**3.1. Laser in glioma treatment**

Since the first implementation of laser therapy for intracranial tissue ablation, treatment of a variety of intracranial lesions was attempted, including metastases, radiation necrosis, meningiomas, ependymomas, as well as gliomas. High grade gliomas constitute 14.9% of primary tumors brain tumors and 47.1% of all malignant primary brain and other CNS tumors. Despite maximal therapy, survival remains poor. Survival without any treatment is 9 weeks [43]. With maximal treatment according to the latest guidelines, the survival is prolonged to 14.6 months [1]. The combined use of radiation and temozolomide protocols increase survival rates to 27% at 2 years [1]. Recently, several retrospective studies have demonstrated that increasing the extent of resection of glioblastoma, improves patient survival [2–5]. Furthermore, intraoperative use of surgical adjuncts such as intraoperative MRI or 5-ALA that allow visualization of the partially resected tumor and thus allow for a better extent of resection correlate with prolonged progression free survival [44, 45].

Many newly diagnosed glioblastomas involve deep or eloquent cortical or subcortical areas thus rendering these lesions difficult to resect or unresectable from an open surgery perspective. In these situations, the use of destructive, minimally invasive techniques such as LITT is very attractive as a means to cytoreduce the tumor. At other times patients may be too sick to undergo a lengthy open craniotomy for tumor resection. Finally, treatment of recurrent glioblastoma is challenging as very few effective options exist at present, thus the possibility of using laser ablation for treatment of recurrent tumor ads another tool to the neurosurgeon's armamentarium.

In 2013, the first human phase I study was published that used escalating dose of laser therapy to assess safety of the procedure and its efficacy in controlling tumor growth in patients with recurrent high-grade gliomas [41]. The study recruited 11 patients from two institutions and was completed using the NeuroBlate System. Three thermal damage threshold lines were assessed: yellow line (equivalent to heating of tissues to 43°C for 2 min), blue (43°C for 10 min), and white (43°C for 60 min). Ultimately, ten patients underwent LITT treatments and were followed for a minimum of 6 months or until death. Initially three patients were treated to the yellow TDT line and followed for 14 days to assess for signs of toxicity. If two out of three patients developed signs of toxicity, no further dose escalation was performed. If no toxicity was observed, the dose of treatment was escalated to first the blue line, and then the white line. The mean size of treated tumors was 6.8 cm3 , and an average of 78% of total tumor volume was covered. Median overall survival was 10.5 months after LITT which was increased compared to historic controls of 3–9 months [46, 47]. The median PFS at 6 months and median overall survival in the study was >30%. One patient had a new permanent postoperative neurological deficit, and one patient had a vascular injury resulting in a pseudoaneurysm. Both patients were in the white TDT line subgroup. This study demonstrated that LITT is a feasible and safe treatment modality for recurrent high-grade gliomas, and that the blue line should be used as the margin of treated area.

coagulated blood products within the ablated area. On the corresponding CT scans this would appear as a hyperdense area typical in appearance of blood products. With administration of contrast, there is typically an area of peripheral rim enhancement. This is thought to represent an area of sublethal tissue damage with disrupted blood-brain barrier and leaky capillaries [7].

Since the first implementation of laser therapy for intracranial tissue ablation, treatment of a variety of intracranial lesions was attempted, including metastases, radiation necrosis, meningiomas, ependymomas, as well as gliomas. High grade gliomas constitute 14.9% of primary tumors brain tumors and 47.1% of all malignant primary brain and other CNS tumors. Despite maximal therapy, survival remains poor. Survival without any treatment is 9 weeks [43]. With maximal treatment according to the latest guidelines, the survival is prolonged to 14.6 months [1]. The combined use of radiation and temozolomide protocols increase survival rates to 27% at 2 years [1]. Recently, several retrospective studies have demonstrated that increasing the extent of resection of glioblastoma, improves patient survival [2–5]. Furthermore, intraoperative use of surgical adjuncts such as intraoperative MRI or 5-ALA that allow visualization of the partially resected tumor and thus allow for a better extent of resection correlate with

Many newly diagnosed glioblastomas involve deep or eloquent cortical or subcortical areas thus rendering these lesions difficult to resect or unresectable from an open surgery perspective. In these situations, the use of destructive, minimally invasive techniques such as LITT is very attractive as a means to cytoreduce the tumor. At other times patients may be too sick to undergo a lengthy open craniotomy for tumor resection. Finally, treatment of recurrent glioblastoma is challenging as very few effective options exist at present, thus the possibility of using laser ablation for treatment of recurrent tumor ads another tool to the neurosurgeon's armamentarium.

