Reviews

Treatment of recurrent high-grade gliomas

Despite treatment, glioblastoma (GB) inevitably recurs, and there is often no clear standard of care to follow. This article reviews the treatment options for recurrent GB and anaplastic gliomas. The three FDA-approved treatments for recurrent GB are biodegradable carmustine-impregnated wafers; bevacizumab; and the NovoTTF-100A System, which delivers low-intensity, alternating electrical fields to the tumor bed. Treatment decisions must take into consideration prior therapies, the extent and location of recurrence, and the patient’s general medical condition, as well as the rapidity of tumor growth, extent of edema, mass effect, need for steroids, and symptoms. New treatment strategies are emerging based on the identification of prognostic and predictive markers and defining distinct molecular subtypes of GB.



 

Myrna R. Rosenfeld, MD, PhD, Karen Albright, CRNP, and Amy A. Pruitt, MD

University of Pennsylvania School of Medicine, Philadelphia, PA

Manuscript received December 1, 2010; accepted April 15, 2011.

Correspondence to: Myrna R. Rosenfeld, MD, PhD, Department of Neurology, 3 W. Gates, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104; telephone: 215-746-2820; fax: 215-746-2818; e-mail: myrna.rosenfeld@uphs.upenn.edu.

Despite treatment, glioblastoma (GB) inevitably recurs, and there is often no clear standard of care to follow. This article reviews the treatment options for recurrent GB and anaplastic gliomas. The three FDA-approved treatments for recurrent GB are biodegradable carmustine-impregnated wafers; bevacizumab; and the NovoTTF-100A System, which delivers low-intensity, alternating electrical fields to the tumor bed. Treatment decisions must take into consideration prior therapies, the extent and location of recurrence, and the patient’s general medical condition, as well as the rapidity of tumor growth, extent of edema, mass effect, need for steroids, and symptoms. New treatment strategies are emerging based on the identification of prognostic and predictive markers and defining distinct molecular subtypes of GB.

Glioblastoma (grade IV glioma, GB) is the most common of the primary malignant gliomas. Advances in the past decade have clarified that adjuvant treatment can improve quality of life and survival. The current standard of care for newly diagnosed patients with GB after optimal resection is focal radiation with concurrent (chemoradiation) and post-radiation temozolomide (Temodar). This regimen was shown to improve overall survival in a randomized phase III study.1 Furthermore, a subgroup of patients whose tumors were shown to have low levels of O6-methylguanine DNA methyltransferase (MGMT), the enzyme that repairs DNA damage due to temozolomide, showed overall survival of 46% at 2 years and 14% at 5 years.2,3

Biodegradable wafers impregnated with carmustine (Gliadel) implanted at the time of resection are another approved therapy for patients with newly diagnosed high-grade gliomas (GB and anaplastic gliomas, grade III glioma).4 Although short-term survivals for GB patients are similar with Gliadel compared to focal radiation with concurrent and post-radiation temozolomide, the latter results in superior long-term survival (1.9% at 56 months for Gliadel and 9.8% at 60 months for temozolomide).3,5 The nitrosoureas lomustine (CeeNU) and carmustine (BiCNU) were approved in the 1970s for use as single agents or in combination therapy in patients with glioma who had received surgery and/or radiation. These agents no longer have a clear role in the initial treatment of malignant glioma, although practitioners use them, often in combination therapy, for patients with recurrent GB and anaplastic oligodendrogliomas, a ¬chemosensitive subtype of glioma.6

Despite the use of the above approved therapies, GB invariably recurs. In the absence of effective treatment options, treatment approaches for recurrent GB have been varied. This article will review the most common accepted treatment options for recurrent GB and discuss emerging strategies. In the absence of a clear standard of care for newly diagnosed anaplastic gliomas, treatment at recurrence is largely dictated by prior therapies received, as noted below.

Tumor progression or treatment effect?

Glioblastoma recurrence is suspected when a previously stable patient develops recurrent or new neurologic signs and symptoms or when surveillance imaging (preferably MRI with gadolinium) shows increased tumor size or new enhancement likely associated with increased edema. However, clinical and imaging changes may result from perioperative complications such as infection or ischemia, a change in steroid use, or radiation necrosis (also called pseudoprogression). In fact, studies have shown that up to half of patients with presumed early tumor progression during or after chemoradiation actually have radiation necrosis (Figure 1).7 These data have led some clinicians to suggest that a minimum of 3 cycles of adjuvant temozolomide be given before a conclusion of tumor progression is made.

Several imaging modalities, such as magnetic resonance perfusion with or without spectroscopy and positron emission tomography, are used to help distinguish tumor recurrence from pseudoprogression but are not always reliable.8 In these cases, repeat imaging can be useful, although surgery may be necessary to relieve mass effect and obtain a tissue diagnosis.

Approved therapies for recurrent glioblastoma

There are currently three US Food and Drug Administration (FDA)–approved therapies for recurrent GB: Gliadel wafers; bevacizumab (Avastin), a humanized monoclonal antibody that sequesters vascular endothelial growth factor-A (VEGF); and the NovoTTF-100A System (NovoCure; Portsmouth, NH), which delivers low-intensity, alternating electrical fields (called tumor treatment fields) to the tumor bed that may inhibit cell growth by disrupting microtubule formation.9

The prospective randomized study that led to the approval of Gliadel demonstrated a modest increase in overall survival, from 23 weeks in those patients who received placebo wafers to 31 weeks for those receiving Gliadel.4 This study included recurrent anaplastic gliomas and GB, and the benefit in the GB subgroup was smaller than in the group as a whole. Furthermore, this and other studies predated the use of chemoradiation and adjuvant temozolomide, and it is unclear what benefit, if any, Gliadel offers in recurrent GB patients treated with prior temozolomide.

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