Radiation Therapy for Glioblastoma

Fractionated radiotherapy improves overall survival compared with chemotherapy or best supportive care alone after biopsy or resection of newly diagnosed glioblastoma. Whether radiotherapy is indicated in a particular individual may depend on patient characteristics, such as performance status.

Radiation should be initiated as soon as it is safely permissible. Clinical trials have typically initiated treatment 3 to 6 weeks after surgery.

The addition of concurrent and adjuvant temozolomide to fractionated radiotherapy improves overall survival and progression-free survival compared with fractionated radiotherapy alone, with a reasonably low incidence of early adverse events and without impairing quality of life. The guideline panel endorses fractionated radiotherapy with concurrent and adjuvant temozolomide as the standard of care after biopsy or resection of newly diagnosed glioblastoma in patients up to 70 years of age.

The addition of bevacizumab to standard therapy for newly diagnosed glioblastoma (i.e., fractionated radiotherapy with concomitant and adjuvant temozolomide) does not improve overall survival and is associated with a higher incidence of early adverse events.

Bevacizumab may, however, prolong progression-free survival. The panel does not recommend the routine addition of bevacizumab to standard therapy for newly diagnosed glioblastoma outside a clinical trial.

The impact of bevacizumab to standard therapy on health-related quality of life requires further validation.

The addition of other systemic therapies to conventional radiotherapy with or without temozolomide remains investigational.

For patients younger than 70 years of age with good performance status (Karnofsky performance score ≥60), the optimal dose fractionation schedule for external beam radiation therapy after resection or biopsy is 60 Gy in 2-Gy fractions delivered over 6 weeks. Numerous other dose schedules have been explored without definitive benefit. Care should be taken to keep dose to critical structures (e.g. brainstem, optic chiasm/nerves) within acceptable limits.

Older age and poor performance status are associated with shorter survival in patients with glioblastoma. Prognostic considerations should help to guide treatment recommendations for individual patients.

Among elderly patients (≥70 years old) with fair to good performance status (Karnofsky performance score ≥50), the panel recommends external beam radiation therapy after biopsy or resection because radiotherapy (compared with supportive care alone) improves overall survival without impairing quality of life or cognition.

The efficacy of concurrent and adjuvant temozolomide in this population has not been evaluated in a randomized trial but may be considered for selected patients.

Among elderly patients, no evidence shows that conventionally fractionated radiotherapy (60 Gy in 30 fractions over 6 weeks) is more efficacious than hypofractionated radiotherapy (e.g. 40 Gy in 15 fractions over 3 weeks.

Compared with conventionally fractionated radiotherapy, hypofractionated radiotherapy has been associated with superior survival and less corticosteroid requirement.

The optimal dose fractionation schedule has not yet been determined for elderly patients, although recent randomized trials have suggested that shorter regimens may be equivalent to longer-duration treatment.

Given the absence of proven superiority for conventionally fractionated radiotherapy, the panel recommends hypofractionated radiotherapy for elderly patients with fair to good performance status.

Temozolomide monotherapy is an efficacious alternative for elderly patients with O6-methylguanine DNA methyltransferase gene (MGMT) promoter methylation.

However, the panel does not recommend temozolomide monotherapy as first-line therapy for patients with unmethylated MGMT promoters.

Temozolomide monotherapy confers a higher risk of adverse events than radiotherapy, particularly with respect to hematologic toxicity, nausea, and vomiting.

Among elderly patients with good performance status, the addition of concurrent and adjuvant temozolomide to hypofractionated radiotherapy seems to be safe and efficacious without impairing quality of life. In such patients, the panel recommends consideration of concurrent and adjuvant temozolomide. The combination of hypofractionated radiotherapy and temozolomide may be particularly efficacious in those with a methylated MGMT promoter.

Reasonable options for patients with poor performance status include hypofractionated radiotherapy alone, temozolomide alone, or best supportive care.

Although glioblastoma is believed to be diffusely infiltrative, partial-brain radiation therapy leads to no worse survival than whole-brain radiation therapy. The panel endorses partial-brain radiation therapy as the standard treatment paradigm for glioblastoma.

Several strategies for target volume definition produce similar outcomes.

All strategies for target volume definition confer a low risk of isolated marginal or distant failure, with a high risk of local failure as a component of disease progression. Acceptable strategies include, but are not limited to, the following: - Two phase: (1) Primary target volume encompasses edema (hyperintense region on T2 or fluid-attenuated inversion recovery on magnetic resonance imaging) and gross residual tumor/resection cavity, and (2) boost target volume encompasses gross residual tumor/resection cavity. A range of acceptable clinical target volume margins exists. - One phase: Single target volume includes gross residual tumor/resection cavity with wide margins, without specifically targeting edema.

Reduction of target volumes allows less radiation to be delivered to radiographically normal brain. Delivery of less radiation to normal brain should result in less late toxicity, but this remains to be validated.

In younger patients with good performance status, focal reirradiation (e.g. stereotactic radiosurgery, hypofractionated stereotactic radiotherapy, brachytherapy) for recurrent glioblastoma may improve outcomes compared with supportive care or systemic therapy alone. Tumor size and location should be taken into account when deciding whether reirradiation would be safe.

No prospective evidence supports reirradiation in any patient subgroup.