Clinical Investigation
Single versus Multifraction Stereotactic Radiosurgery for Large Brain Metastases: An International Meta-analysis of 24 Trials

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Purpose

Multifraction (MF) stereotactic radiosurgery (SRS) purportedly reduces radionecrosis risk over single-fraction (SF) SRS in the treatment of large brain metastases. The purpose of the current work is to compare local control (LC) and radionecrosis rates of SF-SRS and MF-SRS in the definitive (SF-SRSD and MF-SRSD) and postoperative (SF-SRSP and MF-SRSP) settings.

Methods and Materials

Population, Intervention, Control, Outcomes, Study Design/Preferred Reporting Items for Systematic Reviews and Meta-analyses and Meta-analysis of Observational Studies in Epidemiology guidelines were used to select articles in which patients had “large” brain metastases (Group A: 4-14 cm3, or about 2-3 cm in diameter; Group B: >14 cm3, or about >3 cm in diameter); 1-year LC and/or rates of radionecrosis were reported; radiosurgery was administered definitively or postoperatively. Random effects meta-analyses using fractionation scheme and size as covariates were conducted. Meta-regression and Wald-type tests were used to determine the effect of increasing tumor size and fractionation on the summary estimate, where the null hypothesis was rejected for P < .05.

Results

Twenty-four studies were included, published between 2008 and 2017, with 1887 brain metastases. LC random effects estimate at 1 year was 77.6% for Group A/SF-SRSD and 92.9% for Group A/MF-SRSD (P = .18). LC random effects estimate at 1 year was 77.1% for Group B/SF-SRSD and 79.2% for Group B/MF-SRSD (P = .76). LC random effects estimate at 1 year was 62.4% for Group B/SF-SRSP and 85.7% for Group B/MF-SRSP (P = .13). Radionecrosis incidence random effects estimate was 23.1% for Group A/SF-SRSD and 7.3% for Group A/MF-SRSD (P = .003). Radionecrosis incidence random effects estimate was 11.7% for Group B/SF-SRSD and 6.5% for Group B/MF-SRSD (P = .29). Radionecrosis incidence random effects estimate was 7.3% for Group B/SF-SRSP and 7.5% for Group B/MF-SRSP (P = .85). Metaregression assessing 1-year LC and radionecrosis as a continuous function of increasing tumor volume was not statistically significant.

Conclusions

Treatment for large brain metastases with MF-SRS regimens may offer a relative reduction of radionecrosis while maintaining or improving relative rates of 1-year LC compared with SF-SRS. These findings are hypothesis-generating and require validation by ongoing and planned prospective clinical 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.

References (63)

  • E. Shaw et al.

    Radiosurgery for the treatment of previously irradiated recurrent primary brain tumors and brain metastases: Initial report of Radiation Therapy Oncology Group protocol (90-05)

    Int J Radiat Oncol Biol Phys

    (1996)
  • P.D. Brown et al.

    Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC.3): A multicentre, randomised, controlled, phase 3 trial

    Lancet Oncol

    (2017)
  • R. DerSimonian et al.

    Meta-analysis in clinical trials

    Control Clin Trials

    (1986)
  • J.L. Fleiss et al.

    Meta-analysis in epidemiology, with special reference to studies of the association between exposure to environmental tobacco smoke and lung cancer: A critique

    J Clin Epidemiol

    (1991)
  • R.S. Prabhu et al.

    Single-fraction stereotactic radiosurgery (SRS) alone versus surgical resection and SRS for large brain metastases: A multi-institutional analysis

    Int J Radiat Oncol Biol Phys

    (2017)
  • C.Y. Choi et al.

    What is the optimal treatment of large brain metastases? An argument for a multidisciplinary approach

    Int J Radiat Oncol Biol Phys

    (2012)
  • A. Mahajan et al.

    Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: A single-centre, randomised, controlled, phase 3 trial

    Lancet Oncol

    (2017)
  • F. Pessina et al.

    Role of surgical resection in patients with single large brain metastases: Feasibility, morbidity, and local control evaluation

    World Neurosurg

    (2016)
  • G. Minniti et al.

    Multidose stereotactic radiosurgery (9 Gy x 3) of the postoperative resection cavity for treatment of large brain metastases

    Int J Radiat Oncol Biol Phys

    (2013)
  • G. Minniti et al.

    Single-fraction versus multifraction (3 x 9 Gy) stereotactic radiosurgery for large (>2 cm) brain metastases: A comparative analysis of local control and risk of radiation-induced brain necrosis

    Int J Radiat Oncol Biol Phys

    (2016)
  • L. Feuvret et al.

    Stereotactic radiotherapy for large solitary brain metastases

    Cancer Radiother

    (2014)
  • T. Murai et al.

    Fractionated stereotactic radiotherapy using CyberKnife for the treatment of large brain metastases: A dose escalation study

    Clin Oncol (R Coll Radiol)

    (2014)
  • J.H. Han et al.

    Radiosurgery for large brain metastases

    Int J Radiat Oncol Biol Phys

    (2012)
  • Y. Higuchi et al.

    Three-staged stereotactic radiotherapy without whole brain irradiation for large metastatic brain tumors

    Int J Radiat Oncol Biol Phys

    (2009)
  • M.D. Johnson et al.

    Surgical resection of brain metastases and the risk of leptomeningeal recurrence in patients treated with stereotactic radiosurgery

    Int J Radiat Oncol Biol Phys

    (2016)
  • D.M. Trifiletti et al.

    Stereotactic radiosurgery for brainstem metastases: An international cooperative study to define response and toxicity

    Int J Radiat Oncol Biol Phys

    (2016)
  • S.N. Kalkanis et al.

    The role of surgical resection in the management of newly diagnosed brain metastases: A systematic review and evidence-based clinical practice guideline

    J Neurooncol

    (2010)
  • R.A. Patchell et al.

    Postoperative radiotherapy in the treatment of single metastases to the brain: S randomized trial

    JAMA

    (1998)
  • C.M. McPherson et al.

    Adjuvant whole-brain radiation therapy after surgical resection of single brain metastases

    Neuro Oncol

    (2010)
  • M. Kocher et al.

    Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: Results of the EORTC 22952-26001 study

    J Clin Oncol

    (2011)
  • P.D. Brown et al.

    Effect of radiosurgery alone vs radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: A randomized clinical trial

    JAMA

    (2016)
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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.

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