Laser Interstitial Thermal Therapy as a Primary Treatment for Deep Inaccessible Gliomas

Laser Interstitial Thermal Therapy as a Primary Treatment for Deep Inaccessible Gliomas Abstract BACKGROUND Treatment strategies for deep intracranial gliomas remain limited to stereotactic biopsy in many cases due to the morbidity of aggressive surgical resection. Since no cytoreductive therapy is offered, outcomes have been demonstrably poor compared to patients who are able to undergo primary surgical resection. OBJECTIVE To present our practice, in an effort to reduce morbidity and still offer cytoreductive treatment, of offering the possibility of laser interstitial thermal therapy (LITT) for the primary treatment of intracranial deep gliomas that would be otherwise unamenable for resection. METHODS From 2010 to 2017, 74 patients were identified from a single surgeon at a single tertiary care referral center who had been treated with LITT. We conducted an exploratory cohort study on patients (n = 6) who have undergone contemporaneous biopsy and laser ablation for the treatment of deep gliomas with a mean tumor volume of 10.9 cc (range 4.2-52 cc). RESULTS In our cohort, mean extent of ablation (EOA) was 98.5% on postoperative MRI; mean progression-free survival was 14.3 mo, and 5 patients (83%) remained alive at mean follow-up time of 19.7 mo without any complications. Additionally, there was a negative linear relationship between preoperative lesion size and EOA (P < .04) when analyzed with previously reported series. CONCLUSION Although our series is small, we suggest that LITT can be a safe alternative cytoreductive therapy for deep surgically inaccessible gliomas. Given the known benefit of near gross total resection for high-grade gliomas, we believe LITT may improve survival for these patients and complement adjuvant treatments if patients are appropriately selected. Laser, Treatment, Glioma, Deep, Outcomes, Ablation, Volumetric ABBREVIATIONS ABBREVIATIONS EOA extent of ablation IDH isocitrate dehydrogenase KPS Karnofsky Performance Scale KPS Karnofsky Performance Status LITT laser interstitial thermal therapy PFS progression-free survival Treatment strategies for patients with deep intracranial gliomas remain limited to adjuvant chemotherapy and fractionated radiation. Typically, patients may be offered a stereotactic biopsy for tissue confirmation and profiling of deep inaccessible lesions without any cytoreductive surgical treatment. For this specific subset of patients, overall survival has been reported to be as low as 5-7 mo in some series.1,2 Additionally, 1 and 2-yr mortality risk seems to decrease with any form of resection compared to biopsy of high-grade gliomas, suggesting that subtotal resection or gross total surgical resection may confer some survival benefit.2 Furthermore, recent literature suggests that even in high-grade lesions, extent of resection remains an important predictor of overall survival.3-8 However, naturally these studies are limited to patients who are amenable to surgical resection (ie, patients with superficial, noneloquent tumors), thereby limiting their applicability to a subset of glioma patients with deep “inoperable” lesions. For some of these patients, we suggest that laser interstitial thermal therapy (LITT) may be offered as an adjunct after biopsy for the treatment of primary gliomas who would otherwise not receive any form of cytoreductive treatment. Here, we present an exploratory study from a single surgeon at a single institution assessing the safety and efficacy of LITT for primary deep eloquent region gliomas. FIGURE 1. View largeDownload slide Flow diagram of patient selection. FIGURE 1. View largeDownload slide Flow diagram of patient selection. METHODS After Institutional Review Board approval, a retrospective chart review was conducted. From 2010 to 2017, 74 patients were identified from a single surgeon at a single tertiary care referral center who had been treated with LITT. From this group, we identified 6 patients who underwent LITT for deep gliomas as a primary treatment. No consent was needed given the retrospective nature of this study. All patients were screened by age (> 18 yr), location (deep), and pathology (high-grade glioma). Only patients who were felt to be inoperable via open craniotomy and resection were included. The definition of inoperable/unresectable was left to the discretion of the primary surgeon (R.J.K.), but was primarily determined by the risk of severe neurological morbidity. Patients with multifocal/multicentric gliomas were excluded. All cases of salvage/secondary resection for patients who had previously undergone resection were omitted. Patients with inadequate outcome data, imaging, operative reports, or hospitalization information were excluded. If follow-up was inadequate (< 6 mo), patients were excluded. Figure 1 illustrates stepwise patient selection. Pertinent demographics were obtained including age at diagnosis, sex, tumor location, adjuvant therapies including chemotherapy/radiotherapy, Karnofsky Performance Status (KPS), and follow-up. Genetic mutations for hypermethylated O-6-methylguanine-DNA methyltransferase (MGMT) and mutated isocitrate dehydrogenase (IDH) were reported when available. Low- and high-grade tumors were volumetrically analyzed by measuring hyperintense regions on axial T2-weighted FLAIR images and T1-weighted contrast-enhanced MR images, respectively. Tumors were manually segmented across all slices with region-of-interest analysis to compute pre- and postoperative volume. Residual tumor was calculated using immediate and 24-h postoperative contrast MRI (magnetic resonance imaging), when enhancement shows extent of permanently damaged tissue. Contrast enhancement beyond previous extent of the tumor border was recorded as complete ablation. Extent of ablation (EOA) was calculated using the formula [100 – (postoperative tumor volume/preoperative tumor volume) x 100]. Our EOA was verified by 2 independent reviewers: 1 neurosurgeon and 1 neuroradiologist. Any perioperative morbidity or new neurological deficits after treatment was reported. We estimated time to recurrence as any growth of the lesion after primary treatment, which also included temozolomide and fractionated whole beam radiation fitting with standard practices. Similarly, progression-free survival (PFS) and overall survival were recorded. Surgical Technique LITT treatment was performed as previously described by our group using the Visualase platform (Medtronic, Dublin, Ireland).9-13 This system employs a 980-nanometer diode laser with a full-field diffusing tip. It delivers a maximum power of 15 Watts, though this can be decreased for a gentler, more precise ablation. All patients undergo preoperative volumetric 1 mm slice MRI for planning and stereotactic navigation. An intraoperative computed tomography is taken using the O-arm system (Medtronic) and co-registered to the preoperative MRI. An optimal trajectory is planned that is centered in the lesion and spares functional nontumor tissue and vasculature. Once the trajectory is confirmed with intraoperative navigation, a stereotactic needle is introduced into a superficial aspect of the lesion. Another intraoperative computed tomography is then taken to confirm the location of the biopsy needle within the tumor, and a 3-4 biopsy cores are sent for frozen and permanent section. In all cases, a stereotactic biopsy was performed prior to the initiation of LITT, and a dedicated neuropathologist confirmed a preliminary diagnosis of glioma on frozen section. After confirmation, a laser fiber is introduced and secured into the tumor at its deepest extent, and the patient is transported to the MRI suite for the real-time MR thermography. For all patients included, an attempt to safely maximize the EOA was made when possible. The extent of treatment during LITT sessions was guided by the senior neurosurgeon's evaluation of the temperature map in conjunction with the damage estimate. Just as in open surgery, the goal was to achieve maximal safe cytoreduction. Real-time thermography aided in preventing injury to adjacent eloquent fibers and the amount of thermal energy was manipulated to maximize the ablation volume. To avoid postoperative swelling, preoperative and postoperative steroids were given to all patients. Statistical Analysis Continuous variables were reported with medians and ranges. Categorical variables were reported using frequencies and percentages. Relationships between continuous variables were modeled using linear regression, and a P value of .05 was considered statistically significant. Survival curves were generated with Kaplan Meier analysis. The final analysis includes data points taken from our own study as well as eligible subjects from earlier studies. Subjects were used from the literature review if the study contained EOA and preoperative tumor volume. Only subjects meeting the same criteria for inclusion as our study were included: adequate follow-up, primary treatment, age > 18, high-grade glioma. Mean-weighted average is given in instances where individual subject data were not available from selected studies, taking group average by the number of subjects in the study. All data analysis was conducted using SPSS (version 22, IBM Corp, Armonk, New York). RESULTS Patient Characteristics Six patients identified as having undergone LITT as a primary treatment had a mean age of 58 yr (range 39-69). All patients were symptomatic at the time they presented to our service, with symptomatology characterized by confusion (2/6; 33%), weakness (2/6; 33%), dizziness (1/6; 17%), and seizure (1/6; 17%). Four (67%) tumors were left sided. All patients presented initially with a Karnofsky Performance Scale (KPS) greater than 90. Patient and tumor characteristics are given in Table 1. TABLE 1. Case Series of Primary Treatment of Gliomas Using LITT Pt Side Location/eloquent structure involved Age (yr.) Gender Presenting** symptoms Tumor volume (cm3) EOA (%) Adjuvant therapy Pathology Molecular characteristics# Post-Op complications Follow-up time (mo.)* PFS(mo.) Notes 1 L Splenium 69 F Confusion, memory impairment 27 98 TMZ + RT IV MGMT – IDH1/2 – None 6 NP - 2 R Orbitofrontal/ALIC 51 M Dizziness, poor coordination 1.2 100 TMZ + RT IV - None 35 6 Underwent Craniotomy for RN after 6 months*** 3 L Parieto-occipital 39 F Right lower extremity weakness 127 30 TMZ + RT IV - None 25 NP - 4 L Post. cingulate 59 F Right arm weakness and numbness 6.8 93 TMZ + RT IV MGMT – None 20 18 - 5 L Precuneus 65 M Seizure 5.2 99 TMZ + RT IV - None 18 8 - 6 R Genu 66 F Confusion 15 100 TMZ + RT IV - None 14 12 Expired at 14 months Pt Side Location/eloquent structure involved Age (yr.) Gender Presenting** symptoms Tumor volume (cm3) EOA (%) Adjuvant therapy Pathology Molecular characteristics# Post-Op complications Follow-up time (mo.)* PFS(mo.) Notes 1 L Splenium 69 F Confusion, memory impairment 27 98 TMZ + RT IV MGMT – IDH1/2 – None 6 NP - 2 R Orbitofrontal/ALIC 51 M Dizziness, poor coordination 1.2 100 TMZ + RT IV - None 35 6 Underwent Craniotomy for RN after 6 months*** 3 L Parieto-occipital 39 F Right lower extremity weakness 127 30 TMZ + RT IV - None 25 NP - 4 L Post. cingulate 59 F Right arm weakness and numbness 6.8 93 TMZ + RT IV MGMT – None 20 18 - 5 L Precuneus 65 M Seizure 5.2 99 TMZ + RT IV - None 18 8 - 6 R Genu 66 F Confusion 15 100 TMZ + RT IV - None 14 12 Expired at 14 months * At last known follow-up, no patients had evidence of disease progression. RT: radiotherapy; TMZ: temozolomide; RN: radiation necrosis; NP: no progression to date ** All patients presented with a Karnofsky Performance Scale (KPS) of 100 #Molecular characteristics of tumor were included. MGMT + refers to presence of hypermethylated MGMT (O-6-methylguanine-DNA methyltransferase) gene and IDH1 + refers to presence of mutated isocitrate dehydrogenase gene. *** The initial lesion was abutting the anterior limb of the internal capsule, however, the recurrence occurred lateral and anterior to the initial area of ablation allowing for safe open resection View Large TABLE 1. Case Series of Primary Treatment of Gliomas Using LITT Pt Side Location/eloquent structure involved Age (yr.) Gender Presenting** symptoms Tumor volume (cm3) EOA (%) Adjuvant therapy Pathology Molecular characteristics# Post-Op complications Follow-up time (mo.)* PFS(mo.) Notes 1 L Splenium 69 F Confusion, memory impairment 27 98 TMZ + RT IV MGMT – IDH1/2 – None 6 NP - 2 R Orbitofrontal/ALIC 51 M Dizziness, poor coordination 1.2 100 TMZ + RT IV - None 35 6 Underwent Craniotomy for RN after 6 months*** 3 L Parieto-occipital 39 F Right lower extremity weakness 127 30 TMZ + RT IV - None 25 NP - 4 L Post. cingulate 59 F Right arm weakness and numbness 6.8 93 TMZ + RT IV MGMT – None 20 18 - 5 L Precuneus 65 M Seizure 5.2 99 TMZ + RT IV - None 18 8 - 6 R Genu 66 F Confusion 15 100 TMZ + RT IV - None 14 12 Expired at 14 months Pt Side Location/eloquent structure involved Age (yr.) Gender Presenting** symptoms Tumor volume (cm3) EOA (%) Adjuvant therapy Pathology Molecular characteristics# Post-Op complications Follow-up time (mo.)* PFS(mo.) Notes 1 L Splenium 69 F Confusion, memory impairment 27 98 TMZ + RT IV MGMT – IDH1/2 – None 6 NP - 2 R Orbitofrontal/ALIC 51 M Dizziness, poor coordination 1.2 100 TMZ + RT IV - None 35 6 Underwent Craniotomy for RN after 6 months*** 3 L Parieto-occipital 39 F Right lower extremity weakness 127 30 TMZ + RT IV - None 25 NP - 4 L Post. cingulate 59 F Right arm weakness and numbness 6.8 93 TMZ + RT IV MGMT – None 20 18 - 5 L Precuneus 65 M Seizure 5.2 99 TMZ + RT IV - None 18 8 - 6 R Genu 66 F Confusion 15 100 TMZ + RT IV - None 14 12 Expired at 14 months * At last known follow-up, no patients had evidence of disease progression. RT: radiotherapy; TMZ: temozolomide; RN: radiation necrosis; NP: no progression to date ** All patients presented with a Karnofsky Performance Scale (KPS) of 100 #Molecular characteristics of tumor were included. MGMT + refers to presence of hypermethylated MGMT (O-6-methylguanine-DNA methyltransferase) gene and IDH1 + refers to presence of mutated isocitrate dehydrogenase gene. *** The initial lesion was abutting the anterior limb of the internal capsule, however, the recurrence occurred lateral and anterior to the initial area of ablation allowing for safe open resection View Large Treatment and Outcomes All patients received adjuvant therapy with temozolomide and radiation. Mean tumor volume was 10.9 cc (interquartile range 4.2 cc-52 cc), and mean EOA was 98.5% (range 30%-100%). Five patients were alive at last follow-up, and 1 patient expired at 14 mo after LITT. Additionally, 1 patient (17%) had evidence of radiation necrosis that necessitated a craniotomy at 6 mo. Mean PFS was 14.3 (7.7-21.0) mo and mean follow-up for our patient cohort was 19.7 (12-27.5) mo (see Figure 2). There were no complications from LITT in our small case series. Patient demographics of our cohort are summarized in Table 2. Additionally, there was a negative linear relationship between preoperative lesion size and EOA (P < .04) when analyzed with previously reported series. Figure 3 includes 4 subjects from Hawasli et al, 3 subjects from Wright et al, and 6 subjects from the present work.14,15 FIGURE 2. View largeDownload slide Kaplan–Meier analysis of PFS after primary LITT for gliomas. FIGURE 2. View largeDownload slide Kaplan–Meier analysis of PFS after primary LITT for gliomas. FIGURE 3. View largeDownload slide Relationship between preoperative lesion volume (cm3) and EOA. FIGURE 3. View largeDownload slide Relationship between preoperative lesion volume (cm3) and EOA. TABLE 2. Baseline Characteristics of the 7 Patients With Deep Gliomas Patient characteristics (n = 7) Age (years) (IQR) 59 (39-69) Gender  Male n (%) 3 (42.9%)  Female n (%) 4 (57.1%) Mean Volume (cc) (IQR) 10.9 (4.2-52) Mean EOA (%) 98.5% WHO  I n (%) 0  II n (%) 1 (14.3)  III n (%) 0  IV n (%) 6 (85.7) Mean PFS (95% CI) 14.3 (7.7-21.0) Mean follow-up (mo) 19.7 (12-27.5) Patient characteristics (n = 7) Age (years) (IQR) 59 (39-69) Gender  Male n (%) 3 (42.9%)  Female n (%) 4 (57.1%) Mean Volume (cc) (IQR) 10.9 (4.2-52) Mean EOA (%) 98.5% WHO  I n (%) 0  II n (%) 1 (14.3)  III n (%) 0  IV n (%) 6 (85.7) Mean PFS (95% CI) 14.3 (7.7-21.0) Mean follow-up (mo) 19.7 (12-27.5) View Large TABLE 2. Baseline Characteristics of the 7 Patients With Deep Gliomas Patient characteristics (n = 7) Age (years) (IQR) 59 (39-69) Gender  Male n (%) 3 (42.9%)  Female n (%) 4 (57.1%) Mean Volume (cc) (IQR) 10.9 (4.2-52) Mean EOA (%) 98.5% WHO  I n (%) 0  II n (%) 1 (14.3)  III n (%) 0  IV n (%) 6 (85.7) Mean PFS (95% CI) 14.3 (7.7-21.0) Mean follow-up (mo) 19.7 (12-27.5) Patient characteristics (n = 7) Age (years) (IQR) 59 (39-69) Gender  Male n (%) 3 (42.9%)  Female n (%) 4 (57.1%) Mean Volume (cc) (IQR) 10.9 (4.2-52) Mean EOA (%) 98.5% WHO  I n (%) 0  II n (%) 1 (14.3)  III n (%) 0  IV n (%) 6 (85.7) Mean PFS (95% CI) 14.3 (7.7-21.0) Mean follow-up (mo) 19.7 (12-27.5) View Large Sample Cases Case 1 A 69-yr-old female with history of confusion and headaches presented to the clinic with subtle alexia, and visual field testing demonstrated a left homonymous hemianopsia. On imaging, a ring enhancing lesion in the splenium was discovered. Given the lesion's size, the patient underwent a right parietal stereotactic needle biopsy and LITT. Frozen section confirmed suspicion for high-grade glioma. The patient underwent the aforementioned procedure with a 98% lesional ablation (see Figure 4). There were no complications. The patient was discharged home the following day, and she was started on adjuvant chemotherapy and radiation. She was last seen at 6 mo follow-up and had no evidence of tumor recurrence at that time. FIGURE 4. View largeDownload slide A, Axial T1 contrasted MRI demonstrating a heterogeneously enhancing lesion within the splenium of the corpus callosum. B, Intraoperative MRI demonstrating laser catheter within the lesion with iatrogenic air artifact from intraoperative biopsy. C, Intraoperative real-time thermometry. D, Postoperative MRI demonstrating near-total ablation of lesion. FIGURE 4. View largeDownload slide A, Axial T1 contrasted MRI demonstrating a heterogeneously enhancing lesion within the splenium of the corpus callosum. B, Intraoperative MRI demonstrating laser catheter within the lesion with iatrogenic air artifact from intraoperative biopsy. C, Intraoperative real-time thermometry. D, Postoperative MRI demonstrating near-total ablation of lesion. Case 3 This is a 39-yr-old female with a history of breast cancer who presented with progressive right lower extremity weakness. Her imaging demonstrated a frontoparietal enhancing mass within the posterior aspect of the corpus callosum and extending to deep corticospinal tracts. Given the location, she underwent a left stereotactic needle biopsy and LITT. During LITT, thermal imaging demonstrated near-ablative temperature limits bordering the corticospinal tracts at a low power intensity. Despite a low power intensity, the EOA was approaching functional motor tracts; therefore, ablation was aborted with an EOA of nearly 30%. Pathology was consistent with glioblastoma, and she was started on adjuvant temozolomide and radiation therapy. She tolerated the therapy well, and had no evidence of recurrence or new symptoms after 2 yr of follow up (see Figure 5). FIGURE 5. View largeDownload slide Axial A, and Sagittal B, contrast MRI demonstrating enhancing lesion along centrum semiovale and corpus callosum. Postoperative axial C, and sagittal D, demonstrating new ring of enhancement (partial ablation) after LITT. FIGURE 5. View largeDownload slide Axial A, and Sagittal B, contrast MRI demonstrating enhancing lesion along centrum semiovale and corpus callosum. Postoperative axial C, and sagittal D, demonstrating new ring of enhancement (partial ablation) after LITT. Case 4 This is a 59-yr-old female with a history of nausea and focal seizures who presented to clinic with a heterogeneous ring enhancing lesion in the posterior cingulate gyrus. On physical examination, she was neurologically intact. Given the size and depth of the lesion, she underwent a left frontal stereotactic biopsy and LITT with a 93% ablation (see Figure 6). She was started on adjuvant temozolomide and radiation therapy. She did well postoperatively, and was noted at 18-mo follow-up to have imaging changes that favored radiation necrosis over tumor recurrence. FIGURE 6. View largeDownload slide A, Sagittal contrast MRI demonstrating ring enhancing lesion along the posterior cingulate gyrus. B, Intraoperative MRI demonstrating laser catheter within the lesion. C, Postoperative MRI demonstrating new area of ring-enhancement demonstrating near total ablation of lesion. FIGURE 6. View largeDownload slide A, Sagittal contrast MRI demonstrating ring enhancing lesion along the posterior cingulate gyrus. B, Intraoperative MRI demonstrating laser catheter within the lesion. C, Postoperative MRI demonstrating new area of ring-enhancement demonstrating near total ablation of lesion. DISCUSSION LITT is a relatively young technique that affords a minimally invasive cytoreductive option for patients. The premise for LITT therapy was first described for solid tumors since the early 1980s, but was sparingly used for intracranial lesions.9,11 With the advent of MR-based thermal imaging and stereotactic navigation systems, LITT recovered popularity as a safe alternative to traditional craniotomies. LITT therapy, currently available under 2 main systems (Neuroblate, Monteris Medical, Kalamazoo, Michigan; and Visualase, Medtronic), utilizes thermal energy to deliver a focal necrosis within the target tissue while preventing overablation and damage to nontarget tissues. The extent of lesional ablation is limited by the energy delivered and tissue diffusion, which can be monitored in real-time through magnetic resonance imaging.16 Both LITT systems allow for protection of adjacent critical structures via unidirectional or concentric thermal ablation or temperature limits. Indications As such, LITT remains a useful alternative for patients who are poor-surgical candidates who cannot tolerate a traditional craniotomy. Several factors including the patient's comorbid state and lesion size remain paramount when opting for LITT as a primary treatment for suspected high-grade gliomas. For frail patients who cannot tolerate prolonged general anesthesia or blood loss, LITT may be a reasonable alternative. LITT can be effective for lesions smaller than 2.5 cm in any given dimension, and can afford minimal risk of injuring critical adjacent structures, thereby making it an ideal candidate for deep tumors. For LITT to be effective as a primary treatment for high-grade gliomas, we estimate that surgeons