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Mayur Sharma, Daria Krivosheya, Hamid Borghei-Razavi, Gene H. Barnett and Alireza M. Mohammadi

Laser interstitial thermal therapy (LITT) is a minimally invasive stereotactic technique that causes tumor ablation using thermal energy. LITT has shown to be efficacious for the treatment of deep-seated brain lesions, including those near eloquent areas. In this video, the authors present the case of a 62-year-old man with a history of metastatic melanoma who presented with worsening right-sided hemiparesis. MRI revealed a contrast-enhancing lesion in left centrum semiovale in close proximity to corticospinal tracts, consistent with radiation necrosis. The authors review their stepwise technique of LITT with special attention to details for a lesion located near eloquent area.

The video can be found here: https://youtu.be/ndrTgi6MXqE.

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Mayur Sharma, Ghaith Habboub, Mandana Behbahani, Danilo Silva, Gene H. Barnett and Alireza M. Mohammadi

OBJECTIVE

Laser interstitial thermal therapy (LITT) has been increasingly used to treat deep-seated tumors. Despite its being minimally invasive, there is a risk of LITT damaging adjacent critical structures, including corticospinal tracts (CSTs). In this study, the authors investigated the predictive value of overlap between the hyperthermic field and CSTs in determining postoperative motor deficit (PMDs).

METHODS

More than 140 patients underwent an LITT procedure in our institution between April 2011 and June 2015. Because of the tumor's proximity to critical structures, 80 of them underwent preoperative diffusion tensor imaging and were included in this study. Extent of the hyperthermic field was delineated by the software as thermal-damage-threshold (TDT) lines (yellow [43°C for 2 minutes], blue [43°C for 10 minutes], and white [43°C for 60 minutes]). The maximum volume and the surface area of overlaps between motor fibers and the TDT lines were calculated and compared with the PMDs.

RESULTS

High-grade glioma (n = 46) was the most common indication for LITT. Postoperative motor deficits (partial or complete) were seen in 14 patients (11 with permanent and 3 with temporary PMDs). The median overlap volumes between CSTs with yellow, blue, and white TDT lines in patients with any PMD (temporary or permanent) were 1.15, 0.68, and 0.41 cm3, respectively. The overlap volumes and surface areas revealed significant differences in those with PMDs and those with no deficits (p = 0.0019 and 0.003, 0.012 and 0.0012, and 0.001 and 0.005 for the yellow, blue, and white TDT lines, respectively). The receiver operating characteristic was used to select the optimal cutoff point of the overlapped volumes and areas. Cutoff points for overlap volumes and areas based on optimal sensitivity (92%–100%) and specificity (80%–90%) were 0.103, 0.068, and 0.046 cm3 and 0.15, 0.07, and 0.11 mm2 for the yellow, blue, and white TDT lines, respectively.

CONCLUSIONS

Even a minimal overlap between the TDT lines and CSTs can cause a PMD after LITT. Precise planning and avoidance of critical structures and important white matter fibers should be considered when treating deep-seated tumors.

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Michael A. Vogelbaum, Cathy Brewer, Gene H. Barnett, Alireza M. Mohammadi, David M. Peereboom, Manmeet S. Ahluwalia and Shenqiang Gao

OBJECTIVE

Progress in management of high-grade gliomas (HGGs) has been hampered by poor access of potential therapeutics to the CNS. The Cleveland Multiport Catheter (CMC), which deploys 4 independent delivery microcatheters, was developed to be a reliable, high-volume delivery device for delivery of therapeutic agents to the brain and other solid organs. The authors undertook this first-in-human clinical trial effort to evaluate the delivery characteristics of the CMC in patients with HGGs.

METHODS

A series of pilot studies were launched after approval of a sponsor-investigator IND (investigational new drug) application to evaluate the delivery of topotecan and gadolinium-DTPA (Gd-DTPA) via the CMC in patients with recurrent HGG. The first pilot trial evaluated delivery into enhancing tumor and nonenhancing, tumor-infiltrated brain. Two catheters were placed with the use of a conventional frameless stereotactic technique following a biopsy to confirm tumor recurrence, and drug infusion was performed both intraoperatively and postoperatively for a total of 96 hours with the same rate for all microcatheters. Delivery was assessed by intermittent MRI.

RESULTS

Three patients were enrolled in the first pilot study. MRI demonstrated delivery from all 6 catheters (24 microcatheters). The volume of distribution (Vd) of Gd-DTPA was heavily dependent upon CMC location (enhancing vs nonenhancing) with an approximately 10-fold difference in Vd observed (p = 0.005). There were no hemorrhages related to catheter placement or removal, and all 3 patients completed the protocol-defined treatment.

