Radiation therapy for high-grade gliomas

INTRODUCTION — High-grade gliomas are malignant brain tumors that include the most common malignant primary brain tumor in adults, isocitrate dehydrogenase (IDH)-wildtype glioblastoma, as well as grade 3 and 4 IDH-mutant astrocytomas and anaplastic oligodendroglioma, IDH-mutant and 1p/19q-codeleted (algorithm 1) [1]. (See "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors".)

Most high-grade gliomas are managed with a combined-modality approach, incorporating adjuvant postoperative radiation therapy (RT) and adjuvant chemotherapy following initial surgery. An overview of the use of RT in patients with high-grade glioma is presented here.

Other patient management topics that are covered separately include:

●Initial surgical management of high-grade gliomas (see "Clinical presentation, diagnosis, and initial surgical management of high-grade gliomas")

●Concurrent and adjuvant chemotherapy (see "Initial treatment and prognosis of IDH-wildtype glioblastoma in adults")

●Glioblastoma in older adults (see "Management of glioblastoma in older adults")

●IDH-mutant astrocytomas and oligodendrogliomas (see "Treatment and prognosis of IDH-mutant astrocytomas in adults" and "Treatment and prognosis of IDH-mutant, 1p/19q-codeleted oligodendrogliomas in adults")

●Recurrent high-grade gliomas (see "Management of recurrent high-grade gliomas")

SURGICAL RESECTION — A histologic diagnosis is required for optimal treatment of patients with gliomas. This can be accomplished by surgical resection or with a stereotactic biopsy. Biopsy alone is used in situations where the lesion is not amenable to resection, a meaningful amount of tumor tissue cannot be removed, or the patient's overall clinical condition will not permit a more aggressive surgery.

For patients with a newly diagnosed high-grade glioma, maximal surgical resection consistent with preservation of neurologic function is preferred. Although gross total resection is preferred whenever possible, subtotal resection or stereotactic biopsy may be required depending upon the location and extent of the tumor. (See "Clinical presentation, diagnosis, and initial surgical management of high-grade gliomas", section on 'Extent of resection'.)

ADJUVANT RT — High-grade gliomas are infiltrative tumors with microscopic disease extending into the adjacent brain parenchyma to the gross tumor, which is typically defined by the radiographic abnormality. Adjuvant RT directed to residual microscopic and gross disease is not curative but improves local control and survival after resection compared with surgery or chemotherapy alone [2-9].

Treatment target — Involved field RT is the standard approach for adjuvant RT in patients with high-grade gliomas. The rationale for limiting the RT field is based upon the observation that recurrent high-grade glioma following whole brain RT (WBRT) develops within 2 cm of the original tumor site in 80 to 90 percent of cases, while less than 10 percent are multifocal [10-13].

To encompass infiltrating tumor cells, the RT dose (typically 60 Gy) is usually delivered to the tumor plus a margin of radiographically appearing normal tissue. Most commonly, the RT target volume is defined primarily by T2-weighted magnetic resonance imaging (MRI) abnormality best appreciated on a fluid-attenuated inversion recovery (FLAIR) series with a 1.0 to 2.0 cm margin. If the T1 contrast-enhancement volume is used for radiation planning, this is typically a subset of the T2-defined tumor, and a margin of 2.0 to 2.5 cm is often used to define the target volume to be treated to 60 Gy.

Dose selection — Adequate doses of RT are required to maximize the survival benefit. In early studies of RT for malignant glioma, patients who had RT doses of 50 to 60 Gy had a longer median survival than those who received lower postoperative RT doses [5-8]. These studies established 60 Gy, delivered over six weeks in 2 Gy fractions, as the standard target dose for glioblastoma [14].

There are no data comparing optimal dose and schedule in anaplastic gliomas versus glioblastoma. However, many radiation oncologists use a dose of 59.4 Gy in 1.8 Gy fractions for grade 3 tumors versus 60 Gy in 2 Gy fractions for grade 4 tumors with the expectation that the 10 percent dose reduction per fraction may lead to reduced late normal tissue effects for patients with projected longer-term survival.

Dose escalation above 60 Gy using conventionally fractionated RT, hyperfractionation, brachytherapy, or stereotactic radiosurgical boost has not been shown to provide further benefit [7,8,15-18]. Dose escalation to the contrast-enhancing volume using contemporary techniques continues to be investigated in glioblastoma and is the subject of an ongoing clinical trial (NCT02179086) [19,20].