should be able to ablate at least 80% of the tumor to achieve a meaningful survival benefit. This cytoreductive threshold has been extrapolated from surgical series where it has been estimated that the tumor resection must exceed 78% of radiographic tumor in order to achieve an improvement in overall survival.7,8,12,17-19 Therefore, LITT may be a useful substitute for patients with deep eloquent tumors that would otherwise be offered a biopsy alone. Outcomes Our series suggests that LITT may be offered as an advantageous cytoreductive primary treatment for deep inaccessible gliomas with median EOA of 98%. We hypothesize that LITT ablation may potentially enhance overall survival in our patient subgroup who would have otherwise only qualify for a stereotactic biopsy. All of the patients in our series had EOA > 78% with the exception of one patient who was underablated to avoid damaging adjacent motor fibers. From our series, LITT for deep inaccessible gliomas may be safe with minimal perioperative morbidity. Typically, survival for patients who receive a biopsy followed by chemotherapy and radiation has been reported to be less than 7 mo in many contemporaneous series.1,2,12 However, our data demonstrates that all of our patient population has surpassed that OS threshold, suggesting a treatment benefit with LITT therapy, though larger numbers of patients are needed to confirm this trend. Additionally, a recent meta-analysis by Ivan et al12 reported a median OS of 14.2 mo, which parallels OS for patients who receive conventional surgical resection and adjuvant chemoradiation.20 In our series, mean follow-up was 19.7 mo. Only 1 patient underwent a craniotomy for resection following LITT therapy for radiation necrosis after 6 mo after primary LITT treatment. In order to better understand outcomes of primary LITT treatment for deep gliomas, we conducted a brief literature review that is summarized in Table 3. Our review identified 49 patients who underwent LITT as primary treatment for deep-seeded tumors involving eloquent tissue. Within the literature, 3 of the 8 patient series reported ablation volumes similar to our series with EOA (91-93%), albeit mean preoperative tumor volumes were not consistently reported (16.7-79.6 cm3). From the literature, mean-weighted PFS was 4.2 mo (2.0-11.5 mo) with a mean overall follow-up time of 9.8 mo. Based on our review, outcomes in the literature remain sparsely reported due to the novelty of LITT technology and lack of volumetric analysis in the past. Previous reviews have found median overall survival for patients with high-grade glioma treated with chemotherapy and radiation alone to be 9 mo.21 Any comparisons with our analysis are guarded given the limited availability of survival data; however, our recorded PFS of 14.3 mo is certainly encouraging. Our study enhances these previously reported patient series, which ultimately proposes the safety and efficacy of LITT as a primary treatment for deep gliomas. TABLE 3. Review of Literature, LITT for Primary Treatment of Gliomas Study Age (yr) Number of cases Pathology PreOp volume (mean, cm3) EOA (mean) PFS (mean, mo.) Follow-up (mean, mo.) Hawasli 201314 54 6 HGG 16.7 91% 2.9 4.5 Jethwa 201224 64 4 HGG NS NS NS NS Mohammadi 201425 NS 16 HGG NS NS 3.5 7.2 Pisipati 201626 NS 3 HGG 79.6 NS NS NS Schroeder 201327 47 5 HGG 18.9 93% 11.5 9.4 Thomas 201628 61 8 HGG 22.4 NS 2 ≥ 6.0 Wright 201615 74 3 HGG 33.3 93% 3.8 5.2 Study Age (yr) Number of cases Pathology PreOp volume (mean, cm3) EOA (mean) PFS (mean, mo.) Follow-up (mean, mo.) Hawasli 201314 54 6 HGG 16.7 91% 2.9 4.5 Jethwa 201224 64 4 HGG NS NS NS NS Mohammadi 201425 NS 16 HGG NS NS 3.5 7.2 Pisipati 201626 NS 3 HGG 79.6 NS NS NS Schroeder 201327 47 5 HGG 18.9 93% 11.5 9.4 Thomas 201628 61 8 HGG 22.4 NS 2 ≥ 6.0 Wright 201615 74 3 HGG 33.3 93% 3.8 5.2 EOA: extent of ablation; HGG: high grade glioma; PFS: progression free survival; PreOp: preoperative View Large TABLE 3. Review of Literature, LITT for Primary Treatment of Gliomas Study Age (yr) Number of cases Pathology PreOp volume (mean, cm3) EOA (mean) PFS (mean, mo.) Follow-up (mean, mo.) Hawasli 201314 54 6 HGG 16.7 91% 2.9 4.5 Jethwa 201224 64 4 HGG NS NS NS NS Mohammadi 201425 NS 16 HGG NS NS 3.5 7.2 Pisipati 201626 NS 3 HGG 79.6 NS NS NS Schroeder 201327 47 5 HGG 18.9 93% 11.5 9.4 Thomas 201628 61 8 HGG 22.4 NS 2 ≥ 6.0 Wright 201615 74 3 HGG 33.3 93% 3.8 5.2 Study Age (yr) Number of cases Pathology PreOp volume (mean, cm3) EOA (mean) PFS (mean, mo.) Follow-up (mean, mo.) Hawasli 201314 54 6 HGG 16.7 91% 2.9 4.5 Jethwa 201224 64 4 HGG NS NS NS NS Mohammadi 201425 NS 16 HGG NS NS 3.5 7.2 Pisipati 201626 NS 3 HGG 79.6 NS NS NS Schroeder 201327 47 5 HGG 18.9 93% 11.5 9.4 Thomas 201628 61 8 HGG 22.4 NS 2 ≥ 6.0 Wright 201615 74 3 HGG 33.3 93% 3.8 5.2 EOA: extent of ablation; HGG: high grade glioma; PFS: progression free survival; PreOp: preoperative View Large Limitations The inherent reliance on the reliability of the frozen section in our cases poses a significant challenge in utilizing LITT as a primary treatment of gliomas. In our patients, the frozen section from the stereotactic biopsy (immediately before LITT) suggested high-grade glioma. However, this method is limited by the accuracy/quality of the intraoperative frozen section and the experience of the neuropathologists. In the event that the frozen section is equivocal on the diagnosis of glioma, the surgeon should exercise caution before proceeding with LITT. In our experience, patients with ambiguous frozen section diagnoses, may benefit from LITT in a delayed fashion after confirmation of final diagnosis and adequate patient recovery. As in all cases, the permanent specimen should be prioritized over the frozen section in cases where tumor specimen is limited. In our practice, we try to avoid LITT in patients with significant mass effect. Transient mild worsening of preoperative deficits has been noted in some cases, but is generally responsive to a short course of steroids. As noted in older reports, in very large lesions LITT carries a significant risk of massive edema, sometimes requiring debulking following ablation. We try to avoid LITT in such cases in order to prevent the need for what is essentially a 2-stage surgery. In our eyes, the need for a second, open resection essentially negates the benefit of a minimally invasive technique like LITT. Ultimately, our series is limited by the nature of many retrospective studies, including (i) selection bias for patients who would likely benefit from LITT, (ii) the lack of long-term follow-up, and (iii) inherent informational bias from the volumetric analysis of the postoperative MRI. Given the relatively small size of our cohort and the lack of long-term follow-up, there is not sufficient data to compare PFS or overall survival. Only 1 patient expired during the duration of this study, and only 2 others demonstrated definitive evidence of disease progression. The nature of our series selected patients with lesions that could be amenable for LITT (single lesions, small diameter, good preoperative functional status), and therefore caution must be exercised prior to extrapolating our results to broader patient groups. Additionally, available literature allows only for a limited meta-analysis, but the review we offer is as complete as possible in addressing the question at hand. Specific points of interest in this study (location, tumor volume) preclude use of other studies from the earlier meta-analysis. Future Directions Our study suggests an increasingly vital role of LITT in the primary treatment of deep gliomas; however larger prospective studies are warranted. In the future, prospectively randomizing patients between LITT + biopsy vs biopsy alone could further elucidate the role of LITT as a primary treatment modality in this subgroup. Additionally, there is some suggestion that LITT may potentiate chemotherapy and radiation by transiently opening the blood brain barrier and generating sublethal damage to adjacent neoplastic tissue respectively.22,23 The transient disruption of the blood brain barrier described by Leuthardt et al23 peaked 7-14 d after LITT and persisted up to 6 wk after treatment, which may serve as a possible time window for adjuvant chemotherapeutics. LITT’s efficacy in improving cytotoxicity of available chemotherapy regimens has yet to be firmly established. CONCLUSION Although we recognize that LITT treatment does not afford a gross total resection, we believe that it accomplishes enough cytoreduction and blood brain barrier disruption to improve the efficacy of adjuvant chemotherapy and radiation. For patients who are typically not candidates for debulking or resection, LITT should be considered as a minimally invasive safe alternative for primary treatment of high-grade neoplasms. 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Chaichana KL , Jusue-Torres I , Navarro-Ramirez R et al. Establishing percent resection and residual volume thresholds affecting survival and recurrence for patients with newly diagnosed intracranial glioblastoma . Neuro Oncol . 2014 ; 16 ( 1 ): 113 – 122 . Google Scholar CrossRef Search ADS PubMed 5. Grabowski MM , Recinos PF , Nowacki AS et al. Residual tumor volume versus extent of resection: predictors of survival after surgery for glioblastoma . J Neurosurg . 2014 ; 121 ( 5 ): 1115 – 1123 . Google Scholar CrossRef Search ADS PubMed 6. Kuhnt D , Becker A , Ganslandt O , Bauer M , Buchfelder M , Nimsky C . Correlation of the extent of tumor volume resection and patient survival in surgery of glioblastoma multiforme with high-field intraoperative MRI guidance . Neuro-oncol . 2011 ; 13 ( 12 ): 1339 – 1348 . Google Scholar CrossRef Search ADS PubMed 7. Oppenlander ME , Wolf AB , Snyder LA et al. An extent of resection threshold for recurrent glioblastoma and its risk for neurological morbidity . J Neurosurg . 2014 ; 120 ( 4 ): 846 – 853 . Google Scholar CrossRef Search ADS PubMed 8. Sanai N , Polley MY , McDermott MW , Parsa AT , Berger MS . An extent of resection threshold for newly diagnosed glioblastomas . J Neurosurg . 2011 ; 115 ( 1 ): 3 – 8 . Google Scholar CrossRef Search ADS PubMed 9. Banerjee C , Snelling B , Berger MH , Shah A , Ivan ME , Komotar RJ . The role of magnetic resonance-guided laser ablation in neurooncology . Br J Neurosurg . 2015 ; 29 ( 2 ): 192 – 196 . Google Scholar CrossRef Search ADS PubMed 10. Diaz R , Ivan ME , Hanft S et al. Laser interstitial thermal therapy: lighting the way to a new treatment option in neurosurgery . Neurosurgery . 2016 ; 79 ( Suppl 1 ): S3 – S7 . Google Scholar CrossRef Search ADS PubMed 11. Ivan ME , Diaz RJ , Berger MH et al. Magnetic resonance-guided laser ablation for the treatment of recurrent dural-based lesions: a series of five cases . World Neurosurg . 2017 ; 98 : 162 – 170 . Google Scholar CrossRef Search ADS PubMed 12. Ivan ME , Mohammadi AM , De Deugd N et al. Laser ablation of newly diagnosed malignant gliomas: a meta-analysis . Neurosurgery . 2016 ; 79 ( Suppl 1 ): S17 – S23 . Google Scholar CrossRef Search ADS PubMed 13. Jermakowicz WJ , Diaz RJ , Cass SH , Ivan ME , Komotar RJ . Use of a mobile intraoperative computed tomography scanner for navigation registration during laser interstitial thermal therapy of brain tumors . World Neurosurg . 