Radiation Oncology Synopsis

PEDS CNS: Low Grade Gliomas

Background

Astrocytomas are the most common CNS tumors in children. Most are low grade gliomas. They are the most common tumors of the supratentorium. PNETs (ie medulloblastomas) are the most common infra-tentorial tumors.

These tumors are a diverse group of tumors that have variable management based on the location, patient age, genetics of the tumor (presence of mutations), and patient/parental preference.

Outcomes of low grade gliomas are generally favorable and the goal of treatment is durable disease control or cure with preservation of function. The most frequent site of origin is in the cerebellum, followed by the deep midline diencephalon. The most common site for hemispheric tumors are the frontal lobes. The deep midline diencephalon sites are:

The majority of pediatric supratentorial astrocytomas are low grade. Adult astrocytomas are predominantly high grade. A diffuse presentation with no obvious dominant mass lesion is occasionally seen. These lesions extend across two or three lobes and are classified as gliomatosis cerebri.

Typical unifocal low grade gliomas occasionally present with subarachnoid dissemination. The incidence is approximately 3% and is most often seen in those tumors of diencephalon origin.

Astrocytomas -- Low Grade Gliomas -- WHO Grade I -- Juvenile Pilocytic Astrocytoma (JPA).

The most common supratentorial location is within the diencephalon and is the second most common tumor within the telencephalon. These tumors have a characteristic Rosenthal fibers on microscopy. Dissemination is seen in about 10% and these may represent a JPA variant known as pilomyxoid astrocytoma (PXA).

JPA has intense enhancement on MRI T2 sequences. They are isointense on MRI T1 and CT imaging. They do not enhance with gadolinium contrast. Some degree of cyst formation is common with JPA and there may be small scattered calcifications. MRI is the imaging media of choice. T1 sequences may not provide the best borders.

Histology is characterized by low cellularity, little nuclear atypia, and few mitotic figures. The various histologies differ in the degree of infiltration, relative aggressiveness and prognosis. JPAs and diffuse fibrillary astrocytomas comprise the majorit of pediatric low grade gliomas.

Treatment of WHO Grade I/II Astrocytmas

LGG of grade II are "differentiated astrocytomas. 20% of all LGG are Grade II. There are no specific guidelines on treatment. For GTR, observation is sufficient. For STR observation or chemotherapy or radiotherapy. For recurrent disease treat with radiotherapy if no prior radiotherapy.

Treatment

Surgery

For low grade gliomas anatomically amenable to complete resection, surgery is the first and sole mode of treatment. GTR provides excellent control of disease. Total resection is usually feasible for tumors arising in teh cerebral hemispheres. Reports indicate GTR in 90% of low grade gliomas arising in the cerebral hemispheres. Low recurrence rates are reported in JPA and fibrillary astrocytomas after total resection from the CCG and POG study of primary surgery for low grade gliomas. CCG/POG studies indicate PFS-5 is:

Resection of the dominant medial temporal lobe, motor strip region or Broca's area may not be possible without severe neurologic sequalae. Partial resection may provide decompression and histologic diagnosis.

Resection of LGG of hte diencephalon are technically difficult due to the deep locationof the eloquent area. Contemporary series report successful resection for selected tumors in this group. Long term diseas control is typically achieved by total resection.

Radiation Therapy

Radiation therapy is an established and effective treatment for LGG, achieving tumor response and durable diseas control in a significant proportion of pediatric cases. Pollack showed improved disease control at 10 years after irradiation following complete resection. He demonstrated 82% PFS with radiation after STR/biopsy and 42% after surgery alone. However, the study did not show a difference in overall survival. More recently Merchant demonstrated similar results with 3D conformal RT: 82% PFS at 5 years and 74% at 10 years with OS-10 at 90%.

There are no contemporary data demonstrating a benefit for radiation following gross total resection. For less than GTR, early radiation may not be benificial. Current indications for radiation therapy after a near total resection with imaging evidence of residual disease, include signs/symptoms of disease that might improve with radiation or a surgically inaccessible area. Chemotherapy may be used prior to radiation therapy in those patients who are very young, or for patients with neurofibromatosis (NF1) or cognitive delay.

A POG/CCG LGG trial confirmed institutional data that a significant portion of incompletely resected astrocytomas remain indolent over a 3 - 5 year period with PFS-5 at 55% after a near total resection.

Radiotherapy Volumes and doses

Fusion MRI with CT is ideal to determine the extent of disease defining the GTV for treatment planning. T1 post-gadolinium may be ideal for JPA and diffuse Grade II astrocytomas. T2/T2-FLAIR is useful where the tumor rarely shows contrast enhancement throughout. CTV is the GTV as defined from MRI/CT with a 1 cm margin per St. Jude. Smaller margins may provide adequate control. COG is studying whether smaller margins will provide adquate control. Smaller margins require precise GTV definition with very careful attention to detail including all cystic and solid components of the tumors. Similar guidelines appear to be appropriate for Grade II (fibrillary astrocytomas. These volumes are taken to total doses of 50.4 Gy.

Diffuse astrocytomas involving both hemispheres of the diencephalon, although appearing to be LGG, behave much more aggressively and may indicate a greater degree of aggressiveness requiring larger volumes. Gliomatosis cerebri may require whole brain radiation if both hemispheres are extensively involved to a dose of at least 40 - 45 Gy before using the imaging studies to boost the area of enhancing lesions.

Astrocytomas with spinal axis seeding or multifocal subarachnoid space seeding are generally treated with craniospinal irradiation. The need to treat the entire neuroaxis is controversial and unproven.

Chemotherapy

Chemotherapy has been used with increasing frequency to delay radiation therpay. Chemotherapy use has been largely confined to central lesions occuring in younger patients which are less amenable (or not amenable) to surgery. Chemotherapy can provide control for months to years, achieving mostly stable disease or partial response. Most tumors do progress on chemotherapy at 3 - 4 years, requiring radiotherapy at the time of progression.

Chemotherapy cutoff ages are controversial. Packer reported age to be the only significant prognostic factor in PFS-3: