high dose methotrexate). Hartman et al16 reported lower muscle strength and physical performance battery scores among 92 children (age range 5.1-12.9 years) after treatment for ALL, Wilms tumor, non-Hodgkin lymphoma and malignant mesenchymal tumors compared to 155 healthy controls. Similarly, in a study that evaluated fitness and strength among 183 survivors (mean age 13.5 (SD 2.5 years)) of leukemia, lymphoma, CNS tumors, and bone and soft tissue sarcoma and 147 siblings (mean age 13.4 (SD 2.4) years), survivors performed lower than siblings on measures of fitness and leg strength.21 Bone sarcoma survivors had the largest deficits in muscle strength. In this study, an analysis was done to evaluate the hypothesis that survivors and siblings who participated in similar levels of physical activity would perform similarly on physical function measures. Although there were strong associations between activity levels and physical performance for both survivors and siblings, for any given level of physical activity, survivors performed lower than siblings on every measure of physical function.21 This suggests the possibility that cancer or treatment-related injury to underlying structure(s) or physiologic process(es) is responsible for functional loss, even when lifestyle is optimized.

Cognitive correlates of frailty in childhood cancer survivors

In cohorts of aging adults, physical frailty and cognitive function are highly correlated.52, 53 This association may be present among survivors of childhood cancer, some of who have evidence of cognitive decline during young adulthood. Edelstein et al54 evaluated changes in neurocognitive function among 18 survivors of medulloblastoma (median age 21.9 (range 18-47 years), and reported both early impairment and declining working memory over time. Similarly, Armstrong et al,55 in a study of 265 ALL survivors (mean age 40.9 (SD 4.4) years), reported immediate and delayed memory impairments among 33.8% and 30.2% of those treated with 24 gray(Gy) CRT. Mean performance on a long-term narrative memory task was consistent with scores reported among persons in their eighth decade of life; neurocognitive impairments were associated with changes in brain structure and activation. Schuitema et al15 compared neuropsychological and imaging outcomes between 93 survivors of childhood leukemia or lymphoma 20-30 years after diagnosis (mean age 29.8 (SD 4.9) years) and 49 controls. Survivors treated with CRT had neuropsychological dysfunction and associated deficits in white matter integrity in frontal, parietal and temporal regions. These authors attributed the trajectory of declining white matter integrity among survivors exposed to CRT to accelerated aging. Although reports of age related cognitive deficits among survivors of childhood brain tumors or ALL appear to be related to CRT exposure, childhood cancer survivors with treatment exposures that impact the cardiopulmonary system may also be at risk. Krull et al14 documented impaired neurocognitive function and associated structural changes in both cardiopulmonary function and brain structure among 62 survivors of Hodgkin lymphoma (HL) (mean age 42.2 (SD 4.77)) exposed to high dose thoracic radiation or lower dose thoracic radiation and anthracycline.

Potential biological markers of frail health

The pathobiology of frail health among survivors of childhood cancer is unknown. Imaging studies of the brain, skeletal muscle and heart documenting atrophy, sarcopenia and cardiomyopathy, suggest some degree of initial cancer- or treatment- related damage to normal, non-malignant cells, like neurons, skeletal muscle cells and cardiac myocytes. We hypothesize that this is compounded by DNA damage that induces cellular senescence, growth arrest that occurs when cells with regenerative potential are exposed to oncogenic insults.56 In fact, recent data indicate that even post-mitotic cells can develop a senescent-like phenotype in response to DNA damage.57 An overabundance of senescent cells is associated with aging and is also documented in progeroid syndromes.58 A similar accumulation of senescent cells is also possible in children with cancer, whose disease is hallmarked by the presence of rapidly dividing cells, and whose treatment exposures can confer new onset DNA damage59 and mutations,60 telomere shortening,61 protein aggregation,62 and increased production of reactive oxygen species.63, 64 Although telomere shortening is reported in tumor tissue among children with Wilms tumor,65 and in buccal cells among survivors of childhood cancer who develop second malignant neoplasms,61 there have been few reports in the literature evaluating other biological markers of cellular senescence among childhood cancer survivors. In a small pilot study (N=10), Marcoux et al,66 reported that among children previously treated with cranial radiation for acute lymphoblastic leukemia (ALL), expression of p16INK4a, a marker of cellular senescence, was 5.8 times higher in skin biopsies from the scalp than in skin biopsies from the buttocks.