2016 ; 94 : 418 – 425 . Google Scholar CrossRef Search ADS PubMed 14. Hawasli AH , Bagade S , Shimony JS , Miller-Thomas M , Leuthardt EC . Magnetic resonance imaging-guided focused laser interstitial thermal therapy for intracranial lesions: single-institution series . Neurosurgery . 2013 ; 73 ( 6 ): 1007 – 1017 . Google Scholar CrossRef Search ADS PubMed 15. Wright J , Chugh J , Wright CH et al. Laser interstitial thermal therapy followed by minimal-access transsulcal resection for the treatment of large and difficult to access brain tumors . Neurosurg Focus . 2016 ; 41 ( 4 ): E14 . Google Scholar CrossRef Search ADS PubMed 16. McNichols RJ , Gowda A , Kangasniemi M , Bankson JA , Price RE , Hazle JD . MR thermometry-based feedback control of laser interstitial thermal therapy at 980 nm . Lasers Surg. Med . 2004 ; 34 ( 1 ): 48 – 55 . Google Scholar CrossRef Search ADS PubMed 17. Chaudhry NS , Shah AH , Ferraro N et al. Predictors of long-term survival in patients with glioblastoma multiforme: advancements from the last quarter century . Cancer Invest . 2013 ; 31 ( 5 ): 287 – 308 . Google Scholar CrossRef Search ADS PubMed 18. Laws ER , Parney IF , Huang W et al. Survival following surgery and prognostic factors for recently diagnosed malignant glioma: data from the Glioma Outcomes Project . J Neurosurg . 2003 ; 99 ( 3 ): 467 – 473 . Google Scholar CrossRef Search ADS PubMed 19. Quigley M , Huang X , Yang Y . Extent of stimulation controls the formation of memory CD8 T cells . J Immunol . 2007 ; 179 ( 9 ): 5768 – 5777 . Google Scholar CrossRef Search ADS PubMed 20. Stupp R , Mason WP , van den Bent MJ et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma . N Engl J Med . 2005 ; 352 ( 10 ): 987 – 996 . Google Scholar CrossRef Search ADS PubMed 21. Trifiletti DM , Alonso C , Grover S , Fadul CE , Sheehan JP , Showalter TN . Prognostic implications of extent of resection in glioblastoma: analysis from a large database . World Neurosurg . 2017 ; 103 : 330 – 340 . Google Scholar CrossRef Search ADS PubMed 22. Lee I , Kalkanis S , Hadjipanayis CG . Stereotactic laser interstitial thermal therapy for recurrent high-grade gliomas . Neurosurgery . 2016 ; 79 ( Suppl 1 ): S24 – S34 . Google Scholar CrossRef Search ADS PubMed 23. Leuthardt EC , Duan C , Kim MJ et al. Hyperthermic laser ablation of recurrent glioblastoma leads to temporary disruption of the peritumoral blood brain barrier . PLoS One . 2016 ; 11 ( 2 ): e0148613 . Google Scholar CrossRef Search ADS PubMed 24. Jethwa PR , Barrese JC , Gowda A , Shetty A , Danish SF . Magnetic resonance thermometry-guided laser-induced thermal therapy for intracranial neoplasms: initial experience . Neurosurgery . 2012 ; 71 ( 1 ): 133 – 145 . Google Scholar PubMed 25. Mohammadi AM , Hawasli AH , Rodriguez A et al. The role of laser interstitial thermal therapy in enhancing progression-free survival of difficult-to-access high-grade gliomas: a multicenter study . Cancer Med . 2014 ; 3 ( 4 ): 971 – 979 . Google Scholar CrossRef Search ADS PubMed 26. Pisipati S , Smith KA , Shah K , Ebersole K , Chamoun RB , Camarata PJ . Intracerebral laser interstitial thermal therapy followed by tumor resection to minimize cerebral edema . Neurosurg Focus . 2016 ; 41 ( 4 ): E13 . Google Scholar CrossRef Search ADS PubMed 27. Schroeder JL , Missios S , Barnett GH , Mohammadi AM . Laser interstitial thermal therapy as a novel treatment modality for brain tumors in the thalamus and basal ganglia . Photon Laser Med . 2014 ; 3 ( 2 ): 151 – 158 . Google Scholar CrossRef Search ADS 28. Thomas JG , Rao G , Kew Y , Prabhu SS . Laser interstitial thermal therapy for newly diagnosed and recurrent glioblastoma . Neurosurg Focus . 2016 ; 41 ( 4 ): E12 . Google Scholar CrossRef Search ADS PubMed Neurosurgery Speaks! Audio abstracts available for this article at www.neurosurgery-online.com. COMMENTS The authors present an interesting single center retrospective study of 6 cases from a single surgeon at a tertiary care center regarding the use of laser interstitial thermal therapy (LITT) for treatment of deep intracranial gliomas that are unable to be resected surgically. In this small but informative chart review, data regarding tumor pathology, tumor volume, and extent of ablation (EOA) are discussed in comparison with progression-free survival (PFS). In addition, 3 of the 7 cases are presented in greater detail such that the reader can learn more about the utility of the new technology. Based on the small sample size, statistical analysis was limited and potentially unreliable, but the data presented are valuable and will help contribute to the limited amount available in the literature regarding the use of LITT and its outcomes for gliomas in or near areas of eloquence. A recent meta-analysis by Barnett et al1 includes data from 8 studies and features similar patient population as this study. Of the 79 total patients included, the mean EOA was 85.4 ± 10.6% using LITT in high-grade gliomas in or near areas of eloquence. Another meta-analysis, from Ivan et al,2 showed that for 25 patients with high grade gliomas, the mean EOA was 82.9%, the mean follow-up time was 7.6 months, and mean PFS was 5.1 months. In this current study of 6 patients, median EOA was 98%. This resulted in a mean PFS of 14.3 months. Thus, the data presented in this paper are encouraging with respect to EOA and PFS, and perhaps will assist with further development of inclusion/exclusion criteria for LITT in the future. Additionally, the outcomes of this study should encourage larger prospective randomized studies evaluating the efficacy of LITT. Furthermore, LITT has been shown to disrupt the peritumoral blood brain barrier, which is determined to be a direct consequence of the regional hyperthermia. A study by Leuthardt et al3 demonstrated that a peak permeability occurred 1–2 weeks after LITT and returned to baseline 4–6 weeks following LITT, thus allowing for a window of increased therapeutic efficacy. Coupling this with the ability to treat previously inoperable gliomas, LITT provides an exciting new treatment paradigm. Michael Stellon Jonathan H. Sherman Washington, District of Columbia 1. Barnett GH, Voigt JD, Alhuwalia MS. A Systematic Review and Meta-Analysis of Studies Examining the Use of Brain Laser Interstitial Thermal Therapy versus Craniotomy for the Treatment of High-Grade Tumors in or near Areas of Eloquence: An Examination of the Extent of Resection and Major Complication Rates Associated with Each Type of Surgery . Stereotact Funct Neurosurg . 2016 ; 94 ( 3 ): 164 – 173 . CrossRef Search ADS PubMed 2. Ivan ME, Mohammadi AM, De Deugd N, et al . Laser Ablation of Newly Diagnosed Malignant Gliomas: a Meta-Analysis . Neurosurgery . 2016 ; 79 ( Suppl 1 ): S17 – S23 . PubMed 3. Leuthardt EC, Duan C, Kim MJ, et al . Hyperthermic Laser Ablation of Recurrent Glioblastoma Leads to Temporary Disruption of the Peritumoral Blood Brain Barrier . Abdollahi A , ed. PLoS One . 2016 ; 11 ( 2 ): e0148613 . Google Scholar CrossRef Search ADS PubMed TThe authors present a small series of patients with newly diagnosed deep/eloquent region glioma treated upfront with laser interstitial thermal therapy (LITT). In this highly selected cohort, the authors found this to be a safe procedure with efficacy presumably surpassing historical controls. While controversy has long surrounded the extent of resection discussion regarding glioma and glioblastoma in particular, the body of evidence strongly suggests that maximal safe resection provides an advantage over biopsy alone. The question remains, however, what is safe and how much is enough to garner a survival benefit over biopsy alone. Traditionally, deep seated, small tumors have been treated with biopsy followed by standard chemoradiation as the risk for resection was felt to be high and outweighing the potential benefits from a resection. With advances in technology, LITT has become a viable options for the management of multiple pathologies. There are several inherent advantages, including minimal access, favorable morbidity profile, and ability to target deep lesions safely. Several prior manuscripts have demonstrated the safety and potential efficacy of LITT in the management of glioblastoma. The focus here on newly diagnosed lesions is unique, but the data regarding efficacy is significantly limited by the study design/methodology. The authors should be encouraged to provide contemperaneous data for patients who underwent biopsy only for newly diagnosed glioma. How did those cohorts differ at baseline and how did their PFS/OS differ relative to patients undergoing LITT? While this certainly does not amount to a randomize controled trial, it would significantly enhance the impact and interest of this manuscript. Despite methodological limitations, which render solid conclusions regarding efficacy difficult, this manuscript provides a good introduction to the use of this technology in patients harboring deep-seated high grade glioma. Given the paucity of efficacious therapies for high- grade glioma and in particular for those patients in whom a resection is not attempted, LITT stands to have a significant positive impact. Robust data will require a prospective trial, but until that time series such as this will slowly push this entity forward. Brad E. Zacharia Hershey, Pennsylvania Neurosurgery Speaks (Audio Abstracts) Listen to audio translations of this paper's abstract into select languages by choosing from one of the selections below. Chinese: Kai Wang, MD. Department of Neurosurgery Weihai Central Hospital, Weihai Shandong, China Chinese: Kai Wang, MD. Department of Neurosurgery Weihai Central Hospital, Weihai Shandong, China Close French: Georges Abi Lahoud, MD, MSc, MS. Department of Neurosurgery Sainte-Anne University Hospital Paris Descartes University Paris, France French: Georges Abi Lahoud, MD, MSc, MS. Department of Neurosurgery Sainte-Anne University Hospital Paris Descartes University Paris, France Close Japanese: Toshiaki Hayashi, MD, PhD. Department of Neurosurgery Sendai City Hospital Sendai, Japan Japanese: Toshiaki Hayashi, MD, PhD. Department of Neurosurgery Sendai City Hospital Sendai, Japan Close Korean: Hye Ran Park, MD. Department of Neurosurgery Soonchunhyang University Seoul Hospital Seoul, Republic of Korea Korean: Hye Ran Park, MD. Department of Neurosurgery Soonchunhyang University Seoul Hospital Seoul, Republic of Korea Close Portuguese: Marcos Dellaretti, MD. Department of Neurosurgery Santa Casa de Belo Horizonte Belo Horizonte, Brazil Portuguese: Marcos Dellaretti, MD. Department of Neurosurgery Santa Casa de Belo Horizonte Belo Horizonte, Brazil Close Spanish: Luis Ascanio-Cortez, MD. Division of Neurosurgery Beth Israel Deaconess Medical Center Boston, Massachusetts Spanish: Luis Ascanio-Cortez, MD. Division of Neurosurgery Beth Israel Deaconess Medical Center Boston, Massachusetts Close Greek: Marios Themistocleous, MD. Department of Neurosurgery Aghia Sophia Children's Hospital Athens, Greece Greek: Marios Themistocleous, MD. Department of Neurosurgery Aghia Sophia Children's Hospital Athens, Greece Close Copyright © 2018 by the Congress of Neurological Surgeons This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurosurgery Oxford University Press

Laser Interstitial Thermal Therapy as a Primary Treatment for Deep Inaccessible Gliomas

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Congress of Neurological Surgeons
Copyright
Copyright © 2018 by the Congress of Neurological Surgeons
ISSN
0148-396X
eISSN
1524-4040
D.O.I.