Planning and delivery methods — Three-dimensional conformal RT (3D-CRT) and intensity-modulated RT (IMRT) are two of the most common methods of planning and delivering involved field RT for high-grade gliomas.

3D-conformal RT — The use of 3D treatment planning has enabled a significant decrease in the amount of normal brain irradiated as compared with the two-dimensional planning era [21,22].

Current 3D-CRT uses computed tomography (CT)-based treatment planning with dosimetric software to create composite treatment plans. Fusion of planning CT with MRI is extremely helpful in assisting with target definition [21-23]. Photons of 6 to 8 megavolts (MV) are most commonly used with three to four or more angled radiation beams.

Radiation oncologists work with medical physicists and dosimetrists to design optimal treatment plans. Considerations in treatment planning include beam energy, field size and shape, beam modifiers, irradiated tissue density and heterogeneity, and radiation tolerance of surrounding normal tissues.

Intensity-modulated RT — IMRT is a technique that relies upon more advanced radiation planning and delivery software to vary the shapes of radiation beam and dose intensity across each treatment field. IMRT provides particular advantages when the target is juxtaposed with radiation-sensitive structures. IMRT most commonly employs five, seven, or nine treatment beams from different directions, with each field being from a stationary direction, but in which the radiation output varies across the field with time of irradiation. (See "Radiation therapy techniques in cancer treatment", section on 'Intensity-modulated radiation therapy'.)

Volumetric modulation arc radiotherapy (VMAT) is a form of IMRT that utilizes arc-based treatment delivery in which the radiation source is moving in an arc around the patient while delivering the radiation treatment. VMAT delivery is more efficient and requires approximately half the time that IMRT requires.

The application of IMRT and VMAT in the treatment of high-grade gliomas has become increasingly prevalent, as it significantly decreases the volume of normal tissue treated to high doses, which may decrease radiation-related adverse effects [24]. IMRT and VMAT also enable better radiation dose coverage to the parts of the tumor target close to radiation-sensitive structures (eg, optic chiasm and optic nerves), where radiation dose limits result in the tradeoff of lower dose to nearby tumor. IMRT and VMAT can also be used to more safely escalate doses to the tumor, but there are no proven benefits to delivering doses beyond 60 Gy [24,25].

The most appropriate application of IMRT in the brain is likely to be when the radiation target approximates radiation-sensitive structures such as the eyes, optic nerves, optic chiasm, or brainstem. The disadvantages of IMRT include increased low-dose radiation distribution to surrounding nontarget tissues and the higher complexity of radiation planning that requires more time.

Side effects — Acute side effects occurring during standard fractionated brain RT are typically mild and manageable with basic supportive care. Fatigue, loss of appetite, radiation dermatitis, and alopecia are the most commonly encountered toxicities during brain RT. Management of these and other side effects is reviewed separately. (See "Acute complications of cranial irradiation".)

There are multiple potential long-term complications of brain irradiation, including neurocognitive toxicity, RT-induced leukoencephalopathy, and endocrinopathies. The use of involved field RT lowers the risk of some but not all of these toxicities compared with WBRT. Risk also varies by dose, age, area of the brain receiving radiation, and concurrent therapies. (See "Delayed complications of cranial irradiation".)

Monitoring during use of concurrent temozolomide — Patients receiving temozolomide chemotherapy during RT are at risk for hematologic toxicity and hepatotoxicity. Patients require weekly complete blood counts for hematologic monitoring during RT. Liver biochemical tests should be performed at baseline, midway through RT, and before each monthly cycle of temozolomide. (See "Initial treatment and prognosis of IDH-wildtype glioblastoma in adults", section on 'Side effects and monitoring'.)

Moderate to severe thrombocytopenia is the most common hematologic adverse effect, occurring in approximately 10 to 20 percent of patients [26]. Radiation is not known to increase bleeding risk and can be continued safely during periods of mild to moderate thrombocytopenia. In patients with severe thrombocytopenia (eg, counts fewer than 10,000 to 20,000/microL), some practitioners elect to hold RT until hematologic stability has been achieved.

