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

OBJECTIVEFractionated 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.METHODSThe 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.RESULTSBetween 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.CONCLUSIONSIn 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.

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MLTI-15. A CASE SERIES OF PRE-OPERATIVE GAMMA-KNIFE RADIOSURGERY FOR RESECTABLE BRAIN METASTASES

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz014.074 ◽

2019 ◽

Vol 1 (Supplement_1) ◽

pp. i17-i17

Author(s):

Tatsuya Takezaki ◽

Haruaki Yamamoto ◽

Naoki Shinojima ◽

Jun-ichiro Kuroda ◽

Shigeo Yamashiro ◽

...

Keyword(s):

Brain Metastases ◽

Stereotactic Radiosurgery ◽

Gamma Knife ◽

Systemic Treatment ◽

Radiation Necrosis ◽

Gamma Knife Radiosurgery ◽

Case Series ◽

Phase 3 ◽

Optimal Sequence ◽

Median Margin

Abstract Recent advances in the systemic treatment of various cancers have resulted in longer survival and higher incidence of brain metastases. Phase 3 trials in north America and in Japan have demonstrated that stereotactic radiosurgery will be a standard adjuvant modality following surgery for resectable brain metastases. However, we don’t know the optimal sequence of this combination therapy. We hypothesized that pre-operative stereotactic radiosurgery for resectable brain metastases provides favorable rates of local control, overall survival, leptomeningeal dissemination and symptomatic radiation necrosis. We have experienced 4 cases of resected brain metastases within 1–7 days after Gamma-knife surgery (median margin dose:22Gy) and have been following their clinical course. We will show the repressive cases.

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Systemic Treatment and Radiation Necrosis Following Gamma Knife Radiosurgery in the Treatment of Brain Metastases

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2014.05.1035 ◽

2014 ◽

Vol 90 (1) ◽

pp. S310

Author(s):

R.J. Colaco ◽

P. Martin ◽

J.S. Bond ◽

R.S. Bindra ◽

J.N. Contessa ◽

...

Keyword(s):

Brain Metastases ◽

Gamma Knife ◽

Systemic Treatment ◽

Radiation Necrosis ◽

Gamma Knife Radiosurgery

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Cavity-directed radiosurgery as adjuvant therapy after resection of a brain metastasis

Journal of Neurosurgery ◽

10.3171/2010.11.jns10939 ◽

2011 ◽

Vol 114 (6) ◽

pp. 1585-1591 ◽

Cited By ~ 105

Author(s):

Courtney A. Jensen ◽

Michael D. Chan ◽

Thomas P. McCoy ◽

J. Daniel Bourland ◽

Allan F. deGuzman ◽

...

Keyword(s):

