Acute toxicities:
Late Toxicities
Brain radiotherapy is administered in a variety of fashions from single fraction high dose, limited volume treatments (stereotactic radiosurgery) to well fractionated longer term treatments. Radionecrosis is a function of BED dose with an α/β = 3 (Per T. Lawrence) The risk of radionecrosis is both a function of overal dose and dose/fraction with an approximate limit of around 105 BED3 although there was necrosis found in some as low as 75 Gy BED. This effect was more pronounced at larger fraction sizes (≥ 2.5 Gy/fraction) and even more so with BID treatments.
A German study did neurocognitive analysis pre- and post-irradiation examining several dose-fraction schemes. This study found that dose/fraction > 3 Gy was significantly associated with longer term sequalae. Dose ≤ 3 Gy had reduced neurocognitive toxicity. There have also been reports of increasing leukoencephalopathy in brain irradiation as a late effect in patients who are surviving longer as our ability to control systemic disease continues to improve.
Generally accepted dose limits (Emami, EQD2):
Brain toxicity increases with younger ages. Most CCG/POG protocols attempt to defer brain radiotherapy until the child is older than 3 years. A median dose of 24 Gy is associated with substantial IQ reduction at 5 years post radiation. Toxicities are lower if dose is reduced to 18-24 Gy. Medulloblastoma treatments demonstrate 10-15 point reduction in IQ when a dose of 36 Gy was used over 23.4 Gy.
SRS was investigated by RTOG 9005. This study of recurrent brain mets demonstrated a volume dependent toxicity profile for single fraction treatments. The maximum tolerated dose in this study giving acute toxicity of 0% and late toxicity between 0 and 20%:
| Volume | Dose Limit |
|---|---|
| ≤ 2 cm | 24 Gy |
| 2.1 - 3 cm | 18 Gy |
| 3.1 cm - 4.0 cm | 15 Gy |
Re-irradiation of the whole brain is performed for recurrent, multiple brain metastases which are not amenable to SRS. Mayer and Sminia (Graz, Austria), discussed partial brain irradiation in the setting of GBM. Brain re-irradiation intervals were 3 to 55 months. There were no identified cases of radionecrosis when the EQD2 dose was kept below 100 Gy with an α/β ratio of 2 Gy. In primary CNS lymphoma WBRT is associated iwth higher risk of cognitive delcine in older (age > 60) patients. Lower doses of 23.4 Gy are associated with decrease neurocognitive toxicity.
The above data does not discuss re-irradiation of the whole brain after whole brain irradiation and data is sparse. Son, et al, DUMC with Loeffler reported at an abstract poster presentation at ASTRO on outcomes of 17 patients with recurrent intracranial disease after prior WBRT. The initial courses were between 28 - 40 Gy at 2 - 3 Gy/fraction. The median initial dose was 35 Gy and the median re-irradiation dose was 21.8 Gy at 1.8 Gy/fraction. The re-irradiation interval was 17 months with a range of 3.8 months to 3.6 - 48 months.
The findings were a median overall survival from initial RT of 24.7 months, and 5.2 months after re-irradiation. Those who had fully controlled primary disease did better. It is unclear that for patients with progressive extra-cranial disease there is significant benefit from re-irradiation. Radiobiological calculations were not done by Son et al, in their re-irradiation study, but based on their data with an initial dose of 30 Gy in 10 fractions at 3 Gy/fraction and a re-irradiation of 21.60 Gy at 1.8 Gy/fraction the EQD2 dose is 58.02 Gy based on an α/β ratio of 2 Gy as above. This seems to be consistent with the Mayer data which did not include whole brain re-irradiation and was specifically focused on Glioblastoma multiforme.
The optic apparatus is the dose limiting organ system in many head and neck and brain tumors. Damage is rare, but devastating. Toxicities include:
60 Gy appears to be the upper limit for radiation dose toxicity. The average maximum chiasm dose and optic nerve dose is kept less than 55 Gy. Dmax=64 Gy with 25% volume > 60 Gy resulted in moderate to severe complications of treatment. For SRS the maximum recommended dose to the ON/Chiasm is 8 Gy in single fractions. Toxicity risk appears to increase with age. Injury risk in children has not been widely reported.
max ≤ 55 Gy at fraction sizes ≤ 2 Gy, setting this risk at 2%. The risk increases to 5-7% if dose is increased to 55 - 60 Gy.
Radiation to the brain, base of skull and head and neck can deliver significant doses to the brainstem. Radiation injury to the brainstem follows the following deficits:
Reported incidence of brainstem radiation injury is low. Survival time, irrespective of radiation is short when the brainstem is involved with disease, and injury descriptions are not well quantified, and are thus subjective.
Emami data defined dose limiting toxicities of 1/3, 2/3 and whole brainstem doses of 60 Gy, 53 Gy and 50 Gy. Perez states that the data is not adequate to fully quantify the brainstem risk at these doses, but it appears they may be conservative.
QUANTEC concludes the entire brainstem may safely receive 54 Gy with limited risk of severe or permanent neurologic effects. The risk appears to significantly increase after >64 Gy.
Radiation injury to the cord (myelopathy) can be devastating. Fortunately, this injury is rare. In severe cases, it results in:
Myelopathy is classified as Grade 2 or higher myelitis. This includes appearance of signs and symptoms of sensory motor deficits, loss of function or pain. Radiation myelopathy rarely occurs less than 6 months after completing radiotherapy but generally within 3 years.
Spinal cord irradiation is frequently incident to the need to irradiate adjacent regions. RTOG has defined the cord volume for the purpose of computing radiation dose-volume histograms as the unexpanded cord seen on MRI with extension of cord 5-6 mm above and below the irradiated field. The overall rate of reported myelopathy is very low at doses ≤ 50 Gy at 2 Gy/fraction.
Chemotherapy may play a role in increased risk of myelopathy. There have been a few case reports of myelopathy at relatively low radiation doses to the spine, post chemotherapy. Many chemotherapeutic agents are directly neurotoxic and should be avoided during the irradiation of the CNS.