Full Guideline: Hypothalamic–Pituitary and Growth Disorders in Survivors of Childhood Cancer: An Endocrine Society Clinical Practice Guideline
JCEM August 2018
Charles A. Sklar (Chair), Zoltan Antal, Wassim Chemaitilly, Laurie E. Cohen, Cecilia Follin, Lillian Meacham, M. Hassan Murad
The 2018 guideline on hypothalamic–pituitary and growth disorders in survivors of childhood cancer:
- Provides recommendations for the diagnosis and treatment of hypothalamic-pituitary abnormalities and management of impaired growth in childhood cancer survivors
- Emphasizes improving the quality of life and reducing morbidity of cancer survivors
- Prioritizes routine lifelong follow-up with an appropriate specialist
Essential Points
- Establishes a framework for the appropriate diagnosis and treatment of these high-risk individuals;
- Hypothalamic-pituitary dysfunction is frequently observed in childhood cancer survivors, especially those with tumors involving the hypothalamic-pituitary region or those previously exposed to radiation to the central nervous system;
- Radiation-induced hypothalamic-pituitary dysfunction is both dose- and time-dependent; doses to the hypothalamus-pituitary <30 Gy are associated primarily with GH deficiency and precocious puberty whereas deficits of LH/FSH, TSH and ACTH are seen following hypothalamic-pituitary doses >30 Gy, often years after completion of cancer therapy;
- Impaired linear growth and short adult height are most common in survivors exposed at a young age to central nervous system, spinal or total body irradiation;
- While the testing for and treatment of many of these disorders in cancer survivors are like that in the non-cancer population, the guideline emphasizes key differences and unique features/findings that are specific to the cancer survivor.
List of Recommendations
+ 1.0 SHORT STATURE/IMPAIRED LINEAR GROWTH IN CHILDHOOD CANCER SURVIVORS
Diagnosis and Monitoring of Short Stature/Impaired Linear Growth in Childhood Cancer Survivors
- 1.1 We recommend prospective follow-up of linear growth for childhood cancer survivors at high risk for short adult height, namely those exposed to cranial radiation therapy, craniospinal irradiation, or total body irradiation at a young age and those with a history of inadequate weight gain or prolonged steroid requirement.(1 |⊕⊕⊕O)
- 1.2 We recommend measuring standing height and sitting height in childhood cancer survivors treated with radiation that included the spine (i.e., total body irradiation, craniospinal irradiation, as well as radiation to the chest, abdomen, or pelvis). (1 |⊕⊕OO)
Technical Remark
Sitting height is measured directly using a sitting height stadiometer, and lower segment can be determined by subtracting sitting height from standing height. Alternatively, lower segment can be determined by measuring from the pubic symphysis to the floor, and upper segment can be determined by subtracting leg length from height. Upper to lower segment ratio can then be calculated but differ depending on method used and ethnicity. In situations where clinicians are unable to measure sitting height, measuring arm span and comparing it to standing height will provide an estimate of spinal foreshortening due to prior spinal radiation.
Treatment of Short Stature/Impaired Linear Growth in Childhood Cancer Survivors
- 1.3 We suggest against using growth hormone in cancer survivors who do not have growth hormone deficiency to treat for short stature and/or poor linear growth following spinal irradiation. (2|⊕OOO)
- 1.4 We suggest against treatment with growth hormone in children with short stature and/or impaired linear growth who are being treated with tyrosine kinase inhibitors. (2|⊕OOO)
+ 2.0 GROWTH HORMONE DEFICIENCY IN CHILDHOOD CANCER SURVIVORS
Diagnosis of Growth Hormone Deficiency in Childhood Cancer Survivors
- 2.1 We recommend lifelong periodic clinical assessment for growth hormone deficiency in survivors treated for tumors in the region of the hypothalamic-pituitary axis and in those exposed to hypothalamic-pituitary axis radiation treatment >18 Gy (e.g., various brain tumors, nasopharyngeal carcinoma, acute lymphoblastic leukemia, lymphoma). (1|⊕⊕⊕O)
Technical Remark
The consensus of the writing committee is to assess height in children every 6-12 months.