CONCLUSIONS

The CMC is capable of providing backflow-resistant drug delivery to the brain and brain tumors. The volume of distribution is heavily dependent upon the integrity of the blood-brain barrier. Assessment of delivery is essential for development of loco-regionally applied therapeutics in the CNS.

Clinical trial registration no.: NCT02278510 (clinicaltrials.gov)

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Michael A. Vogelbaum, Cathy Brewer, Gene H. Barnett, Alireza M. Mohammadi, David M. Peereboom, Manmeet S. Ahluwalia and Shenqiang Gao

OBJECTIVE

Progress in management of high-grade gliomas (HGGs) has been hampered by poor access of potential therapeutics to the CNS. The Cleveland Multiport Catheter (CMC), which deploys 4 independent delivery microcatheters, was developed to be a reliable, high-volume delivery device for delivery of therapeutic agents to the brain and other solid organs. The authors undertook this first-in-human clinical trial effort to evaluate the delivery characteristics of the CMC in patients with HGGs.

METHODS

A series of pilot studies were launched after approval of a sponsor-investigator IND (investigational new drug) application to evaluate the delivery of topotecan and gadolinium-DTPA (Gd-DTPA) via the CMC in patients with recurrent HGG. The first pilot trial evaluated delivery into enhancing tumor and nonenhancing, tumor-infiltrated brain. Two catheters were placed with the use of a conventional frameless stereotactic technique following a biopsy to confirm tumor recurrence, and drug infusion was performed both intraoperatively and postoperatively for a total of 96 hours with the same rate for all microcatheters. Delivery was assessed by intermittent MRI.

RESULTS

Three patients were enrolled in the first pilot study. MRI demonstrated delivery from all 6 catheters (24 microcatheters). The volume of distribution (Vd) of Gd-DTPA was heavily dependent upon CMC location (enhancing vs nonenhancing) with an approximately 10-fold difference in Vd observed (p = 0.005). There were no hemorrhages related to catheter placement or removal, and all 3 patients completed the protocol-defined treatment.

CONCLUSIONS

The CMC is capable of providing backflow-resistant drug delivery to the brain and brain tumors. The volume of distribution is heavily dependent upon the integrity of the blood-brain barrier. Assessment of delivery is essential for development of loco-regionally applied therapeutics in the CNS.

Clinical trial registration no.: NCT02278510 (clinicaltrials.gov)

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Alireza Mohammad Mohammadi, Pablo F. Recinos, Gene H. Barnett, Robert J. Weil, Michael A. Vogelbaum, Samuel T. Chao, John H. Suh, Nicholas F. Marko, Paul Elson, Gennady Neyman and Lilyana Angelov

Object

The authors evaluated overall survival and factors predicting outcome in patients with ≥ 5 brain metastases who were treated with Gamma Knife surgery (GKS).

Methods

Medical records from patients with ≥ 5 brain metastases treated with GKS between 1997 and 2010 at the Cleveland Clinic Gamma Knife Center were retrospectively reviewed. Patient demographics, tumor characteristics, treatment-related factors, and outcome data were evaluated.

Results

One hundred seventy patients were identified, with a median age of 58 years. The female/male ratio was 1.2:1. Gamma Knife surgery was used as an upfront treatment in 35% of patients and as salvage treatment in 65% of patients with multiple brain metastases. The median overall survival after GKS was 6.7 months (95% CI 5.5–8.1). At the time of GKS, 128 patients (75%) had concurrent extracranial metastases, and in 69 patients (41%) multiple extracranial sites were involved. Ninety-two patients (54%) had a history of whole-brain radiation therapy, and 158 patients (93%) had a Karnofsky Performance Scale (KPS) score ≥ 70. The median total intracranial disease volume was 3.2 cm3 (range 0.2–37.2 cm3). A total intracranial tumor volume ≥ 10 cm3 was observed in 32 patients (19%). Lower KPS score at the time of treatment (p < 0.0001), patient age > 60 years (p = 0.004), multiple extracranial metastases (p = 0.0001), and greater intracranial burden of disease (p = 0.03) were prognostic factors for poor outcome in the univariate and multivariate analyses.

Conclusions

In this study, GKS was safe and effective for upfront and salvage treatment in patients with ≥ 5 brain metastases. Gamma Knife surgery should be considered as an additional treatment modality for these patients, especially in the subset of patients with favorable prognostic factors.

