Although the development of stereotactic radiosurgery (SRS) has fundamentally reshaped the treatment paradigm for brain metastases (BMs),1,16 there is an evolving recognition of its limitations. For tumor histological types that possess increased intrinsic resistance to radiation, such as melanoma, treatment failure can be observed in > 25% of patients with BMs.6 For larger BMs or those adjacent to critical anatomical structures, delivery of radiation doses required for tumor control may incur neurological injury.8 Finally, as overall survival improves for select patient populations, reports of BM progression after SRS-induced growth arrest are emerging.11,13
Therapeutic options for BMs that recur after SRS remain limited. Repeat SRS is an option;19 however, it is associated with increased risk of radiation necrosis.5 Effective chemotherapeutic options in this setting remain elusive.3 It is in this context that stereotactic laser ablation (SLA) has been used. For SLA treatment of SRS-resistant metastases, a fiberoptic probe with laser-firing capacity is inserted into the cancerous tissue, where activation of the laser induces tissue destruction through thermocoagulation.4,9,17 Because clinical experiences with this technique remain limited, we present the pooled experience of 4 institutions where 26 BMs that recurred after SRS were treated with SLA.
Methods
Patient Population and Data Collection
The study was conducted under protocols approved by the institutional review boards at the following institutions: University of California San Diego (UCSD); Barrow Neurological Institute (BNI); Cleveland Clinic (CC); and Case Western (CW). Patient characteristics (age, sex, primary tumor histology, tumor location), corticosteroid regimens, and surgical morbidity information were collected through chart review. For BMs treated using the NeuroBlate system (Monteris Medical), tumor volume and percent of ablation covered by the blue isotherm line (tissue heated to 43°C for ≥ 10 minutes) were calculated by the company software. Information pertaining to percent tumor ablation for lesions treated with the Visualase (Medtronic) system was not available. Tumor volumes for these lesions were calculated using 3D Slicer (www.slicer.org), ImageJ (https://imagej.nih.gov/ij/), or by estimation based on maximal diameters. Surveillance MRIs were performed every 1–2 months after SLA for all treated patients. Radiographic responses were assessed based on the Neurologic Assessment in Neuro-Oncology (NANO) criteria at the time of the last follow-up.12
The SLA Procedures
The SLA procedures were performed by the following authors: C.C.C. (UCSD); G.B. and A.M. (CC); K.S. (BNI); and A.S. (CW). Details of NeuroBlate and Visualase treatment have been reported elsewhere.2,15 All patients were treated with the NeuroBlate system, with the exceptions of the patients in Cases 12–14, who were treated using Visualase. All UCSD procedures were performed in a conventional MRI suite. Procedures at CC, BNI, and CW were done in intraoperative MRI suites.
Adjuvant Hypofractionated SRS
All patients treated at UCSD received postoperative hypofractionated SRS. Approximately 1 month after SLA, these patients underwent thin-cut MRI (1-mm cut) obtained with contrast (wherein images are obtained after systemic administration of contrast to better visualize blood vessel permeability) and CT scans obtained without contrast (35-cm field of view, 512 × 512 pixel size, 1.25-mm axial slice interval). Both MRI and CT studies were transferred to the treatment planning system, fused using a rigid autoregistration tool, and manually verified by the physicist and treating physicians. Planning was performed using Eclipse software, version 8.9 (Varian Medical Systems). The contrast-enhancing volume was contoured as clinical target volume by the treating neurosurgeon (C.C.C.) and radiation oncologist. The lesion was subsequently treated with SRS to the clinical target volume (5 Gy daily × 5 days).
Results
Patient and Tumor Characteristics
There were 7 male and 16 female patients (Table 1). Two patients each underwent 2 SLAs for separate lesions in a single operation, and a third patient underwent 2 serial SLAs for discrete BMs. The mean age of the cohort was 59 ± 11 years. Histological findings in the BMs included the following: breast (n = 6); lung (n = 6); melanoma (n = 5); colon (n = 2); ovarian (n = 1); bladder (n = 1); esophageal (n = 1); and sarcoma (n = 1). All BMs treated involved either the deep gray matter or eloquent cortex.
