Chapter 49: Endocrine Problems in Pediatric Cancer Survivors

INTRODUCTION

Survival rates for pediatric cancers continue to improve. Overall 5-year survival for all types has increased from 58.1% for childhood cancers diagnosed in the 1970s to 82.5% for those diagnosed between 2001 and 2007.^1,2 As a result, the population of childhood cancer survivors expands, and it is estimated 1:570 young adults living in the United States is a survivor of childhood cancer.³ However, curative cancer treatment comes with a price; radiation, chemotherapy, surgery, and bone marrow transplant (BMT) can all negatively affect endocrine function. In many cases, children are treated with multimodal therapy and may be at risk for multiple endocrine late effects. Complications of cancer therapy may be acute-onset and transient, like weight loss; acute-onset and chronic, like acute ovarian failure; or late in onset, like infertility and hypothyroidism.

Radiation therapy destroys cancer cells but also damages surrounding normal tissue. Radiation to the hypothalamus/pituitary, reproductive organs, thyroid, pancreas, or bone can cause primary injury to those tissues. Multiple hormones may be affected by central nervous system (CNS) radiation in doses commonly used to treat childhood brain tumors. The hypothalamus is more sensitive to the effects of radiation than the pituitary gland. Of the pituitary hormones, growth hormone (GH) is the most likely to be affected, followed by gonadotropins, adrenocorticotropic hormone (ACTH), and thyrotropin/TSH. Vasopressin is not altered by radiation, but hyperprolactinemia may occur.⁴ Radiation to the neck, spine, and upper chest may result in hypothyroidism, and increases the risk for thyroid nodules and thyroid cancer.^5,6 Late effects of radiation on the reproductive organs may include infertility, hypogonadism, and damage to the uterus/uterine vasculature. As a result, pregnancies occurring in women who received pelvic irradiation as children are more likely to be affected by prematurity, stillbirth, or low birth weight.⁷ Total body irradiation may affect the hypothalamic-pituitary axis (including GH production), the thyroid, the gonads, and increases risk for diabetes mellitus.^8,9,10

The toxic effects of chemotherapy during the acute phase of cancer treatment are well known. Children often experience malaise, cachexia, lethargy, electrolyte disturbances, hyperglycemia, and growth failure. Most often these acute effects resolve with the cessation of treatment, but growth failure, when related to unresolved low body mass index (BMI), may persist as a late effect. Chemotherapy, particularly with the alkylating chemotherapeutic agents, is known to cause primary gonadal damage,¹¹ and some chemotherapies adversely affect bone density.¹²

BMT has the potential to cause a wide range of endocrine late effects, depending on the preparatory regimens used, which may include chemotherapy with or without radiation. The effects of these agents need to be considered in the context of the cumulative exposure from prior cancer therapy. In addition, chronic steroids used to treat graft-versus-host disease can impair normal growth and bone mineral acquisition. Cancer survivors treated with BMT may have significant growth failure, primary and/or secondary hypothyroidism, ...