Pediatric cancer survivors often face endocrine, cardiometabolic issues later in life
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Children with cancer are particularly vulnerable to the adverse effects of treatments such as chemotherapy, radiation and hematopoietic stem cell transplantation.
However, some treatment effects may not become apparent until years later. As primary care providers or other specialists follow these patients over the course of their lives, they may not anticipate this “delayed reaction” to long-ago cancer treatment.
According to Laurie E. Cohen, MD, director of the neuroendocrinology program at Boston Children’s Hospital, member of the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and associate professor of pediatrics at Harvard Medical School, the majority of survivors of pediatric cancer should be followed by a multidisciplinary team of providers throughout their lives.
Survivors at higher risk for endocrine late effects should be monitored more closely, she said.
“For a patient at high risk for an endocrinopathy, it’s important to have a pediatric endocrinologist monitor them over time, starting when they are younger,” Cohen said in an interview with Healio. “For lower-risk patients, the pediatrician, the oncologist or the clinic may be able to do the monitoring.”
‘Anything can be affected’
Of the many late effects of treatment that childhood cancer survivors may experience, endocrine effects are among the most common, Cohen said.
“If you look at all types of cancer survivors as a group, certainly endocrinopathies are among the most common late effects, occurring in at least 40% to 50% of children,” Cohen said. “The endocrine system contains multiple glands that affect growth, development, reproduction and metabolism.”
Cohen said the hypothalamus and pituitary gland can be damaged by cranial radiation. Immune checkpoint modulators may cause hypophysitis, or inflammation of the hypothalamic/pituitary area, she added. Likewise, the thyroid gland can be impacted by radiation, tyrosine kinase inhibitors and immune checkpoint modulators, and the gonads can be affected by chemotherapy and radiation; long-term effects of TKIs are less clear. Other glands can be affected, as well.
Growth hormone deficiency
A common late effect of pediatric cancer treatment is growth hormone (GH) deficiency linked to treatment of central nervous system tumors, Cohen said. Treatments such as radiation can cause the pituitary gland to not produce enough GH. In children, this is identifiable through slowed growth, with a decline in height percentiles, according to Cohen.
GH is produced throughout life, and GH deficiency can occur at any age, she said.
“Adult GH deficiency in the cancer survivor has the same symptoms as in the general population,” she said. “These include altered body composition with increased body fat and decreased lean body mass, abnormal lipid profile, increased cardiovascular morbidity, decreased bone mineral density and impaired quality of life.”
Treatment with GH may be indicated for such a deficiency, Cohen said. Additionally, increased efforts have been made at the time of treatment to prevent off-target effects.
“With high-risk leukemia, for example, the cranial radiation dose has decreased over the years, making it less likely to cause GH deficiency,” she said. “But for the most part, what we really like to do is monitor these patients so that if they develop deficiencies, they’re caught early, before any of the side effects of the deficiency can occur.”
Fertility considerations
The risk for infertility later in life for survivors of pediatric cancer is an important consideration. It is particularly elevated for those treated with alkylating chemotherapy medications and radiation to the gonads, Cohen said.
“In males, these treatments affect germ cell function and the Sertoli cells that are the nurse helper cells for sperm production,” she said. “Sperm preservation prior to treatment is one way to address this potential late effect.”
Males who received cancer treatment as children also should be monitored for hypoandrogenism (decreased testosterone production) as they approach puberty, although it takes higher doses of these agents to affect the Leydig cells that produce testosterone.
Pubertal onset may be difficult to recognize in boys who have received treatments that damage the testes.
“The first sign of the onset of puberty in boys is testicular enlargement, and in these cases, the testes will be small at each stage of development,” Cohen said.
In girls, these same therapies affect both the production of the hormones estrogen and progesterone and the production of eggs. Individuals may fail to enter puberty, have arrested development during puberty or have a premature menopause.
For females not yet ready to try to conceive, oocyte cryopreservation may be an option. “At-risk patients should see a fertility specialist,” Cohen said.
Additionally, radiation to the hypothalamic/pituitary area may lead to fertility and hormonal problems by causing deficiencies of the gonadotropins that stimulate the gonads.
Cardiometabolic late effects
Although childhood cancer treatments are often invaluable in adding years to a young patient’s life, the survivorship of these patients may be complicated — or even shortened — by cardiometabolic late effects.
“Survivors of childhood cancer are at risk [for] developing cardiometabolic late effects, including obesity, hypertension, dyslipidemias and abnormalities in glucose metabolism,” Carmen Wilson, PhD, assistant faculty member in the epidemiology and cancer control department of St. Jude Children’s Research Hospital, said in an interview with Healio. “The prevalence of these cardiometabolic conditions is often dependent on prior exposure to certain cancer therapies and thus varies by primary childhood cancer diagnosis.”