Demographic and clinical characteristics in 23 patients with BMs after SRS
| Case No. | Age | Sex | Primary Tumor | Location of Metastasis | Institution |
|---|---|---|---|---|---|
| 1 | 67 | F | Colon | Lt thalamus | UCSD |
| 2 | 58 | F | Melanoma | Lt thalamus | UCSD |
| 3 | 54 | F | Breast | Rt thalamus | UCSD |
| 4 | 60 | F | Breast | Lt frontal | UCSD |
| 4* | Lt parietal | UCSD | |||
| 5 | 42 | F | Breast | Lt frontal | CC |
| 5* | Lt thalamus | CC | |||
| 6 | 64 | F | Bladder | Lt motor strip | CC |
| 7 | 44 | F | Breast | Rt insula | CC |
| 8 | 48 | F | Breast | Lt basal ganglia | CC |
| 9 | 48 | F | Breast | Lt basal ganglia | CC |
| 10 | 42 | F | Lung | Rt frontal | CC |
| 11 | 74 | F | Colon | Lt cerebellum | CC |
| 12 | 73 | M | Sarcoma | Rt parietal | BNI |
| 13 | 58 | M | Melanoma | Lt frontal | BNI |
| 14 | 70 | F | Ovarian | Lt parietal | BNI |
| 14* | Lt occipital | BNI | |||
| 15 | 77 | F | Lung | Lt frontal | BNI |
| 16 | 54 | F | Lung | Lt frontal | CW |
| 17 | 55 | M | Lung | Lt thalamus | CW |
| 18 | 58 | F | Melanoma | Rt occipitoparietal | CW |
| 19 | 45 | F | Melanoma | Lt frontal | CW |
| 20 | 74 | M | Lung | Lt occipitoparietal | CW |
| 21 | 64 | M | Melanoma | Lt frontal | CW |
| 22 | 54 | M | Esophagus | Lt frontal | CW |
| 23 | 77 | M | Lung | Rt occiptal | CW |
In these patients 2 lesions were treated with SLA.
The SLA Parameters
The median size of the lesion treated was 4.9 cm3 (range 0.4–28.9 cm3). The majority of the lesions were treated using single-trajectory SLA (n = 22, or 85%). Two BMs required 2 trajectories (8%), and 2 BMs required 3 trajectories (8%). On average, 84% of the tumor was ablated using SLA (range 44.6%–100%, Table 2). Complete ablation of the entire tumor volume, defined as 100% coverage of the tumor volume by the blue isotherm line, was achieved in only 3 of the 26 lesions (12%).
Treatment characteristics associated with SLA
| Case No. | Ablation Characteristics | Radiographic Response, per RANO Criteria | Surgical Morbidity &/or New Deficits | |||
|---|---|---|---|---|---|---|
| Vol (cm3) | No. of Trajectories | % Tumor Vol Covered by Blue Isotherm Line | Duration of FU (days) | |||
| 1 | 3.4 | 2 | 77.4 | 351 | PR | None |
| 2 | 4.5 | 1 | 74.6 | 102 | PR | Hydrocephalus requiring ventricular drainage |
| 3 | 5.5 | 1 | 98.2 | 252 | PR | None |
| 4 | 3.2 | 1 | 92.4 | 138 | PR | None |
| 4* | 1.9 | 1 | 100 | 101 | PR | None |
| 5 | 6.3 | 2 | 96.5 | 99 | SD | None |
| 5* | 5.3 | 1 | 63.0 | 94 | PD | Transient rt hemiparesis 4/5† |
| 6 | 8.2 | 3 | 76.43 | 109 | PD | Transient rt hemiparesis 4/5† |
| 7 | 16.9 | 3 | 86.45 | 64 | SD | None |
| 8 | 3.5 | 1 | 97.86 | 146 | PR | None |
| 9 | 28.9 | 1 | 99.28 | 83 | PR | Acute neurological deterioration requiring hemicraniectomy |
| 10 | 2.7 | 1 | 100 | 170 | PR | None |
| 11 | 2.6 | 1 | 100 | 145 | SD | None |
| 12 | 2.3 | 1 | NA | 433 | PD | None |
| 13 | 11.6 | 1 | NA | 77 | PD | None |
| 14 | 10.1 | 1 | NA | 386 | PR | None |
| 14* | 0.4 | 1 | NA | 386 | PR | None |
| 15 | 2.1 | 1 | 88.9 | 80 | PD | None |
| 16 | 5.5 | 1 | 44.6 | 202 | PD | Transient rt hemiparesis 4/5† |
| 17 | 12.1 | 1 | 73.6 | 652 | PR | None |
| 18 | 4.1 | 1 | 86.2 | 338 | PD | None |
| 19 | 3.7 | 1 | 69.3 | 795 | PR | None |
| 20 | 9.6 | 1 | 67.8 | 124 | PD | None |
| 21 | 11.2 | 1 | 88.3 | 323 | PR | None |
| 22 | 13.1 | 1 | 70.1 | 91 | PD | None |
| 23 | 4.4 | 1 | 88.6 | 76 | SD | None |
CR = complete response; FU = follow-up; NA = not available; PD = progressive disease; PR = partial response; RANO = Radiologic Assessment in Neuro-Oncology; SD = stable disease.
