Increasing exercise in long‐term survivors of pediatric cancer and their siblings: Should treatment be a family affair?

I n this issue of Pediatric Blood & Cancer, Miller et al. report that exercise capacity was significantly lower in survivors of pediatric cancer—particularly in females—regardless of the type of cancer than in their siblings, whose fitness was also well below normal. Older age, higher percentages of body fat, methotrexate exposure, and extremes of left ventricular mass and function were associated with lower VO2 max, the maximum volume of oxygen that the body can use during exercise. The authors conclude that survivors of childhood cancer should be encouraged to exercise regularly to improve exercise capacity, weight, mental status, and cardiometabolic risk. However, these patients, especially those with chemotherapyor radiation-induced restrictive cardiomyopathy, should be closely monitored during exercise because they may be limited by low cardiac reserves and non-cardiac exertional symptoms. Exercise capacity is one of the most important aspects of children’s health because physical activity is the most common stress placed on the body. Exercise requires coordinated activity over time with inputs from multiple organ systems. Exercise capacity can be reduced by cancer and other diseases, by therapies and their side effects, and by deconditioning from a sedentary lifestyle [1–3]. Despite the increasing number of pediatric cancer survivors reaching adulthood (at present, more than 300,000 in the US), with considerable diseaseand treatment-related co-morbidities, few studies have compared long-term survivors of different types of pediatric cancer and treatments with their siblings on exercise capacity and risk factors for reduced physical capacity. These studies are small, single-centered, and without long-term follow-up. Miller et al. compared measures of physical fitness—VO2 max, time to anaerobic threshold and time to peak exercise—from 72 survivors with those of 32 siblings without cancer at a mean of 13.4 years after cancer diagnosis (range, 4.5–31.6 years). Survivors were similar in age at diagnosis, time since diagnosis, and chemotherapeutic agents received. Importantly, they had a mix of cancer diagnoses, which should improve the generalizability of the results. The use of sibling controls also strengthens the validity of the results. The study provides compelling evidence that survivors had significantly lower exercise capacity, less endurance, and lower anaerobic thresholds than did their siblings. The study also confirms other reports that VO2 max is lower in young adult survivors than in their siblings, even years after treatment, and that it is lower in women [3,4]. Among other implications, these findings emphasize the importance of including controls in trials of physical fitness interventions or outcomes to avoid confounding sociodemographic influences. In some women, elevated concentrations of NT-proBNP, consistent with cardiomyopathy were not associated with lower VO2 max possibly, because lower VO2 max had non-cardiac causes [3]. Abnormal left ventricular mass was related to lower VO2 max in some men, several of whom had restrictive cardiomyopathy resulting from chemotherapy or chest irradiation with left ventricular diastolic dysfunction and reduced cardiac output. Surprisingly, among all survivors, anthracycline chemotherapy was not associated with reduced VO2 max, but it was associated with reduced VO2 max in males, although not significantly so. One study of long-term survivors reported that exercise capacity was reduced after anthracycline exposure in almost all of 23 patients and that this reduction was associated with abnormal cardiac function, leading to a restrictive cardiomyopathy, rhythm disturbances, and ischemic changes [5]. Anthracycline cardiotoxicity can now be prevented by dexrazoxane, especially in girls [6], suggesting the value in determining whether dexrazoxane can also prevent an anthracycline-induced decline in exercise capacity. Can exercise training, initiated during or after treatment, increase dexrazoxane-mediated protection against delayed-onset, anthracycline-induced cardiotoxicity? Such questions can be answered with controlled trials. In both the bivariate and multivariate models, the authors report a significant association between greater body fat and lower exercise capacity, with survivors carrying more body fat, which confirms and extends previous reports [7]. The fact that exercise capacity for survivors and siblings was well below normal for age and sex may reflect, in part, the current epidemic of obesity—as the authors suggest—but may also indicate that psychological factors in the families concerned may be important. The limitations of this seminal study are clearly presented (discordant numbers of survivors and siblings, unmatched research design, only non-Hispanic white survivors, exclusion of subjects after sub-maximal tests), but they should not detract from the key findings, which should stimulate the creation of innovative, tailored physical activity programs to improve both nutritional and cardiac conditions for long-term survivors and their