The majority of patients also develop some degree of lymphopenia and are at risk for Pneumocystis jirovecii pneumonia (PJP). Pneumocystis pneumonia prophylaxis should be administered to all patients receiving daily temozolomide during RT. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)

The role of adjuvant chemotherapy in patients with high-grade glioma is discussed separately. (See "Initial treatment and prognosis of IDH-wildtype glioblastoma in adults" and "Treatment and prognosis of IDH-mutant, 1p/19q-codeleted oligodendrogliomas in adults".)

Older adults — De-escalated therapy is often appropriate for older adults with high-grade gliomas and those with poor performance status. The role of RT in older adults and potential modifications in dose and schedule are discussed separately. (See "Management of glioblastoma in older adults", section on 'Radiation therapy alone'.)

ASSESSMENT OF RESPONSE AND PROGRESSION — Patient management decisions require an assessment of both initial response to treatment as well as surveillance and subsequent considerations at the time of progressive disease.

Clinical and neuroimaging follow-up — Patients undergoing RT for high-grade glioma require regular clinical follow up to manage symptoms and glucocorticoid dosing and to monitor for adverse effects of treatment. MRI is performed approximately one month after completion of RT to assess initial response. (See "Initial treatment and prognosis of IDH-wildtype glioblastoma in adults", section on 'Follow-up and monitoring'.)

Pseudoprogression — Pseudoprogression is a subacute treatment-related effect with MRI features mimicking tumor progression that most commonly occurs within the first three months after completion of chemoradiation for high-grade glioma. The diagnosis is typically made retrospectively, based upon spontaneous improvement or stabilization of imaging findings in the setting of continuation of the original therapy for at least six months.

Pseudoprogression is difficult to differentiate from true progression but should be considered in patients who develop new or enlarging enhancement within the high-dose RT field within the first three to six months after completion of RT with concurrent temozolomide, especially those with methylguanine-DNA-methyltransferase (MGMT) promoter hypermethylated glioblastoma. (See "Management of recurrent high-grade gliomas", section on 'Early progression versus pseudoprogression'.)

REIRRADIATION

Patients with radiation-induced gliomas — Previous exposure to radiation of any dose is a known risk factor for the subsequent development of both benign and malignant brain tumors, including gliomas. Treatment of gliomas in patients with a history of prior cranial irradiation is a particular concern because of the increased risk of late radiation-related side effects, including neurocognitive deficits and radiation necrosis. (See "Risk factors for brain tumors", section on 'Ionizing radiation' and "Delayed complications of cranial irradiation".)

In general, partial brain reirradiation to therapeutic doses for gliomas is considered acceptable with at least a five-year interval between radiation exposures. The survival benefit and safety of reirradiation as a component of therapy in glioma patients with prior cranial irradiation was supported by a review of the literature that identified a total of 92 cases of secondary high-grade glioma related to prior brain RT (mostly for a prior brain tumor or leukemia), of which 35 underwent reirradiation to a median dose of 50 Gy [27]. The one- and two-year survival rates were increased compared with the 57 patients who were not reirradiated (59 versus 15, and 21 versus 3 percent, respectively).

Role in recurrent glioblastoma — The role of reirradiation in patients with recurrent glioblastoma is uncertain, and clinical trials are ongoing. While reirradiation has been shown to be feasible in selected patients in retrospective studies, there is no consensus regarding treatment volume, dose, and fractionation, or factors that predict benefit (eg, tumor volume, interval since prior radiation, performance status, molecular tumor characteristics, prior treatments) [28]. (See "Management of recurrent high-grade gliomas", section on 'Reirradiation'.)

OTHER TECHNIQUES — A number of other RT techniques have been evaluated in patients with high-grade glioma, but do not have an established role.

Interstitial brachytherapy — Interstitial brachytherapy uses the intraoperative placement of radioisotope seeds (most commonly iodine-125 or cesium-131) into the tumor or resection cavity. These seeds release low-dose rate (LDR) irradiation for the duration of the life of the radioisotope [29,30]. Brachytherapy permits the delivery of a large radiation dose to the tumor volume, with rapid falloff in surrounding tissues.

Despite the theoretical dosimetric and radiobiologic advantages of brachytherapy, randomized clinical trials have shown marginal or no benefit for the use of brachytherapy in the treatment of high-grade gliomas [16,17,30,31].

