Hypothalamic–Pituitary and Growth Disorders in Survivors of Childhood Cancer

An Endocrine Society Clinical Practice Guideline

Charles A. Sklar; Zoltan Antal; Wassim Chemaitilly; Laurie E. Cohen; Cecilia Follin; Lillian R. Meacham; M. Hassan Murad

Disclosures

J Clin Endocrinol Metab. 2018;103(8):2761-2784. 

In This Article

Introduction

Cancers are relatively rare in the pediatric age group and account for only ~1% of the cancer burden in the entire population.[1] Due to improvements in treatment and supportive care, current 5-year survival rates are >80% overall.[2] The number of childhood cancers survivors is ever increasing and by the year 2020, it is estimated that there will be half a million survivors of childhood cancer residing in the United States. As the number of survivors has increased, there has been a growing awareness that survivors are at far greater risk of developing serious medical complications compared with noncancer controls.[3] In particular, endocrine disorders are highly prevalent among cancer survivors; recent data indicate that 40% to 50% of survivors will develop at least one endocrinopathy over the course of their lifetime.[4,5] Risk of developing endocrine disorders is dependent on a wide range of variables, including host (e.g., age, sex, genetic background), disease (e.g., diagnosis, tumor location), and treatment (e.g., surgery, chemotherapy, radiation) factors. Radiation exposure to key endocrine organs (e.g., hypothalamus, pituitary, thyroid and gonads) is the single most important risk factor and puts survivors at extremely high risk of developing an endocrine abnormality over time. Importantly, radiation-induced abnormalities are, in general, both dose- and time-dependent such that the higher the dose and the longer the interval following treatment, the greater the risk. Thus, endocrine disorders may not develop for decades after completion of cancer treatment, underscoring the critical importance of lifelong surveillance for those at ris.[4,5]

The current guideline focuses on the diagnosis and treatment of abnormalities of the hypothalamic–pituitary (HP) (Figure 1) and management of growth disorders commonly encountered in childhood cancer survivors. Impaired linear growth and short AH can be due to both endocrine [e.g., central precocious puberty (CPP), GHD] and nonendocrine (e.g., medications, poor nutrition, radiation to the spine) factors. Not surprisingly, those diagnosed and treated for cancer at the youngest ages are the most affected. Currently, the only proven therapies for short stature are confined to the treatment of CPP and GHD, which follow the same general principles used in children without a cancer history.

Figure 1.

Common hypothalamic pituitary late effects in survivors of childhood cancer.

Abnormalities of the HP are observed in survivors with tumors in the region of the HP, following surgery in the region of the HP, or, most commonly, following radiation to the HP (Figure 1). Although HP dysfunction is generally observed acutely in individuals with tumors and/or surgery in the region of the HP, HP dysfunction is usually not observed for months to years following HP radiation. Whereas CPP and GHD occur following relatively low doses of HP radiation [e.g., ≥18 Gy following standard fractionation, ≥12 Gy following hyperfractionation in the setting of total body irradiation (TBI)], deficits of the other anterior pituitary hormones [LH/FSH, thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH)] develop almost exclusively in survivors previously exposed to HP doses ≥30 Gy. For the most part, the diagnosis and treatment of anterior pituitary deficits in cancer survivors follow the same general principles as are used in the noncancer population.

Although there have been a large number of excellent studies assessing disordered growth and HP abnormalities in this population that have informed this guideline, limitations exist. The focus of most studies has been on understanding prevalence and risk factors for the various outcomes, with fewer studies addressing diagnosis and management. Most of the data are descriptive and often limited to relatively small case series. Furthermore, much of the data relate to survivors treated in prior decades with therapies that may have been abandoned [e.g., prophylactic cranial radiation therapy (CRT) for acute lymphoblastic leukemia] or modified in the current era [e.g., reduced dose craniospinal irradiation (CSI) for medulloblastoma]. Data on the late effects of newer treatments such as targeted biologicals, immune modulators, and conformal radiation with protons are extremely limited. Additional areas requiring further research include: management of impaired growth following spinal radiation and in those receiving long-term therapy with tyrosine kinases such as imatinib; optimal frequency and duration of screening studies following HP radiation; and risks and benefits of GHT in adult survivors of childhood cancer.

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