Childhood Cancer Survivors: Cured but With Long-Term Health Risks

November 15, 2015

This evolving issue is increasingly concerning, as studies regarding the causes of non-relapse late mortality in childhood cancer survivors consistently include cardiovascular disease as one of the major contributors to this mortality risk.

In this issue of ONCOLOGY, Barnea et al review the important topic of obesity and metabolic disease after therapy for childhood cancer.[1] This evolving issue is increasingly concerning, as studies regarding the causes of non-relapse late mortality in childhood cancer survivors consistently include cardiovascular disease as one of the major contributors to this mortality risk.[2,3] Our success at treating childhood cancer has resulted in an increasing number of survivors who are now adults, but who often lack appropriate follow-up, given their prior cancer treatment history and increased risk of cardiovascular and other chronic conditions.[4] Very few programs for ongoing follow-up of this adult-aged population exist, and these survivors are, for the most part, inadequately prepared to advocate for their own healthcare needs after they transition out of pediatric-based care.[5]

In the general population, a common theme behind cardiovascular risk is obesity, which establishes a state of insulin resistance and hyperlipidemia, and increases the risk of diabetes mellitus (DM).[6] Although obesity influences the development of cardiovascular risk factors in childhood cancer survivors, treatment exposure is the primary contributing factor.[7] In particular, as Barnea et al state in their review, radiation therapy plays an important role in the etiology of obesity, dyslipidemias, and insulin resistance seen in childhood cancer survivors; the risk is primarily related to three specific radiation exposures: total body irradiation (TBI) delivered as part of the preparative regimen prior to hematopoietic stem cell transplant (HCT), cranial radiation therapy (CRT) given for treatment of leukemia or brain tumors, and abdominal radiation used for certain solid tumors.[1]

In HCT survivors who have received TBI, an alteration in body composition characterized by a decrease in muscle mass and an increase in visceral fat mass in the setting of a lack of abdominal obesity has been described.[8] This pattern of “sarcopenic obesity” is associated with the development of insulin resistance and dyslipidemia, which, although the exact mechanisms are not clearly understood, is likely secondary to a loss of myocyte insulin receptors combined with an increase in visceral fat mass.

Leptin and adiponectin are adipocyte hormones involved in the regulation of appetite and energy expenditure and storage. In patients exposed to CRT, hypothalamic injury may result in a state of central leptin resistance, leading to higher leptin levels but loss of the inhibitory impact on appetite, thus contributing to obesity. Adiponectin, which normally enhances insulin secretion, glucose utilization, and fatty acid oxidation, is produced at levels inversely proportional to fat mass; thus, reduced levels in survivors with a higher fat mass may contribute to insulin resistance.[9] Studies of both acute lymphoblastic leukemia (ALL) survivors and those who received HCT have demonstrated higher levels of leptin and lower levels of adiponectin associated with insulin resistance in these patients.[10,11]

Several studies have now reported the link between abdominal radiation and the risk of DM. Correlations were observed between higher radiation doses to the tail of the pancreas, where insulin-producing pancreatic ß cells reside, and a higher risk of DM.[1] This has primarily been seen in patients with abdominal solid tumors, such as neuroblastoma, Wilms tumor, and soft tissue sarcomas, in which relatively high doses of radiation are sometimes utilized.

Although treatment methods are extremely important risk factors in the causal pathway leading to obesity and metabolic syndrome in childhood cancer survivors, factors that impact the risk of these same outcomes in the general population, such as poor dietary habits and sedentary lifestyle, cannot be overlooked. Currently, the overall body of evidence remains limited, but childhood cancer survivors have been shown to be less physically active and less likely to adhere to healthy dietary guidelines as compared with healthy controls.[1] In addition to previously mentioned factors, other effects such as treatment-related neuropathy and cognitive limitations, as well as altered lifestyle habits acquired during prolonged treatment duration (2 to 3 years for ALL patients), may be significant. It is clear, however, in the general population that change of diet and lifestyle, weight loss, and increased physical activity are all powerful modifiers of the risk of cardiovascular disease and DM.[6]

Whether these interventions will have the same degree of positive impact and reduction in risk in childhood cancer survivors is unknown, although early studies have been encouraging.[1] However, it remains to be seen if the sarcopenic phenotype induced by radiation can be reversed with exercise alone. Much research is also still needed to explore the most effective intervention (cardiorespiratory fitness, muscle endurance, or strength training, etc) and timing in relation to treatment (during, after, and/or both), as well as how to help childhood cancer survivors maintain a physically active lifestyle and healthy diet for a lifetime.

Moving forward, additional research should also focus on determining whether genetic factors that impact susceptibility to cellular damage by chemotherapy and radiation, or those that affect regulation of metabolic pathways, are important among childhood cancer survivors. Pharmacologic interventions also need to be studied to determine whether there is a role for insulin-sensitizing agents in patients who are at high risk for DM. Coupled with this is a need for better screening recommendations for childhood cancer survivors as they transition into adulthood, as well as education of the primary care community regarding the long-term follow-up care of this unique and growing population. Changes and advancements in the way that cancer therapy is delivered, with less reliance on cytotoxic chemotherapy and elimination or reduction of radiation, and greater reliance on more targeted therapies, may ultimately eliminate or ameliorate some of the adverse outcomes in childhood cancer survivors.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Barnea D, Raghunathan N, Novetsky Friedman D, Tonorezos ES. Obesity and metabolic disease after childhood cancer. Oncology (Williston Park). 2015;29:849-55.

2. Mertens AC, Liu Q, Neglia JP, et al. Cause-specific late mortality among 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst. 2008;100:1368-79.

3. Reulen RC, Winter DL, Frobisher C, et al. Long-term cause-specific mortality among survivors of childhood cancer. JAMA. 2010;304:172-9.

4. Robison LL, Hudson MM. Survivors of childhood and adolescent cancer: life-long risks and responsibilities. Nat Rev Cancer. 2014;14:61-70.

5. Henderson TO, Friedman DL, Meadows AT. Childhood cancer survivors: transition to adult-focused risk-based care. Pediatrics. 2010;126:129-36.

6. Steinberger J, Daniels SR, Eckel RH, et al. Progress and challenges in metabolic syndrome in children and adolescents: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in the Young Committee of the Council on Cardiovascular Disease in the Young; Council on Cardiovascular Nursing; and Council on Nutrition, Physical Activity, and Metabolism. Circulation. 2009;119:628-47.

7. Lipshultz SE, Adams MJ, Colan SD, et al. Long-term cardiovascular toxicity in children, adolescents, and young adults who receive cancer therapy: pathophysiology, course, monitoring, management, prevention, and research directions: A scientific statement from the American Heart Association. Circulation. 2013;128:1927-95.

8. Baker KS, Chow E, Steinberger J. Metabolic syndrome and cardiovascular risk in survivors after hematopoietic cell transplantation. Bone Marrow Transplant. 2012;47:619-25.

9. Antuna-Puente B, Feve B, Fellahi S, Bastard JP. Adipokines: the missing link between insulin resistance and obesity. Diabetes Metab. 2008;34:2-11.

10. Oeffinger KC, Adams-Huet B, Victor RG, et al. Insulin resistance and risk factors for cardiovascular disease in young adult survivors of childhood acute lymphoblastic leukemia. J Clin Oncol. 2009;27:3698-704.

11. Chow EJ, Simmons JH, Roth CL, et al. Increased cardiometabolic traits in pediatric survivors of acute lymphoblastic leukemia treated with total body irradiation. Biol Blood Marrow Transplant. 2010;16:1674-81.