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Childhood most cancers survivors typically face endocrine cardiometabolic issues later in life – Healio

October 22, 2020

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Cohen and Wilson do not report any relevant financial information.

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Children with cancer are particularly vulnerable to the adverse effects of treatments such as chemotherapy, radiation, and haematopoietic stem cell transplantation.

However, some treatment effects may not become apparent for years. Because first responders or other specialists accompany these patients throughout their lives, they cannot foresee this “delayed response” to cancer treatment long ago.

According to Laurie E. E. Cohen, MD, As the director of the Neuroendocrinology Program at Boston Children's Hospital, a member of the Dana Farber / Boston Center for Childhood Cancer and Blood Diseases, and an Associate Professor of Pediatrics at Harvard Medical School, the majority of childhood cancer survivors should be supported by a multidisciplinary team of Providers are accompanied throughout their lives.

Survivors at higher risk of endocrine disruptions should be monitored more closely, she said.

Laurie E. Cohen, MD

Laurie E. Cohen

"For a patient at high risk for endocrinopathy, it is important that a pediatric endocrinologist monitor them over time, starting in their teens," Cohen said in an interview with Healio. "The pediatrician, oncologist, or clinic may be able to monitor for patients at lower risk."

"Everything can be affected"

Of the many late effects of treatment that childhood cancer survivors can experience, endocrine effects are among the most common, Cohen said.

"When you look at all types of cancer survivors as a group, endocrinopathies are certainly among the most common long-term sequelae, affecting at least 40% to 50% of children," Cohen said. "The endocrine system contains several glands that influence growth, development, reproduction and metabolism."

Cohen said that skull radiation can damage the hypothalamus and pituitary gland. Immune checkpoint modulators can cause hypophysitis or inflammation of the hypothalamus / pituitary area, she added. Similarly, the thyroid can be affected 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 also be affected.

Growth hormone deficiency

A common late-stage effect of childhood cancer treatment is growth hormone deficiency (GH), which is linked to the treatment of central nervous system tumors, Cohen said. Treatments like radiation can prevent the pituitary gland from producing enough GH. In children, according to Cohen, this can be seen as slower growth with a decrease in altitude percentiles.

GH is produced throughout life and GH deficiency can occur at any age, she said.

"Adult GH deficiency in cancer survivors 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, an abnormal lipid profile, increased cardiovascular morbidity, decreased bone mineral density and impaired quality of life."

Treatment with GH might be indicated for such a deficiency, Cohen said. In addition, at the time of treatment, increased efforts were made to prevent side effects.

"For example, in high-risk leukemia, the dose of radiation from the skull has decreased over the years, making GH deficient less likely," she said. "But for the most part, we really want to monitor these patients so that if they develop deficiencies, they can be identified early before any of the deficiency side effects can occur."

Fertility Considerations

The risk of subsequent infertility for childhood cancer survivors is an important consideration. It's especially elevated for those treated with alkylating chemotherapy drugs and radiation to the gonads, Cohen said.

"In men, these treatments affect germ cell function and the Sertoli cells, which are the helper cells for sperm production," she said. "Preserving the sperm before treatment is one way of addressing this potential late effect."

Men who received cancer treatment as children should also be monitored for hypoandrogenism (decreased testosterone production) as they near puberty, although higher doses of these agents are needed to affect the Leydig cells that produce testosterone.

The onset of puberty can be difficult to tell in boys who have received treatments that damage the testicles.

"The first sign of puberty onset in boys is testicular enlargement. In these cases, the testicles are small at every stage of development," Cohen said.

In girls, the same therapies affect both the production of the hormones estrogen and progesterone and the production of eggs. Individuals may not be able to enter puberty, have stopped development during puberty, or have premature menopause.

For women who are not ready to conceive, egg cryopreservation may be an option. "Patients at risk should see a fertility specialist," Cohen said.

Additionally, irradiation of the hypothalamic / pituitary area can lead to fertility and hormonal problems by causing a lack of gonadotropins that stimulate the gonads.

Cardiometabolic long-term effects

Although childhood cancer treatments are often invaluable in adding years to a young patient's life, long-term cardiometabolic sequelae can complicate or even shorten these patients' survival.

"Childhood cancer survivors are at risk for long-term cardiometabolic sequelae, including obesity, high blood pressure, dyslipidemia, and abnormalities in glucose metabolism." Carmen Wilson, PhD, The assistant faculty member in the Department of Epidemiology and Cancer Control at St. Jude Children's Research Hospital said in an interview with Healio. "The prevalence of these cardiometabolic disorders often depends on previous exposure to certain cancer therapies and therefore varies depending on the primary cancer diagnosis in children."