10.1093/neuros/nyy238
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Abstract

Abstract BACKGROUND Treatment strategies for deep intracranial gliomas remain limited to stereotactic biopsy in many cases due to the morbidity of aggressive surgical resection. Since no cytoreductive therapy is offered, outcomes have been demonstrably poor compared to patients who are able to undergo primary surgical resection. OBJECTIVE To present our practice, in an effort to reduce morbidity and still offer cytoreductive treatment, of offering the possibility of laser interstitial thermal therapy (LITT) for the primary treatment of intracranial deep gliomas that would be otherwise unamenable for resection. METHODS From 2010 to 2017, 74 patients were identified from a single surgeon at a single tertiary care referral center who had been treated with LITT. We conducted an exploratory cohort study on patients (n = 6) who have undergone contemporaneous biopsy and laser ablation for the treatment of deep gliomas with a mean tumor volume of 10.9 cc (range 4.2-52 cc). RESULTS In our cohort, mean extent of ablation (EOA) was 98.5% on postoperative MRI; mean progression-free survival was 14.3 mo, and 5 patients (83%) remained alive at mean follow-up time of 19.7 mo without any complications. Additionally, there was a negative linear relationship between preoperative lesion size and EOA (P < .04) when analyzed with previously reported series. CONCLUSION Although our series is small, we suggest that LITT can be a safe alternative cytoreductive therapy for deep surgically inaccessible gliomas. Given the known benefit of near gross total resection for high-grade gliomas, we believe LITT may improve survival for these patients and complement adjuvant treatments if patients are appropriately selected. Laser, Treatment, Glioma, Deep, Outcomes, Ablation, Volumetric ABBREVIATIONS ABBREVIATIONS EOA extent of ablation IDH isocitrate dehydrogenase KPS Karnofsky Performance Scale KPS Karnofsky Performance Status LITT laser interstitial thermal therapy PFS progression-free survival Treatment strategies for patients with deep intracranial gliomas remain limited to adjuvant chemotherapy and fractionated radiation. Typically, patients may be offered a stereotactic biopsy for tissue confirmation and profiling of deep inaccessible lesions without any cytoreductive surgical treatment. For this specific subset of patients, overall survival has been reported to be as low as 5-7 mo in some series.1,2 Additionally, 1 and 2-yr mortality risk seems to decrease with any form of resection compared to biopsy of high-grade gliomas, suggesting that subtotal resection or gross total surgical resection may confer some survival benefit.2 Furthermore, recent literature suggests that even in high-grade lesions, extent of resection remains an important predictor of overall survival.3-8 However, naturally these studies are limited to patients who are amenable to surgical resection (ie, patients with superficial, noneloquent tumors), thereby limiting their applicability to a subset of glioma patients with deep “inoperable” lesions. For some of these patients, we suggest that laser interstitial thermal therapy (LITT) may be offered as an adjunct after biopsy for the treatment of primary gliomas who would otherwise not receive any form of cytoreductive treatment. Here, we present an exploratory study from a single surgeon at a single institution assessing the safety and efficacy of LITT for primary deep eloquent region gliomas. FIGURE 1. View largeDownload slide Flow diagram of patient selection. FIGURE 1. View largeDownload slide Flow diagram of patient selection. METHODS After Institutional Review Board approval, a retrospective chart review was conducted. From 2010 to 2017, 74 patients were identified from a single surgeon at a single tertiary care referral center who had been treated with LITT. From this group, we identified 6 patients who underwent LITT for deep gliomas as a primary treatment. No consent was needed given the retrospective nature of this study. All patients were screened by age (> 18 yr), location (deep), and pathology (high-grade glioma). Only patients who were felt to be inoperable via open craniotomy and resection were included. The definition of inoperable/unresectable was left to the discretion of the primary surgeon (R.J.K.), but was primarily determined by the risk of severe neurological morbidity. Patients with multifocal/multicentric gliomas were excluded. All cases of salvage/secondary resection for patients who had previously undergone resection were omitted. Patients with inadequate outcome data, imaging, operative reports, or hospitalization information were excluded. If follow-up was inadequate (< 6 mo), patients were excluded. Figure 1 illustrates stepwise patient selection. Pertinent demographics were obtained including age at diagnosis, sex, tumor location, adjuvant therapies including chemotherapy/radiotherapy, Karnofsky Performance Status (KPS), and follow-up. Genetic mutations for hypermethylated O-6-methylguanine-DNA methyltransferase (MGMT) and mutated isocitrate dehydrogenase (IDH) were reported when available. Low- and high-grade tumors were volumetrically analyzed by measuring hyperintense regions on axial T2-weighted FLAIR images and T1-weighted contrast-enhanced MR images, respectively. Tumors were manually segmented across all slices with region-of-interest analysis to compute pre- and postoperative volume. Residual tumor was calculated using immediate and 24-h postoperative contrast MRI (magnetic resonance imaging), when enhancement shows extent of permanently damaged tissue. Contrast enhancement beyond previous extent of the tumor border was recorded as complete ablation. Extent of ablation (EOA) was calculated using the formula [100 – (postoperative tumor volume/preoperative tumor volume) x 100]. Our EOA was verified by 2 independent reviewers: 1 neurosurgeon and 1 neuroradiologist. Any perioperative morbidity or new neurological deficits after treatment was reported. We estimated time to recurrence as any growth of the lesion after primary treatment, which also included temozolomide and fractionated whole beam radiation fitting with standard practices. Similarly, progression-free survival (PFS) and overall survival were recorded. Surgical Technique LITT treatment was performed as previously described by our group using the Visualase platform (Medtronic, Dublin, Ireland).9-13 This system employs a 980-nanometer diode laser with a full-field diffusing tip. It delivers a maximum power of 15 Watts, though this can be decreased for a gentler, more precise ablation. All patients undergo preoperative volumetric 1 mm slice MRI for planning and stereotactic navigation. An intraoperative computed tomography is taken using the O-arm system (Medtronic) and co-registered to the preoperative MRI. An optimal trajectory is planned that is centered in the lesion and spares functional nontumor tissue and vasculature. Once the trajectory is confirmed with intraoperative navigation, a stereotactic needle is introduced into a superficial aspect of the lesion. Another intraoperative computed tomography is then taken to confirm the location of the biopsy needle within the tumor, and a 3-4 biopsy cores are sent for frozen and permanent section. In all cases, a stereotactic biopsy was performed prior to the initiation of LITT, and a dedicated neuropathologist confirmed a preliminary diagnosis of glioma on frozen section. After confirmation, a laser fiber is introduced and secured into the tumor at its deepest extent, and the patient is transported to the MRI suite for the real-time MR thermography. For all patients included, an attempt to safely maximize the EOA was made when possible. The extent of treatment during LITT sessions was guided by the senior neurosurgeon's evaluation of the temperature map in conjunction with the damage estimate. Just as in open surgery, the goal was to achieve maximal safe cytoreduction. Real-time thermography aided in preventing injury to adjacent eloquent fibers and the amount of thermal energy was manipulated to maximize the ablation volume. To avoid postoperative swelling, preoperative and postoperative steroids were given to all patients. Statistical Analysis Continuous variables were reported with medians and ranges. Categorical variables were reported using frequencies and percentages. Relationships between continuous variables were modeled using linear regression, and a P value of .05 was considered statistically significant. Survival curves were generated with Kaplan Meier analysis. The final analysis includes data points taken from our own study as well as eligible subjects from earlier studies. Subjects were used from the literature review if the study contained EOA and preoperative tumor volume. Only subjects meeting the same criteria for inclusion as our study were included: adequate follow-up, primary treatment, age > 18, high-grade glioma. Mean-weighted average is given in instances where individual subject data were not available from selected studies, taking group average by the number of subjects in the study. All data analysis was conducted using SPSS (version 22, IBM Corp, Armonk, New York). RESULTS Patient Characteristics Six patients identified as having undergone LITT as a primary treatment had a mean age of 58 yr (range 39-69). All patients were symptomatic at the time they presented to our service, with symptomatology characterized by confusion (2/6; 33%), weakness (2/6; 33%), dizziness (1/6; 17%), and seizure (1/6; 17%). Four (67%) tumors were left sided. All patients presented initially with a Karnofsky Performance Scale (KPS) greater than 90. Patient and tumor characteristics are given in Table 1. TABLE 1. Case Series of Primary Treatment of Gliomas Using LITT Pt Side Location/eloquent structure involved Age (yr.) Gender Presenting** symptoms Tumor volume (cm3) EOA (%) Adjuvant therapy Pathology Molecular characteristics# Post-Op complications Follow-up time (mo.)* PFS(mo.) Notes 1 L Splenium 69 F Confusion, memory impairment 27 98 TMZ + RT IV MGMT – IDH1/2 – None 6 NP - 2 R Orbitofrontal/ALIC 51 M Dizziness, poor coordination 1.2 100 TMZ + RT IV - None 35 6 Underwent Craniotomy for RN after 6 months*** 3 L Parieto-occipital 39 F Right lower extremity weakness 127 30 TMZ + RT IV - None 25 NP - 4 L Post. cingulate 59 F Right arm weakness and numbness 6.8 93 TMZ + RT IV MGMT – None 20 18 - 5 L Precuneus 65 M Seizure 5.2 99 TMZ + RT IV - None 18 8 - 6 R Genu 66 F Confusion 15 100 TMZ + RT IV - None 14 12 Expired at 14 months Pt Side Location/eloquent structure involved Age (yr.) Gender Presenting** symptoms Tumor volume (cm3) EOA (%) Adjuvant therapy Pathology Molecular characteristics# Post-Op complications Follow-up time (mo.)* PFS(mo.) Notes 1 L Splenium 69 F Confusion, memory impairment 27 98 TMZ + RT IV MGMT – IDH1/2 – None 6 NP - 2 R Orbitofrontal/ALIC 51 M Dizziness, poor coordination 1.2 100 TMZ + RT IV - None 35 6 Underwent Craniotomy for RN after 6 months*** 3 L Parieto-occipital 39 F Right lower extremity weakness 127 30 TMZ + RT IV - None 25 NP - 4 L Post. cingulate 59 F Right arm weakness and numbness 6.8 93 TMZ + RT IV MGMT – None 20 18 - 5 L Precuneus 65 M Seizure 5.2 99 TMZ + RT IV - None 18 8 - 6 R Genu 66 F Confusion 15 100 TMZ + RT IV - None 14 12 Expired at 14 months * At last known follow-up, no patients had evidence of disease progression. RT: radiotherapy; TMZ: temozolomide; RN: radiation necrosis; NP: no progression to date ** All patients presented with a Karnofsky Performance Scale (KPS) of 100 #Molecular characteristics of tumor were included. MGMT + refers to presence of hypermethylated MGMT (O-6-methylguanine-DNA methyltransferase) gene and IDH1 + refers to presence of mutated isocitrate dehydrogenase gene. *** The initial lesion was abutting the anterior limb of the internal capsule, however, the recurrence occurred lateral and anterior to the initial area of ablation allowing for safe open resection View Large TABLE 1. Case Series of Primary Treatment of Gliomas Using LITT Pt Side Location/eloquent structure involved Age (yr.) Gender Presenting** symptoms Tumor volume (cm3) EOA (%) Adjuvant therapy Pathology Molecular characteristics# Post-Op complications Follow-up time (mo.)