Surgical options in the management of glioma include stereotactic biopsy, subtotal resection, or more extensive surgery with attempts at gross total resection. Because of the location and invasiveness of many gliomas, complete surgical resection is often unachievable. Unfortunately, in addition, even when all visible tumors can be excised, viable microscopic glioma cells generally remain and eventually regrow. Therefore, except in cases of certain WHO grade I gliomas, where gross total resection can be curative, surgery alone is generally inadequate to serve as definitive therapy in the management of gliomas. Still, determining the extent of resection is an important consideration in the approach to glioma treatment. Because of feasibility, it has been difficult to conduct prospective randomized trials to determine whether there is a survival benefit from more extensive surgical resection. However, existing retrospective evidence and post hoc subset analyses of prospectively conducted studies support maximal safe resection and demonstrate a survival advantage with gross or near-gross total resection over biopsy. Of course, retrospective surgical data can be confounded by selection bias, as there is some evidence that tumors amendable to more extensive resection may have a more favorable prognosis independent of the extent of their resection. Still, in most cases, maximal safe resection is the goal, where the extent of resection is balanced with preservation of neurologic function. Because many gliomas can be difficult to distinguish from surrounding normal brain, intraoperative assessments of resection are often inaccurate, and the extent of resection should be measured by a postoperative MRI within 72 hours of the procedure. Functional magnetic resonance imaging (fMRI), intraoperative mapping, and the emerging use of intraoperative imaging can enable more extensive resection, particularly when tumors occupy eloquent brain regions. Even in the case of partial resection, surgery can often improve neurologic function, reduce symptoms and mass effect, and decrease corticosteroid requirements. In addition, because tissue obtained at surgery is important not only for diagnosis but also for molecular and clinical trial testing, subtotal resection can be a reasonable approach in many cases. In those cases where no significant resection can be achieved because of tumor location, a stereotactic biopsy should be performed in order to establish the diagnosis, although the limited amount of tissue obtained may preclude molecular
characterization. In the end, the major objectives of surgery for most gliomas are to obtain adequate tissue for an accurate histologic diagnosis, to reduce mass effect when necessary, and if possible, to remove as much of the tumor as can be safely resected. Following surgery for many glioma subtypes, radiation and chemotherapy can serve as important adjuncts, although the optimal timing and dose may vary.

Radiation therapy (RT) induces DNA strand breaks either directly (in the case of particle therapy) or indirectly through the production of reactive oxygen free radicals (in the case of photon therapy). Cells undergoing mitosis are more sensitive to the damaging effects of RT, and cancer cells are targeted by virtue of their rapid division and impaired DNA repair mechanisms. RT is generally delivered in repeated doses known as fractions in order to allow normal cells to repair sublethal damage. The radiation tolerance of the CNS is primarily influenced by the dose per fraction, and radiation side effects in the late-reacting CNS tend to appear months to years after RT is completed. Most RT for glioma involves fractionated external beam photon (x-ray) therapy generated by linear accelerators. Treatment involves delivery of radiation beams from several directions converging on the treatment area of interest. Dose varies depending on the tumor type, but fractions of 1.8 to 2 Gy are typically delivered to a total dose of 40 to 60 Gy. RT planning involves targeting the T2/FLAIR-defined glioma volume plus a 1.5- to 2-cm margin for subclinical infiltrative disease and a small volume for uncertainties in planning or treatment delivery.

A number of RT techniques improve the ability to more precisely target tumor while sparing normal surrounding brain tissue with the intent of minimizing toxicity. Intensity-modulated radiation therapy (IMRT), together with 3D conformal planning, allows for delivery of RT that better conforms to the contours of the intended treatment area. Single fraction stereotactic radiosurgery (SRS) or radiotherapy (SRT) given in a few fractions, involves the use of many focused radiation beams to target a small, well-defined area while delivering minimal dose to surrounding structures. Because of its small well-defined target volume, SRS/SRT is not ideal for most infiltrating gliomas and is not used routinely for initial radiotherapy, although it is occasionally used for focal recurrences. Proton beam RT is a particle-based therapy whose advantage is the delivery of ionizing radiation at a defined target depth while sparing tissue both superficial and deep to the target. Because of limited availability and waiting time, proton therapy is generally reserved for pediatric patients with low-grade tumors who are likely to benefit most from decreased risk of long-term side effects following RT to a developing brain. In spite of high-dose focal RT, most gliomas eventually recur at the original site of treatment, suggesting persistence of residual disease. Unfortunately, efforts to increase RT dose and to develop RT sensitizers have been unsuccessful to date. Reirradiation carries an increased risk of neurotoxicity and radiation necrosis, although it can be considered when tumor growth occurs outside of the prior radiation field or when substantial time has elapsed since the prior treatment.

Because of the infiltrative nature of glial neoplasms, microscopic cancer cells extend beyond the area of MRI abnormality. Local therapy with surgery and RT are often not enough to prevent tumor recurrence, and systemic therapy is generally required. Numerous chemotherapeutic agents have been used in the treatment of both LGGs and HGGs, including alkylating agents, antimetabolites, topoisomerase inhibitors, and taxanes, to name a few. Most traditional chemotherapeutics work by inducing DNA damage or blocking DNA replication, with the greatest effect seen in rapidly dividing cells. Unfortunately, very few drugs have been proven to be effective in the treatment of gliomas. Alkylating agents such as the nitrosoureas and temozolomide have been the most successful agents in the treatment of glioma and remain a mainstay of current therapy (Table 96.1).

More recently, molecularly targeted agents have been developed in an attempt to inhibit glioma growth. Bevacizumab is a humanized monoclonal antibody that binds vascular endothelial growth factor (VEGF) preventing activation of VEGF receptors (VEGFRs), one of the major signals used by tumors to recruit new blood vessels. In highly vascular HGGs, bevacizumab has been shown to normalize abnormal tumor vessels and improve enhancement, mass effect, and edema. Bevacizumab is used in the treatment of recurrent HGGs and occasionally newly diagnosed HGGs in select circumstances, although its ultimate benefits and role are still being defined. A large number of other molecularly targeted agents are being tested in clinical trials with gliomas. Significant preclinical research and clinical trial work aimed at identifying effective treatments for glioma are ongoing.