In these patients 2 lesions were treated with SLA. Patients treated with Visualase and % tumor treated were not calculated by the available software.
Graded according to the MRC scale (Medical Research Council: Aids to examination of the peripheral nervous system. Memorandum no. 45. London: Her Majesty's Stationery Office, 1976).
Radiographic Follow-Up
All patients were followed with serial MRI studies for at least 2 months. The median follow-up was 141 days (range 64–794 days). Based on the Neurologic Assessment in Neuro-Oncology criteria,12 disease control was achieved in 17 BMs (defined as stable disease [Fig. 1], or partial response [Fig. 2]). Nine BMs (35%) showed disease progression after SLA. All instances of disease progression occurred in lesions that underwent < 80% ablation. In contrast, no disease progression was observed in BMs in which ≥ 80% ablation was achieved (Table 2).
MR images demonstrating stable BM disease control following SLA. A: Pretreatment axial (panel i), coronal (panel ii), and sagittal (panel iii) T1-weighted MR images obtained after administration of contrast and a FLAIR (panel iv) MR image of a deep left-sided BM. B–E: Axial (panel i), coronal (panel ii), and sagittal (panel iii) T1-weighted MR images obtained after administration of contrast, and a FLAIR (panel iv) MR image obtained 1 month (B), 3 months (C), 6 months (D), and 12 months (E) post-SLA, demonstrating no local recurrence.
MR images demonstrating partial treatment response of a BM following SLA. A: Pretreatment axial (panel i), coronal (panel ii), and sagittal (panel iii) T1-weighted MR images obtained after administration of contrast and a FLAIR (panel iv) MR image of a left-sided infratentorial BM. B and C: Axial (panel i), coronal (panel ii), and sagittal (panel iii) T1-weighted MR images obtained after administration of contrast, and a FLAIR (panel iv) MR image obtained 1 day (B) and 5 months (C) post-SLA, demonstrating a partial treatment response to SLA.
Adjuvant Hypofractionated SRS Following SLA
Five BMs were treated with SLA, followed by adjuvant SRS (5 Gy daily × 5 days) 1 month later. The median follow-up time for these 5 BMs was 138 days (range 101–351 days), and no tumor growth was observed during followup. Twenty-one BMs were treated with SLA without subsequent SRS. With a median follow-up of 145 days, 9 of the 21 SLA-treated BMs showed radiographic evidence of tumor growth (43%). The frequency of disease progression in BMs treated with SLA followed by hypofractionated SRS was significantly lower than that observed in BMs treated with SLA alone (p < 0.05, Student t-test). No evidence of radiation necrosis or progressive FLAIR signal abnormalities was observed in the patients treated with adjuvant, hypofractionated SRS following SLA.
Postoperative Corticosteroid Management
There is significant heterogeneity in dexamethasone management after SLA (Table 3). The highest dose regimen in this case series was 10 mg dexamethasone 4 times daily (QID) tapered over a span of 2 months. The most commonly used regimen was 4 mg dexamethasone 3 times daily (TID) tapered over a span of 2 weeks. In 1 patient a pretreatment MRI revealed minimal peri-BM edema, and this patient tolerated SLA without postoperative dexamethasone treatment.
