Central Nervous System
Radiation Therapy Late Effects
Late radiation injury is a major, dose- limiting complication of brain RT.
Two types:
- Focal
- Asymptomatic focal edema is commonly seen on CT and MR following focal or large-volume irradiation.
- Focal necrosis has the CT and MR characteristics of a mass lesion, with focal neurologic abnormalities and raised intracranial pressure (called radionecrosis).
- Microscopically characteristic vascular changes and white matter pathology ranging from demyelination to coagulative necrosis.
- Diffuse
- Diffuse radiation injury is characterized by periventricular decrease in attenuation of CT and increased signal on proton-density and T2-weighted MR images.
- Most patients are asymptomatic.
- Impairment of mental function most prominent feature
There is a wide spectrum of abnormalities, from subclinical changes detectable only by MR imaging to brain necrosis.
Pathologic findings in focal and diffuse radiation necrosis are similar.
Late radiation injury of large arteries is an occasional
cause of postradiation cerebral injury, and cerebral atrophy and
mineralizing microangiopathy are common radiologic findings of
uncertain clinical significance.
The risk of radiation damage to the brain depends on:
- Total dose of RT
- Volume of radiation
- RT fraction size
- Concurrent chemotherapy
- Patient age
- Time from therapy
Treatment Total Dose
In adults, doses of 50 Gy to whole brain in 1.8 Gy to 2.0 Gy fractions are reasonably well tolerated. In children the threshold dose is 30 Gy to 35 Gy, beyond this children less than 10 years old have a significant risk of neurocognitive delay.
Higher doses have more impact – especially in young children.
The POG (Pediatric Oncology Group)/CCG (Children’s Cancer Study Group) did a study for “good risk” medulloblastoma and found that younger children (aged less than 9 years) treated with 23.4 Gy craniospinal RT had a 10–15 IQ point advantage over those treated with 36 Gy. Older children did not demonstrate the same degree of benefit.
Treatment Volume
The larger the treatment volume, the more severe the intellectual sequelae.
Patients who have whole-brain RT have a significantly worse decline in IQ compared with those who receive either no or posterior fossa RT alone.
Dose-volume parameters of the whole brain, individual temporal lobes, supratentorial brain and infratentorial brain have been used to model changes in IQ as a function of time in children.
RT Fraction size
Larger fraction sizes are associated with an increased risk of damage. It is now recommended that children are not treated with fraction sizes greater than 1.8 Gy
Concurrent Chemotherapy
Concurrent chemotherapy have a variety of effects on long-term neurotoxicity in combination with RT that seems to be both drug and disease specific:
Carboplatinum is used as a radiosensitizer for some treatment protocols (for example in the treatment of metastatic medulloblastoma). This may be associated with an increased risk of neurotoxicity.
MTX has significant adverse effects in both children with leukemia and brain tumors. In addition, several infant brain tumor studies used MTX as part of their treatment regimen, which improved efficacy, however, long-term neurotoxicity data is not yet available.
Alkylating agents can increase the risk of radionecrosis.
Beta-interferon is contra-indicated during RT – it can lead to tumor necrosis and may cause necrosis of surrounding brain tissue.
Valproate use has been shown to be associated with a lower risk of radionecrosis.
The addition of vincristine and CCNU did not appear to have a measurable impact.
Age
The younger a child is, the more vulnerable their brain is to damage. This is especially so in the first 3 years of life because of rapid brain development during this time. In addition, many brain tumors of infancy are very large and supratentorial, which significantly increases the risk of treatment-induced dementia.
Evidence:
Comparing different age groups of children at the time of therapy:
- Aged 1–5 years had a mean IQ of 72 after therapy and 50% of patients had scores less than 80.
- Children 6–10 years had a mean IQ of 93 and 14% had IQ scores of less than 80.
- Children 11- 15 years had a mean IQ of 107 and 9% had IQ scores of less than 80.
A retrospective review of children diagnosed with medulloblastoma or cerebellar astrocytoma who were administered a test of memory functioning an average of 3.5 years after treatment revealed that IQ and memory were significantly lower than those of the normative population. No significant differences were found between the verbal and nonverbal IQ, or verbal and visual memory. The IQ scores of children less than 6 years of age at diagnosis were significantly lower than those of children diagnosed when over 6 years of age.
In another study 45% of children less than 3 years old that were given RT for medulloblastoma initially had IQs had IQs of less than 80 at 5 years following treatment but by 10 years, none of them had IQs of more than 80.
It was also noted that baseline developmental assessments were abnormal in a majority of children before therapy, thereby indicating that the influence of the tumor and/or surgery also has a significant impact on cognitive function.
Time from Therapy
Radiation-induced dementia is a progressive disease that continues to worsen as time from treatment increases. This is likely due to progressive microvasculopathy.
Evidence:
In a series of children followed after therapy for medulloblastoma:
- 58% had IQ of greater than 80, 5 years following diagnosis , however, this dropped to at 15% 10 years following treatment.
- 40% of patients were in normal academic settings at 5 years, however, this dropped to 11% at 10 years following treatment
- 10 years following treatment 36% of patients were unemployed and 64% worked in a protected environment
Radiation therapy can cause:
- Radiation necrosis
- Radiation myelopathy
- Cerebrovascular damage