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Jacob A. Miller, Ehsan H. Balagamwala, Camille A. Berriochoa, Lilyana Angelov, John H. Suh, Edward C. Benzel, Alireza M. Mohammadi, Todd Emch, Anthony Magnelli, Andrew Godley, Peng Qi and Samuel T. Chao

OBJECTIVE

Spine stereotactic radiosurgery (SRS) is a safe and effective treatment for spinal metastases. However, it is unknown whether this highly conformal radiation technique is suitable at instrumented sites given the potential for microscopic disease seeding. The authors hypothesized that spinal decompression with instrumentation is not associated with increased local failure (LF) following SRS.

METHODS

A 2:1 propensity-matched retrospective cohort study of patients undergoing SRS for spinal metastasis was conducted. Patients with less than 1 month of radiographic follow-up were excluded. Each SRS treatment with spinal decompression and instrumentation was propensity matched to 2 controls without decompression or instrumentation on the basis of demographic, disease-related, dosimetric, and treatment-site characteristics. Standardized differences were used to assess for balance between matched cohorts.

The primary outcome was the 12-month cumulative incidence of LF, with death as a competing risk. Lesions demonstrating any in-field progression were considered LFs. Secondary outcomes of interest were post-SRS pain flare, vertebral compression fracture, instrumentation failure, and any Grade ≥ 3 toxicity. Cumulative incidences analysis was used to estimate LF in each cohort, which were compared via Gray’s test. Multivariate competing-risks regression was then used to adjust for prespecified covariates.

RESULTS

Of 650 candidates for the control group, 166 were propensity matched to 83 patients with instrumentation. Baseline characteristics were well balanced. The median prescription dose was 16 Gy in each cohort. The 12-month cumulative incidence of LF was not statistically significantly different between cohorts (22.8% [instrumentation] vs 15.8% [control], p = 0.25). After adjusting for the prespecified covariates in a multivariate competing-risks model, decompression with instrumentation did not contribute to a greater risk of LF (HR 1.21, 95% CI 0.74–1.98, p = 0.45). The incidences of post-SRS pain flare (11% vs 14%, p = 0.55), vertebral compression fracture (12% vs 22%, p = 0.04), and Grade ≥ 3 toxicity (1% vs 1%, p = 1.00) were not increased at instrumented sites. No instrumentation failures were observed.

CONCLUSIONS

In this propensity-matched analysis, LF and toxicity were similar among cohorts, suggesting that decompression with instrumentation does not significantly impact the efficacy or safety of spine SRS. Accordingly, spinal instrumentation may not be a contraindication to SRS. Future studies comparing SRS to conventional radiotherapy at instrumented sites in matched populations are warranted.

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Alireza M. Mohammadi, Jason L. Schroeder, Lilyana Angelov, Samuel T. Chao, Erin S. Murphy, Jennifer S. Yu, Gennady Neyman, Xuefei Jia, John H. Suh, Gene H. Barnett and Michael A. Vogelbaum

OBJECTIVE

The impact of the stereotactic radiosurgery (SRS) prescription dose (PD) on local progression and radiation necrosis for small (≤ 2 cm) brain metastases was evaluated.

METHODS

An institutional review board–approved retrospective review was performed on 896 patients with brain metastases ≤ 2 cm (3034 tumors) who were treated with 1229 SRS procedures between 2000 and 2012. Local progression and/or radiation necrosis were the primary end points. Each tumor was followed from the date of radiosurgery until one of the end points was reached or the last MRI follow-up. Various criteria were used to differentiate tumor progression and radiation necrosis, including the evaluation of serial MRIs, cerebral blood volume on perfusion MR, FDG-PET scans, and, in some cases, surgical pathology. The median radiographic follow-up per lesion was 6.2 months.

