Outcome evaluation of patients treated with fractionated Gamma Knife radiosurgery for large (> 3 cm) brain metastases: a dose-escalation study

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OBJECTIVE

Fractionated Gamma Knife radiosurgery (GKS) represents a feasible option for patients with large brain metastases (BM). However, the dose-fractionation scheme balanced between local control and radiation-induced toxicity remains unclear. Therefore, the authors conducted a dose-escalation study using fractionated GKS as the primary treatment for large (> 3 cm) BM.

METHODS

The exclusion criteria were more than 3 lesions, evidence of leptomeningeal disease, metastatic melanoma, poor general condition, and previously treated lesions. Patients were randomized to receive 24, 27, or 30 Gy in 3 fractions (8, 9, or 10 Gy per fraction, respectively). The primary endpoint was the development of radiation necrosis assessed by a neuroradiologist blinded to the study. The secondary endpoints included the local progression-free survival (PFS) rate, change in tumor volume, development of distant intracranial progression, and overall survival.

RESULTS

Between September 2016 and April 2018, 60 patients were eligible for the study, with 46 patients (15, 17, and 14 patients in the 8-, 9-, and 10-Gy groups, respectively) available for analysis. The median follow-up duration was 9.6 months (range 2.5–25.1 months). The 6-month estimated cumulative incidence of radiation necrosis was 0% in the 8-Gy group, 13% (95% confidence interval [CI] 0%–29%) in the 9-Gy group, and 37% (95% CI 1%–58%) in the 10-Gy group. Being in the 10-Gy group was a significant risk factor for the development of radiation necrosis (p = 0.047; hazard ratio [HR] 7.2, 95% CI 1.1–51.4). The 12-month local PFS rates were 65%, 80%, and 75% in the 8-, 9-, and 10-Gy groups, respectively. Being in the 8-Gy group was a risk factor for local treatment failure (p = 0.037; HR 2.5, 95% CI 1.1–29.6). The mean volume change from baseline was a 47.5% decrease in this cohort. Distant intracranial progression and overall survival did not differ among the 3 groups.

CONCLUSIONS

In this dose-escalation study, 27 Gy in 3 fractions appeared to be a relevant regimen of fractionated GKS for large BM because 30 Gy in 3 fractions resulted in unacceptable toxicities and 24 Gy in 3 fractions was associated with local treatment failure.

ABBREVIATIONS BED = biologically effective dose; BM = brain metastases; CBCT = cone-beam computed tomography; CI = confidence interval; GKS = Gamma Knife radiosurgery; HR = hazard ratio; KPS = Karnofsky Performance Scale; PFS = progression-free survival; rCBV = relative cerebral blood volume; RTOG = Radiation Therapy Oncology Group; SRS = stereotactic radiosurgery; V12Gy = volume of brain receiving 12 Gy.

Article Information

Correspondence Jung-Il Lee: Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. jilee@skku.edu.

INCLUDE WHEN CITING Published online August 16, 2019; DOI: 10.3171/2019.5.JNS19222.

K.H.K. and D.S.K. contributed equally to this work.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

© AANS, except where prohibited by US copyright law.

Headings

Figures

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    Flow diagram of study progress.

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    Representative cases of radiation necrosis (A and B) and successful local control (C and D). All images are contrast-enhanced T1-weighted axial MR images. A: A 60-year-old man presented with a large single metastatic lesion (22.4 cm3) that originated from non–small-cell lung cancer. GKS was administered in 3 fractionated treatments of 10 Gy (for a total of 30 Gy) to the 50% isodose line (yellow line). B: At 5 months after GKS, extensive radiation necrosis with surrounding edema developed. C: A 32-year-old man with a large brain metastasis (21.8 cm3) from lung cancer underwent fractionated GKS (27 Gy in 3 fractions, yellow line). D: After 3 months, a new metastatic lesion was developed and treated with GKS, while the lesion treated by fractionated GKS was successfully controlled, i.e., a 90% decrease in volume compared to the original tumor (blue line indicates original tumor margin). Figure is available in color online only.

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    Cumulative incidence of radiation necrosis in the 3 treatment groups. Figure is available in color online only.

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    Forest plot for the HR of radiation necrosis development derived from a Cox proportional hazards model. *When analyzing tumor volume and other factors, the V12Gy was not included in multivariate analysis, because V12Gy was not an independent variable for the tumor volume.

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    Graphs of local PFS (A), distant intracranial PFS (B), and overall survival (C) in the 3 treatment groups. Figure is available in color online only.

  • View in gallery

    Change in tumor volume from baseline. Figure is available in color online only.

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