Radiosurgery for recurrent glioblastoma: a review article

Glioblastoma (GB) is the most common primary brain tumor in adults, accounting for more than half of all diffuse gliomas with an agressive disease course despite multimodality management. Too few patients with GB live more than 5 years, and there are several prognostic factors including age, performance status, and MGMT promoter methylation which is associated with response to Temozolomide treatment. Standard of care in newly diagnosed GB has been established in 2005 as concurrent chemoradiotherapy, based on the landmark European Organisation for Research and Treatment of Cancer (EORTC)/National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) study demonstrating a clinically meaningful and significant median overall survival benefit with the addition of Temozolomide to conventionally fractionated partial brain radiotherapy. However, recurrence is very common in an overwhelming majority of the patients with a grim prognosis. Several therapeutic strategies are employed in the recurrent setting with no established standard of care. Reoperation, repeat radiotherapy, chemotherapy, tumor treating fields, antiangiogenic and other targeted agents, experimental treatments and combinations of modalities have been used for management of patients with recurrent GB depending on tumor and patient characteristics. Herein, we review the use of radiosurgery for management of recurrent GB in light of the literature. Correspondence to: Omer Sager, MD, Associate Professor, University of Health Sciences, Gulhane Medical Faculty, Department of Radiation Oncology, Gn.Tevfik Saglam Cad. 06018, Etlik, Kecioren Ankara/TURKEY. Tel: +90 312 304 4683, E-mail: omersager@gmail.com


Introduction
Glioblastoma (GB) is the most common primary brain tumor in adults, accounting for more than half of all diffuse gliomas with an agressive disease course despite multimodality management [1]. Too few patients with GB live more than 5 years, and there are several prognostic factors including age, performance status, and MGMT promoter methylation which is associated with response to Temozolomide treatment [2][3][4][5].
Standard of care in newly diagnosed GB has been established in 2005 as concurrent chemoradiotherapy, based on the landmark European Organisation for Research and Treatment of Cancer (EORTC)/ National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) study demonstrating a clinically meaningful and significant median overall survival benefit with the addition of Temozolomide to conventionally fractionated partial brain radiotherapy [6]. However, recurrence is very common in an overwhelming majority of the patients with a grim prognosis. Several therapeutic strategies are employed in the recurrent setting with no established standard of care. Reoperation, repeat radiotherapy, chemotherapy, tumor treating fields, antiangiogenic and other targeted agents, experimental treatments and combinations of modalities have been used for management of patients with recurrent GB depending on tumor and patient characteristics. Treatment at the recurrent setting is typically more complex due to already received previous treatments at the initial diagnosis along with the diffusely infiltrating nature of the disease following an aggressive course with a rapid proliferative rate. Repeat surgery may be hampered by involvement of the eloquent cortex in an infiltrative manner with an increased risk of complications in the recurrent disease setting. Nevertheless, surgery may be particularly useful for relieving symptoms of the mass effect in selected patients with recurrent disease located in a non-eloquent brain region, and the extent of surgical removal of the recurrent GB lesion may impact overall survival [7,8]. Also, establishing the accurate diagnosis with confirmation of the initial histology may be achieved by surgery along with detection of molecular markers for potential therapeutic exploitation [9]. Herein, we review the use of radiosurgery for management of recurrent GB in light of the literature.

Radiosurgery for recurrent glioblastoma
Given the advances in the discipline of radiation oncology, precisely focused stereotactic irradiation in a contemporary fashion has been widely accepted in management of several benign and malign conditions with considerable success [10-25]. In the context of recurrent GB, several reports have assessed the role of radiosurgery delivered either in a single session or in a hypofractionated manner with or without integration of other agents [7,9,11,25,.
The utility of salvage radiotherapy in recurrent GB management has dramatically expanded with the incorporation of radiosurgery in the radiotherapeutic armamentarium. Improved spatial target localization by virtue of advanced neuroimaging techniques allows for precisely focused delivery of high effective target doses with optimal normal tissue sparing through steep dose gradients achieved via robust stereotactic localization and intensity-modulated computerized treatment planning for accurate radiosurgery applications [53,54].

Rationale for radiosurgery
High effective radiation doses delivered in a limited number of treatment fractions lead to enhanced killing of malignant cells with diminished tumor repopulation, and the tumoricidal effect of radiosurgery may be accomplished through DNA injury, induced apoptosis and vascular endothelial damage [55,56].
In terms of patient convenience, radiosurgery with a condensed radiation treatment schedule provides shortening of overall radiotherapy time and recovery as an outpatient procedure resulting in improved patient compliance. As the applications of radiosurgery expanded, there has been a rapid incorporation of innovative technologies improving treatment precision with decreased costs, and radiosurgery beginned serving as a very favorable and affordable radiotherapeutic strategy comprising an indespensable part of both neurosurgery and radiation oncology practice [57].

Outcomes of radiosurgery
Overall, studies of radiosurgery for recurrent GB suggest a moderate therapeutic benefit with an improved toxicity profile and the reported survival rates are promising at the least if not better compared to other salvage treatment options. Clearly, vigilance is required for patient selection in the salvage treatment setting since any therapeutic intervention may induce morbidity with substantial burden on the patients typically exhausted with the previous treatments. In this respect, a multidisciplinary approach is warranted with thorough consideration of several factors including age, performance status, time interval from initial surgery and radiotherapy, tumor location and volume, MGMT promoter methylation status, extent of surgery, details of initial radiotherapy, patient preference and quality-oflife. Nevertheless, salvage management of patients with recurrent GB should be strongly considered given the relentless disease course without treatment and improved toxicity profile of contemporary treatments with low adverse effect on patients' quality-of-life. [27,28].
Radiosurgery may be a viable radiotherapeutic alternative for management of recurrent GB patients with high performance status, young age, and small tumor size appropriate for focused irradiation.

Future perspectives and conclusion
Attempts to improve radiosurgical outcomes for recurrent GB management include the addition of antiangiogenic agents, which may have a potential role in improving the toxicity profile through decreased radiation necrosis along with normalization of tumor vasculature providing potentially enhanced radiotherapeutic activity due to increased oxygenation. [26,41,61].
In conclusion, radiosurgery offers a viable non-invasive treatment strategy for patients with recurrent GB. Comparison of different therapeutic modalities is confounded by diverse patient and treatment characteristics, however, randomized controlled trials may shed light on optimal management of recurrent GB. The utility of radiosurgery has expanded thanks to recent advances in technology and improvements in neuroimaging, radiosurgery techniques, equipment, treatment planning and delivery systems. Incorporation of antiangiogenic and other agents may improve outcomes of radiosurgery despite the need for further studies.

Conflict of interest
There is no conflict of interest.