**6. Use of LITT in gliomas**

ablation in a concentric fashion. The probes are inserted using frameless stereotactic guid‐ ance. The Monteris® Mini-Bolt provides rigid skull fixation and allows a direct interface to the NeuroBlate laser probe. The system is a MRI-guided laser ablation system, which is connect‐ ed to a computer workstation capable of displaying real-time thermography data at the target location. The NeuroBlate software displays the extent of thermal energy delivered as ther‐ mal-damage-threshold (TDT) lines. The yellow line surrounds the target volume that has received the thermal energy equivalent of 43*°C* for at least 2 min; the blue line surrounds the target volume that has been exposed to 43*°C* for at least 10 min; finally, the white line corresponds to tissue exposed to 43*°C* for 60 min. Tissues located outside the yellow TDT line are expected to have no permanent damage, while tissue volume inside the blue line under‐ goes severe thermal damage and tissue volume within the white line experiences coagula‐

**Figure 1.** (a–d) show the individual components of NeuroBlate® System including the bolts (b), laser probes (c) and robotic motor drive (d). Figures 1e–f depict the integration of robotic motor drive with the MRI scanner. *(Images used by permission from Monteris Medical Corporation, Plymouth, MN, USA. The use of any Monteris Medical photo or image does not*

**Disclosures:** Drs. Gene Barnett and Alireza Mohammadi are consultants of Monteris Medical Company (NeuroBlate System). Figure 1 is provided by Monteris Medical Company and is

Various canine [32, 64, 65] and murine [48, 66–68] animal models of brain tumors have been used to investigate the efficacy of laser thermal therapy on tumors and surrounding brain

tion necrosis [22, 45] (**Figure 1**).

288 Neurooncology - Newer Developments

*imply Monteris' review or endorsement of any article or publication).*

the only contribution of this company in this chapter.

**5. Animal models and preclinical studies**

High-grade glioma or glioblastoma multiforme (GBM, WHO grade IV), in particular, is a significant clinical challenge in the field of neuro-oncology with a high rate of morbidity and mortality. GBM constitutes approximately 45% of all malignant primary glial neoplasms [70]. Gross total surgical resection with concurrent chemo-radiotherapy is the mainstay treatment modality for this aggressive tumor [71]. However, even with the best available treatment options, 5-year overall survival (OS), progression-free survival (PFS) and median survival have been reported to be 9.9%, 6.9 months and 14.6 months, respectively [59, 71, 72]. The median survival decreases to 12.1 months with post-resection radiotherapy alone instead of concurrent chemo-radiotherapy and to 6.2 months in patients with progressive disease following standard treatment regimen [71, 72]. There is controversial data regarding optimal management (surgical vs. medical) in patients with recurrent GBM. Extent ofresection greater than 80% has been shown to have improved overall survival in carefully selected patients with recurrent GBM [73–75]. Young patients with good performance status have been shown to have improved overall survival following surgical resection for recurrent GBM [76, 77]; however, after adjusting for age, no significant benefit was achieved following repeat surgery [77]. In addition, redo craniotomy for progressive GBM is associated with increased risk of per-operative complications including neurological deficits (18–22%) [78, 79]. Also,

there is a cumulative risk of these complications following each craniotomy with maximum risk between first and second procedures [80]. There is insufficient evidence supporting the role of radiosurgery, stereotactic fractionated radiation therapy or interstitial brachytherapy in patients with recurrent GBM [81, 82]. Of note, radiosurgery has also been shown to be associated with increased toxicity in patients with recurrent disease [81]. Survival benefit of 9.3 months have been reported in patients (good performance status) receiving interstitial brachytherapy for recurrent GBM [82]. Given a high incidence of this primary brain tumor with lack of effective therapies and dismal outcome, significant research is directed toward developing effective medical and surgical treatment modalities to improve overall and progression free survival. Laser interstitial thermal therapy (LITT) is one of the advance‐ ments in the surgical management of these tumors. LITT is a minimally invasive procedure, which involves stereotactic-guided placement of laser probe and utilizes thermal energy to cause protein coagulation and cell death [83, 84]. Advances in neuroimaging coupled with stereotactic techniques have led to the resurgence of interest in the utility of laser thermacoa‐ gulation in patients with brain tumors. In addition, integration of MR thermography to LITT made it possible to deliver thermal energy under real-time monitoring, thus avoiding injury to surrounding normal brain tissue [85]. Given these advantages of LITT, this technique has been utilized for a variety of neurosurgical indications such as deep-seated gliomas [1, 4, 86, 87], epilepsy [20, 88], brain metastasis with radiation necrosis [19, 23, 24, 49] and cinguloto‐ my for intractable pain [12, 89].

