Background
Retrospective cohort study. 222 pediatric and young adult patients (median age 9 years) treated with cranial RT for CNS tumors or ALL at Boston Children's Hospital/Dana-Farber. Evaluated the relationship between radiation dose to hypothalamus and pituitary gland and rates of endocrine deficiencies (growth hormone deficiency, central hypothyroidism, ACTH deficiency, gonadotropin deficiency, central precocious puberty) on serial endocrine testing. Vatner RE et al, JCO 2018. PMID 30118397.
Interventions and follow up
Arm A: Various cranial RT regimens: CSI (23.4–36 Gy) + boost, whole brain RT (18–24 Gy), or focal cranial RT; proton and photon patients included
Primary endpoint: Actuarial incidence of endocrine deficiencies by hypothalamic-pituitary dose
mFollow up: 7.2 year
Primary endpoint: Actuarial incidence of endocrine deficiencies by hypothalamic-pituitary dose
mFollow up: 7.2 year
Results
Comparison: Dose-response analysis — hypothalamic and pituitary Dmax and mean dose vs incidence/latency of each endocrine deficiency
GHD incidence (hypothalamic Dmax >30 Gy): 60% at 5 years vs <30 Gy 20%, P<.001
Central hypothyroidism threshold: Pituitary mean dose >30 Gy associated with 40% incidence
ACTH deficiency: Pituitary mean dose >50 Gy required for significant incidence
Proton vs photon: Proton significantly reduces hypothalamic/pituitary dose for non-centrally-located tumors
GHD incidence (hypothalamic Dmax >30 Gy): 60% at 5 years vs <30 Gy 20%, P<.001
Central hypothyroidism threshold: Pituitary mean dose >30 Gy associated with 40% incidence
ACTH deficiency: Pituitary mean dose >50 Gy required for significant incidence
Proton vs photon: Proton significantly reduces hypothalamic/pituitary dose for non-centrally-located tumors
Adverse events
Main adverse events: Endocrine: GHD most common (50% at 10 years for cranial RT patients); central hypothyroidism 20%; adrenal insufficiency 8%; gonadotropin deficiency 12%. All endocrine deficiencies require hormone replacement. Growth failure from GHD impairs final adult height if not treated early.
Conclusions
Hypothalamic and pituitary dose are the key determinants of RT-induced endocrine deficiency in children. Dose thresholds are clearly defined: GHD sensitive at >18 Gy hypothalamic Dmax; central hypothyroidism and ACTH deficiency require higher doses (>30–50 Gy). Proton therapy can meaningfully reduce hypothalamic-pituitary dose for many pediatric CNS tumors.
Key Limitations
Key Limitations: Retrospective; endocrine testing intervals varied. Not all patients had proton vs photon assignment randomized. Confounding by age, tumor location, and chemotherapy. Long-term endocrine follow-up beyond 10 years required to capture all late-onset deficiencies.
Clinical Context
Vatner et al data inform dose constraints for hypothalamus and pituitary in pediatric RT planning. Proton therapy reduces hypothalamic-pituitary dose for tumors away from the midline (e.g., ependymoma, medulloblastoma boost). Serial endocrine monitoring (annual GH stimulation, TFTs, cortisol, FSH/LH) is mandatory after cranial RT in children. GH replacement when GHD confirmed — started after minimum 1-year tumor remission.
References