RESULTS

The median patient age was 56 years, and 56% of the patients were female. The most common primary pathology was non–small cell lung cancer (44%), followed by breast cancer (19%), renal cell carcinoma (14%), melanoma (11%), and small cell lung cancer (5%). The median tumor volume and median largest diameter were 0.16 cm3 and 0.8 cm, respectively. In total, 1018 lesions (34%) were larger than 1 cm in maximum diameter. The PD for 2410 tumors (80%) was 24 Gy, for 408 tumors (13%) it was 19 to 23 Gy, and for 216 tumors (7%) it was 15 to 18 Gy. In total, 87 patients (10%) had local progression of 104 tumors (3%), and 148 patients (17%) had at least radiographic evidence of radiation necrosis involving 199 tumors (7%; 4% were symptomatic). Univariate and multivariate analyses were performed for local progression and radiation necrosis. For local progression, tumors less than 1 cm (subhazard ratio [SHR] 2.32; p < 0.001), PD of 24 Gy (SHR 1.84; p = 0.01), and additional whole-brain radiation therapy (SHR 2.53; p = 0.001) were independently associated with better outcome. For the development of radiographic radiation necrosis, independent prognostic factors included size greater than 1 cm (SHR 2.13; p < 0.001), location in the corpus callosum (SHR 5.72; p < 0.001), and uncommon pathologies (SHR 1.65; p = 0.05). Size (SHR 4.78; p < 0.001) and location (SHR 7.62; p < 0.001)—but not uncommon pathologies—were independent prognostic factors for the subgroup with symptomatic radiation necrosis.

CONCLUSIONS

A PD of 24 Gy results in significantly better local control of metastases measuring < 2 cm than lower doses. In addition, tumor size is an independent prognostic factor for both local progression and radiation necrosis. Some tumor pathologies and locations may also contribute to an increased risk of radiation necrosis.

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Mayur Sharma, Jason L. Schroeder, Paul Elson, Antonio Meola, Gene H. Barnett, Michael A. Vogelbaum, John H. Suh, Samuel T. Chao, Alireza M. Mohammadi, Glen H. J. Stevens, Erin S. Murphy and Lilyana Angelov

OBJECTIVE

Glioblastoma (GBM) is the most malignant form of astrocytoma. The average survival is 6–10 months in patients with recurrent GBM (rGBM). In this study, the authors evaluated the role of stereotactic radiosurgery (SRS) in patients with rGBMs.

METHODS

The authors performed a retrospective review of their brain tumor database (1997–2016). Overall survival (OS) and progression-free survival (PFS) after salvage SRS were the primary endpoints evaluated. Response to SRS was assessed using volumetric MR images.

RESULTS

Fifty-three patients with rGBM underwent salvage SRS targeting 75 lesions. The median tumor diameter and volume were 2.55 cm and 3.80 cm3, respectively. The median prescription dose was 18 Gy (range 12–24 Gy) and the homogeneity index was 1.90 (range 1.11–2.02). The median OS after salvage SRS was estimated to be 11.0 months (95% CI 7.1–12.2) and the median PFS after salvage SRS was 4.4 months (95% CI 3.7–5.0). A Karnofsky Performance Scale score ≥ 80 was independently associated with longer OS, while small tumor volume (< 15 cm3) and less homogeneous treatment plans (homogeneity index > 1.75) were both independently associated with longer OS (p = 0.007 and 0.03) and PFS (p = 0.01 and 0.002, respectively). Based on these factors, 2 prognostic groups were identified for PFS (5.4 vs 3.2 months), while 3 were identified for OS (median OS of 15.2 vs 10.5 vs 5.2 months).

CONCLUSIONS

SRS is associated with longer OS and/or PFS in patients with good performance status, small-volume tumor recurrences, and heterogeneous treatment plans. The authors propose a prognostic model to identify a cohort of rGBM patients who may benefit from SRS.

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Manmeet Ahluwalia, Gene H. Barnett, Di Deng, Stephen B. Tatter, Adrian W. Laxton, Alireza M. Mohammadi, Eric Leuthardt, Roukoz Chamoun, Kevin Judy, Anthony Asher, Marco Essig, Jorg Dietrich and Veronica L. Chiang

OBJECTIVE

Laser Ablation After Stereotactic Radiosurgery (LAASR) is a multicenter prospective study of laser interstitial thermal (LITT) ablation in patients with radiographic progression after stereotactic radiosurgery for brain metastases.

METHODS

Patients with a Karnofsky Performance Scale (KPS) score ≥ 60, an age > 18 years, and surgical eligibility were included in this study. The primary outcome was local progression-free survival (PFS) assessed using the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Secondary outcomes were overall survival (OS), procedure safety, neurocognitive function, and quality of life.

