High Grade Glioma

Malignant Glioma

=Anaplastic Glioma ( WHO grade III ) and GBM ( WHO grade IV )

These two are distinct disease but respond to treatment in a same way.

General Consideration:

  • 1/2 of primary brain tumors
  • Rapidly growing tumors
  • Directly invade the brain parenchyma
    • Diffusely infiltrating
  • Rarely metastasize outside the CNS
  • Most often present in late adulthood

Anaplastic Glioma

GBM

Anaplastic Astrocytoma
Levin et al. (130) randomized patients with anaplastic gliomas or GBM to receive radiotherapy with adjuvant BCNU or PCV. The use of PCV was found to be associated with an improved outcome in patients with anaplastic glioma. In contrast, a retrospective review of 432 patients with newly diagnosed anaplastic astrocytoma treated with BCNU or PCV on RTOG studies showed no improvement in survival with chemotherapy (186).
A prospective phase III trial by the United Kingdom Medical Research Council randomized 674 patients of whom 117 (17%) had anaplastic astrocytoma after surgery to radiotherapy alone or radiotherapy followed by PCV (143). There was no advantage for adjuvant PCV in any subgroup. The median survival of patients with anaplastic astrocytoma, 13 to 15 months, was substantially lower than the median survival of 2 to 3 years reported in previous trials, which has led to debate over the applicability of these results.
The addition of difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, to PCV in adjuvant treatment of anaplastic gliomas was evaluated in a phase III trial by Levin et al. (129). Patients were randomized to PCV alone or PCV plus DFMO, following radiotherapy. Of the 228 evaluable patients, the majority had anaplastic astrocytoma (69.3% and 78.1%, respectively). Although the hazard function showed a significant difference in survival over the first 2 years of the study (hazard ratio 0.53; p = .02), this did not continue after 2 years (hazard ratio 1.06; p = .84). Differences in overall survival and progression-free survival were not significant.
A phase II trial by Levin et al. (131) investigated the safety of accelerated fractionated radiotherapy combined with carboplatin followed by PCV in patients with anaplastic gliomas. A total of 90 patients (76.7% with anaplastic astrocytoma) were enrolled. Median survival for anaplastic glioma patients was 28.7 months. Neurologic deterioration and/or dementia were seen in 10% of patients. The authors concluded that while excessive CNS toxicity from this intense regimen may have been a major contributing factor to the inferior median survival found in patients in this study, patients with treatment-induced necrosis had a significantly longer survival compared to those without any radiologic or histologic evidence of necrosis.
Temozolomide has shown activity in patients with recurrent anaplastic astrocytoma. In a phase II trial by Yung et al. (270), 162 patients with anaplastic astrocytoma were treated with temozolomide (150โ€“200 mg/m2/day on days 1โ€“5 every 28 days) at first relapse. The 6-month progression-free survival was 46% and overall survival was 13.6 months. The objective response rate was 35% (complete response 8%, partial response 27%). The agent was well tolerated, with mild to moderate hematologic toxicity in <10% of patients. The results of this trial suggest that temozolomide has antitumor activity with an acceptable safety profile for anaplastic astrocytoma.
Anaplastic Oligodendroglioma/Oligoastrocytoma
Anaplastic oligodendroglioma and oligoastrocytoma are generally thought of as chemosensitive primarily based on high response rates to PCV in several studies. However, two large randomized trials investigating the use of sequential chemoradiotherapy in patients with anaplastic oligodendroglioma and oligoastrocytoma failed to show any survival advantage over radiotherapy alone with chemotherapy reserved for salvage (27,254). In one, RTOG 94โ€“02, reported by Cairncross et al. (27) 289 patients with newly diagnosed anaplastic oligodendroglioma and oligoastrocytoma were randomized to either radiotherapy alone or neoadjuvant PCV (CCNU 130 mg/m2 day 1, procarbazine 75 mg/m2 days 8 to 21, vincristine 1.4 mg/m2 days 8 and 29, every 6 weeks for up to four cycles) followed by radiotherapy. With 3-year follow-up on all patients, no difference in survival was found. Median survival was 4.9 years after PCV plus radiotherapy and 4.7 years after radiotherapy alone (p = .26). Progression-free survival was better in the group treated with PCV followed by radiotherapy, 2.6 years versus 1.7 years for radiotherapy alone (p = .008). However, grade 3 or 4 toxicity was observed much more frequently, occurring in 65% of patients treated with PCV and resulting in one death.