* PFS(mo.) Notes 1 L Splenium 69 F Confusion, memory impairment 27 98 TMZ + RT IV MGMT – IDH1/2 – None 6 NP - 2 R Orbitofrontal/ALIC 51 M Dizziness, poor coordination 1.2 100 TMZ + RT IV - None 35 6 Underwent Craniotomy for RN after 6 months*** 3 L Parieto-occipital 39 F Right lower extremity weakness 127 30 TMZ + RT IV - None 25 NP - 4 L Post. cingulate 59 F Right arm weakness and numbness 6.8 93 TMZ + RT IV MGMT – None 20 18 - 5 L Precuneus 65 M Seizure 5.2 99 TMZ + RT IV - None 18 8 - 6 R Genu 66 F Confusion 15 100 TMZ + RT IV - None 14 12 Expired at 14 months Pt Side Location/eloquent structure involved Age (yr.) Gender Presenting** symptoms Tumor volume (cm3) EOA (%) Adjuvant therapy Pathology Molecular characteristics# Post-Op complications Follow-up time (mo.)* PFS(mo.) Notes 1 L Splenium 69 F Confusion, memory impairment 27 98 TMZ + RT IV MGMT – IDH1/2 – None 6 NP - 2 R Orbitofrontal/ALIC 51 M Dizziness, poor coordination 1.2 100 TMZ + RT IV - None 35 6 Underwent Craniotomy for RN after 6 months*** 3 L Parieto-occipital 39 F Right lower extremity weakness 127 30 TMZ + RT IV - None 25 NP - 4 L Post. cingulate 59 F Right arm weakness and numbness 6.8 93 TMZ + RT IV MGMT – None 20 18 - 5 L Precuneus 65 M Seizure 5.2 99 TMZ + RT IV - None 18 8 - 6 R Genu 66 F Confusion 15 100 TMZ + RT IV - None 14 12 Expired at 14 months * At last known follow-up, no patients had evidence of disease progression. RT: radiotherapy; TMZ: temozolomide; RN: radiation necrosis; NP: no progression to date ** All patients presented with a Karnofsky Performance Scale (KPS) of 100 #Molecular characteristics of tumor were included. MGMT + refers to presence of hypermethylated MGMT (O-6-methylguanine-DNA methyltransferase) gene and IDH1 + refers to presence of mutated isocitrate dehydrogenase gene. *** The initial lesion was abutting the anterior limb of the internal capsule, however, the recurrence occurred lateral and anterior to the initial area of ablation allowing for safe open resection View Large Treatment and Outcomes All patients received adjuvant therapy with temozolomide and radiation. Mean tumor volume was 10.9 cc (interquartile range 4.2 cc-52 cc), and mean EOA was 98.5% (range 30%-100%). Five patients were alive at last follow-up, and 1 patient expired at 14 mo after LITT. Additionally, 1 patient (17%) had evidence of radiation necrosis that necessitated a craniotomy at 6 mo. Mean PFS was 14.3 (7.7-21.0) mo and mean follow-up for our patient cohort was 19.7 (12-27.5) mo (see Figure 2). There were no complications from LITT in our small case series. Patient demographics of our cohort are summarized in Table 2. Additionally, there was a negative linear relationship between preoperative lesion size and EOA (P < .04) when analyzed with previously reported series. Figure 3 includes 4 subjects from Hawasli et al, 3 subjects from Wright et al, and 6 subjects from the present work.14,15 FIGURE 2. View largeDownload slide Kaplan–Meier analysis of PFS after primary LITT for gliomas. FIGURE 2. View largeDownload slide Kaplan–Meier analysis of PFS after primary LITT for gliomas. FIGURE 3. View largeDownload slide Relationship between preoperative lesion volume (cm3) and EOA. FIGURE 3. View largeDownload slide Relationship between preoperative lesion volume (cm3) and EOA. TABLE 2. Baseline Characteristics of the 7 Patients With Deep Gliomas Patient characteristics (n = 7) Age (years) (IQR) 59 (39-69) Gender  Male n (%) 3 (42.9%)  Female n (%) 4 (57.1%) Mean Volume (cc) (IQR) 10.9 (4.2-52) Mean EOA (%) 98.5% WHO  I n (%) 0  II n (%) 1 (14.3)  III n (%) 0  IV n (%) 6 (85.7) Mean PFS (95% CI) 14.3 (7.7-21.0) Mean follow-up (mo) 19.7 (12-27.5) Patient characteristics (n = 7) Age (years) (IQR) 59 (39-69) Gender  Male n (%) 3 (42.9%)  Female n (%) 4 (57.1%) Mean Volume (cc) (IQR) 10.9 (4.2-52) Mean EOA (%) 98.5% WHO  I n (%) 0  II n (%) 1 (14.3)  III n (%) 0  IV n (%) 6 (85.7) Mean PFS (95% CI) 14.3 (7.7-21.0) Mean follow-up (mo) 19.7 (12-27.5) View Large TABLE 2. Baseline Characteristics of the 7 Patients With Deep Gliomas Patient characteristics (n = 7) Age (years) (IQR) 59 (39-69) Gender  Male n (%) 3 (42.9%)  Female n (%) 4 (57.1%) Mean Volume (cc) (IQR) 10.9 (4.2-52) Mean EOA (%) 98.5% WHO  I n (%) 0  II n (%) 1 (14.3)  III n (%) 0  IV n (%) 6 (85.7) Mean PFS (95% CI) 14.3 (7.7-21.0) Mean follow-up (mo) 19.7 (12-27.5) Patient characteristics (n = 7) Age (years) (IQR) 59 (39-69) Gender  Male n (%) 3 (42.9%)  Female n (%) 4 (57.1%) Mean Volume (cc) (IQR) 10.9 (4.2-52) Mean EOA (%) 98.5% WHO  I n (%) 0  II n (%) 1 (14.3)  III n (%) 0  IV n (%) 6 (85.7) Mean PFS (95% CI) 14.3 (7.7-21.0) Mean follow-up (mo) 19.7 (12-27.5) View Large Sample Cases Case 1 A 69-yr-old female with history of confusion and headaches presented to the clinic with subtle alexia, and visual field testing demonstrated a left homonymous hemianopsia. On imaging, a ring enhancing lesion in the splenium was discovered. Given the lesion's size, the patient underwent a right parietal stereotactic needle biopsy and LITT. Frozen section confirmed suspicion for high-grade glioma. The patient underwent the aforementioned procedure with a 98% lesional ablation (see Figure 4). There were no complications. The patient was discharged home the following day, and she was started on adjuvant chemotherapy and radiation. She was last seen at 6 mo follow-up and had no evidence of tumor recurrence at that time. FIGURE 4. View largeDownload slide A, Axial T1 contrasted MRI demonstrating a heterogeneously enhancing lesion within the splenium of the corpus callosum. B, Intraoperative MRI demonstrating laser catheter within the lesion with iatrogenic air artifact from intraoperative biopsy. C, Intraoperative real-time thermometry. D, Postoperative MRI demonstrating near-total ablation of lesion. FIGURE 4. View largeDownload slide A, Axial T1 contrasted MRI demonstrating a heterogeneously enhancing lesion within the splenium of the corpus callosum. B, Intraoperative MRI demonstrating laser catheter within the lesion with iatrogenic air artifact from intraoperative biopsy. C, Intraoperative real-time thermometry. D, Postoperative MRI demonstrating near-total ablation of lesion. Case 3 This is a 39-yr-old female with a history of breast cancer who presented with progressive right lower extremity weakness. Her imaging demonstrated a frontoparietal enhancing mass within the posterior aspect of the corpus callosum and extending to deep corticospinal tracts. Given the location, she underwent a left stereotactic needle biopsy and LITT. During LITT, thermal imaging demonstrated near-ablative temperature limits bordering the corticospinal tracts at a low power intensity. Despite a low power intensity, the EOA was approaching functional motor tracts; therefore, ablation was aborted with an EOA of nearly 30%. Pathology was consistent with glioblastoma, and she was started on adjuvant temozolomide and radiation therapy. She tolerated the therapy well, and had no evidence of recurrence or new symptoms after 2 yr of follow up (see Figure 5). FIGURE 5. View largeDownload slide Axial A, and Sagittal B, contrast MRI demonstrating enhancing lesion along centrum semiovale and corpus callosum. Postoperative axial C, and sagittal D, demonstrating new ring of enhancement (partial ablation) after LITT. FIGURE 5. View largeDownload slide Axial A, and Sagittal B, contrast MRI demonstrating enhancing lesion along centrum semiovale and corpus callosum. Postoperative axial C, and sagittal D, demonstrating new ring of enhancement (partial ablation) after LITT. Case 4 This is a 59-yr-old female with a history of nausea and focal seizures who presented to clinic with a heterogeneous ring enhancing lesion in the posterior cingulate gyrus. On physical examination, she was neurologically intact. Given the size and depth of the lesion, she underwent a left frontal stereotactic biopsy and LITT with a 93% ablation (see Figure 6). She was started on adjuvant temozolomide and radiation therapy. She did well postoperatively, and was noted at 18-mo follow-up to have imaging changes that favored radiation necrosis over tumor recurrence. FIGURE 6. View largeDownload slide A, Sagittal contrast MRI demonstrating ring enhancing lesion along the posterior cingulate gyrus. B, Intraoperative MRI demonstrating laser catheter within the lesion. C, Postoperative MRI demonstrating new area of ring-enhancement demonstrating near total ablation of lesion. FIGURE 6. View largeDownload slide A, Sagittal contrast MRI demonstrating ring enhancing lesion along the posterior cingulate gyrus. B, Intraoperative MRI demonstrating laser catheter within the lesion. C, Postoperative MRI demonstrating new area of ring-enhancement demonstrating near total ablation of lesion. DISCUSSION LITT is a relatively young technique that affords a minimally invasive cytoreductive option for patients. The premise for LITT therapy was first described for solid tumors since the early 1980s, but was sparingly used for intracranial lesions.9,11 With the advent of MR-based thermal imaging and stereotactic navigation systems, LITT recovered popularity as a safe alternative to traditional craniotomies. LITT therapy, currently available under 2 main systems (Neuroblate, Monteris Medical, Kalamazoo, Michigan; and Visualase, Medtronic), utilizes thermal energy to deliver a focal necrosis within the target tissue while preventing overablation and damage to nontarget tissues. The extent of lesional ablation is limited by the energy delivered and tissue diffusion, which can be monitored in real-time through magnetic resonance imaging.16 Both LITT systems allow for protection of adjacent critical structures via unidirectional or concentric thermal ablation or temperature limits. Indications As such, LITT remains a useful alternative for patients who are poor-surgical candidates who cannot tolerate a traditional craniotomy. Several factors including the patient's comorbid state and lesion size remain paramount when opting for LITT as a primary treatment for suspected high-grade gliomas. For frail patients who cannot tolerate prolonged general anesthesia or blood loss, LITT may be a reasonable alternative. LITT can be effective for lesions smaller than 2.5 cm in any given dimension, and can afford minimal risk of injuring critical adjacent structures, thereby making it an ideal candidate for deep tumors. For LITT to be effective as a primary treatment for high-grade gliomas, we estimate that surgeons should be able to ablate at least 80% of the tumor to achieve a meaningful survival benefit. This cytoreductive threshold has been extrapolated from surgical series where it has been estimated that the tumor resection must exceed 78% of radiographic tumor in order to achieve an improvement in overall survival.7,8,12,17-19 Therefore, LITT may be a useful substitute for patients with deep