First report of utilization of Nd-YAG laser thermal therapy in five patients with deep-seated brain tumors was published in 1990 [90]. Later, several studies with a smaller (*n* < 8) sample size reported the utility of this modality in patients with grade II/III gliomas [36, 87, 91–93]. In 2001, Leonardi et al. [94] reported the utility of stereotactic-guided laser-induced intersti‐ tial thermotherapy (SLITT) in 24 patients with residual/recurrent brain tumors [94]. Twentyfour patients with primary glial tumors (17 high grade and 7 low grade gliomas) underwent 30 Nd-YAG laser (1064 nm) procedures under local anesthesia using 0.2T MRI guidance [94]. Interestingly, the tumor ablation was monitored using 3D turbo-FLASH T-1W MRI while laser was applied in steps. Two different lesion architectures at 1108, 1393 J and tissue necrosis at 2979 J were observed on MR imaging during laser ablation. No correlation between the tissue response to thermal treatment and the grade of the tumor was observed in this study [94]. Of note, tumor response rate and clinical outcomes were not reported in this study [94]. Complications such as neurological deficits (*n* = 4), seizures (*n* = 2) and superficial wound infection (*n* = 1) were reported following LITT in this study. A year later, same investigators reported an overall survival of 34, 30 and 9 months in patients with low-grade astrocytoma, anaplastic gliomas and GBM, respectively, following LITT in 24 patients with brain tumors. Similarly, mean time to progression (PFS) for low-grade astrocytoma, anaplastic gliomas and GBM was reported to be 16, 10 and 4 months, respectively, in this study [86]. In 2005, Schwarzmaier et al. [95] reported MR-guided (0.5T) partial ablation using LITT in two patients with recurrent GBM. One of these patients had multifocal GBM, which was found during follow up of primary tumor and underwent LITT forthe second focus, whereas second patient had GBM recurrence after standard treatment. Survival of 16 and 20 months following GBM recurrence was reported in this study, thus implicating the role of LITT in achieving im‐

