International Journal of Radiation Oncology*Biology*Physics
Clinical InvestigationSingle versus Multifraction Stereotactic Radiosurgery for Large Brain Metastases: An International Meta-analysis of 24 Trials
Introduction
Metastatic brain tumors represent the most common intracranial neoplasm, occurring in up to 30% of patients with cancer.1 This incidence is expected to increase further because of expanded screening efforts using magnetic resonance imaging and improved systemic therapies. The optimal management of brain metastases is highly patient specific; therefore, age, performance status, comorbidities, and primary disease status all play a role in guiding treatment.2
The two major treatment modalities for brain metastases are surgery and radiation. Previous clinical trials have shown that surgical resection alone demonstrates insufficient rates of local control (LC), although the addition of postoperative whole brain radiation therapy (WBRT) has resulted in markedly improved LC rates, this did not result in a survival benefit.3, 4, 5 WBRT is considered by many to be standard treatment after resection of brain metastases, but its association with cognitive decline has given many clinicians pause.6, 7, 8
Single-fraction (SF) stereotactic radiosurgery (SRS) involves the administration of a high dose of targeted radiation delivered in a single session; it has become an increasingly popular treatment option in the definitive (SF-SRSD) and postoperative (SF-SRSP) settings. However, the development of radionecrosis after SF-SRS is concerning, particularly when treating large tumors and cavities.9, 10, 11 The development of radionecrosis is correlated with the volume of brain irradiation; it has been demonstrated that the risk of radionecrosis is up to 60% when at least 10 cm3 of normal brain tissue receives doses of 12 Gy.9, 10, 11, 12, 13, 14, 15
Multifraction (MF) SRS is a radiosurgical technique that has gained traction in recent years with the expansion of frameless SRS techniques in both the definitive (MF-SRSD) and postoperative (MF-SRSP) settings. The goal of MF-SRS is to reduce the risk of radionecrosis while providing similar, or perhaps improved, levels of LC in the treatment of brain metastases. Although MF-SRS is used increasingly in clinical practice, there is a paucity of available data to validate its use. Therefore, a meta-analysis was conducted to determine the efficacy (1-year LC) and safety (incidence of radionecrosis) in MF-SRS compared with SF-SRS in the definitive and postoperative treatment of large brain metastases.
Section snippets
Evidence acquisition
Literature inclusion criteria was defined using the Population, Intervention, Control, Outcomes, Study Design method (Table E1; available online at https://dx.doi.org/10.1016/j.ijrobp.2018.10.038).16, 17, 18 In addition, the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) selection algorithm (Fig. E1; available online at https://dx.doi.org/10.1016/j.ijrobp.2018.10.038) was designed.19 Guidelines from the PRISMA checklist19 (Table E2; available online at //dx.doi.org/10.1016/j.ijrobp.2018.10.038
Study characteristics
Twenty-four studies were included in the meta-analysis25, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57 which were published between 2008 and 2017. Patients were treated from 1998 to 2016. The studies were conducted in the United States,25, 35, 36, 37, 38, 39, 47, 48, 49, 54 Japan,40, 50, 51, 53, 56 Korea,41, 55 Italy42, 43, 44, 45 France,52 and Germany.57 Radiosurgery was administered definitively in 17 of the studies35, 37, 39, 40, 41, 43, 45, 46,
Discussion
The National Comprehensive Cancer Network recommends SRS as a treatment option for suitable patients with brain metastases, where the SRS dose typically depends on tumor volume.58 However, there are limited data available indicating which dose and fractionation scheme should be used, particularly when treating large brain metastases. Our results demonstrate several key findings regarding the use of SRS in the treatment of large brain metastases. For large brain metastases measuring 4 to 14cm3
Conclusion
In the treatment of large brain metastases with radiosurgery in the definitive and postoperative settings, MF-SRS may offer a relative reduction of radionecrosis while maintaining or improving relative rates of 1-year LC compared to SF-SRS. The hypothesis-generating nature of these findings must be validated with currently ongoing and planned prospective trials.
Acknowledgments
The authors thank Keith Anderson, Xiomara Carrero, and Jesse Dixon of Alliance Statistics for their assistance with obtaining data from NCCTG N107/CEC3.
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Conflict of interest: P.D.B. has received honoraria from UpToDate and is a member of Novella Clinical DSMB. A.S. is a speaker for Medtronic, serves on the Elekta AB Medical Advisory Board, is a speaker for Varian Medical Systems, and received the Accuray Incorporated Research Grant from Elekta AB. S.T.C. has received honoraria from Varian. D.M.T. has received clinical research funding from Novocure.