Systemic Therapy for Recurrent High-Grade Glioma

Current available chemotherapy is not curative and recurrence or progression of malignant glioma will eventually occur. There is currently no established standard systemic therapy for patients who have experienced treatment failure.

Chemotherapy

Continuous temozolomide (50mg/m2) is a treatment option in patients with recurrent or progressive malignant glioma. The RESCUE study, a phase II study, demonstrated good 6-month PFS rates of 23.9% and 35.7% in glioblastoma and anaplastic astrocytoma patients respectively.31Other possible regimes include temozolomide at 200mg/m2/day for 5 days in 28-day cycles for chemotherapy-nave patients and 150-200mg/m2/day for 5 days in 28-day cycles for patients previously treated with chemotherapy.32-34

The role of PCV in recurrent oligodendroglioma was examined retrospectively in a cohort of patients treated with first line temozolomide within the EORTC study 26971, and demonstrated a modest response rate of 17% and 6-month PFS of 50%.35Brada et al. conducted the first randomized trial of temozolomide versus PCV in chemotherapy-nave patients with recurrent high grade glioma, and demonstrated no clear significant survival benefits of temozolomide over PCV.32This study also compared two temozolomide treatment schedules and showed that the 5-day schedule (200mg/m2 /day for 5 days in 28-day cycle) improved overall PFS, OS and global quality of life when compared to the 21-day schedule (100mg/m2/day for 21 days in 28-day cycle).

Lomustine, another treatment option, was used as a comparator in the first phase III trial conducted in patients with recurrent glioblastoma.36 The trial was terminated early as study drug, enzasturin, failed to demonstrate superior PFS to lomustine (6-month PFS 11.1% vs 19.0%; p=0.13). A subsequent phase III trial also failed to demonstrate significant PFS improvement with cediranib, an oral pan-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, as monotherapy (HR 1.05; 95 %CI 0.74-1.50; p=0.90) or in combination with lomustine (HR 0.76; 95%CI 0.53-1.08; p=0.16), versus lomustine alone in patients with recurrent glioblastoma.37

Two phase II studies of cyclophosphamide conducted in patients with recurrent, temozolomide-refractory glioblastoma and anaplastic astrocytoma showed 6-month PFS of 20% and 30% respectively.38, 39

For recurrent or progressive oligodendroglioma patients treated with surgery, RT, PCV and temozolomide, carboplatin and teniposide are also treatment options. Use of carboplatin and teniposide as third-line chemotherapy is supported by a phase II study demonstrating a 6-months PFS of 34.8%.40

Other treatment options include etoposide (VP16) in patients with recurrent supratentorial malignant glioma previously treated with RT and nitrosurea 41, and CPT-11 (irinotecan) in patients with recurrent temozolomide-refractory anaplastic astrocytoma42and anaplastic oligodendroglioma.43In a pooled analysis of 596 patients enrolled in The North American Brain Tumor Consortium (NABTC) phase II studies conducted from 1998 to 2002, 6-month PFS was 28% and 16%, and median OS was 39 weeks and 30 weeks, for patients with recurrent grade III and grade IV tumours respectively.44The data serves as historical controls.

Bevacizumab

Bevacizumab is a humanized monoclonal antibody against VEGF and inhibits angiogenesis. Its role in recurrent glioblastoma has been defined by two phase II studies. Friedman et al. evaluated the efficacy of bevacizumab, alone and in combination with irinocetan, in patients with recurrent glioblastoma, and demonstrated MRI-defined objective response rates (ORR) of 28.2% and 37.8% as well as 6-month PFS rates of 42.6% and 50.3% respectively.45The PFS demonstrated was similar to a previous trial.46In the other pivotal phase II study by Kreisl et al., bevacizumab monotherapy yielded ORR of71% and 35% based on Levin and MacDonald criteria respectively, 6-month PFS of 29% (95% CI 18-48%), and median OS of 31 weeks (95% CI 21-54weeks). 47Treatment with bevacizumab was associated with a reduction of corticosteroids requirement in both trials.

In patients with recurrent anaplastic gliomas, treatment with single-agent bevacizumab demonstrated median OS of 12 months (95% CI 6.08-22.8), median PFS of 2.93 months (2.01 to 4.93) and 6-month PFS of 20.9% (10.3 to 42.5).48A pooled analysis of 96 patients with recurrent grade III malignant glioma enrolled in three consecutive phase II bevacizumab salvage trials demonstrated 6-month PFS and median OS of 39.1% and 9.2 months respectively among patients who continued bevacizumab therapy after study progression, compared to 23.1% and 10.3 months in patients who initiated non-bevacizumab containing therapy, suggesting that salvage therapies following bevacizumab failure have modest activity independent of further use of bevacizumab.49 Reported serious adverse events associated with bevacizumab include hypertension, spontaneous colon perforation, poor wound healing and thromboembolic events.50

Combination therapies with bevacizumab have also been studied in prospective trials. In a phase II trial, treatment with bevacizumab and irinotecan in patients with recurrent grade III glioma demonstrated 6-month PFS of 55% and 6-month OS of 79%.51In a more recent open-label, multicenter phase II study of lomustine, bevacizumab or combination treatment with lomustine and bevacizumab in patients with first recurrence of glioblastoma, only the combination therapy arm met prespecified criteria for further assessment in phase III studies (9-month OS: lomustine 43% (95% CI 29-57); bevacizumab 38% (25-52); lomustine 90 mg/m2+ bevacizumab 59% (43-73)).52

Cost-effectiveness

Due to the lack of statistically significant extension of median survival time and quality of life data, estimation of cost per QALY is difficult. For glioblastoma, the incremental cost per progression-free week for temozolomide was estimated at USD $1534 when compared to procarbazine, and USD $613 when compared to placebo (assuming placebo would give no cost and no effect).53For anaplastic astrocytoma, cost per progression-free week for temozolomide against placebo was USD $629. There is no local study on cost-effectiveness.