proved tumor control and overall survival [95]. A year later, same investigators reported the results of MRgLITT in 16 patients with recurrent GBM with a mean follow up of 9.1 ± 6.3 months [1]. The mean tumor volume treated was 21.6±18.6 cm3 , six patients had two proce‐ dures and three patients had three LITT procedures. Of these 16 patients, 15 had surgery, 16 had radiotherapy and 6 had chemotherapy prior to LITT and all patients received chemother‐ apy following LITT. Authors have reported median survival of 5.2 and 11.2 months after recurrence in first the 10 and later 6 patients, respectively, with an overall median survival of 9.4 months after recurrence and 6.9 months after LITT. Authors have attributed this difference in median survival between the first (*n* = 10) and the later cohort (*n* = 6) of patients to the "learning curve" in terms of delay between the tumor recurrence and LITT (2 months vs. 0.3 months in first and later group) [1]. Neurological complications including transient weakness in right upper limb in one patient and non-neurological complications such as neutropenia (*n* = 3), thrombocytopenia (*n* = 1) and deranged liverfunction tests (*n* = 1) following LITT was reported in this study [1]. Of note, the length of hospital stay was 12.0±4.2 days with no ICU stay and 12 out of 16 patients were dead at the end of the study (7 deaths were due to tumor progression and 5 deaths were due to pulmonary embolism, septic mycosis, gastrointestinal bleeding, sigmoid perforation with peritonitis). Carpentier et al. [96] reported utility of MRgLITT (1.5 T) as a salvage therapy in four patients with recurrent GBM following standard treatment regimen. Five recurrent tumors in four patients (two temporal, one corpus callosum, one centrum semiovale and one temporal) with mean diameter of 16.4 mm under total ablation using Visualase system in this study. All patients except one underwent complete resection prior to salvage LITT. Recurrence was noted following a mean progression-free survival of 37 days and mean overall survival of 10.5 months following LITT, which is longer than the overall survival in patients with recurrent GBM (approximately 4–6 months) [71, 72]. Of note, local recurrence was noted in two patients (45, 30 and 19 days) and another two patients (30 and 60 days) had distant recurrences following LITT. The procedure was well tolerated in all patients with transient adverse effects such as single episode of seizure (*n* = 1), supplementary motor syndrome (*n* = 1) and CSF leak (*n* = 1) [96]. In 2013, the first human phase I study investigating the safety and efficacy of escalating dose of thermal energy using LITT in patients with recurrent GBM was published [4]. This was a multicenter study and enrol‐ led 11 patients at two centers (Cleveland Clinic and UH-case Western Medical Center) from September 2008 to October 2009. Inclusion criterion sued in this study was: adult patients with recurrent GBM following standard treatment regimen, KPS≥ 60, tumor size 15–40 mm crosssectional dimension, supratentorial location of the tumor, stable medical comorbidities and no concurrent adjunct therapies. Of note, the primary end point of the study was the safety and feasibility of the NeuroBlate**®** system whereas the overall survival, progression-free survival, improvement in KP score and change in tumor volumes were the secondary end points [4]. Three thermal dose threshold lines [TDT, yellow (43°C for 2 min), blue (43°C for 10 min) and white lines (43°C for 60 min)] were chosen forthe study based on previous animal studies. Ten patients underwent LITT procedure and were followed up for a minimum of 6 months or until death, which ever was earlier. All patients died secondary to disease progression following LITT therapy with a median follow up of 8 months. Three patients were initially enrolled for yellow thermal dose threshold line (43°C for 2 min) to the tumor margin. These three pa‐

there is a cumulative risk of these complications following each craniotomy with maximum risk between first and second procedures [80]. There is insufficient evidence supporting the role of radiosurgery, stereotactic fractionated radiation therapy or interstitial brachytherapy in patients with recurrent GBM [81, 82]. Of note, radiosurgery has also been shown to be associated with increased toxicity in patients with recurrent disease [81]. Survival benefit of 9.3 months have been reported in patients (good performance status) receiving interstitial brachytherapy for recurrent GBM [82]. Given a high incidence of this primary brain tumor with lack of effective therapies and dismal outcome, significant research is directed toward developing effective medical and surgical treatment modalities to improve overall and progression free survival. Laser interstitial thermal therapy (LITT) is one of the advance‐ ments in the surgical management of these tumors. LITT is a minimally invasive procedure, which involves stereotactic-guided placement of laser probe and utilizes thermal energy to cause protein coagulation and cell death [83, 84]. Advances in neuroimaging coupled with stereotactic techniques have led to the resurgence of interest in the utility of laser thermacoa‐ gulation in patients with brain tumors. In addition, integration of MR thermography to LITT made it possible to deliver thermal energy under real-time monitoring, thus avoiding injury to surrounding normal brain tissue [85]. Given these advantages of LITT, this technique has been utilized for a variety of neurosurgical indications such as deep-seated gliomas [1, 4, 86, 87], epilepsy [20, 88], brain metastasis with radiation necrosis [19, 23, 24, 49] and cinguloto‐