Overall Survival ◽

High Resolution ◽

Brain Metastasis ◽

Mr Imaging ◽

Brain Metastases ◽

Treatment Failure ◽

Local Treatment ◽

Resection Cavity ◽

Kaplan Meier ◽

Cause Specific Survival

Object As a strategy to delay or avoid whole-brain radiotherapy (WBRT) after resection of a brain metastasis, the authors used high-resolution MR imaging and cavity-directed radiosurgery for the detection and treatment of further metastases. Methods Between April 2001 and October 2009, 112 resection cavities in 106 patients with no prior WBRT were treated using radiosurgery directed to the tumor cavity and for any synchronous brain metastases detected on high-resolution MR imaging at the time of radiosurgical planning. A median dose of 17 Gy to the 50% isodose line was prescribed to the gross tumor volume, defined as the rim of enhancement around the resection cavity. Patients were followed up via serial imaging, and new brain metastases were generally treated using additional radiosurgery, with salvage WBRT typically reserved for local treatment failure at a resection cavity, numerous failures, or failures occurring at short time intervals. Local and distant treatment failures were determined based on imaging results. Kaplan-Meier curves were generated to estimate local and distant treatment failure rates, overall survival, neurological cause–specific survival, and time delay to salvage WBRT. Results Radiosurgery was delivered to the resection cavity alone in 57.5% of patients, whereas 24.5% of patients also received treatment for 1 synchronous metastasis, 11.3% also received treatment for 2 synchronous metastases, and 6.6% also received treatment for 3–10 additional lesions. The median overall survival was 10.9 months. Overall survival at 1 year was 46.8%. The local tumor control rate at 1 year was 80.3%. The disease control rate in distant regions of the brain at 1 year was 35.4%, with a median time of 6.9 months to distant failure. Thirty-nine of 106 patients eventually received salvage WBRT, and the median time to salvage WBRT was 12.6 months. Kaplan-Meier estimates showed that the rate of requisite WBRT at 1 year was 45.9%. Neurological cause–specific survival at 1 year was 50.1%. Leptomeningeal failure occurred in 8 patients. One patient had treatment failure within the resection tract. Seven patients required reoperation: 2 for resection cavity recurrence, 3 for radiation necrosis, 1 for hydrocephalus, and 1 for a CSF cutaneous fistula. On multivariate analysis, a preoperative tumor diameter > 3 cm was predictive of local treatment failure. Conclusions Cavity-directed radiosurgery combined with high-resolution MR imaging detection and radiosurgical treatment of synchronous brain metastases is an effective strategy for delaying and even foregoing WBRT in most patients. This technique provides acceptable local disease control, although distant treatment failure remains significant.

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Novel biomarker identification using metabolomic profiling to differentiate radiation necrosis and recurrent tumor following Gamma Knife radiosurgery

Journal of Neurosurgery ◽

10.3171/2016.8.jns161395 ◽

2017 ◽

Vol 127 (2) ◽

pp. 388-396 ◽

Cited By ~ 8

Author(s):

Alex Y. Lu ◽

Jack L. Turban ◽

Eyiyemisi C. Damisah ◽

Jie Li ◽

Ahmed K. Alomari ◽

...

Keyword(s):

Brain Metastases ◽

Gamma Knife ◽

Radiation Necrosis ◽

Imaging Techniques ◽

Statistical Significance ◽

Gamma Knife Radiosurgery ◽

Metabolic Imaging ◽

Management Decision ◽

Recurrent Tumor ◽

Metabolite Profiles

OBJECTIVEFollowing an initial response of brain metastases to Gamma Knife radiosurgery, regrowth of the enhancing lesion as detected on MRI may represent either radiation necrosis (a treatment-related inflammatory change) or recurrent tumor. Differentiation of radiation necrosis from tumor is vital for management decision making but remains difficult by imaging alone. In this study, gas chromatography with time-of-flight mass spectrometry (GC-TOF) was used to identify differential metabolite profiles of the 2 tissue types obtained by surgical biopsy to find potential targets for noninvasive imaging.METHODSSpecimens of pure radiation necrosis and pure tumor obtained from patient brain biopsies were flash-frozen and validated histologically. These formalin-free tissue samples were then analyzed using GC-TOF. The metabolite profiles of radiation necrosis and tumor samples were compared using multivariate and univariate statistical analysis. Statistical significance was defined as p ≤ 0.05.RESULTSFor the metabolic profiling, GC-TOF was performed on 7 samples of radiation necrosis and 7 samples of tumor. Of the 141 metabolites identified, 17 (12.1%) were found to be statistically significantly different between comparison groups. Of these metabolites, 6 were increased in tumor, and 11 were increased in radiation necrosis. An unsupervised hierarchical clustering analysis found that tumor had elevated levels of metabolites associated with energy metabolism, whereas radiation necrosis had elevated levels of metabolites that were fatty acids and antioxidants/cofactors.CONCLUSIONSTo the authors' knowledge, this is the first tissue-based metabolomics study of radiation necrosis and tumor. Radiation necrosis and recurrent tumor following Gamma Knife radiosurgery for brain metastases have unique metabolite profiles that may be targeted in the future to develop noninvasive metabolic imaging techniques.

