The approval of bevacizumab for recurrent GB in the United States was based on two clinical trials that evaluated bevacizumab as a single agent or combined with irinotecan in patients with tumor recurrence after initial treatment with chemoradiation and adjuvant temozolomide. The comparative study enrolled 167 patients, 85 in the bevacizumab-alone arm and 82 in the bevacizumab plus irinotecan arm.10 The objective response rate was 25.9% in patients who received bevacizumab monotherapy. There were no complete responses per outside review. The median duration of response was 4.2 months, and the 6-month progression-free survival (PFS-6) was 36.0 %. The single-arm study enrolled 56 patients with recurrent high-grade glioma.11 Objective response as determined by independent review was 19.6%. The median duration of response was 3.9 months.
The FDA approved bevacizumab for use as a single agent based on the improvement in objective response rate in these studies (albeit without improvement in disease-related symptoms or increased survival) and on the fact that patients receiving bevacizumab as a single agent had less toxicity than those receiving the combination with irinotecan and similar outcomes. Subsequent studies with bevacizumab as a single agent in recurrent GB have shown similar PFS-6 rates of between 29% and 42%; smaller studies in recurrent anaplastic gliomas reported response rates ranging between 34% and 68% and PFS-6 rates ranging between 32% and 68%.12,13
The NovoTTF-100A System received approval in the spring of 2011 based on the results of a single multinational study of 237 patients with recurrent GB.14 Patients were randomized to receive either the NovoTTF-100A System or chemotherapy of their physician’s choice. The NovoTTF device includes a battery pack (weighing about 6 pounds) and electrodes, which are placed on the scalp and designed to be worn for about 20 hours a day. The results showed that patients who used the NovoTTF-100A System had higher objective response rates (12% for NovoTTF compared with 6% in the chemotherapy group) and a favorable overall survival rate of 6.6 months compared with 6.0 months for the chemotherapy group. The device was well tolerated, with a significantly higher incidence of toxicities (hematologic and other) in the patients receiving chemotherapy.
Temozolomide is approved in Europe for recurrent high-grade gliomas, including both GB and anaplastic astrocytoma, but in the United States, it is only approved for recurrent anaplastic astrocytoma. These approvals were based on studies in mostly chemotherapy-naive patients, and although it is less clear that rechallenge with temozolomide is useful, as noted below, ongoing studies may clarify this issue.
Approach to the patient with recurrent GB
In the absence of enrollment in a clinical trial, which is encouraged for all glioma patients, the approach to the patient with recurrent GB should take into consideration prior therapies, extent of recurrence and location, and general medical condition. An initial consideration is whether the patient is a candidate for further resection and/or radiation. Re-resection can relieve mass effect and reduce the need for steroids, can provide histologic confirmation of the diagnosis, and likely can increase survival, although this has not been shown in randomized studies.15 For a patient with contraindications for further systemic chemotherapy and who is undergoing resection, Gliadel is a reasonable consideration, and it does not preclude use of bevacizumab or NovoTTF.
Re-irradiation with single-fraction or fractionated stereotactic radiation is feasible in patients with localized recurrent disease. Small, single-arm prospective studies and retrospective reviews suggest a benefit, and the focused delivery modalities reduce the dose to surrounding brain tissue, minimizing the risk of radiation toxicity.16 In some studies, low-dose temozolomide or bevacizumab was combined with re-irradiation with results suggesting both tolerability and efficacy.17 We have found re-irradiation to be a good alternative for those patients who develop profound and prolonged myelosuppression (usually thrombocytopenia) during initial treatment with temozolomide and who have tumor progression before recovery of the counts.
Bevacizumab is currently the most common single agent used for glioma recurrence and is usually dosed at 10 mg/kg every 2 weeks until disease progression, unacceptable toxicity, or the decision to discontinue care. Due to its potent anti-VEGF activity, which results in normalization of highly permeable tumor vessels, bevacizumab often produces rapid and marked reduction in edema and contrast enhancement on neuroimaging.18 This can produce rapid clinical and imaging responses, although whether this reflects true antiglioma activity remains under debate.
Resolution of mass effect and contrast enhancement can also coexist with progression of nonenhancing fluid-attenuated recovery (FLAIR) abnormality that reflects a phenotypically invasive tumor recurrence pattern, with GB co-option of normal cerebral vessels and diffuse, multilobar perivascular spread of tumor cells. The imaging changes can make evaluation of tumor response and progression difficult if one relies on the standard criteria of two-dimensional measurement of enhancing disease; new criteria that take into consideration nonenhancing signal abnormality changes have been proposed.19