Radiation Oncology Synopsis

Low Grade Gliomas

Background

Low grade gliomas include WHO Grade I and II disease. These tumors account for about 15% of all primary CNS tumors and are more commonly found in whites over others by a 2:1 ratio. Low grade gliomas are subdivided into non-infiltrative (WHO Grade I) or infiltrative (WHO Grade II) disease. The histologic subtypes associated with these grades are:

WHO Grading is based on 4 pathologic features:

Gemistocytic subtype low grade glioma has the worst prognosis of the Grade II gliomas. It tends to de-differentiate and some advocate treating it as a high grade glioma.

Grade I Low Grade Gliomas

JPA most commonly presents in the posterior fossa with 80% occuring in the cerebellum while the other 20% are supratentorial. JPA's are associated with Rosenthal fibers which are characteristic. JPA's are predominantly a disease of young children with the most common age of presentation 10 - 20 years.

Grade II Low Grade Gliomas

Most Grade II low grade gliomas commonly present in the supratentorium. Grade II low grade gliomas present at a later age, generally being adults in their 30s and 40s.

PMA (pylomyxoid astrocytoma) tends to occur in infants between 10 and 18 months. The disease is mostly in the chiasmatic-hypothalmus regions. PMAs are considered an atypical JPA with a higher rate of CSF dissemination and recurrence.

Oligodendrogliomas occur in the cerebral hemisphers over 80% of the time. They are Grade II gliomas which have a characteristic fried egg appearance histologically. These are small round cells with a nuclear halo which are characteristic of oligodendrogliomas. Loss of heterozygosity of 1p/19q occurs in 50% - 70% and is a favorable prognostic indicator.

Anaplastic transformation occurs in many low grade gliomas with reports of transformation as high as 70% - 80%, based on the EORTC 22845 study.

The EORTC 22845 was a study of prognostic factors for survival in adult cerebral low grade gliomas by Pignatti (JCO 2002), This study looked at 322 patients and identified several poor prognosis factors:

Pignatti noted no impact from extent of surgery on prognosis.

Oligodendrogliomas

In those who have LOH 1p19q the median overall survival is 13 years. For those without LOH 1p19q, the median survival is 9 years.

Workup and Staging

The workup for a suspected glioma is an H&P, basic labs and MRI of the brain. A tissue diagnosis should be obtained by maximum safe resection. otherwise, b stereotactic biopsy.

Gliomas on MRI are hypodense on T1 imaging and are non-enhancing with Gd contrast. They show T2 enhancement. JPA are identified on MRI by a well circumscribed cystic mass, with an intensely enhancing solid mural nodule. Oligodendgrogliomas present with calcifications. these calcifications are a prominent feature of oligodendrogliomas.

MRI Spectroscopy will demonstrated increased choline, low creatine, and low N-acetyl-aspartate markers which are suggestive of malignancy on MR spectroscopy.

Tissue diagnosis is important as 30% of non-enhancing gliomas are Grade III. 65% are low grade gliomas.

While there is formal WHO grading, there is no formal stagng for CNS primary tumors.

Treatment and Prognosis

General Treatment Pardigm

The general treatment for low grade gliomas is maximum safe resection followed by observation for gross total resection and subtotal resection. Radiotherapy is reserved for recurrence or progression. Salvage chemotherapy may be used. The typical adjuvant chemotherapy regimens are:

Surgical Management

About 1/3 of all patients with low grade gliomas have a gross total resection. A post operative MRI should be done within 48 - 72 hours of surgery to assess for residual disease and to determine the extent of resection. Per the Pignatti/EORTC 22844 trial extent of surgery is not reflective on prognosis.

The RFS-10 in JPA is 95% in those treated with gross total resection alone.

Radiation Therapy

Radiation therapy for low grade gliomas plays a somewhat limited role. The main role is for patients with STR/Biopsy and with symptoms of disease. In addition, radiotherapy is indicated for patients with at least 3 of the following 5 adverse risk factors per the EORTC 22845 index:

  1. Age > 40
  2. Astrocytoma histology
  3. Tumors > 6 cm
  4. Tumors crossing midline
  5. Pre-operative neurologic deficits.
 NEED AT LEAST 3 OF 5 FOR RT

Low grade gliomas are treated with radiation commonly to doses of 50.4 - 54 Gy.