First report of utilization of Nd-YAG laser thermal therapy in five patients with deep-seated brain tumors was published in 1990 [90]. Later, several studies with a smaller (*n* < 8) sample size reported the utility of this modality in patients with grade II/III gliomas [36, 87, 91–93]. In 2001, Leonardi et al. [94] reported the utility of stereotactic-guided laser-induced intersti‐ tial thermotherapy (SLITT) in 24 patients with residual/recurrent brain tumors [94]. Twentyfour patients with primary glial tumors (17 high grade and 7 low grade gliomas) underwent 30 Nd-YAG laser (1064 nm) procedures under local anesthesia using 0.2T MRI guidance [94]. Interestingly, the tumor ablation was monitored using 3D turbo-FLASH T-1W MRI while laser was applied in steps. Two different lesion architectures at 1108, 1393 J and tissue necrosis at 2979 J were observed on MR imaging during laser ablation. No correlation between the tissue response to thermal treatment and the grade of the tumor was observed in this study [94]. Of note, tumor response rate and clinical outcomes were not reported in this study [94]. Complications such as neurological deficits (*n* = 4), seizures (*n* = 2) and superficial wound infection (*n* = 1) were reported following LITT in this study. A year later, same investigators reported an overall survival of 34, 30 and 9 months in patients with low-grade astrocytoma, anaplastic gliomas and GBM, respectively, following LITT in 24 patients with brain tumors. Similarly, mean time to progression (PFS) for low-grade astrocytoma, anaplastic gliomas and GBM was reported to be 16, 10 and 4 months, respectively, in this study [86]. In 2005, Schwarzmaier et al. [95] reported MR-guided (0.5T) partial ablation using LITT in two patients with recurrent GBM. One of these patients had multifocal GBM, which was found during follow up of primary tumor and underwent LITT forthe second focus, whereas second patient had GBM recurrence after standard treatment. Survival of 16 and 20 months following GBM recurrence was reported in this study, thus implicating the role of LITT in achieving im‐

my for intractable pain [12, 89].

290 Neurooncology - Newer Developments

tients were followed for 14 days and assessed for any toxicity (defined as decrease of 20 or more points on KPS score). If an independent committee in two out of three patients noted toxicity, the thermal dose was either modified or the trial was halted. If there were no consequences during the follow up of 14 days, another three patients were enrolled for blue and white thermal dose threshold lines subsequently using the same protocol [4]. Mean total and treated tumor volume in all treated patients were 6.8 ± 5 cm3 and 5± 3.2 cm3 (78% of total tumor volume), respectively, in this study [4]. The procedure took approximately 2–8 mins/ slice and was well tolerated in all the patients with a median hospital stay of 3 days. One entry site infection at 147 days following LITT was reported with no other significant procedurerelated complications. Adverse events such as dysphasia with upper limb weakness (*n* = 1), homonymous hemianopia with contralateral weakness (*n* = 1), intracerebral hemorrhage due to rupture of pseudo aneurysm (*n* = 1, 6 weeks after LITT and was managed by endovascu‐ lar coil placement), white matter injury with hemiparesis (*n* = 1), deep vein thrombosis (*n* = 3), pulmonary embolism (*n* = 1) and grade 3 neutropenia (*n* = 1) were reported following LITT in this study. Post-LITT edema was noted at 48 h MRI and was managed with steroids. Interestingly, one patient with gliosarcoma developed tumor seeding along the biopsy tract involving the skull and epicranial tissue 9 months after the LITT procedure [4]. The median progression-free survival at 6 months and median overall survival were reported to be ≥ 30 % (compared to 15% reported in the literature) and 316 days, respectively, following LITT in this study. Two deaths were reported during the follow up and the authors concluded LITT to be safe and effective (especially with blue and white TDT ablated zones) in carefully selected patients with recurrent deep-seated GBMs. DTI tractography and angiography might improve the safety profile of LITT, by delineating the critical neural and vascular structures along the tract of laser probe [4]. Mohammadi et al. [97] investigated the efficacy of LITT in 34 patients with high-grade gliomas HGG (GBM, *n* = 24 and anaplastic astrocytoma/oligodendroglioma, *n* = 10) in difficult-to-access (DTA) areas in a multicenter retrospective study. Of these 34 patients, 16 patients (16 procedures) underwent LITT as an upfront therapy and 18 patients (19 procedures) underwent LITT for recurrent disease. Median time from initial diagnosis of HGG was 29 months for LITT therapy in patients with recurrent disease with a median follow up of 7.2 months following LITT. Following LITT, all patients had standard adjunct treat‐ ment and were monitored with serial follow-up MRIs every 3 months. Progression-free survival was the primary end point, whereas overall survival and complications were considered as secondary end points in this study. Frontal lobe was the most common location (*n* = 15), followed by thalamus (*n* = 7), parietal and temporal (*n* = 5 each) and corpus callosum in a single patient. The median tumor volume that was treated using LITT was 10.13 cm3 and 3 cm was the maximum tumor diameter in this study [97]. And, 98% of tumor volume was covered with yellow TDT lines and 91% with blue TDT lines, with median hospital stay of 3 days. Progression-free survival during the median follow up of 7.2 months was 5.1 months and 71% of treated patients had progressive disease. Majority (52%) of tumor progression following LITT was noted at the periphery of tumor, followed by at the center of the ablated zone (22%), outside the treatment field (22%) and in the contralateral hemisphere (4%). One year estimated survival was 68± 9 % and 12 patients (35%) expired due to disease progres‐ sion during the follow up. Based on the volume of tumor covered by yellow and blue TDT