Preoperative and postoperative steroid treatment regimens in patients who underwent SLA
| Case No. | Preop Dexamethasone Regimen | Postop Dexamethasone Regimen |
|---|---|---|
| 1 | 4 mg QID | 4 mg TID × 4 d; 3 mg TID × 4 d; 2 mg TID × 4 d; 1 mg TID × 4 d; DC |
| 2 | 4 mg QID | 4 mg TID × 4 d; 3 mg TID × 4 d; 2 mg TID × 4 d; 1 mg TID × 4 d; DC |
| 3 | 4 mg QID | 4 mg TID × 4 d; 3 mg TID × 4 d; 2 mg TID × 4 d; 1 mg TID × 4 d; DC |
| 4 | 4 mg QID | 4 mg TID × 1 d; 3 mg TID × 1 d; 2 mg TID × 1 d; 1 mg TID × 1 d; DC |
| 4* | 4 mg TID × 1 d; 3 mg TID × 1 d; 2 mg TID × 1 d; 1 mg TID × 1 d; DC | |
| 5 | 4 mg QID | 4 mg TID × 6 d; 4 mg OD & 2 mg BID × 6 d; 2 mg TID × 6 d; 2 mg BID until DC |
| 6 | 2 mg BID | 4 mg TID × 6 d; 2 mg BID × 6 d; 2 mg TID × 6 d; 2 mg BID × 6 d; DC |
| 7 | 4 mg BID | 4 mg BID × 5 d; 2 mg TID × 5 d; 2 mg BID × 5 d; DC |
| 8 | None | 10 mg QID × 5 d; 6 mg QID × 5 d; 6 mg TID × 5 d; 4 mg QID × 5 d; 4 mg TID × 5 d; 4 mg BID × 5 d; 2 mg TID × 5 d; 2 mg BID × 20 d; DC |
| 9 | 4 mg BID | 10 mg QID × 5 d; 6 mg QID × 5 d; 6 mg TID × 5 d; 4 mg QID × 5 d; 4 mg TID × 5 d; 4 mg BID × 5 d; 2 mg TID × 5 d; 2 mg BID × 20 d; DC |
| 10 | 4 mg BID | 4 mg QID × 3 d; 4 mg TID × 4 d; 2 mg TID × 7 d; 1 mg BID × 7 d; DC |
| 11 | None | 4 mg TID × 5 d; 4 mg BID × 5 d; 2 mg TID × 4 d; 2 mg BID × 4 d; DC |
| 12 | None | None |
| 13 | 4 mg BID | 4 mg QID × 2 d; 4 mg TID × 4 d; 2 mg BID × 4 d; 2 mg QD × 2 d; DC |
| 14 | 4 mg BID | 4 mg BID × 3 d; 2 mg BID × 3 d; 2 mg QD × 3 d; DC |
| 15 | 4 mg BID | 4 mg BID × 3 d; 2 mg BID × 3 d; 2 mg QD × 3 d; DC |
| 16 | 4 mg BID | 10 mg QID × 3 d; 6 mg TID × 3 d; 4 g BID × 3 d; 2 mg BID until postop visit in 2–3 wks |
| 17 | 4 mg BID | 10 mg QID × 3 d; 6 mg TID × 3 d; 4 g BID × 3 d; 2 mg BID until postop visit in 2–3 wks |
| 18 | 4 mg BID | 10 mg QID × 3 d; 6 mg TID × 3 d; 4 g BID × 3 d; 2 mg BID until postop visit in 2–3 wks |
| 19 | 4 mg BID | 10 mg QID × 3 d; 6 mg TID × 3 d; 4 g BID × 3 d; 2 mg BID until postop visit in 2–3 wks |
| 20 | 4 mg BID | 10 mg QID × 3 d; 6 mg TID × 3 d; 4 g BID × 3 d; 2 mg BID until postop visit in 2–3 wks |
| 21 | 4 mg BID | 10 mg QID × 3 d; 6 mg TID × 3 d; 4 g BID × 3 d; 2 mg BID until postop visit in 2–3 wks |
| 22 | 4 mg BID | 10 mg QID × 3 d; 6 mg TID × 3 d; 4 g BID × 3 d; 2 mg BID until postop visit in 2–3 wks |
| 23 | 4 mg BID | 10 mg QID × 3 d; 6 mg TID × 3 d; 4 g BID × 3 d; 2 mg BID until postop visit in 2–3 wks |
BID = twice daily; d = day(s); DC = discontinued; OD = once daily; QD = daily.
In this patient 2 lesions were treated with SLA.
Posttreatment Complications
Of the 23 SLA-treated patients, 3 suffered transient hemiparesis (13%) that recovered within 1 month of SLA; one of these patients underwent SLA for a BM located in the thalamus, another for a BM in the left frontal lobe, and the remaining patient underwent SLA for a BM located in the left motor strip. One patient with a left thalamic melanoma metastasis adjacent to the ventricle developed hydrocephalus after SLA, requiring temporary ventricular drainage (4%). One patient with a 28.9-cm3 lesion suffered malignant cerebral edema after SLA, requiring an emergency hemicraniectomy (4%), and remained hemiplegic for the remainder of her life (83 days [Fig. 3]).