Carmen Wilson, PhD

Carmen Wilson

Wilson said obesity, insulin resistance, and type 2 diabetes are more common in cancer survivors than in non-cancer controls. In fact, some studies have reported that obesity, hyperglycemia, and hypertriglyceridemia can occur in up to about half of childhood cancer survivors. In addition, up to two-thirds of the survivors have been reported to have low HDL cholesterol levels (from ttage and colleagues).

"Metabolic syndrome, which relates to the coexistence of insulin resistance, obesity, atherogenic dyslipidemia, and high blood pressure, is estimated to occur in up to a third of survivors," said Wilson.

These sequelae have been linked to various pediatric cancer treatments, according to Wilson. Whole-body radiation and abdominal radiation therapy have been linked to an increased risk of insulin resistance, type 2 diabetes, decreased muscle mass, and abnormal distribution of body fat. Whole-body radiation has also been linked to high blood pressure and hypertriglyceridemia. Additionally, treatment that may affect the hypothalamus, which controls metabolism, can in turn affect weight.

"Survivors with hypothalamic injuries as a result of tumor localization or surgical resection are at very high risk of obesity and other metabolic and endocrine disorders," said Wilson. "The risk factors for metabolic syndrome are similar to the components used to define the disease."

A recipe for risk

Cardiometabolic effects associated with some pediatric cancer treatments together can increase the risk profile for cardiovascular disease.

"Cardiac causes are the second leading cause of death among childhood cancer survivors, and death from these causes is approximately six times higher in survivors compared to the general population," said Wilson. "Long-term cardiometabolic sequelae are of concern for survivors as these conditions increase the risk of developing many cardiovascular diseases in the general population, including atherosclerosis, coronary artery disease, myocardial infarction, stroke and type 2 diabetes."

The effects of these long-term cardiometabolic effects can be aggravated if the cancer treatments have an adverse effect on the cardiovascular system. Wilson cited the results of the Childhood Cancer Survivor Study, which examined more than 10,000 childhood cancer survivors.

“This study (by Armstrong and colleagues) showed that the risk of (for) coronary artery disease, heart failure, and valve disease in survivors with comorbid hypertension or dyslipidemia was between four and 90 times higher. Diabetes or obesity, ”she said.

Monitoring and Mitigation

There are few known strategies for minimizing the potential cardiometabolic late effects of childhood cancer therapies at the time of treatment.

According to the guidelines of the Children’s Oncology Group, survivors of the treatment of childhood cancer should be assessed annually for overweight or obesity using measurements of height, weight and BMI. Doctors should also regularly evaluate blood pressure and nutritional status.

"Survivors previously treated with whole-body radiation or abdominal radiation therapy, regardless of BMI, are recommended to have a fasting lipid profile and screen for type 2 diabetes using fasting blood sugar or hemoglobin A1c at least every two years," she said.

Survivors should be educated about the value of a healthy diet and exercise to minimize cardiometabolic risk, as all patients should be, Wilson said.

"Interventions that target lifestyle behaviors – including following a heart-healthy diet, regular exercise, and maintaining a healthy weight – have successfully improved lipid parameters and insulin sensitivity in non-cancer populations," she said. "These interventions represent key areas of potential research among childhood cancer survivors."

References:

  • Armstrong GT et al. J Clin Oncol. 2013; doi: 10.1200 / JCO.2013.48.3205.
  • Oncology group for children. Long-term Follow-Up Guidelines for Survivors of Child, Adolescent, and Young Adult Cancer Survivors, Version 5.0. Available at: www.survivorshipguidelines.org. Accessed October 15, 2020.
  • Gurney JG et al. Cancer. 2006; doi: 10.1002 / cncr.22120.
  • Hoffman KE et al. Pediatric blood cancer. 2008; doi: 10.1002 / pbc.21363.
  • Mulrooney DA et al. BMJ. 2009; doi: 10.1136 / bmj.b4606.
  • ttage 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. Pediatric 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 Biomarker 2020; doi: 10.1158 / 1055-9965.EPI-19-1321.

For more informations:

Laurie E. Cohen, MD, reachable at: laurie.cohen@childrens.harvard.edu.

Carmen Wilson, PhD, reachable at: carmen.wilson@stjude.org.

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