Cellular senescence can be associated with a sterile pro-inflammatory state, or senescence associated secretory phenotype (SASP), resulting in elevated levels of inflammatory markers, including Interleukin-6, tumor necrosis factor alpha and immune cell cytokines.56 This chronic inflammation is thought to contribute to the development and progression of chronic conditions like insulin resistance, diabetes, hypertension, and atherosclerosis.67 Among childhood cancer survivors, published data is consistent with this hypothesis. Baker et al reported increased risk for insulin resistance among 319 adolescents (mean age 14.5 (range 9-18) years) previously treated with CRT and cisplatin or glucocorticoids when compared to siblings. Nottage et al68 reported increased risk for metabolic syndrome among adult survivors of childhood ALL (n = 784, median age 31·7 years (18.9-59.1)) treated with CRT when compared to population based controls. Holmquist et al69 reported an increased risk for diabetes in a population-based registry of childhood cancer survivors (N=32,903). Survivors of Wilms tumor, leukemia, CNS tumors, germ cell tumors, malignant bone tumors and HL were at greatest risk.69 Coronary artery disease, detected with computed tomography angiography, was prevalent among 39% of 31 survivors of HL (median age 40 (range 26-55 years)) exposed to chest radiation during childhood.70 Finally, Sulicka et al reported a chronic pro-inflammatory state among 27 survivors of childhood ALL (age range 18-27 years) when compared to normal controls.71 ALL survivors exhibited elevated levels of pentraxin 3, soluble vascular cell adhesion molecule-1, osteoprotegerin, tumor necrosis factor-related apoptosis-inducing ligand and counts of intermediate monocytes.71

Although a pro-inflammatory state likely influences function across every organ system; organs that are directly exposed to toxins are most vulnerable. This is evidenced by the increased risk for heart disease among children exposed to chest radiation and/or chemotherapy72 and by the increased risk for neuroendocrine73 or neurocognitive74 decline among children exposed to CRT. This is probably also true at the cellular level. Mitochondria produce energy (adenosine tri-phosphatase (ATP)) and are a major source of reactive oxygen species (ROS), which when produced in excess, can be highly damaging to cells. Likely because of the proximity of Mitochondrial (mtDNA) to sites of ROS generation, mtDNA is prone to accumulating mutations with age,75, 76 and after exposure to chemotherapy and radiation.77 The contributions of these MtDNA mutations to the pathogenesis of age-related disorders are suggested by the phenotype of mtDNA mutator mice (polgD257A/D257A), genetically engineered to accumulate somatic mtDNA mutations at an accelerated rate. These mice show reduced levels of oxidative phosphorylation with age and develop a variety of age-related disorders, including osteoporosis, neurodegeneration, cardiomyopathy, diabetes and muscle wasting.78, 79 In addition, inherited mitochondrial disorders are often characterized by muscle atrophy and weakness, reduced exercise capacity and fatigue,80 all components of the frailty phenotype described among aging adults42 and among childhood cancer survivors.41 Thus, we hypothesize that mitochondrial dysfunction resulting from the therapy related increase in somatic mtDNA mutations and/or the suboptimal microenvironment conferred by the SASP56 contributes to the development of the frailty phenotype in aging childhood cancer survivors.

Preventing and treating frail health

Interventions specifically designed to prevent or remediate frailty among childhood cancer survivors have not been tested, but likely will include pharmaceutical or nutriceutical agents and lifestyle modifications.81 Therapies designed to interfere with damage caused by radical oxygen species,82 mimic the known protective effects of caloric restriction,82 or clear dysfunctional senescent cells83 show promise in some human and animal models, although additional work is needed to bring these agents to clinical trials in childhood cancer survivors. Behavioral interventions designed to optimize a healthy lifestyle, including caloric restriction and exercise, are possibilities with demonstrated efficacy in aging human populations,84, 85 and are probably the most immediately accessible possibilities for current childhood cancer survivors with frailty or at risk for frailty. Two recent studies indicate that lifestyle is as important as treatment-related risk factors for metabolic86 and cardiac health87 in childhood cancer survivors; another study indicates that exercise in this population, even in the presence of known cardiac dysfunction is safe, and likely effective.88 However, data have shown that childhood cancer survivors may not respond to lifestyle changes in the same way that others respond,21 interventions may need tailoring to account for the unique needs of this population.

Conclusion

Childhood cancer survivors are at risk for frail health, a proportion demonstrating an aging-like phenotype characterized by muscle wasting and weakness, slow walking speed, reduced energy expenditure, fatigue and in some cases cognitive decline. Although the information in this review is based on cohorts that include some survivors treated with modalities eliminated from, or modified in, today's therapeutic protocols (e.g. cranial radiation for central nervous system prophylaxis among children with low or standard risk ALL, high dose thoracic radiation for children with Hodgkin lymphoma), it continues to be relevant. The frailty phenotype described was not limited to those who received radiation therapy.41 Additionally, many chemotherapy agents used in older treatment protocols continue to provide the backbone for today's therapeutic interventions.89, 90 Research is needed to determine if the prevalence of frailty remains significant among survivors with less common diagnoses (sarcoma, other solid tumors) treated on contemporary protocols. In addition, to determine the pathobiology of this phenomenon, aging research focused on cellular senescence, sterile inflammation and mitochondrial dysfunction has potential to provide insight for future interventions. Currently accessible interventions like medical management of chronic disease or behavioral management of diet/exercise should include relevant endpoints like quality of life, functional decline and long term survival.

Précis.

This manuscript provides a review of the evidence documenting physiologic frailty among childhood cancer survivors and describes potential biological mechanisms for this phenotype.

Figure 2.

Figure 2

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Pathobiology of frail health

Acknowledgments

This work was supported by a Cancer Center Support Grant from the National Cancer Institute (CA 21765) and by ALSAC.

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