Surgery for high grade astrocytomas
These tumors are resected whenever possible.
Degree of tumor resection is the most important clinical prognostic factor.
Sub-total resection is associated with a high recurrence rate and surgery alone is rarely curative.
Chemotherapy for high grade astrocytomas
Adjuvant chemotherapy is typically added to surgery and radiation therapy.
Children’s Cancer Group study CCG-943 demonstrated a superior 5y PFS (46%) in children who received radiation and adjuvant chemotherapy (prednisone, CCNU and vincristine) compared to those that received radiation alone (18%).
Children’s Cancer Group study CCG-945 compared prednisone, CCNU and vincristine with an “8 in 1” regimen and found no statistical difference with 5y PFS rates of 35%. This study did document the favorable prognostic factor of extent of surgical resection.
One of the most important findings from CCG-945 was the observation of the unfavorable prognostic significance of mutation of the TP53 gene and / or over expression of the p53 protein in childhood malignant gliomas.
A recent phase II COG study, ACNS0126, investigated the use of temozolomide, a DNA methylating agent, given concurrently with radiation in children with high grade astrocytomas after surgical resection.
Preliminary results for ACNS0126 suggest that outcomes do not significantly differ from historical controls (CCG-945) with event free survival 37% at one year.
Mechanisms of resistance to temozolomide may include O6-alkylguanine alkyltransferase (AGT) which restores DNA to intact state after exposure to chlorethylateing and methylating agents, such as procarbazine, temozolamide and nitrosureas. AGT is often over expressed in malignant gliomas and this may correlate with worse clinical outcome.
The Pediatric Brain Tumor Consortium is investigating the use of temozolomide in combination with O6-benzylguanine, (O6-BG) which may overcome temozolamide resistance mediated by AGT.
High dose chemotherapy and autologous stem cell rescue may have a role for some patients, although treatment related toxicity is significant.
Radiation therapy for high grade astrocytomas
Always given post-operatively and improves local control and disease free survival after resection.
Radiotherapy Guidelines for high grade glioma
- A mask is made for immobilization and the placing of reference marks.
- CT scan for radiotherapy planning is then done with the patient in the mask.
- Fusion image registration software is used to identify GTV on MR and transfer that image to the CT planning scan.
- A typical total dose would be 5940 cGy in 180 cGy fractions (33 fractions in total) using a combination of an initial and boost field.
- If a Gross Total Resection has been performed, there is no boost and the total dose is 5400 cGy in 180 cGy fractions. Usually there is residual disease and therefore the total dose is usually 5940 cGy.
- Contrast-enhanced pre and post op MRI used to define clinical target volumes.
- Fusion image registration software is used to identify GTV.
Different treatment volumes are defined
GTV = Gross tumor volume = All areas of enhancement seen on a PREoperative MR scan .
CTV = Clinical target volume. Which is the GTV expanded to cover any areas of microscopic disease extension
If there is a boost – then there is an initial larger CTV1 and then treatment focuses in on a smaller boost CTV2.
PTV = Planning target volume = Volume further expanded to cover any amount of variability in set up.
CTV-1 = GTV (all enhancing areas of brain tissue on pre-operative T1 enhanced MRI study) + 2 cm margin in all directions.
Planning target volume 1 = PTV1 = CTV-1 + a 0.3 to 0.5 cm margin
CTV-2 =External Beam Boost.
Only given to patients with gross residual tumor.
CTV-2 = Enhancing residual tumor seen on T1 POSToperative MR + a 1 cm margin.
Planning target volume 2 = PTV-2 = CTV-2 + a 0.3 to 0.5 cm margin.
Heavy Particle Beam Radiation Therapy:
Neutron therapy was used historically – but there was no increase in survival compared to fractionated photon external beam radiation therapy. While it could induce tumor stabilization, this was at the expense of extensive radiation necrosis. The use of charged particles has the same theoretical advantages of neutron therapy, but can be better targeted.
Stereotactic Radiosurgery:
- Gamma knife and linear accelerator based systems can be used
- Both able to deliver a single high dose of ionizing radiation to a small target with a sharp dose fall-off
- Allows sparing of surrounding normal tissue
- This technique is often used to treat metastatic disease, but can be used as a boost for glioblastoma multiforme postoperatively, in addition to conventional focal external beam radiation
- Dose levels are similar to those used in adults