lines, patients were stratified as favorable (<0.05 cm3 tumor volume missed by yellow TDT lines and <1.5 cm3 of tumor volume between yellow and blue TDT lines) and unfavorable groups (≥0.05 cm<sup>3</sup> tumor volume missed by yellow TDT lines and ≥1.5 cm<sup>3</sup> of tumor volume between yellow and blue TDT lines) [97]. The median PFS in favorable group was 9.7 months, whereas it was 4.6 months in unfavorable group. Interestingly, when controlled for tumor volume of >10 cc, the effect of TDT line coverage on PFS did notreach significance in this study. In terms of adverse events, 13 adverse events (37%) were noted in this study. Transient (*n* = 5) and permanent (*n* = 2) worsening of preoperative neurological deficits, superficial infection (*n* = 1), deep vein thrombosis (*n* = 1), ventriculitis (*n* = 1), seizure (*n* = 1), hyponatremia (*n* = 1), hydrocephalus (*n* = 1), intracerebral hematoma (*n* = 3) and mortality due to intracerebral hematoma (*n* = 1) were the complications following LITT noted in this study [97]. This study showed LITT to be an efficacious therapy in patients with primary or recurrent high-grade gliomas in difficult to access areas. However, major limitations of this study were its retro‐ spective nature and small sample size. A recent single center retrospective study reported the utility of LITT in patients with a variety of intracranial pathologies including gliomas (*n* = 34) [98]. Total operative time and ablation time were 2.9±0.6 hrs and 9.3±6.5 mins, respectively. Median ICU and hospital stay was 1.0 day each and average hospital stay was 3.6±5.4 days following LITT in this study. There was an overall increase in size of lesion immediately following LITT, followed by a gradual reduction in size 24 h after the procedure which was similar to that at first follow up [98]. Postoperative complications such as neurological worsening (*n* = 7), hemorrhage (*n* = 2), edema (*n* = 4), infection (*n* = 1), inaccurate catheter placement (*n* = 2) and deaths (*n* = 2) were reported [98]. Mortality occurred in two patients with glioblastoma multiforme (midbrain/pons in one patient) who developed malignant cerebral edema following LITT. One patient underwent hemicraniectomy with no successful out‐ come and died in the same admission. The 30-day readmission rate was 5.6% in this study. Of note, outcome measures such as overall survival, progression-free survival orrecurrence were not reported in this study [98].

