Multifraction stereotactic radiosurgery (MF-SRS) purportedly reduces radionecrosis risk over single fraction SRS (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.

PICOS/PRISMA/MOOSE guidelines were used to select articles where patients: diagnosed with “large” brain metastases (Group A: 4-14 cm3, or about 2-3 cm; Group B: >14 cm3, or > 3 cm); 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<0.05.

RESULTS: Twenty-four studies were included, published between 2008-2017 with 1,887 brain metastases. Local control random effects estimate at 1-year for Group A/SF-SRSD was 77.6% and for Group A/MF-SRSD was 92.9% (p=0.18). Local control random effects estimate at 1-year for Group B/SF-SRSD was 77.1% and for Group B/MF-SRSD was 79.2% (p=0.76). Local control random effects estimate at 1-year for Group B/SF-SRSP was 62.4% and for Group B/MF-SRSP was 85.7% (p=0.13). Radionecrosis incidence random effects estimate for Group A/SF-SRSD was 23.1% and for Group A/MF-SRSD was 7.3% (p=0.003). Radionecrosis incidence random effects estimate for Group B/SF-SRSD was 11.7% and for Group B/MF-SRSD was 6.5% (p=0.29). Radionecrosis incidence random effects estimate for Group B/SF-SRSP was 7.3% and for Group B/MF-SRSP was 7.5% (p=0.85). Meta-regression assessing 1-year LC and radionecrosis as a continuous function of increasing tumor volume was not statistically significant.

CONCLUSION: 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 when compared to SF-SRS. These findings are hypothesis-generating and require validation by ongoing and planned prospective randomized control trials ¹⁾.

1: Lehrer EJ, Peterson JL, Zaorsky NG, Brown PD, Sahgal A, Chiang VL, Chao ST, Sheehan JP, Trifiletti DM. Single versus multifraction stereotactic radiosurgery for large brain metastases: An international meta-analysis of 24 trials. Int J Radiat Oncol Biol Phys. 2018 Nov 2. pii: S0360-3016(18)33927-0. doi: 10.1016/j.ijrobp.2018.10.038. [Epub ahead of print] PubMed PMID: 30395902.

2: Jhaveri J, Chowdhary M, Zhang X, Press RH, Switchenko JM, Ferris MJ, Morgan TM, Roper J, Dhabaan A, Elder E, Eaton BR, Olson JJ, Curran WJ Jr, Shu HG, Crocker IR, Patel KR. Does size matter? Investigating the optimal planning target volume margin for postoperative stereotactic radiosurgery to resected brain metastases. J Neurosurg. 2018 Apr 20:1-7. doi: 10.3171/2017.9.JNS171735. [Epub ahead of print] PubMed PMID: 29676690; PubMed Central PMCID: PMC6195865.

3: Minniti G, Scaringi C, Paolini S, Lanzetta G, Romano A, Cicone F, Osti M, Enrici RM, Esposito V. Single-Fraction Versus Multifraction (3 × 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 Jul 15;95(4):1142-8. doi: 10.1016/j.ijrobp.2016.03.013. Epub 2016 Mar 19. PubMed PMID: 27209508.

4: Muldermans JL, Romak LB, Kwon ED, Park SS, Olivier KR. Stereotactic Body Radiation Therapy for Oligometastatic Prostate Cancer. Int J Radiat Oncol Biol Phys. 2016 Jun 1;95(2):696-702. doi: 10.1016/j.ijrobp.2016.01.032. Epub 2016 Jan 29. PubMed PMID: 27131082; PubMed Central PMCID: PMC5154616.

5: Ghia AJ, Chang EL, Bishop AJ, Pan HY, Boehling NS, Amini B, Allen PK, Li J, Rhines LD, Tannir NM, Tatsui CE, Brown PD, Yang JN. Single-fraction versus multifraction spinal stereotactic radiosurgery for spinal metastases from renal cell carcinoma: secondary analysis of Phase I/II trials. J Neurosurg Spine. 2016 May;24(5):829-36. doi: 10.3171/2015.8.SPINE15844. Epub 2016 Jan 22. PubMed PMID: 26799117.

6: Amini B, Beaman CB, Madewell JE, Allen PK, Rhines LD, Tatsui CE, Tannir NM, Li J, Brown PD, Ghia AJ. Osseous Pseudoprogression in Vertebral Bodies Treated with Stereotactic Radiosurgery: A Secondary Analysis of Prospective Phase I/II Clinical Trials. AJNR Am J Neuroradiol. 2016 Feb;37(2):387-92. doi: 10.3174/ajnr.A4528. Epub 2015 Oct 22. PubMed PMID: 26494690; PubMed Central PMCID: PMC4752915.

7: Pollom EL, Alagappan M, von Eyben R, Kunz PL, Fisher GA, Ford JA, Poultsides GA, Visser BC, Norton JA, Kamaya A, Cox VL, Columbo LA, Koong AC, Chang DT. Single- versus multifraction stereotactic body radiation therapy for pancreatic adenocarcinoma: outcomes and toxicity. Int J Radiat Oncol Biol Phys. 2014 Nov 15;90(4):918-25. doi: 10.1016/j.ijrobp.2014.06.066. Epub 2014 Oct 18. PubMed PMID: 25585785.

8: Trakul N, Chang CN, Harris J, Chapman C, Rao A, Shen J, Quinlan-Davidson S, Filion EJ, Wakelee HA, Colevas AD, Whyte RI, Dieterich S, Maxim PG, Hristov D, Tran P, Le QT, Loo BW Jr, Diehn M. Tumor volume-adapted dosing in stereotactic ablative radiotherapy of lung tumors. Int J Radiat Oncol Biol Phys. 2012 Sep 1;84(1):231-7. doi: 10.1016/j.ijrobp.2011.10.071. Epub 2012 Feb 28. PubMed PMID: 22381907.

9: Goldsmith B, McDermott MW. Meningioma. Neurosurg Clin N Am. 2006 Apr;17(2):111-20, vi. Review. PubMed PMID: 16793503.

10: Knisely JP, Bond JE, Yue NJ, Studholme C, de Lotbinière AC. Image registration and calculation of a biologically effective dose for multisession radiosurgical treatments. Technical note. J Neurosurg. 2000 Dec;93 Suppl 3:208-18. PubMed PMID: 11143251.

11: Souhami L, Olivier A, Podgorsak EB, Villemure JG, Pla M, Sadikot AF. Fractionated stereotactic radiation therapy for intracranial tumors. Cancer. 1991 Nov 15;68(10):2101-8. PubMed PMID: 1913448.