eloquent tumors that would otherwise be offered a biopsy alone. Outcomes Our series suggests that LITT may be offered as an advantageous cytoreductive primary treatment for deep inaccessible gliomas with median EOA of 98%. We hypothesize that LITT ablation may potentially enhance overall survival in our patient subgroup who would have otherwise only qualify for a stereotactic biopsy. All of the patients in our series had EOA > 78% with the exception of one patient who was underablated to avoid damaging adjacent motor fibers. From our series, LITT for deep inaccessible gliomas may be safe with minimal perioperative morbidity. Typically, survival for patients who receive a biopsy followed by chemotherapy and radiation has been reported to be less than 7 mo in many contemporaneous series.1,2,12 However, our data demonstrates that all of our patient population has surpassed that OS threshold, suggesting a treatment benefit with LITT therapy, though larger numbers of patients are needed to confirm this trend. Additionally, a recent meta-analysis by Ivan et al12 reported a median OS of 14.2 mo, which parallels OS for patients who receive conventional surgical resection and adjuvant chemoradiation.20 In our series, mean follow-up was 19.7 mo. Only 1 patient underwent a craniotomy for resection following LITT therapy for radiation necrosis after 6 mo after primary LITT treatment. In order to better understand outcomes of primary LITT treatment for deep gliomas, we conducted a brief literature review that is summarized in Table 3. Our review identified 49 patients who underwent LITT as primary treatment for deep-seeded tumors involving eloquent tissue. Within the literature, 3 of the 8 patient series reported ablation volumes similar to our series with EOA (91-93%), albeit mean preoperative tumor volumes were not consistently reported (16.7-79.6 cm3). From the literature, mean-weighted PFS was 4.2 mo (2.0-11.5 mo) with a mean overall follow-up time of 9.8 mo. Based on our review, outcomes in the literature remain sparsely reported due to the novelty of LITT technology and lack of volumetric analysis in the past. Previous reviews have found median overall survival for patients with high-grade glioma treated with chemotherapy and radiation alone to be 9 mo.21 Any comparisons with our analysis are guarded given the limited availability of survival data; however, our recorded PFS of 14.3 mo is certainly encouraging. Our study enhances these previously reported patient series, which ultimately proposes the safety and efficacy of LITT as a primary treatment for deep gliomas. TABLE 3. Review of Literature, LITT for Primary Treatment of Gliomas Study Age (yr) Number of cases Pathology PreOp volume (mean, cm3) EOA (mean) PFS (mean, mo.) Follow-up (mean, mo.) Hawasli 201314 54 6 HGG 16.7 91% 2.9 4.5 Jethwa 201224 64 4 HGG NS NS NS NS Mohammadi 201425 NS 16 HGG NS NS 3.5 7.2 Pisipati 201626 NS 3 HGG 79.6 NS NS NS Schroeder 201327 47 5 HGG 18.9 93% 11.5 9.4 Thomas 201628 61 8 HGG 22.4 NS 2 ≥ 6.0 Wright 201615 74 3 HGG 33.3 93% 3.8 5.2 Study Age (yr) Number of cases Pathology PreOp volume (mean, cm3) EOA (mean) PFS (mean, mo.) Follow-up (mean, mo.) Hawasli 201314 54 6 HGG 16.7 91% 2.9 4.5 Jethwa 201224 64 4 HGG NS NS NS NS Mohammadi 201425 NS 16 HGG NS NS 3.5 7.2 Pisipati 201626 NS 3 HGG 79.6 NS NS NS Schroeder 201327 47 5 HGG 18.9 93% 11.5 9.4 Thomas 201628 61 8 HGG 22.4 NS 2 ≥ 6.0 Wright 201615 74 3 HGG 33.3 93% 3.8 5.2 EOA: extent of ablation; HGG: high grade glioma; PFS: progression free survival; PreOp: preoperative View Large TABLE 3. Review of Literature, LITT for Primary Treatment of Gliomas Study Age (yr) Number of cases Pathology PreOp volume (mean, cm3) EOA (mean) PFS (mean, mo.) Follow-up (mean, mo.) Hawasli 201314 54 6 HGG 16.7 91% 2.9 4.5 Jethwa 201224 64 4 HGG NS NS NS NS Mohammadi 201425 NS 16 HGG NS NS 3.5 7.2 Pisipati 201626 NS 3 HGG 79.6 NS NS NS Schroeder 201327 47 5 HGG 18.9 93% 11.5 9.4 Thomas 201628 61 8 HGG 22.4 NS 2 ≥ 6.0 Wright 201615 74 3 HGG 33.3 93% 3.8 5.2 Study Age (yr) Number of cases Pathology PreOp volume (mean, cm3) EOA (mean) PFS (mean, mo.) Follow-up (mean, mo.) Hawasli 201314 54 6 HGG 16.7 91% 2.9 4.5 Jethwa 201224 64 4 HGG NS NS NS NS Mohammadi 201425 NS 16 HGG NS NS 3.5 7.2 Pisipati 201626 NS 3 HGG 79.6 NS NS NS Schroeder 201327 47 5 HGG 18.9 93% 11.5 9.4 Thomas 201628 61 8 HGG 22.4 NS 2 ≥ 6.0 Wright 201615 74 3 HGG 33.3 93% 3.8 5.2 EOA: extent of ablation; HGG: high grade glioma; PFS: progression free survival; PreOp: preoperative View Large Limitations The inherent reliance on the reliability of the frozen section in our cases poses a significant challenge in utilizing LITT as a primary treatment of gliomas. In our patients, the frozen section from the stereotactic biopsy (immediately before LITT) suggested high-grade glioma. However, this method is limited by the accuracy/quality of the intraoperative frozen section and the experience of the neuropathologists. In the event that the frozen section is equivocal on the diagnosis of glioma, the surgeon should exercise caution before proceeding with LITT. In our experience, patients with ambiguous frozen section diagnoses, may benefit from LITT in a delayed fashion after confirmation of final diagnosis and adequate patient recovery. As in all cases, the permanent specimen should be prioritized over the frozen section in cases where tumor specimen is limited. In our practice, we try to avoid LITT in patients with significant mass effect. Transient mild worsening of preoperative deficits has been noted in some cases, but is generally responsive to a short course of steroids. As noted in older reports, in very large lesions LITT carries a significant risk of massive edema, sometimes requiring debulking following ablation. We try to avoid LITT in such cases in order to prevent the need for what is essentially a 2-stage surgery. In our eyes, the need for a second, open resection essentially negates the benefit of a minimally invasive technique like LITT. Ultimately, our series is limited by the nature of many retrospective studies, including (i) selection bias for patients who would likely benefit from LITT, (ii) the lack of long-term follow-up, and (iii) inherent informational bias from the volumetric analysis of the postoperative MRI. Given the relatively small size of our cohort and the lack of long-term follow-up, there is not sufficient data to compare PFS or overall survival. Only 1 patient expired during the duration of this study, and only 2 others demonstrated definitive evidence of disease progression. The nature of our series selected patients with lesions that could be amenable for LITT (single lesions, small diameter, good preoperative functional status), and therefore caution must be exercised prior to extrapolating our results to broader patient groups. Additionally, available literature allows only for a limited meta-analysis, but the review we offer is as complete as possible in addressing the question at hand. Specific points of interest in this study (location, tumor volume) preclude use of other studies from the earlier meta-analysis. Future Directions Our study suggests an increasingly vital role of LITT in the primary treatment of deep gliomas; however larger prospective studies are warranted. In the future, prospectively randomizing patients between LITT + biopsy vs biopsy alone could further elucidate the role of LITT as a primary treatment modality in this subgroup. Additionally, there is some suggestion that LITT may potentiate chemotherapy and radiation by transiently opening the blood brain barrier and generating sublethal damage to adjacent neoplastic tissue respectively.22,23 The transient disruption of the blood brain barrier described by Leuthardt et al23 peaked 7-14 d after LITT and persisted up to 6 wk after treatment, which may serve as a possible time window for adjuvant chemotherapeutics. LITT’s efficacy in improving cytotoxicity of available chemotherapy regimens has yet to be firmly established. CONCLUSION Although we recognize that LITT treatment does not afford a gross total resection, we believe that it accomplishes enough cytoreduction and blood brain barrier disruption to improve the efficacy of adjuvant chemotherapy and radiation. For patients who are typically not candidates for debulking or resection, LITT should be considered as a minimally invasive safe alternative for primary treatment of high-grade neoplasms. Future multicenter randomized clinical trials using LITT as a primary treatment for deep inaccessible gliomas are warranted. Disclosure The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. REFERENCES 1. Fazeny-Dorner B , Wenzel C , Veitl M et al. Survival and prognostic factors of patients with unresectable glioblastoma multiforme . Anticancer Drugs . 2003 ; 14 ( 4 ): 305 – 312 . Google Scholar CrossRef Search ADS PubMed 2. Brown TJ , Brennan MC , Li M et al. Association of the Extent of Resection With Survival in Glioblastoma: A Systematic Review and Meta-analysis . JAMA Oncol . 2016 ; 2 ( 11 ): 1460 – 1469 . Google Scholar CrossRef Search ADS PubMed 3. Bloch O , Han SJ , Cha S et al. Impact of extent of resection for recurrent glioblastoma on overall survival: clinical article . J Neurosurg . 2012 ; 117 ( 6 ): 1032 – 1038 . Google Scholar CrossRef Search ADS PubMed 4. Chaichana KL , Jusue-Torres I , Navarro-Ramirez R et al. Establishing percent resection and residual volume thresholds affecting survival and recurrence for patients with newly diagnosed intracranial glioblastoma . Neuro Oncol . 2014 ; 16 ( 1 ): 113 – 122 . Google Scholar CrossRef Search ADS PubMed 5. Grabowski MM , Recinos PF , Nowacki AS et al. Residual tumor volume versus extent of resection: predictors of survival after surgery for glioblastoma . J Neurosurg . 2014 ; 121 ( 5 ): 1115 – 1123 . Google Scholar CrossRef Search ADS PubMed 6. Kuhnt D , Becker A , Ganslandt O , Bauer M , Buchfelder M , Nimsky C . Correlation of the extent of tumor volume resection and patient survival in surgery of glioblastoma multiforme with high-field intraoperative MRI guidance . Neuro-oncol . 2011 ; 13 ( 12 ): 1339 – 1348 . Google Scholar CrossRef Search ADS PubMed 7. Oppenlander ME , Wolf AB , Snyder LA et al. An extent of resection threshold for recurrent glioblastoma and its risk for neurological morbidity . J Neurosurg . 2014 ; 120 ( 4 ): 846 – 853 . Google Scholar CrossRef Search ADS PubMed 8. Sanai N , Polley MY , McDermott MW , Parsa AT , Berger MS . An extent of resection threshold for newly diagnosed glioblastomas . J Neurosurg . 2011 ; 115 ( 1 ): 3 – 8 . Google Scholar CrossRef Search ADS PubMed 9. Banerjee C , Snelling B , Berger MH , Shah A , Ivan ME , Komotar RJ . The role of magnetic resonance-guided laser ablation in neurooncology . Br J Neurosurg . 2015 ; 29 ( 2 ): 192 – 196 . Google Scholar CrossRef Search ADS PubMed 10. Diaz R , Ivan ME , Hanft S et al. Laser interstitial thermal therapy: lighting the way to a new treatment option in neurosurgery . Neurosurgery . 2016 ; 79 ( Suppl 1 ): S3 – S7 . Google Scholar CrossRef Search ADS PubMed 11. Ivan ME , Diaz RJ , Berger MH et al. Magnetic resonance-guided laser ablation for the treatment of recurrent dural-based lesions: a series of five cases . World Neurosurg . 2017 ; 98 : 162 – 170 . Google Scholar CrossRef Search ADS PubMed 12. Ivan ME , Mohammadi AM , De Deugd N et al. Laser ablation of newly diagnosed malignant gliomas: a meta-analysis . Neurosurgery . 