Fitness deficits in long-term ALL survivors

In this issue of Blood,Ness et al report that, despite the omission of prophylactic cranial radiotherapy (CRT) in the treatment of acute lymphoblastic leukemia (ALL), adult survivors of childhood ALL remain at risk for impaired fitness, body composition, and energy balance.¹ 

Survival rates for most childhood cancers have increased dramatically over the last 40 years, with >80% of pediatric patients diagnosed with ALL becoming 5-year survivors.²  Unfortunately, healthspan is not keeping pace, and the challenge now is to reduce treatment-related chronic health problems that occur in ∼70% of long-term survivors.³  Childhood cancer survivors are twice as likely to be obese compared with their siblings,⁴  and adult survivors of childhood ALL are at an increased risk of adiposity, dyslipidemia, diabetes, and cardiovascular disease.^5-7  Furthermore, many studies have reported additive long-term detrimental effects of receiving prophylactic CRT during primary cancer treatment.^5-7  Once a standard treatment of ALL, CRT has all but been replaced with intrathecal and systemic chemotherapy to reduce radiation-associated late complications such as cancer recurrence, cognitive decline, and metabolic risk.²  However, for the sake of future childhood ALL survivors, it is important to know if omitting CRT has alleviated long-term health problems associated with excess adiposity and poor cardiorespiratory fitness.

Ness et al determined the impact of CRT on the well-characterized decrements in body composition, energy balance, and physical fitness in adult survivors of childhood ALL. All participants (n = 365) were >18 years of age, at least 10 years from diagnosis, had a mean survival time of 21.9 years, and were previously treated for ALL at St. Jude Children’s Research Hospital (SJCRH) when <18 years of age. A noncancer comparison group that was age, sex, and race matched to the study participants was recruited from SJCRH visitors. The study recruited 87.7% of all eligible patients, and the “gold standard” techniques of indirect calorimetry, dual x-ray absorptiometry, and doubly labeled water were used to assess physical fitness, body composition, and energy expenditure, respectively.

Survivors exposed to CRT had higher body mass index and percentage of body fat scores than survivors not exposed to CRT, but only male non-CRT survivors had less favorable body composition scores than the comparative group. Body-mass–adjusted total daily energy expenditure and activity energy expenditure were also lower in CRT compared with non-CRT survivors. Moreover, cardiorespiratory fitness (peak oxygen uptake) and muscular strength (handgrip and quadriceps) and endurance (quadriceps) were lower in CRT-exposed survivors compared with non-CRT survivors. Measures of cardiorespiratory fitness, peripheral sensory integrity, proximal muscle strength, and flexibility were markedly lower in ALL survivors than in the comparative group. Although CRT exposed survivors had the lowest mean values for most physical fitness measures, non–CRT-exposed survivors still had large fitness deficits relative to the comparison group, particularly for proximal muscle strength and aerobic exercise capacity. Ness et al also reported for the first time that cumulative exposure to asparaginase and glucocorticoids was associated with impaired flexibility and weak hand strength, respectively. They also confirmed previously reported associations between vincristine dose and peripheral neuropathy and between intrathecal methotrexate dose and balance problems.

It is intuitive to speculate that the detrimental effects of CRT exposure on body composition and fitness are due to treatment-related deficiencies in hypothalamic pituitary hormones. Another recent study on the same cohort revealed significant associations between cumulative CRT doses and deficiencies in growth hormone (GH), luteinizing hormone/follicle-stimulating hormone (LH/FSH), thyroid-stimulating hormone, and adrenocorticotropic hormone.⁸  Survivors with untreated GH deficiency had decreased muscle mass and exercise tolerance, whereas both untreated GH and LH/FSH deficiency were independently associated with abdominal obesity, low energy expenditure, and muscle weakness.⁸  It has also been suggested that CRT may damage appetite-regulatory sensors in the brain that may lead to leptin resistance and overeating.⁷  Indeed, leptin per kilogram of fat mass is elevated in adult survivors of childhood ALL and is further elevated in those exposed to CRT.^5,6 

The findings by Ness et al and others indicate that the omission of prophylactic CRT for the treatment of childhood ALL has certainly lowered the risk of physical fitness and body composition impairments in adult survivors.^6,7,9  The magnitude of this risk reduction appears to be greater for body composition than for fitness, as non-CRT survivors may have the same likelihood of being overweight or obese as the general population.⁷  Indeed, Ness et al found this to be the case for females, who had body composition scores comparable to their peers. Thus, the notion that childhood ALL results in long-term impairments in body composition independently of prior CRT exposure remains contentious. However, Ness et al do provide strong evidence that the elimination of CRT does not completely prevent fitness deficits in long-term survivors of childhood ALL and that health problems associated with impaired fitness are still likely to exist in future survivors. The extent of exposure to chemotherapy may be 1 factor, as anthracycline dose is inversely correlated with impaired exercise capacity and left ventricular cardiac function in adult survivors of childhood ALL.¹⁰  One limitation is that Ness et al compared fitness and body-composition scores between childhood ALL survivors and a comparative group of individuals who were generally overweight and less fit than the general population. It is likely, therefore, that the magnitude of energy balance and fitness impairment in the ALL survivors has been unduly masked, particularly for peak oxygen uptake in which the group differences were in the order of only 1 to 1.5 metabolic equivalents.

This formative study by Ness et al provides the most detailed and comprehensive assessment of body composition and physical fitness in adult survivors of childhood ALL to date. The finding that adult survivors of ALL remain at risk for proximal muscle weakness and poor exercise tolerance, despite the omission of CRT, is of great importance given the well-established relationships among physical fitness, energy balance, adiposity, and morbidity and mortality in the general population. These findings highlight the need to implement randomized controlled trials to determine the effectiveness of lifestyle interventions on health outcomes and quality of life across the entire cancer care continuum.