Malignant cerebral edema following SLA for a large BM. A: The SLA trajectory for a 28.9-cm3 thalamic BM. B: Coronal T1-weighted MR image obtained after administration of contrast following hemicraniectomy for symptomatic cerebral edema post-SLA.
Discussion
In this report we provide radiographic follow-up for 26 BMs (in 23 patients) that recurred after SRS and were treated with SLA at 4 different institutions. The results indicate that SLA is an effective treatment option for BMs in which SRS fails. When ≥ 80% of the lesion is ablated, tumor control was uniformly observed. Consideration of the morbidities encountered in this series suggests that resection might be indicated instead of SLA for BMs previously treated with SRS that exceed 20 cm3 in volume. Additionally, careful monitoring of hydrocephalus after SLA for periventricular BMs is warranted. Transient or permanent neurological deficits may be expected after SLA of thalamic and motor-strip lesions.
Our study further suggests that when < 80% of a BM is ablated by SLA, the efficacy of disease control may be augmented by adjuvant hypofractionated SRS (5 Gy daily × 5 days). Because SLA is typically preferred when the location of a BM involves regions of deep gray matter or eloquent cortex, incomplete ablation may be necessary to minimize the risk of neurological deficits. Our results indicate that hypofractionated SRS may augment the local control of these incompletely ablated tumors. Although the risk of radiation necrosis related to repeat SRS is a consideration,5 it is likely to be mitigated by SLA ablation of the tumor mass.10,18 Supporting this hypothesis, we did not observe radiographic evidence of radiation necrosis in patients treated with adjuvant, hypofractionated SRS following SLA. Nevertheless, the number of patients treated with combined SRS and hypofractionated SRS was limited. Validation of these results in future studies is warranted.
Temporary increases in cerebral edema after SLA is a well-described phenomenon.14 For this reason, most of the patients in this series were treated with corticosteroids after SLA. Although there are significant differences in surgeon preference regarding corticosteroid management, the most common regimen involved 4 mg dexamethasone TID tapered over a 2-week period. In cases in which the treating surgeon was concerned about the risk of malignant edema, 10 mg dexamethasone QID tapered over a 2-month period was used. Given that 1 patient tolerated SLA-related edema without postprocedure corticosteroids, this treatment may not be necessary in select patients with minimal peri-BM edema.
The findings reported here are subject to all limitations inherent to case series in which there are a small number of patients and heterogeneous clinical practices. Admittedly, most patients in this series were followed for a limited duration, but this follow-up (median 141 days) must be taken in the context of the poor survival expectation of patients with Stage IV cancer with BMs in which SRS has failed.7 That said, assessment of radiation necrosis in patients who underwent adjuvant, hypofractionated SRS after SLA will require longer follow-up than that carried out in this study. Despite these limitations, we believe that our results offer pilot data for guiding future studies of SLA as a treatment for BMs in which SRS has failed.
Conclusions
Stereotactic laser ablation is an effective treatment option for patients suffering BM recurrence after SRS. Ablation of ≥ 80% of BMs is desirable to minimize risk of disease progression. The efficacy of SLA may be augmented by adjuvant hypofractionated SRS.
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Disclosures
Dr. Chen is a consultant for Monteris Medical and has consulted for MRI Interventions. Drs. Mohammadi and Sloan are consultants for Monteris Medical, Inc. Dr. Smith is a consultant for Monteris Medical, Inc.; Medtronic, Inc.; and OsteoMed.
Author Contributions
Conception and design: Chen. Acquisition of data: Chen, Hamelin, Chang, Lemkuil, Sharma, Barnholtz-Sloan, Myers, Barnett, Smith, Mohammadi, Sloan. Analysis and interpretation of data: Chen, Ali, Carroll, Rennert, Hamelin, Chang, Lemkuil, Sharma, Barnholtz-Sloan, Myers, Barnett, Smith, Mohammadi. Drafting the article: Chen, Ali, Carroll, Rennert, Sloan. Critically revising the article: Chen, Ali, Carroll, Rennert, Sharma, Barnholtz-Sloan, Barnett, Smith, Mohammadi, Sloan. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Chen.
