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

ACTHD in Childhood Cancer Survivors

Epidemiology, Morbidity, and Mortality

ACTHD is characterized by inadequate cortisol secretion due to impaired production/secretion of ACTH. It can result from damage to the hypothalamus and/or pituitary gland due to tumors and/or surgery in the HP region (e.g., craniopharyngiomas, suprasellar germinomas, optic pathway gliomas)[45,164,165] or to HP injury following high-dose (>30 Gy) HP radiation.[47]

The prevalence of ACTHD (excluding exogenous steroid use) varies by tumor type and treatment.[164–166] ACTHD has been associated with increased morbidity and mortality in pediatric survivors.[167,168]

Etiology and Clinical Manifestations

We list the major risk factors for ACTHD in Table 1. Although transient ACTHD secondary to exogenous glucocorticoids is very common in this population, particularly during active cancer treatment, this guideline focuses on permanent forms of ACTHD. The clinical symptoms most commonly associated with ACTHD in cancer survivors are similar to those described in the noncancer population.[79] Given the nonspecific nature of these symptoms, it may be very difficult to distinguish between symptoms related to the underlying cancer, comorbidities from the disease and its treatment, or the presence of ACTHD. Partial ACTHD may be asymptomatic; thus, clinicians might not diagnose it unless they have a high degree of suspicion.

Diagnosing ACTHD in Childhood Cancer Survivors

   6.1 We recommend lifelong annual screening for ACTHD in childhood cancer survivors treated for tumors in the HP region and in those exposed to ≥30 Gy HP radiation. (1∣⊕⊕⊕O)

   6.2 We suggest screening for ACTHD in childhood cancer survivors exposed to between ≥24 Gy and 30 Gy HP radiation who are >10 years postradiation or develop clinical symptoms suggestive of ACTHD. (2∣⊕OOO)

   6.3 We advise using the same screening and dynamic testing procedures to diagnose ACTHD in childhood cancer survivors as are used in the noncancer population (Table 2). (Ungraded Good Practice Statement)

    Technical remark: Clinicians should consider the influence of oral estrogen on total cortisol levels, as it can increase cortisol-binding globulin raising total, but not free, cortisol levels.

Evidence. Radiation-induced ACTHD is known to be both time- and dose-dependent.[169] Following HP radiation, ACTHD appears to occur less commonly than GH and LH/FSH deficiencies and is present primarily in childhood cancer survivors treated with doses of HP radiation >30 Gy,[47,151,166,170,171] although the precise prevalence varies depending on the population studied, length of follow-up, and the type of biochemical testing used (4% to 43%). The two largest studies to assess ACTHD risk following HP radiation reported most cases of ACTHD in survivors exposed to >30 to 40 Gy HP radiation.[47,166] Although ACTHD is uncommon in subjects treated with HP doses ≤24 Gy,[47,166,170,172] a recent study of adult survivors of acute leukemia followed for >10 years reported biochemical evidence of ACTHD in more than a third of survivors exposed to a mean HP dose of 24 Gy.[173] Data indicate that new cases of ACTHD emerge as late as 25 or more years after HP radiation.[47]

A variety of tests are available for diagnosing ACTHD, including the ITT, standard- and low-dose ACTH stimulation test, glucagon stimulation test, and the overnight oral metyrapone test. Controversy exists as to which modality is the most reliable in establishing a diagnosis of ACTHD, irrespective of the underlying cause.[90,166,169,174,175] Additionally, several factors can affect the determination of cortisol levels in plasma, including changes in cortisol-binding globulin. Of note, females taking oral contraceptives have elevated cortisol-binding globulin levels, which can make the interpretation of cortisol levels difficult.[174] Although many view the ITT as the "gold standard" to diagnose ACTHD, most clinicians use the ACTH stimulation test due to its convenience and safety profile.[174] The Endocrine Society's guideline on hormonal replacement in hypopituitarism in adults[79] includes recommendations for testing for ACTHD. Two recently published systematic reviews and meta-analyses on ACTH stimulation tests for diagnosing adrenal insufficiency—one performed by the Endocrine Society in both adults and children[176] and one confined only to ACTHD in children[177]—concluded that the standard- and low-dose ACTH stimulation tests had similar accuracy for diagnosing ACTHD. Moreover, the study by Ospina et al.[176] concluded that both standard- and low-dose ACTH stimulation tests are adequate to rule in, but not rule out, ACTHD. Depending on the dilution method used when performing the low-dose ACTH stimulation test, there may be considerable variation in the actual dose delivered, raising the risk of inaccurate dosing and invalid results.[178] Appreciation of the pretest probability of ACTHD and the limitations of the assays for cortisol (as well as the limitations of the various dynamic tests) are critical in establishing a diagnosis of ACTHD.

Treating ACTHD in Childhood Cancer Survivors

   6.4 We advise that clinicians use the same glucocorticoid regimens as replacement therapy in childhood cancer survivors with ACTHD as are used in the noncancer population with ACTHD (Table 2). (Ungraded Good Practice Statement)

   6.5 We recommend that clinicians instruct all patients with ACTHD regarding stress dose and emergency glucocorticoid administration and instruct them to obtain an emergency card/bracelet/necklace regarding adrenal insufficiency and an emergency kit containing injectable high-dose glucocorticoid. (1∣⊕⊕⊕O)

Evidence. The Endocrine Society's guidelines on primary adrenal insufficiency[179] and treating ACTHD in adults[79] include recommendations for physiologic daily replacement and for treating suspected adrenal crisis. Separate studies exist for treating ACTHD during childhood and adolescence.[174] However, there are no specific studies addressing the treatment of ACTHD in childhood cancer survivors. Glucocorticoid deficiency has been shown to impair free water clearance, which can mask the symptoms of polyuria in subjects with central diabetes insipidus.[180] Thus, when initiating glucocorticoid replacement therapy, clinicians should monitor for the development of diabetes insipidus in at-risk patients and the exacerbation of symptoms in those with pre-existing partial diabetes insipidus. Some antiepileptics enhance hepatic CYP450 isoenzyme activity (e.g., phenytoin, carbamazepine, oxcarbazepine, and topiramate), which can affect the metabolism of glucocorticoids, especially dexamethasone. A recent guideline reviews the management of glucocorticoids in subjects taking enzyme-inducing antiepileptics.[79]

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....