Brachytherapy is technically complex, and its applicability is limited because the effective radiation dose is limited to within a few millimeters of the seeds, and gliomas are inherently infiltrative into normal-appearing brain. Given these characteristics, the full extent of disease is not effectively treated by brachytherapy.

These constraints eliminate up to 75 percent of high-grade glioma patients from consideration for brachytherapy [32]. Interest in brachytherapy has waned with the use of intensity-modulated RT (IMRT) and stereotactic RT techniques to deliver a radiation boost, both of which offer dosimetric advantages similar to that of brachytherapy.

Particle RT — Charged heavy particles (helium and neon ions), protons (light-charged particles), and neutrons have been used alone and as a boost to conventional photon radiation. The physical properties of charge particle beams that are useful clinically are their finite path lengths and the ability to concentrate the majority of their dose at the end of their path length, with little exit dose [33]. The latter property permits a reduction of radiation exposure to surrounding normal tissue. (See "Radiation therapy techniques in cancer treatment", section on 'Particle therapy'.)

●Proton beam RT – Proton beam RT is becoming more widely available and is commonly used to treat pediatric brain tumors such as medulloblastoma. There are limited data on its potential utility in high-grade gliomas, much less superiority, as compared with conformal photon RT. Whereas the highly conformal radiation delivery with the use of protons can permit dose escalation, its potential application in treating glioblastoma may be better suited to simply limiting RT-related side effects. The role of dose-escalated protons is being tested in an ongoing multicenter trial (NCT02179086). (See "Delayed complications of cranial irradiation", section on 'Brain tissue necrosis'.)

●Neutrons – Boron neutron capture therapy (BNCT) has evolved to enable irradiation of deeper tissues using nonoperative techniques. Several institutions have reported experiences with BNCT in patients with glioblastoma without clear benefit to photon techniques [34-36]. Lacking a clear benefit, the added complexity of BNCT makes it less attractive to use than standard RT.

Radiation sensitizers — Radiation sensitizers are compounds that are given concurrently with RT in an effort to increase its therapeutic effect. Several classes of radiosensitizers have been studied in clinical trials, but none of these have been approved for high-grade gliomas or are in widespread use.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary brain tumors".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Glioblastoma (The Basics)")

●Beyond the Basics topic (see "Patient education: High-grade glioma in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Introduction – Involved field radiation therapy (RT) is a standard component of initial multimodality therapy in patients with isocitrate dehydrogenase (IDH)-wildtype glioblastoma as well as high-grade IDH-mutant diffuse gliomas (algorithm 1). (See 'Adjuvant RT' above and "Initial treatment and prognosis of IDH-wildtype glioblastoma in adults".)

●Dose selection – Adequate doses of RT are required to maximize the survival benefit. Typical doses of RT used for high-grade glioma are 59.4 Gy in 1.8 Gy fractions for grade 3 tumors and 60 Gy in 2 Gy fractions for glioblastoma. Dose escalation above 60 Gy has not been shown to provide further benefit. (See 'Dose selection' above.)

●Treatment target – RT is delivered to the tumor plus a margin of radiographically apparently normal tissue to encompass infiltrating tumor cells. Intensity-modulated RT (IMRT), including the subtype of volumetric modulation arc radiotherapy (VMAT), is increasingly the preferred standard RT technique to achieve best radiation dose coverage to the clinical target(s) with minimization of collateral high doses to surrounding normal tissues. (See 'Treatment target' above.)

●Side effects – Fatigue, loss of appetite, radiation dermatitis, and alopecia are the most commonly encountered side effects during brain RT. Patients receiving temozolomide chemotherapy during RT are at risk for hematologic toxicity and should be monitored with weekly complete blood counts. (See 'Side effects' above and 'Monitoring during use of concurrent temozolomide' above.)

●Response assessment – Brain MRI with contrast should be obtained approximately four weeks after completion of RT, then every two to four months for two to three years, and less frequently thereafter. (See 'Assessment of response and progression' above.)

●Reirradiation – In patients with radiation-induced gliomas related to prior history of brain RT, therapeutic reirradiation can generally be performed with at least a five-year interval between radiation exposures. The role of reirradiation in patients with recurrent high-grade gliomas is uncertain, and clinical trials are ongoing. (See 'Patients with radiation-induced gliomas' above and 'Role in recurrent glioblastoma' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Tracy Batchelor, MD, MPH, who contributed to an earlier version of this topic review.