What are the side effects of whole brain radiation therapy?

Side Effects of Whole Brain Radiation Therapy

Whole brain radiation therapy (WBRT) commonly causes neurocognitive dysfunction in up to 90% of patients, significantly impacting quality of life through effects on job function, relationships, motor vehicle operation, and self-care. 1

Acute Side Effects

• Fatigue - One of the most common immediate side effects
• Skin reactions - Radiation dermatitis, particularly in head and neck regions
• Alopecia (hair loss)
• Headaches
• Nausea and vomiting
• Anorexia (loss of appetite)
• Exacerbation of existing neurologic symptoms 2

Early-Delayed Side Effects (Weeks to Months)

• Somnolence syndrome - Characterized by excessive sleepiness, fatigue, and sometimes mild fever
• Temporary worsening of neurologic symptoms
• Serous otitis media - Fluid buildup in the middle ear
• Parotitis - Inflammation of the parotid glands 2

Late Side Effects (Months to Years)

Neurocognitive Effects

• Memory deficits - Occur in up to 50% of treated patients over several months 3
• Learning impairments - Progressive deterioration in spatial learning abilities 4
• Working memory disruption 4
• Attention deficits
• Processing speed reduction
• Executive function impairment 1

Pathophysiological Mechanisms

• Cerebrovascular damage - Radiation causes rarefaction of blood vessels in the brain, particularly in the hippocampus 3, 4
• Oxidative stress - Increased pro-oxidative pathways 5
• Neuroinflammation - Activation of pro-inflammatory pathways 5
• Disruption of the extracellular matrix - Through altered matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) 5
• Impaired neurogenesis - Particularly affecting neuronal stem cells 3

Structural Brain Changes

• Radiation necrosis - Occurs in 0-30% of patients undergoing radiosurgery, typically developing 3 months to 3 years after treatment 1, 6
• White matter changes - Progressive demyelination
• Brain atrophy - Volume loss in treated regions 7

Other Late Effects

• Endocrine dysfunction - Particularly hypothyroidism and hypopituitarism 6
• Increased risk of cerebrovascular events - Stroke, carotid stenosis 6
• Secondary malignancies - Rare but serious long-term risk 2
• Increased rate of dementia - Particularly concerning in younger patients treated with WBRT 3

Risk Factors for Severe Side Effects

• Higher radiation dose - Particularly biologically effective doses >120 Gy 7
• Larger treatment volumes
• Concurrent chemotherapy
• Advanced age
• Diabetes
• Fraction size >2.5 Gy - Associated with unpredictable toxicity 7
• Twice-daily fractionation with biologically effective dose >80 Gy 7

Management Strategies

Pharmacological Approaches

• Memantine - NMDA receptor antagonist that may help preserve cognitive function
• Donepezil - Acetylcholinesterase inhibitor showing slight benefits for recognition memory after radiation 1
• Methylphenidate - May improve attention, though evidence is limited 1
• Modafinil - For wakefulness, though randomized trials showed no improvement in fatigue 1
• Glucocorticoids - First-line therapy for symptomatic radiation necrosis 1, 6
• Bevacizumab - For radiation necrosis unresponsive to steroids 1

Non-Pharmacological Approaches

• Cognitive rehabilitation - Compensatory strategies and "cognitive exercise" paradigms have shown positive results 1, 6
• Hippocampal-sparing techniques - When feasible, can reduce neurocognitive side effects 1
• Stereotactic radiosurgery (SRS) - When appropriate as an alternative to WBRT, has fewer cognitive side effects 1
• Surgical resection or laser interstitial thermal therapy (LITT) - For symptomatic radiation necrosis unresponsive to medical management 1

Prevention Strategies

• Hippocampal avoidance WBRT (HA-WBRT) - Reduces radiation dose to the hippocampus while treating the rest of the brain 1
• Intensity-modulated radiotherapy (IMRT) - Improves precision and may reduce toxicity 6
• Fractionation schemes - Using appropriate fraction sizes (<2.5 Gy) may reduce risk of necrosis 7

Monitoring Recommendations

• Regular assessment of cognitive function during and after treatment
• Long-term follow-up to monitor for late effects
• Multidisciplinary approach for management of complex toxicities 6

Patients should be informed about these potential side effects before treatment, with particular emphasis on the risk of neurocognitive decline that may affect quality of life. The decision between WBRT versus stereotactic approaches should consider the extent of disease, patient age, and tumor characteristics, as SRS/SRT has become the predominant upfront strategy for patients with limited intracranial disease due to the cognitive dysfunction associated with WBRT 1.