dose of 10 Gy/1–2 weeks to the tumor, (3) control radiation dose plus 1,3-bis(2-chloroethyl)-l-nitrosourea (BCNU, carbazine), and

(4) control radiation dose plus combination methyl-chloroethyl- cyclohexyl-nitrosourea (CCNU, lomustine) and DTIC (dacarbazine). No treatment option was found to be significantly better than the control. At least several important prognostic factors have been identified: age, histologic type (astrocytoma with anaplastic foci versus GBM), initial performance status, time since first symptoms, and presence or absence of seizure.

2Modern Methods and Strategies

2.3Intensity-Modulated Radiotherapy (IMRT)

Further advances in computer technology enabled the application of nonhomogeneous beams, known as intensitymodulated RT (IMRT). The dose flounce is modified. Such nonuniform doses from several beam orientations are combined to deliver the highly customized dose distributions to the target, optimizing the dose to tumor while sparing normal tissue (Fig. 1). After the physician defines the desired dose distribution to tumor and organs at risk, a reiterative computer algorithm is used to generate an optimized set of beam intensity profiles. This so-called inverse planning is particularly

Versus Involved Field Radiation

Therapy (IFRT)

WBRT initially used opposed lateral cranial portals with 50–60 Gy. The major complications following WBRT included progressive and irreversible radiation necrosis, small blood vessel injury, vascular occlusion, and demyelination (Shapiro 1986). Other late sequelae included asymptomatic narrowing of large vessels, delayed RT-induced leukoencephalopathy, and secondary neoplasia.

The severe effects of high-dose WBRT led to the adoption of IFRT as standard therapy. Up to 80–90 % of recurrent malignant gliomas develop within 2 cm of the original tumor (Wallner et al. 1989). Thus, radiation treatment of the tumor bed plus margin could reduce the recurrence rate with far less toxicity. Initially, this concept was imperfectly realized, with external beam RT coarsely focused using individually formed lead cutouts to protect the surrounding healthy brain tissue.

2.23D Conformal Radiation Therapy

structures, where a steep falloff of dose can be attained. The decreased dose to organs at risk may minimize radiationrelated adverse events (Narayana et al. 2006). This treatment modality depends on a clear delineation of target volumes and of structures that are to spare by the treating physician. The overall complexity of this technologically advanced radiation planning requires sophisticated computer software and hardware, skilled physicist support, and increased delivery time for treatment. Delivery of treatment depends on linear accelerators which can administer radiation through a rapid succession

The use of 3D CRT radiotherapy planning improved the distribution of radiation to the tumor and surrounding tissue. Treatment plans with clearly delineated target volumes are based on tissue density measurements in Hounsfield units of computer tomography (CT). Additional imaging modalities such as magnetic resonance imaging (MRI) or positron emission tomography (PET) can be fused with the planning CT to further define target areas (Glatstein et al. 1985). Considerations in treatment planning include beam sequelae energy, field size and shape, beam modifiers, irradiated tissue density and heterogeneity, and radiation tolerance of surrounding normal tissues. With 3D treatment planning, the target is typically encompassed by multiple treatment beams. Since RT beams deliver a relative homogeneous dose to the target, wedges can be added to modify the intensity profile of the beam. Nevertheless, a significant RT dose is delivered to all tissues in the shadow of the target (Grosu et al. 1998).

Fig. 1 Intensity-modulated radiotherapy (IMRT). The IMRT treatment plan for re-irradiation based on the FET uptake of the patient imaged in this figure. This plan of 39 Gy in 13 fractions consists of two arcs of gantry movement. One arc composed of more than 150 fields, indicated by the yellow circle. The concave and convex dose distribution is best visualized in the blue 50 % isodose line

of apertures, either static or moving, known as “step-and- shoot” and “sliding-window,” respectively.

A nonuniform dose distribution can be intentionally prescribed in dose painting to target tumor areas that are markedly radiation resistant. These areas can be visualized on PET (e.g., hypoxia PET, proliferation PET, etc.) or functional MRI. Alternatively, a more conformal dosage can be obtained by a simultaneous integrated boost in which all target volumes such as viable tumor and residual tumor plus margins are treated concurrently (Piroth et al. 2012). These complex plans are evaluated on the basis of dose-volume tables and histograms that show minimum, mean, and maximum dose to a given structure. Presently there is no proven benefit to delivering doses beyond 60 Gy with IMRT in glioblastoma patients (Chan et al. 2002).