The second study, EORTC 26951, assessed radiotherapy followed by adjuvant PCV chemotherapy. In this trial, reported by van den Bent et al. (254), 368 patients were randomized to receive either radiotherapy alone or radiotherapy followed by up to six cycles of adjuvant PCV. At a median follow-up of 5 years, median progression-free survival was 23 months in the group receiving radiotherapy plus adjuvant PCV compared to 13.2 months in the group receiving radiotherapy alone (p = .0018). Median survival was 40.3 months and 30.6 months, respectively (p = .23).
The effect of salvage therapy in patients treated on the radiotherapy alone arms of the RTOG 94-02 and EORTC 26951 trials has been offered as a possible explanation for the lack of benefit observed in these trials. In RTOG 94-02, 57% of patients treated with radiotherapy alone received salvage chemotherapy with PCV or temozolomide at recurrence. As well, 43% of patients treated with radiotherapy alone were treated with second surgery at recurrence compared to 20% in the PCV plus radiotherapy arm. In EORTC 26951, salvage PCV was given at recurrence to 65% of patients in the radiotherapy only arm and to 11% of patients in the radiotherapy and adjuvant PCV arm. Salvage with any type of chemotherapy was used in 82% of patients in the radiotherapy alone arm, compared to 55% of patients in the radiotherapy plus PCV arm. Given the high percentage of patients receiving salvage therapy, these trials may be interpreted as assessing the benefit of early or delayed chemotherapy.
Temozolomide has produced high response rates in patients with anaplastic oligodendroglioma. Chinot et al. (41) administered temozolomide to 48 patients with anaplastic oligodendroglioma/oligoastrocytoma who had previously failed PCV chemotherapy. The objective response rate was 43.8% (complete response 16.7%, partial response 27.1%). Grade 3 thrombocytopenia occurred in 6.3% patients. Vogelbaum et al. (256) reported the results of RTOG 01-31, a phase II trial in which temozolomide was given preradiotherapy to newly diagnosed patients with anaplastic oligodendroglioma/oligoastrocytoma. In the 27 patients available for review, the objective response rate was 33.3% (complete response 3.7%, partial response 29.6%). The 6-month-progression rate was 10.3%. Toxicity was acceptable. Response to temozolomide has also been shown to be significantly associated with loss of 1p in a small retrospective study (35).
Radiosensitizers
Prados et al. (187) randomized patients with anaplastic astrocytomas to receive conventional radiotherapy with or without bromodeoxyuridine (BUdR) given as an infusion during each week of radiotherapy plus adjuvant PCV. The study was closed before full accrual based on an interim analysis that predicted no survival advantage for the bromodeoxyuridine (BUdR) arm. In the 190 patients who were eligible for analysis, there was no survival benefit found with the addition of BUdR.
Evidence-Based Treatment Summary
Maximal surgical resection, although not tested in a prospective trial, is generally associated with more favorable outcome and is recommended whenever feasible.
Postoperative radiotherapy has been shown to provide a survival advantage in several clinical trials. These trials included
P.737

patients with WHO grade III and IV tumors; no trial for only grade III tumors has been conducted. The standard of care is as for GBM in terms of radiotherapy target volume and dose, typically 60 Gy in 6 weeks.
The role of chemotherapy remains undefined. The most widely tested agent, BCNU, and combination, PCV, have no definite survival benefit. Temozolomide is active in recurrent anaplastic astrocytoma and is currently being tested in the up-front setting.
Patients with codeletions of 1p and 19q have a more favorable prognosis and respond better to both chemotherapy and radiotherapy, but even in this subset, chemoradiotherapy does not have proven survival advantage over radiotherapy alone.