- 2.2 We recommend against relying solely on serum insulin-like growth factor-1 levels in childhood cancer survivors exposed to hypothalamic-pituitary axis radiotherapy in order to make the diagnosis of growth hormone deficiency. (1|⊕⊕OO)
- 2.3 We advise using the same provocative testing to diagnose growth hormone deficiency in childhood cancer survivors as are used for diagnosing growth hormone deficiency in the non-cancer population. (Ungraded Good Practice Statement)
- 2.4 We recommend against the use of growth hormone-releasing hormone alone or in combination with arginine in childhood cancer survivors to diagnose growth hormone deficiency after hypothalamic-pituitary axis radiation. (1|⊕⊕OO)
- 2.5 We suggest against using spontaneous growth hormone secretion (e.g., 12-hour overnight sampling) as a diagnostic test in determining growth hormone deficiency in childhood cancer survivors. (2|⊕OOO)
- 2.6 We recommend that formal testing to establish a diagnosis of growth hormone deficiency is not required in childhood cancer survivors with three other confirmed anterior pituitary hormone deficits. (1|⊕⊕OO)
- 2.7 We recommend retesting adult cancer survivors exposed to hypothalamic-pituitary axis radiation treatment and with a diagnosis of isolated growth hormone deficiency in childhood. (1|⊕⊕OO)
Treatment of Growth Hormone Deficiency in Childhood Cancer Survivors
- 2.8 We recommend offering growth hormone treatment in childhood cancer survivors with confirmed growth hormone deficiency based on the safety and efficacy demonstrated in that population. (1|⊕⊕OO)
- 2.9 We suggest waiting until the patient has been 1 year disease-free, following completion of therapy for malignant disease, before initiating growth hormone treatment. (2|⊕OOO)
- 2.10 In childhood cancer survivors who have chronic stable disease and thus my not ever be “disease-free” (particularly survivors treated for optic pathway tumors), we advise discussing the appropriateness of growth hormone treatment and its timing with their oncologist. (Ungraded Good Practice Statement)
- 2.11 We advise treating growth hormone-deficient childhood cancer survivors with similar growth hormone treatment regimens as are appropriate for individuals with growth hormone deficiency from the non-cancer population. (Ungraded Good Practice Statement)
+ 3.0 CENTRAL PRECOCIOUS PUBERTY IN CHILDHOOD CANCER SURVIVORS
Diagnosis of Central Precocious Puberty in Childhood Cancer Survivors
- 3.1 We recommend periodically assessing childhood cancer survivors for evidence of central precocious puberty if they have a history of hydrocephalus, tumors developing in or near the hypothalamic region, and/or have been exposed to hypothalamic-pituitary radiation. (1|⊕⊕⊕O)
- 3.2 We recommend against using testicular volume as the primary or sole indicator of degree of sexual development in male childhood cancer survivors previously treated with gonadotoxic agents, such as alkylating agents or testicular radiotherapy. (1|⊕⊕⊕O)
- 3.3 We recommend measuring serum testosterone, preferably using liquid chromatography-tandem mass spectroscopy, and luteinizing hormone levels prior to 10 a.m. to complement the clinical assessment of male childhood cancer survivors who are suspected of or are at risk of developing central precocious puberty and were exposed to gonadotoxic treatments. (1|⊕⊕OO)
Technical Remark
Clinicians need to interpret plasma luteinizing hormone levels in patients exposed to gonadotoxic treatments in the context of their medical history and physical examination. Elevated luteinizing hormone levels in such patients may be due to primary gonadal injury rather than to the onset of central puberty.