2.4Stereotactic Radiosurgery (SRS) and Radiotherapy

Stereotactic radiosurgery (SRS) and radiotherapy are delivered using a linear accelerator or Gamma Knife with cobalt-60. Stereotactic radiosurgery is performed in a single high-dose fraction to small (<4 cm) targets, whereas fractionated stereotactic radiosurgery is delivered in several fractions. Stereotactic radiotherapy can also be delivered over multiple fractions.

The Gamma Knife contains a helmet with circular apertures ranging from 4 to 18 mm that collimates cobalt-60 rays onto a single target point. In a linear accelerator, circular collimators ranging from 4 to 40 mm diameter generate a circular pencil beam. The treatment is delivered using multiple non-coplanar arcs that intersect at a single point. The ideal target is spherical in shape. Irregularly formed lesions are treated using multiple circular collimators or collimator helmets placed on different nearby target points to minimize the exposure of normal brain. RTOG study 90–05 recommended the maximum tolerated dose of single fraction SRS to be 24 Gy to a target ≤20 mm, 18 Gy to a target of 21–30 mm, and 15 Gy to a target of 31–40 mm (Shaw et al. 2000).

LINAC radiosurgery is performed by linear accelerators incorporating improved guiding techniques and methods like micromultileaf collimators or intensity modulation for improved accuracy.

CyberKnife is a LINAC-based commercially available system mounted on an industrial robot. The robotic arm can be manipulated in six axes. The LINAC system provides energy of 6 MeV and uses circular collimators. Two orthogonal X-ray apparatus are used for target tracking leading to frameless positioning of the patient. According to the manufacturer, an accuracy of 0.2 mm can be achieved.

RTOG 93–05 trail was unable to demonstrate a benefit from adjuvant SRS in a phase III trial, in which 203 patients

were randomly assigned to stereotactic radiosurgery followed by involved field RT plus carmustine (BCNU) to immediate involved field RT plus carmustine. Median survival was similar on both arms of the study (13.6 and 13.5 months, respectively), as was survival at 2 and 3 years (21 versus 19 % and 9 versus 13 %, respectively) (Souhami et al. 2004). Conversely, stereotactic radiosurgery has also been used to boost fractionated RT for the treatment of newly diagnosed GBM following either biopsy or resection. Results from observational studies have been mixed and are difficult to interpret due to patient selection bias.

Stereotactic radiotherapy is also used in recurrent gliomas for re-irradiation (Shepherd et al. 1997; Grosu et al. 2005b).

2.5Interstitial Brachytherapy

For interstitial brachytherapy, radioisotope seeds are placed intraoperatively within the tumor or resection cavity. Iodine-125, a low-dose rate irradiator, is commonly used. The high-dose isotope iridium-192 has also been tested for selected patients. Although interstitial brachytherapy is frequently used in treatment of other disease entities, such as prostate cancer, its role is limited in the treatment of gliomas.

Brachytherapy enables the delivery of a large radiation dose to the tumor volume, with rapid falloff in surrounding tissues. Despite these theoretical dosimetric and radiobiological advantages, randomized clinical trials have shown marginal or negligible benefit in the treatment of malignant gliomas. In the largest study, 299 patients with malignant gliomas were randomly assigned postoperatively to IFRT plus carmustine with or without interstitial brachytherapy. The difference in median survival with the addition of brachytherapy was not statistically significant, 68 versus 59 weeks without brachytherapy (Selker et al. 2002).

2.6Dose Prescription

An RT dose of 50–60 Gy has been shown to maximize postoperative survival, independent of the extent of resection (Coffey et al. 1998). Dose escalation above 60 Gy did not improve survival and was associated with severe white matter changes which correlate with the total dose of cranial irradiation (Piroth et al. 2012; Corn et al. 1994; Tsien et al. 2009).

Typically, WHO grade III gliomas are treated with a dose of 59.4 Gy in 1.8 Gy fractions versus 60 Gy in 2 Gy fractions for grade IV. This 10 % dose reduction per fraction is postulated to reduce the extent of normal tissue complications in patients with protracted survival, but there is no data comparing these regimens.