tients were followed for 14 days and assessed for any toxicity (defined as decrease of 20 or more points on KPS score). If an independent committee in two out of three patients noted toxicity, the thermal dose was either modified or the trial was halted. If there were no consequences during the follow up of 14 days, another three patients were enrolled for blue and white thermal dose threshold lines subsequently using the same protocol [4]. Mean total

tumor volume), respectively, in this study [4]. The procedure took approximately 2–8 mins/ slice and was well tolerated in all the patients with a median hospital stay of 3 days. One entry site infection at 147 days following LITT was reported with no other significant procedurerelated complications. Adverse events such as dysphasia with upper limb weakness (*n* = 1), homonymous hemianopia with contralateral weakness (*n* = 1), intracerebral hemorrhage due to rupture of pseudo aneurysm (*n* = 1, 6 weeks after LITT and was managed by endovascu‐ lar coil placement), white matter injury with hemiparesis (*n* = 1), deep vein thrombosis (*n* = 3), pulmonary embolism (*n* = 1) and grade 3 neutropenia (*n* = 1) were reported following LITT in this study. Post-LITT edema was noted at 48 h MRI and was managed with steroids. Interestingly, one patient with gliosarcoma developed tumor seeding along the biopsy tract involving the skull and epicranial tissue 9 months after the LITT procedure [4]. The median progression-free survival at 6 months and median overall survival were reported to be ≥ 30 % (compared to 15% reported in the literature) and 316 days, respectively, following LITT in this study. Two deaths were reported during the follow up and the authors concluded LITT to be safe and effective (especially with blue and white TDT ablated zones) in carefully selected patients with recurrent deep-seated GBMs. DTI tractography and angiography might improve the safety profile of LITT, by delineating the critical neural and vascular structures along the tract of laser probe [4]. Mohammadi et al. [97] investigated the efficacy of LITT in 34 patients with high-grade gliomas HGG (GBM, *n* = 24 and anaplastic astrocytoma/oligodendroglioma, *n* = 10) in difficult-to-access (DTA) areas in a multicenter retrospective study. Of these 34 patients, 16 patients (16 procedures) underwent LITT as an upfront therapy and 18 patients (19 procedures) underwent LITT for recurrent disease. Median time from initial diagnosis of HGG was 29 months for LITT therapy in patients with recurrent disease with a median follow up of 7.2 months following LITT. Following LITT, all patients had standard adjunct treat‐ ment and were monitored with serial follow-up MRIs every 3 months. Progression-free survival was the primary end point, whereas overall survival and complications were considered as secondary end points in this study. Frontal lobe was the most common location (*n* = 15), followed by thalamus (*n* = 7), parietal and temporal (*n* = 5 each) and corpus callosum in a single patient. The median tumor volume that was treated using LITT was 10.13 cm3 and 3 cm was the maximum tumor diameter in this study [97]. And, 98% of tumor volume was covered with yellow TDT lines and 91% with blue TDT lines, with median hospital stay of 3 days. Progression-free survival during the median follow up of 7.2 months was 5.1 months and 71% of treated patients had progressive disease. Majority (52%) of tumor progression following LITT was noted at the periphery of tumor, followed by at the center of the ablated zone (22%), outside the treatment field (22%) and in the contralateral hemisphere (4%). One year estimated survival was 68± 9 % and 12 patients (35%) expired due to disease progres‐ sion during the follow up. Based on the volume of tumor covered by yellow and blue TDT

and 5± 3.2 cm3

(78% of total

and treated tumor volume in all treated patients were 6.8 ± 5 cm3

292 Neurooncology - Newer Developments

Although there is no Class 1 evidence supporting the efficacy of LITT in patients with highgrade gliomas, there is also paucity of high-quality data supporting the role of craniotomy and surgical resection in such patients [99]. Given the minimally invasive nature of LITT coupled with advances in neuroimaging stereotactic techniques and thermography, LITT can be a useful treatment modality in patients with poor performance status or medical comorbidi‐ ties and high-grade glioma. The advantages of LITT have led to the exploration of this technique for a variety of intracranial tumors. LITT has been investigated in various prospec‐ tive case-controlled studies and there is a likelihood to have Class 2 evidence data in the next couple of years.