2016 ; 79 ( Suppl 1 ): S17 – S23 . Google Scholar CrossRef Search ADS PubMed 13. Jermakowicz WJ , Diaz RJ , Cass SH , Ivan ME , Komotar RJ . Use of a mobile intraoperative computed tomography scanner for navigation registration during laser interstitial thermal therapy of brain tumors . World Neurosurg . 2016 ; 94 : 418 – 425 . Google Scholar CrossRef Search ADS PubMed 14. Hawasli AH , Bagade S , Shimony JS , Miller-Thomas M , Leuthardt EC . Magnetic resonance imaging-guided focused laser interstitial thermal therapy for intracranial lesions: single-institution series . Neurosurgery . 2013 ; 73 ( 6 ): 1007 – 1017 . Google Scholar CrossRef Search ADS PubMed 15. Wright J , Chugh J , Wright CH et al. Laser interstitial thermal therapy followed by minimal-access transsulcal resection for the treatment of large and difficult to access brain tumors . Neurosurg Focus . 2016 ; 41 ( 4 ): E14 . Google Scholar CrossRef Search ADS PubMed 16. McNichols RJ , Gowda A , Kangasniemi M , Bankson JA , Price RE , Hazle JD . MR thermometry-based feedback control of laser interstitial thermal therapy at 980 nm . Lasers Surg. Med . 2004 ; 34 ( 1 ): 48 – 55 . Google Scholar CrossRef Search ADS PubMed 17. Chaudhry NS , Shah AH , Ferraro N et al. Predictors of long-term survival in patients with glioblastoma multiforme: advancements from the last quarter century . Cancer Invest . 2013 ; 31 ( 5 ): 287 – 308 . Google Scholar CrossRef Search ADS PubMed 18. Laws ER , Parney IF , Huang W et al. Survival following surgery and prognostic factors for recently diagnosed malignant glioma: data from the Glioma Outcomes Project . J Neurosurg . 2003 ; 99 ( 3 ): 467 – 473 . Google Scholar CrossRef Search ADS PubMed 19. Quigley M , Huang X , Yang Y . Extent of stimulation controls the formation of memory CD8 T cells . J Immunol . 2007 ; 179 ( 9 ): 5768 – 5777 . Google Scholar CrossRef Search ADS PubMed 20. Stupp R , Mason WP , van den Bent MJ et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma . N Engl J Med . 2005 ; 352 ( 10 ): 987 – 996 . Google Scholar CrossRef Search ADS PubMed 21. Trifiletti DM , Alonso C , Grover S , Fadul CE , Sheehan JP , Showalter TN . Prognostic implications of extent of resection in glioblastoma: analysis from a large database . World Neurosurg . 2017 ; 103 : 330 – 340 . Google Scholar CrossRef Search ADS PubMed 22. Lee I , Kalkanis S , Hadjipanayis CG . Stereotactic laser interstitial thermal therapy for recurrent high-grade gliomas . Neurosurgery . 2016 ; 79 ( Suppl 1 ): S24 – S34 . Google Scholar CrossRef Search ADS PubMed 23. Leuthardt EC , Duan C , Kim MJ et al. Hyperthermic laser ablation of recurrent glioblastoma leads to temporary disruption of the peritumoral blood brain barrier . PLoS One . 2016 ; 11 ( 2 ): e0148613 . Google Scholar CrossRef Search ADS PubMed 24. Jethwa PR , Barrese JC , Gowda A , Shetty A , Danish SF . Magnetic resonance thermometry-guided laser-induced thermal therapy for intracranial neoplasms: initial experience . Neurosurgery . 2012 ; 71 ( 1 ): 133 – 145 . Google Scholar PubMed 25. Mohammadi AM , Hawasli AH , Rodriguez A et al. The role of laser interstitial thermal therapy in enhancing progression-free survival of difficult-to-access high-grade gliomas: a multicenter study . Cancer Med . 2014 ; 3 ( 4 ): 971 – 979 . Google Scholar CrossRef Search ADS PubMed 26. Pisipati S , Smith KA , Shah K , Ebersole K , Chamoun RB , Camarata PJ . Intracerebral laser interstitial thermal therapy followed by tumor resection to minimize cerebral edema . Neurosurg Focus . 2016 ; 41 ( 4 ): E13 . Google Scholar CrossRef Search ADS PubMed 27. Schroeder JL , Missios S , Barnett GH , Mohammadi AM . Laser interstitial thermal therapy as a novel treatment modality for brain tumors in the thalamus and basal ganglia . Photon Laser Med . 2014 ; 3 ( 2 ): 151 – 158 . Google Scholar CrossRef Search ADS 28. Thomas JG , Rao G , Kew Y , Prabhu SS . Laser interstitial thermal therapy for newly diagnosed and recurrent glioblastoma . Neurosurg Focus . 2016 ; 41 ( 4 ): E12 . Google Scholar CrossRef Search ADS PubMed Neurosurgery Speaks! Audio abstracts available for this article at www.neurosurgery-online.com. COMMENTS The authors present an interesting single center retrospective study of 6 cases from a single surgeon at a tertiary care center regarding the use of laser interstitial thermal therapy (LITT) for treatment of deep intracranial gliomas that are unable to be resected surgically. In this small but informative chart review, data regarding tumor pathology, tumor volume, and extent of ablation (EOA) are discussed in comparison with progression-free survival (PFS). In addition, 3 of the 7 cases are presented in greater detail such that the reader can learn more about the utility of the new technology. Based on the small sample size, statistical analysis was limited and potentially unreliable, but the data presented are valuable and will help contribute to the limited amount available in the literature regarding the use of LITT and its outcomes for gliomas in or near areas of eloquence. A recent meta-analysis by Barnett et al1 includes data from 8 studies and features similar patient population as this study. Of the 79 total patients included, the mean EOA was 85.4 ± 10.6% using LITT in high-grade gliomas in or near areas of eloquence. Another meta-analysis, from Ivan et al,2 showed that for 25 patients with high grade gliomas, the mean EOA was 82.9%, the mean follow-up time was 7.6 months, and mean PFS was 5.1 months. In this current study of 6 patients, median EOA was 98%. This resulted in a mean PFS of 14.3 months. Thus, the data presented in this paper are encouraging with respect to EOA and PFS, and perhaps will assist with further development of inclusion/exclusion criteria for LITT in the future. Additionally, the outcomes of this study should encourage larger prospective randomized studies evaluating the efficacy of LITT. Furthermore, LITT has been shown to disrupt the peritumoral blood brain barrier, which is determined to be a direct consequence of the regional hyperthermia. A study by Leuthardt et al3 demonstrated that a peak permeability occurred 1–2 weeks after LITT and returned to baseline 4–6 weeks following LITT, thus allowing for a window of increased therapeutic efficacy. Coupling this with the ability to treat previously inoperable gliomas, LITT provides an exciting new treatment paradigm. Michael Stellon Jonathan H. Sherman Washington, District of Columbia 1. Barnett GH, Voigt JD, Alhuwalia MS. A Systematic Review and Meta-Analysis of Studies Examining the Use of Brain Laser Interstitial Thermal Therapy versus Craniotomy for the Treatment of High-Grade Tumors in or near Areas of Eloquence: An Examination of the Extent of Resection and Major Complication Rates Associated with Each Type of Surgery . Stereotact Funct Neurosurg . 2016 ; 94 ( 3 ): 164 – 173 . CrossRef Search ADS PubMed 2. Ivan ME, Mohammadi AM, De Deugd N, et al . Laser Ablation of Newly Diagnosed Malignant Gliomas: a Meta-Analysis . Neurosurgery . 2016 ; 79 ( Suppl 1 ): S17 – S23 . PubMed 3. Leuthardt EC, Duan C, Kim MJ, et al . Hyperthermic Laser Ablation of Recurrent Glioblastoma Leads to Temporary Disruption of the Peritumoral Blood Brain Barrier . Abdollahi A , ed. PLoS One . 2016 ; 11 ( 2 ): e0148613 . Google Scholar CrossRef Search ADS PubMed TThe authors present a small series of patients with newly diagnosed deep/eloquent region glioma treated upfront with laser interstitial thermal therapy (LITT). In this highly selected cohort, the authors found this to be a safe procedure with efficacy presumably surpassing historical controls. While controversy has long surrounded the extent of resection discussion regarding glioma and glioblastoma in particular, the body of evidence strongly suggests that maximal safe resection provides an advantage over biopsy alone. The question remains, however, what is safe and how much is enough to garner a survival benefit over biopsy alone. Traditionally, deep seated, small tumors have been treated with biopsy followed by standard chemoradiation as the risk for resection was felt to be high and outweighing the potential benefits from a resection. With advances in technology, LITT has become a viable options for the management of multiple pathologies. There are several inherent advantages, including minimal access, favorable morbidity profile, and ability to target deep lesions safely. Several prior manuscripts have demonstrated the safety and potential efficacy of LITT in the management of glioblastoma. The focus here on newly diagnosed lesions is unique, but the data regarding efficacy is significantly limited by the study design/methodology. The authors should be encouraged to provide contemperaneous data for patients who underwent biopsy only for newly diagnosed glioma. How did those cohorts differ at baseline and how did their PFS/OS differ relative to patients undergoing LITT? While this certainly does not amount to a randomize controled trial, it would significantly enhance the impact and interest of this manuscript. Despite methodological limitations, which render solid conclusions regarding efficacy difficult, this manuscript provides a good introduction to the use of this technology in patients harboring deep-seated high grade glioma. Given the paucity of efficacious therapies for high- grade glioma and in particular for those patients in whom a resection is not attempted, LITT stands to have a significant positive impact. Robust data will require a prospective trial, but until that time series such as this will slowly push this entity forward. Brad E. Zacharia Hershey, Pennsylvania Neurosurgery Speaks (Audio Abstracts) Listen to audio translations of this paper's abstract into select languages by choosing from one of the selections below. Chinese: Kai Wang, MD. Department of Neurosurgery Weihai Central Hospital, Weihai Shandong, China Chinese: Kai Wang, MD. Department of Neurosurgery Weihai Central Hospital, Weihai Shandong, China Close French: Georges Abi Lahoud, MD, MSc, MS. Department of Neurosurgery Sainte-Anne University Hospital Paris Descartes University Paris, France French: Georges Abi Lahoud, MD, MSc, MS. Department of Neurosurgery Sainte-Anne University Hospital Paris Descartes University Paris, France Close Japanese: Toshiaki Hayashi, MD, PhD. Department of Neurosurgery Sendai City Hospital Sendai, Japan Japanese: Toshiaki Hayashi, MD, PhD. Department of Neurosurgery Sendai City Hospital Sendai, Japan Close Korean: Hye Ran Park, MD. Department of Neurosurgery Soonchunhyang University Seoul Hospital Seoul, Republic of Korea Korean: Hye Ran Park, MD. Department of Neurosurgery Soonchunhyang University Seoul Hospital Seoul, Republic of Korea Close Portuguese: Marcos Dellaretti, MD. Department of Neurosurgery Santa Casa de Belo Horizonte Belo Horizonte, Brazil Portuguese: Marcos Dellaretti, MD. Department of Neurosurgery Santa Casa de Belo Horizonte Belo Horizonte, Brazil Close Spanish: Luis Ascanio-Cortez, MD. Division of Neurosurgery Beth Israel Deaconess Medical Center Boston, Massachusetts Spanish: Luis Ascanio-Cortez, MD. Division of Neurosurgery Beth Israel Deaconess Medical Center Boston, Massachusetts Close Greek: Marios Themistocleous, MD. Department of Neurosurgery Aghia Sophia Children's Hospital Athens, Greece Greek: Marios Themistocleous, MD. Department of Neurosurgery Aghia Sophia Children's Hospital Athens, Greece Close Copyright © 2018 by the Congress of Neurological Surgeons This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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NeurosurgeryOxford University Press

Published: Jun 5, 2018

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