Wilson said obesity, insulin resistance and type 2 diabetes have been found to occur more frequently in cancer survivors vs. noncancer controls. In fact, some studies have reported that obesity, hyperglycemia and hypertriglyceridemia may occur in up to about half of childhood cancer survivors. Moreover, low HDL cholesterol has been reported [by Nottage and colleagues] in as many as two-thirds of survivors.
“Metabolic syndrome, which refers to the co-occurrence of insulin resistance, obesity, atherogenic dyslipidemia and hypertension, is estimated to occur in up to a third of survivors,” Wilson said.
These late effects have been associated with several different pediatric cancer treatments, according to Wilson. Total body irradiation and abdominal radiotherapy have been linked to increased risk for insulin resistance, type 2 diabetes, reduced lean mass and abnormal distribution of body fat. Total body irradiation also has been associated with hypertension and hypertriglyceridemia. Additionally, treatment that might impact the hypothalamus, which controls metabolism, can in turn affect weight.
“Survivors with hypothalamic injury as a result of tumor location or from surgical resection are at a very high risk for obesity, as well as other metabolic and endocrine derangements,” Wilson said. “Risk factors for metabolic syndrome are similar for those of the components that are used to define the disease.”
A recipe for risk
Cardiometabolic effects associated with some pediatric cancer treatments can combine to increase the risk profile for cardiovascular disease.
“Cardiac causes [are] the second leading cause of mortality among survivors of childhood cancer, and death from these causes is approximately sixfold higher among survivors relative to the general population,” Wilson said. “Cardiometabolic late effects are of concern among survivors, given that in the general population, these conditions increase the risk [for] developing many cardiovascular conditions, including atherosclerosis, coronary artery disease, myocardial infarction, stroke and type 2 diabetes.”
The impact of these cardiometabolic late effects may be compounded if the cancer treatments have adverse effects on the cardiovascular system. Wilson cited results of the Childhood Cancer Survivor Study, which looked at more than 10,000 childhood cancer survivors.
“This study [by Armstrong and colleagues] showed that among those treated with chest radiotherapy, the risk [for] coronary heart disease, heart failure and valvular disease were increased between four- and 90-fold in survivors with either comorbid hypertension, dyslipidemias, diabetes or obesity,” she said.
Monitoring and mitigating
Few known strategies exist for minimizing potential cardiometabolic late effects of pediatric cancer therapies at the time of treatment.
According to the Children’s Oncology Group guidelines, survivors of pediatric cancer treatment should be screened annually for overweight or obesity using measurements of height, weight and BMI. Clinicians also should evaluate blood pressure and nutritional status regularly.
“Among those survivors previously treated with total body irradiation or abdominal radiotherapy, assessment of a fasting lipid profile and screening for type 2 diabetes using fasting blood glucose or hemoglobin A1c is recommended at least every 2 years, regardless of BMI,” she said.
Survivors should be educated on the value of a healthy diet and physical exercise to minimize cardiometabolic risk, just as all patients should be, Wilson said.
“Interventions directed at lifestyle behaviors — including adherence to a heart-healthy diet, regular physical activity and maintenance of a healthy weight — have been successful in improving lipid parameters and insulin sensitivity among noncancer populations,” she said. “These interventions represent key areas of potential research among pediatric cancer survivors.”
References:
- Armstrong GT, et al. J Clin Oncol. 2013;doi:10.1200/JCO.2013.48.3205.
- Children’s Oncology Group. Long-term follow-up guidelines for survivors of childhood, adolescent, and young adult cancers, version 5.0. Available at: www.survivorshipguidelines.org. Accessed Oct. 15, 2020.
- Gurney JG, et al. Cancer. 2006;doi:10.1002/cncr.22120.
- Hoffman KE, et al. Pediatr Blood Cancer. 2008;doi:10.1002/pbc.21363.
- Mulrooney DA, et al. BMJ. 2009;doi:10.1136/bmj.b4606.
- Nottage KA, et al. Br J Haematol. 2014;doi:10.1111/bjh.12754.
- Oudin C, et al. Blood. 2011;doi:10.1182/blood-2010-09-304899.
- Pietilä S, et al. Pediatr Blood Cancer. 2009;doi:10.1002/pbc.21936.
- Talvensaari KK, et al. J Clin Endocrinol Metab. 1996;doi:10.1210/jcem.81.8.8768873.
- Taskinen M, et al. Lancet. 2000;doi:10.1016/S0140-6736(00)02717-3.
- van Waas M, et al. Ann Oncol. 2010;doi:10.1093/annonc/mdp414.
- Wilson CL, et al. Cancer Epidemiol Biomarkers Prev. 2020;doi:10.1158/1055-9965.EPI-19-1321.
For more information:
Laurie E. Cohen, MD, can be reached at: laurie.cohen@childrens.harvard.edu.
Carmen Wilson, PhD, can be reached at: carmen.wilson@stjude.org.
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