The initial PTV is the preoperative MRI T2 volume plus 0.5 - 1 cm margin. A boost volume is delivered to the post-op T1 + 0.5 cm - 1 cm. Alternatively treat the post-operative T2/FLAIR + 2 cm to 54 Gy with 3D -conformal radiation therapy in accordance with RTOG 9802.

EORTC 22845 supported initial observation for LGG. This trial randomized 290 low grade glioma patients to surgery alone compared with surgery and adjuvant radiation therapy. The study had near total resection in 42%, debulking surgery in 20% and biopsy only in 38%. Progression free survival at 5 years (PFS-5) improved in adjuvant RT arm improving results from 35% to 55%, and improved PFS from 3.4 years to 5.3 years, but made no difference in overall survival at 7.2 years compared with 7.4 years.

EORTC 22845 also identified that 65% of all patients in the observation arm eventually did require radiation therapy for salvage. (Van den Bent, 2005 Lancet). Only 35% will not require radiation therapy, for salvage. This trial also noted that overall survival, when taking into account delayed salvage radiation therapy from the initial observation arm, after first recurrence was better in initally observed patients than those who received up front radiation therapy. Overall survival after first recurrence for those receiving delayed radiation therapy at first recurrence was 3.4 years which was improved over 1 year.

Dose

Shaw, Retrospective Study of dose (1989, J. Neurosurg.) found that in a retrospective review of 126 low grade glioma patients treated with radiation in varying doses that those receiving > 53 Gy had an 18% overall survival advantage at 10 years over doses of < 53 Gy.However, caution is advised as more recent prospective studies (EORTC 22844 and the NCCTG LGG study do not appear to support a benefit of doses above 45 - 50.4 Gy. Present NCCN Guidelines currently recommend (2011) 45 - 54 Gy at 1.8 - 2.0 Gy /fraction to the FLAIR/T2 signal plus 1 - 2 cm margins.

There is no prospective evidence to support dose escalation in low grade gliomas. There are two prospective studies that showed no benefit to dose escalation.

  1. The EORTC 22844 (IJROBP 1996study randomized 343 patients to adjuvant 45 Gy and 59.4 Gy. This study showed no significant difference in OS-5 or PFS-5.
  2. The second study by the INT/NCCTG randomized 203 patients to adjuvant radiation therapy 50.4 Gy compared with 64.8 Gy and found no difference in OS-5 at 65% - 72%. This study also showed 92% of all failures were in-field recurrences. (Shaw, 2002 JCO)

For Pilocytic Astrocytomas (WHO Grade I) after gross total resecton, subtotal resection, or biopsy only, a 2004 study by Brown (IJROBP) followed 20 patients with adult pilocytic astrocyctoma demonstrated that PFS-5 was 95%.

Chemotherapy

There is no clear benefit to adding chemotherapy to radiation therapy for low grade gliomas. The RTOG 9802 study stratified patients into low risk and high risk categories as follows:

  1. Low Risk: Age < 40 and GTR
  2. High Risk: Age > 40 or STR/biopsy only

Low risk patients were observed. High risk patients were randomized to adjuvant RT to 54 Gy or RT and Chemotherapy (PCV + 6 cycles: procarbazine/ccnu/vincristine). Outcomes were better in the chemotherapy arm but did not reach statistical signfificance OS improved from 63% to 72%, and PFS from 46% to 63%. Patients who lived > 2 years had significantly improved PFS and OS with a decreased risk of death by 48% with chemotherapy suggesting a possible delayed benefit. (Shaw, ASCO abstr, 2006)

Temozolomide is being investigated in 2 trials with results not yet reported.

Toxicity

Radiation therapy, surgery and chemotherapy and antiseizure medications all affect quality of life. Based on EORTC 22844 dose escalation study, higher dose RT was significantly associated with malaise and fatigue and insomnia and decreased emotional functioning. Radiation therapy does not appear to predispose low grade gliomas to malignant transformations. EORTC 22845 demonstrated a 70% transformation rate in both adjuvant and observation arms of the trial.

Dose Constraints

Optic chiasm is commonly constrained to 50 - 54 Gy in 1.8 Gy - 2 Gy fractions and 8 Gy in a single fraction

The Inner Ear is constrained to 30 - 35 Gy in 1.8 - 2 Gy fractions. (mean dose)

The brain stem is constrained to a single fraction 12 Gy dose.