Risk of Developing Endocrinopathy Determined in Children and Young Adults after Radiotherapy for Brain Tumours

Age-dependant dose response observed regarding radiotherapy for brain cancer and the development of subsequent endocrinopathy

Although endocrine dysfunction is a common late effect in children and young adults treated with radiotherapy for brain tumours that is associated with significant morbidity and treatment cost for the survivors, little is know about the actual risk of developing endocrine dysfunction according to dose and patient age. 

According to lead author Ralph E. Vatner University of Cincinnati College of Medicine and Cincinnati Children’s Hospital Medical Centre in Cincinnati, USA and colleagues there are sparse data to date that define the dose response of radiation therapy delivered to the hypothalamus and pituitary in paediatric and young adult patients with brain tumours. 

The investigators reported findings from a study that elaborated the relationship of radiotherapy dose to the hypothalamus and pituitary received during treatment and the development of endocrine dysfunction in this patient population in an article appearing in the August 2018 edition of the Journal of Clinical Oncology.  

Their analysis provides dosimetric and clinical data from three prospective studies conducted from 2003 to 2016. 

The studies included children and young adults aged 0.1 to 26 years of age who received proton radiotherapy for brain tumours. The analysis clinically and serologically determined subsequent deficiencies of growth hormone, thyroid hormone, adrenocorticotropic hormone, and gonadotropins subsequent to treatment. The incidence of such deficiencies was estimated using the Kaplan-Meier method and multivariate models were constructed to determine the relationship of radiation dose to any endocrine deficiency. 

Radiotherapy was most likely to affect growth hormone production 

Of the 222 patients in the study, 130 (68.8%) were treated with craniospinal irradiation with boost for medulloblastoma and 56 patients received field radiotherapy; of these 26 (13.8%) patients were treated for ependymoma and 14 (7.4%) for low-grade glioma. 

A total of 189 patients were evaluable by actuarial analysis; 31 (14%) patients were excluded from actuarial analysis for having baseline hormone deficiency and two (0.9%) patients were excluded due to lack of follow-up. Median follow-up was 4.4 years (range, 0.1 to 13.3 years).  

Over the duration of follow-up, the incidence of any hormone deficiency was 48.8%. The incidence of growth hormone deficiency was 37.4%, thyroid hormone was 20.5%,  adrenocorticotropic hormone was 6.9%, and the incidence of gonadotropin deficiency was 4.1%. 

No significant difference in the rate of thyroxin, adrenocorticotropic hormone, or gonadotropin deficiency was observed according to age group. However, a higher rate of growth hormone deficiency was observed in patients aged 6 to 10 years that was increased over these rates reported for patients in the younger and older groups of patients. 

The dose received and the age of treatment both affect the probability of developing subsequent endocrinopathy 

Both the dose of radiation received and the patient’s age at initiation of treatment played a role in the development of endocrine deficiency over time. The incidence of deficiency was highest in patients receiving a hypothalamic and pituitary median dose ≥ 40 GyRBE and lowest among those who receiving ≤ 20 GyRBE

When data were stratified according to the patient’s age at the initiation of radiotherapy, it was observed that patients treated between 6 and 10 years of age had a higher rate of endocrinopathy than patients less than 6 years old at treatment onset. Patients ≥10 years of age at the time of treatment showed the lowest incidence of hormone deficiency. 

In order to highlight the contribution of both dose and age to endocrine deficiency following cranial radiotherapy, the investigators gave the following example: A 5-year-old receiving 20 GyRBE to the hypothalamus and pituitary had a 40% chance of developing endocrinopathy and a 30% chance of developing growth hormone deficiency within 5 years of treatment, whereas a 15-year-old receiving the same dose had just a 23% chance of developing endocrinopathy and a 5% chance of developing growth hormone deficiency within 5 years. 

Conclusions 

The authors pointed out that the relationship between the hypothalamic and pituitary dose received and the development of endocrine deficiency has important implications for treatment. They discussed how more modern radiotherapy techniques using proton or intensity-modulated photon radiotherapy allow for the identification and avoidance of the hypothalamus and pituitary, and suggested that these techniques should decrease the risk of endocrinopathy. This further supports the use of proton radiotherapy or intensity modulated radiotherapy for paediatric brain tumours. 

They further noted that the dose-response relationship is age dependent, thus rendering data from adult patients inappropriate for application to paediatric and young adult patients. 

The investigators presented models for predicting risk of developing growth hormone, thyroid hormone, cortisol, and sex steroid deficiency according to patient age at treatment and the radiation dose to the hypothalamus and pituitary in children and young adults with brain tumours. 

They suggest that these data provide support minimising the dose to the pituitary and hypothalamus when possible using modern radiotherapy techniques. 

Furthermore, they provide models that may be a useful clinical tool in predicting the risk of endocrinopathy after radiotherapy for brain tumours. 

Disclosure 

No external funding was disclosed. 

Reference 

Vatner RE, Niemierko A, Misra M, et al. Endocrine Deficiency as a Function of Radiation Dose to the Hypothalamus and Pituitary in Pediatric and Young Adult Patients With Brain Tumors. J Clin Oncol; Published online 17 August 2018. DOI:  10.1200/JCO.2018.78.1492