Treatment of Central Precocious Puberty in Childhood Cancer Survivors
- 3.4 We advise that the indications and the type of treatment regimens for central precocious puberty in childhood cancer survivors should be similar to those used for central precocious puberty in the non-cancer population. (Ungraded Good Practice Statement)
+ 4.0 HYPOGONADOTROPIC HYPOGONADISM IN CHILDHOOD CANCER SURVIVORS
Diagnosis of Luteinizing Hormone/Follicle-Stimulating Hormone Deficiency in Childhood Cancer Survivors
- 4.1 We recommend screening for luteinizing hormone/follicle-stimulating hormone deficiency in childhood cancer survivors exposed to hypothalamic-pituitary axis radiation at doses ≥30 Gy and in those with a history of tumors or surgery affecting the hypothalamic-pituitary axis region. (1|⊕⊕⊕O)
- 4.2 We advise using the same strategies to diagnose luteinizing hormone/follicle-stimulating hormone deficiency in childhood cancer survivors as are used in the non-cancer population. (Ungraded Good Practice Statement)
Treatment of Luteinizing Hormone/Follicle-Stimulating Hormone Deficiency in Childhood Cancer Survivors
- 4.3 We advise following the same treatment approach to luteinizing hormone/follicle-stimulating hormone deficiency in childhood cancer survivors as is appropriate in the non-cancer population. (Ungraded Good Practice Statement)
+ 5.0 CENTRAL HYPOTHYROIDISM—THYROID-STIMULATING HORMONE DEFICIENCY IN CHILDHOOD CANCER SURVIVORS
Diagnosis of Central Hypothyroidism in Childhood Cancer Survivors
- 5.1 We recommend lifelong annual screening for thyroid-stimulating hormone deficiency in childhood cancer survivors treated for tumors in the region of the hypothalamic-pituitary axis and those exposed to ≥30 Gy hypothalamic-pituitary radiation. (1|⊕⊕⊕O)
- 5.2 We advise using the same biochemical tests to screen for thyroid-stimulating hormone deficiency in childhood cancer survivors as are used in the non-cancer population. (Ungraded Good Practice Statement)
- 5.3 We recommend against using serum triiodothyronine, thyroid-stimulating hormone surge analysis, or thyrotropin-releasing hormone stimulation to diagnose thyroid-stimulating hormone deficiency. (1|⊕⊕OO)
Treatment of Thyroid-Stimulating Hormone Deficiency in Childhood Cancer Survivors
- 5.4 We advise using the same approach to treat thyroid-stimulating hormone deficiency in childhood cancer survivors as is used in the non-cancer population. (Ungraded Good Practice Statement)
+ 6.0 ADRENOCORTICOTROPHIC HORMONE DEFICIENCY IN CHILDHOOD CANCER SURVIVORS
Diagnosing Adrenocorticotrophic Hormone Deficiency in Childhood Cancer Survivors
- 6.1 We recommend lifelong annual screening for adrenocorticotrophic hormone deficiency in childhood cancer survivors treated for tumors in the hypothalamic-pituitary region and in those exposed to >30 Gy hypothalamic-pituitary radiation. (1|⊕⊕⊕O)
- 6.2 We suggest screening for adrenocorticotrophic hormone deficiency in childhood cancer survivors exposed to between ≥24 Gy and 30 Gy hypothalamic-pituitary radiation who are more than 10 years post radiation or develop clinical symptoms suggestive of adrenocorticotrophic hormone deficiency. (2|⊕OOO)
- 6.3 We advise using the same screening and dynamic testing procedures to diagnose adrenocorticotrophic hormone deficiency in childhood cancer survivors as are used in the non-cancer population. (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.
Treating Adrenocorticotrophic Hormone Deficiency in Childhood Cancer Survivors
- 6.4 We advise that clinicians use the same glucocorticoid regimens as replacement therapy in childhood cancer survivors with adrenocorticotrophic hormone deficiency as are used in the non-cancer population with adrenocorticotrophic hormone deficiency. (Ungraded Good Practice Statement)
- 6.5 We recommend that clinicians instruct all patients with adrenocorticotrophic hormone deficiency 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)
