What are the endocrinological and neurocognitive outcomes in pediatric Central Nervous System (CNS) tumors treated with radiotherapy?

Endocrinological and Neurocognitive Outcomes in Pediatric CNS Tumors Treated with Radiotherapy

Serial monitoring of cognitive and endocrine functions with specific batteries following radiotherapy is recommended whenever feasible in pediatric CNS tumor patients, as these represent the most significant long-term sequelae of treatment. 1

Endocrinological Outcomes

Hypopituitarism Development

• Growth hormone deficiency is universally present by 5 years after radiotherapy in children who undergo cranial radiation for CNS tumors 1
• Hypopituitarism with multiple hormone deficiencies evolves progressively over time, with an incidence of approximately 20% at 5 years after radiotherapy and 80% at 10-15 years 1
• Lifelong follow-up for hypopituitarism is mandatory in children who undergo radiotherapy, with planned transition to specialist adult endocrine services 1

Pre-existing Endocrine Dysfunction

• Preirradiation endocrine deficiencies are common, particularly in suprasellar tumors (present in 6 of 6 suprasellar germinomas in one series) 2
• The tumor location itself contributes to endocrine dysfunction independent of radiation effects 1

Dose-Related Considerations

• Even low radiation doses (<20 Gy) delivered to supratentorial brain structures have measurable impact on endocrine function 1
• The radiation dose remains the most clinically significant determinant of endocrine outcomes 1

Neurocognitive Outcomes

Cognitive Decline Patterns

• Neurocognitive decline occurs in up to 90% of patients with brain metastases (though this data is from adult populations, it highlights the severity of radiation-related cognitive effects) 1
• The young brain is more vulnerable to injury from radiation than the adult brain, despite greater neuroplasticity 1
• Neurocognitive effects are directly correlated with the volume of tissue irradiated and dose delivered, and inversely correlated with age at treatment 3

Intelligence Quotient (IQ) Impact

• Long-term follow-up studies demonstrate that radiation dose is the most clinically significant determinant of IQ outcomes 1
• Even low doses such as <20 Gy delivered to the supratentorial brain have measurable impact on IQ 1
• Some studies show no significant differences between pre- and postirradiation full-scale, verbal, and performance IQ scores in germinoma patients treated with craniospinal irradiation, though this may reflect the specific tumor type and treatment approach 2

Age-Specific Vulnerabilities

• Cranial radiation may result in developmental impairments in young children; therefore, it is reasonable to defer or omit radiotherapy in children <3 years of age 1
• Younger children, especially those under 5 years, are at increased risk of vasculopathy and cognitive impairment from radiation 1
• Children receiving radiotherapy are at risk for neurocognitive effects, neuroendocrine dysfunction, hearing loss, vascular anomalies and events, and psychosocial dysfunction 3

Radiation Technique Considerations

Modern Conformal Approaches

• Development of more conformal radiation techniques (intensity-modulated radiation therapy, proton therapy) has decreased inadvertent radiation dose to normal tissues and should decrease long-term treatment sequelae 4
• Proton radiation eliminates exit dose to normal tissues, thereby eliminating approximately 50% of unnecessary radiation to normal tissues 4
• Proton therapy may be particularly useful for posterior fossa ependymomas, as it can spare dose exposure to supratentorial compartments of the brain and auditory structures 1

Radiation Necrosis Risk

• Stereotactic radiosurgery might carry a higher risk of radionecrosis in children and young people compared to standard fractionated external beam radiotherapy 1
• Recent studies suggest that brainstem toxicity, including radiation necrosis, can occur with proton treatment 1

Additional Late Effects

Cerebrovascular and Secondary Malignancy Risk

• Other late effects of concern in children include cerebrovascular events and second malignancies 1
• A 2.4% risk of secondary brain tumors at 20 years after surgery and radiotherapy for pituitary adenoma has been reported in adults 1
• With every 10 years of younger age, the risk of developing a malignant brain tumor increases by 2.4-fold and the risk of meningioma increases by 1.6-fold after radiotherapy 1
• There is a statistically significant increased risk of developing malignant brain tumors and meningiomas after radiotherapy for pituitary tumors, especially when given at age <30 years 1

Hearing Loss

• Children receiving radiotherapy are at risk for hearing loss, which is dose-volume dependent 3

Clinical Management Implications

Monitoring Protocols

• Serial monitoring of cognitive and endocrine functions with specific batteries following radiotherapy is recommended whenever feasible 1
• Follow-up for hypopituitarism needs to be lifelong 1
• Regular assessment should include growth parameters, multiple pituitary hormone axes, and formal neurocognitive testing 1

Treatment Modifications

• For children <3 years, chemotherapy alone is recommended to avoid radiation-related brain injury 1
• When radiation is necessary in young children (12-18 months), doses can be lowered to 54 Gy compared to the standard 59.4 Gy used in older children 1
• Modern volumetric planning and advanced beam characteristics (intensity-modulated photons, protons) should be utilized to limit the volume of tissue irradiated and dose delivered 3