RESULTS

Forty-two patients—19 with biopsy-proven radiation necrosis, 20 with recurrent tumor, and 3 with no diagnosis—were enrolled. The median age was 60 years, 64% of the subjects were female, and the median baseline KPS score was 85. Mean lesion volume was 6.4 cm3 (range 0.4–38.6 cm3). There was no significant difference in length of stay between the recurrent tumor and radiation necrosis patients (median 2.3 vs 1.7 days, respectively). Progression-free survival and OS rates were 74% (20/27) and 72%, respectively, at 26 weeks. Thirty percent of subjects were able to stop or reduce steroid usage by 12 weeks after surgery. Median KPS score, quality of life, and neurocognitive results did not change significantly for either group over the duration of survival. Adverse events were also similar for the two groups, with no significant difference in the overall event rate. There was a 12-week PFS and OS advantage for the radiation necrosis patients compared with the recurrent tumor or tumor progression patients.

CONCLUSIONS

In this study, in which enrolled patients had few alternative options for salvage treatment, LITT ablation stabilized the KPS score, preserved quality of life and cognition, had a steroid-sparing effect, and was performed safely in the majority of cases.

Clinical trial registration no.: NCT01651078 (clinicaltrials.gov)

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Lilyana Angelov, Alireza M. Mohammadi, Elizabeth E. Bennett, Mahmoud Abbassy, Paul Elson, Samuel T. Chao, Joshua S. Montgomery, Ghaith Habboub, Michael A. Vogelbaum, John H. Suh, Erin S. Murphy, Manmeet S. Ahluwalia, Sean J. Nagel and Gene H. Barnett

OBJECTIVE

Stereotactic radiosurgery (SRS) is the primary modality for treating brain metastases. However, effective radiosurgical control of brain metastases ≥ 2 cm in maximum diameter remains challenging and is associated with suboptimal local control (LC) rates of 37%–62% and an increased risk of treatment-related toxicity. To enhance LC while limiting adverse effects (AEs) of radiation in these patients, a dose-dense treatment regimen using 2-staged SRS (2-SSRS) was used. The objective of this study was to evaluate the efficacy and toxicity of this treatment strategy.

METHODS

Fifty-four patients (with 63 brain metastases ≥ 2 cm) treated with 2-SSRS were evaluated as part of an institutional review board–approved retrospective review. Volumetric measurements at first-stage stereotactic radiosurgery (first SSRS) and second-stage SRS (second SSRS) treatments and on follow-up imaging studies were determined. In addition to patient demographic data and tumor characteristics, the study evaluated 3 primary outcomes: 1) response at first follow-up MRI, 2) time to local progression (TTP), and 3) overall survival (OS) with 2-SSRS. Response was analyzed using methods for binary data, TTP was analyzed using competing-risks methods to account for patients who died without disease progression, and OS was analyzed using conventional time-to-event methods. When needed, analyses accounted for multiple lesions in the same patient.

RESULTS

Among 54 patients, 46 (85%) had 1 brain metastasis treated with 2-SSRS, 7 patients (13%) had 2 brain metastases concurrently treated with 2-SSRS, and 1 patient underwent 2-SSRS for 3 concurrent brain metastases ≥ 2 cm. The median age was 63 years (range 23–83 years), 23 patients (43%) had non–small cell lung cancer, and 14 patients (26%) had radioresistant tumors (renal or melanoma). The median doses at first and second SSRS were 15 Gy (range 12–18 Gy) and 15 Gy (range 12–15 Gy), respectively. The median duration between stages was 34 days, and median tumor volumes at the first and second SSRS were 10.5 cm3 (range 2.4–31.3 cm3) and 7.0 cm3 (range 1.0–29.7 cm3). Three-month follow-up imaging results were available for 43 lesions; the median volume was 4.0 cm3 (range 0.1–23.1 cm3). The median change in volume compared with baseline was a decrease of 54.9% (range −98.2% to 66.1%; p < 0.001). Overall, 9 lesions (14.3%) demonstrated local progression, with a median of 5.2 months (range 1.3–7.4 months), and 7 (11.1%) demonstrated AEs (6.4% Grade 1 and 2 toxicity; 4.8% Grade 3). The estimated cumulative incidence of local progression at 6 months was 12% ± 4%, corresponding to an LC rate of 88%. Shorter TTP was associated with greater tumor volume at baseline (p = 0.01) and smaller absolute (p = 0.006) and relative (p = 0.05) decreases in tumor volume from baseline to second SSRS. Estimated OS rates at 6 and 12 months were 65% ± 7% and 49% ± 8%, respectively.

CONCLUSIONS

2-SSRS is an effective treatment modality that resulted in significant reduction of brain metastases ≥ 2 cm, with excellent 3-month (95%) and 6-month (88%) LC rates and an overall AE rate of 11%. Prospective studies with larger cohorts and longer follow-up are necessary to assess the durability and toxicities of 2-SSRS.