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Treatment of multiple brain metastases using gadolinium nanoparticles and radiotherapy: NANO-RAD, a phase I study protocol

BMJ Open ◽

10.1136/bmjopen-2018-023591 ◽

2019 ◽

Vol 9 (2) ◽

pp. e023591 ◽

Cited By ~ 34

Author(s):

Camille Verry ◽

Lucie Sancey ◽

Sandrine Dufort ◽

Geraldine Le Duc ◽

Christophe Mendoza ◽

...

Keyword(s):

Overall Survival ◽

Brain Metastases ◽

Phase I ◽

Dose Escalation ◽

Human Study ◽

National Agency ◽

Open Label ◽

Dose Escalation Study ◽

Multiple Brain Metastases ◽

Reference Number

IntroductionOccurrence of multiple brain metastases is a critical evolution of many cancers with significant neurological and overall survival consequences, despite new targeted therapy and standard whole brain radiotherapy (WBRT). A gadolinium-based nanoparticle, AGuIX, has recently demonstrated its effectiveness as theranostic and radiosensitiser agent in preclinical studies. The favourable toxicity profile in animals and its administration as a simple intravenous injection has motivated its use in patients with this first in human study.Methods and analysisThe NANO-RAD study is a phase I, first in human injection, monocentric, open-label, dose-escalation study to investigate the safety, the tolerability and the spectrum of side effects of AGuIX in combination with WBRT (30 Gy, 10 fractions of 3 Gy) for patients with multiple brain metastases. Five dose escalation cohorts are planned: 15, 30, 50, 75 and 100 mg/kg. A total of 15–18 patients will be recruited into this trial. The primary objective is to determine the maximum-tolerated dose of AGuIX nanoparticles combined with WBRT for the treatment of multiple brain metastases. Toxicity will be assessed using the National Cancer Institute Common Toxicity Criteria V.4.03. Secondary objectives are pharmacokinetic profile, distribution of AGuIX in metastases and surrounding healthy tissue visualised by MRI, intracranial progression-free survival and overall survival. Intracranial response will be determined according to Response Evaluation Criteria in Solid Tumour Criteria V.1.1 comparing MRI performed prior to treatment and at each follow-up visits.Ethics and disseminationApproval was obtained from the ethics committee Sud Est V, France (Reference number 15-CHUG-48). The study was approved by the French National Agency for the Safety of Medicines and Health Products (ANSM) (Reference number 151519A-12). The results will be published in peer-reviewed journals or disseminated through national and international conferences.Trial registration numberNCT02820454; Pre-results.

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Clinical Outcome in Gamma Knife Radiosurgery for Metastatic Brain Tumors from the Primary Breast Cancer : Prognostic Factors in Local Treatment Failure and Survival

Journal of Korean Neurosurgical Society ◽

10.3340/jkns.2013.54.4.329 ◽

2013 ◽

Vol 54 (4) ◽

pp. 329 ◽

Cited By ~ 2

Author(s):

Seung Won Choi ◽

Do Hoon Kwon ◽

Chang Jin Kim

Keyword(s):

Breast Cancer ◽

Prognostic Factors ◽

Brain Tumors ◽

Clinical Outcome ◽

Treatment Failure ◽

Gamma Knife ◽

Primary Breast Cancer ◽

Local Treatment ◽

Gamma Knife Radiosurgery ◽

Metastatic Brain Tumors

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Comparison of treatment results between 3- and 2-stage Gamma Knife radiosurgery for large brain metastases: a retrospective multi-institutional study

Journal of Neurosurgery ◽

10.3171/2018.4.jns172596 ◽

2019 ◽

Vol 131 (1) ◽

pp. 227-237 ◽

Cited By ~ 9

Author(s):

Toru Serizawa ◽

Yoshinori Higuchi ◽

Masaaki Yamamoto ◽

Shigeo Matsunaga ◽

Osamu Nagano ◽

...

Keyword(s):

Overall Survival ◽

Adverse Events ◽

Brain Metastases ◽

Tumor Progression ◽

Gamma Knife ◽

Tumor Volume ◽

Gamma Knife Radiosurgery ◽

Tumor Control ◽

Treatment Results ◽

Matched Study

OBJECTIVEIn order to obtain better local tumor control for large (i.e., > 3 cm in diameter or > 10 cm3 in volume) brain metastases (BMs), 3-stage and 2-stage Gamma Knife surgery (GKS) procedures, rather than a palliative dose of stereotactic radiosurgery, have been proposed. Here, authors conducted a retrospective multi-institutional study to compare treatment results between 3-stage and 2-stage GKS for large BMs.METHODSThis retrospective multi-institutional study involved 335 patients from 19 Gamma Knife facilities in Japan. Major inclusion criteria were 1) newly diagnosed BMs, 2) largest tumor volume of 10.0–33.5 cm3, 3) cumulative intracranial tumor volume ≤ 50 cm3, 4) no leptomeningeal dissemination, 5) no more than 10 tumors, and 6) Karnofsky Performance Status 70% or better. Prescription doses were restricted to between 9.0 and 11.0 Gy in 3-stage GKS and between 11.8 and 14.2 Gy in 2-stage GKS. The total treatment interval had to be within 6 weeks, with at least 12 days between procedures. There were 114 cases in the 3-stage group and 221 in the 2-stage group. Because of the disproportion in patient numbers and the pre-GKS clinical factors between these two GKS groups, a case-matched study was performed using the propensity score matching method. Ultimately, 212 patients (106 from each group) were selected for the case-matched study. Overall survival, tumor progression, neurological death, and radiation-related adverse events were analyzed.RESULTSIn the case-matched cohort, post-GKS median survival time tended to be longer in the 3-stage group (15.9 months) than in the 2-stage group (11.7 months), but the difference was not statistically significant (p = 0.65). The cumulative incidences of tumor progression (21.6% vs 16.7% at 1 year, p = 0.31), neurological death (5.1% vs 6.0% at 1 year, p = 0.58), or serious radiation-related adverse events (3.0% vs 4.0% at 1 year, p = 0.49) did not differ significantly.CONCLUSIONSThis retrospective multi-institutional study showed no differences between 3-stage and 2-stage GKS in terms of overall survival, tumor progression, neurological death, and radiation-related adverse events. Both 3-stage and 2-stage GKS performed according to the aforementioned protocols are good treatment options in selected patients with large BMs.

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Low-Dosage Bevacizumab Treatment: Effect on Radiation Necrosis After Gamma Knife Radiosurgery for Brain Metastases

Frontiers in Surgery ◽

10.3389/fsurg.2021.720506 ◽

2021 ◽

Vol 8 ◽

Author(s):

Yuxiang Weng ◽

Jie Shen ◽

Luyuan Zhang ◽

Zebin Fang ◽

Feng Xiao ◽

...

Keyword(s):

Brain Metastases ◽

Gamma Knife ◽

Low Dose ◽

Radiation Necrosis ◽

Karnofsky Performance Status ◽

Performance Status ◽

Gamma Knife Radiosurgery ◽

High Price ◽

Bevacizumab Treatment ◽

Low Dosage

Cerebral radiation necrosis (RN), a complication of Gamma Knife radiosurgery, is difficult to treat, although bevacizumab seems to be effective. However, clinical data pertaining to bevacizumab treatment for RN are scarce, and its high price is problematic. This study explored the effectiveness of low-dose bevacizumab for RN caused by Gamma Knife. We retrospectively analyzed 22 patients who suffered cerebral RN post-Gamma Knife, and received bevacizumab treatment because of the poor efficacy of glucocorticoids. Low-dose bevacizumab (3 mg/kg) was administered for two cycles at 2-week intervals. T1- and T2-enhanced magnetic resonance imaging (MRI) images were examined for changes in RN status. We also monitored the dose of glucocorticoid, Karnofsky Performance Status (KPS) score, and adverse drug reactions. The mean volume of RN lesions decreased by 45% on T1-weighted images with contrast enhancement, and by 74% on T2-weighted images. All patients discontinued the use of glucocorticoids. According to the KPS scores, all patients showed an improvement in their symptoms and neurological function. No side effects were observed. Low-dosage bevacizumab at a dose of 3 mg/kg every 2 weeks is effective for treating cerebral RN after Gamma knife for brain metastases.

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