In 2013, the first human phase I study was published that used escalating dose of laser therapy to assess safety of the procedure and its efficacy in controlling tumor growth in patients with recurrent high-grade gliomas [41]. The study recruited 11 patients from two institutions and was completed using the NeuroBlate System. Three thermal damage threshold lines were assessed: yellow line (equivalent to heating of tissues to 43°C for 2 min), blue (43°C for 10 min), and white (43°C for 60 min). Ultimately, ten patients underwent LITT treatments and were followed for a minimum of 6 months or until death. Initially three patients were treated to the yellow TDT line and followed for 14 days to assess for signs of toxicity. If two out of three patients developed signs of toxicity, no further dose escalation was performed. If no toxicity was observed, the dose of treatment was escalated to first the blue line, and then

tumor volume was covered. Median overall survival was 10.5 months after LITT which was increased compared to historic controls of 3–9 months [46, 47]. The median PFS at 6 months

, and an average of 78% of total

**3. Application of laser therapy for treatment of intracranial disease**

**3.1. Laser in glioma treatment**

192 Glioma - Contemporary Diagnostic and Therapeutic Approaches

prolonged progression free survival [44, 45].

the white line. The mean size of treated tumors was 6.8 cm3

The first multicenter study to investigate whether cytoreduction achieved with the use of laser for difficult to access high-grade gliomas could have a similar survival benefit compared to surgery was a retrospective study that looked at outcomes in 34 patients with high grade gliomas that were treated with LITT, 19 of them treated upfront, and 16 patients as salvage therapy [48]. The median overall survival was not reached in the study. One year estimated overall survival was 68%, and median progression free survival was 5.1 months. They also demonstrated that increased coverage by the thermal damage threshold lines correlated with better progression free survival of 9.7 vs. 4.6 months. The latter also relates to tumor volume with smaller tumors being easier to achieve complete coverage with TDT lines. When looking at failure patterns, 5 tumors recurred within the treatment field, 12 patients recurred at the periphery of the treated volume, 5 tumors recurred within 2 cm of the original area of enhancement, and one case had a remote recurrence. Overall, the authors concluded that LITT is an effective treatment modality for newly diagnosed and recurrent high-grade gliomas with improved outcomes correlating with extent of tumor coverage by analogy with extent of resection in surgical series.

Recently, a meta-analysis of the efficacy of LITT treatment of newly diagnosed and recurrent high-grade gliomas was published [49]. Ivan et al. extracted information and analyzed the data pertaining to treatment and outcomes of newly diagnosed high-grade gliomas treated with LITT. They identified four articles that reported treatment of 25 patients with newly identified gliomas. Tumor volume was available for 22 patients and the mean was 16.5 cm3 , whereas the extent of volume treated with laser was available for 9 patients with an average of 82.9% tumor coverage. Complications data was available for 13 patients, and there were no intraoperative mortality or complications. Serious postoperative complications occurred in two patients, one succumbing to postoperative central nervous system infection, and another one requiring hemicraniectomy for malignant post treatment cerebral edema. No permanent new postoperative neurological complications were noticed among these patients. Outcome analysis revealed a mean follow up of 7.6 months, with 12 patients still followed or lost to follow-up. Median overall survival was 14.2 months and the average PFS was 5.1 months. These results are similar to results reported in the literature that vary from 8.5 to 14.5 months [50, 51]. Thus, this systematic review demonstrates that LITT is a safe and effective procedure for newly diagnosed high-grade gliomas achieving outcomes similar to cases with open surgical resection.

Even with the full complement of modern treatments, the survival of glioblastoma patients remains poor in the range of 14–16 months after surgery, chemotherapy and radiation. Recurrence is the rule rather than the exception, at which point the prognosis is quite poor with the 6-month progression free survival rates of 5–15% [52, 53]. Reoperation in the recurrent setting was shown to be of benefit [54]. The risk of complications needs to be weighed against potential survival benefit, which is where the role for the use of LITT in recurrent high-grade gliomas could be exploited the most. A recent systematic review summarized the outcomes of laser-mediated cytoreduction in high-grade gliomas [55]. Six articles were identified that included outcome analysis for treatment of 64 lesions in 63 patients. The range of pre-treatment tumor volumes was from 0.37 cm<sup>3</sup> to 68.9 cm<sup>3</sup> . Postoperatively, serious complications included a permanent neurological deficit in 7 patients (12%), vascular injuries in 3 patients (3%), and wound infection in 1 patient (2%). The authors did not comment on outcome measures due to differences in outcome metrics used in the studies. Thus, they concluded that currently there is insufficient evidence to recommend LITT for treatment of recurrent high-grade gliomas. It is a technique that allows safe and accurate ablation of tumor tissue, though the complication rate associated with this procedure remains around 15% that is similar to open craniotomy procedures [56, 57].

Furthermore, LITT is a thermal ablating technique, which means that at the time of tumor recurrence the procedure can be repeated. That is not always the case with ionizing radiation, for example, since there is cumulative accumulation of radiation dose that limits the number of treatments that can be safely offered. The procedure also offers the advantage of obtaining a tissue specimen, when combined with needle biopsy, for updated pathology and biomarkers to follow tumor evolution and response to therapy. Finally, the minimally invasive nature of the procedure allows continued use of adjuvant treatments around the time of the surgery, or very shortly thereafter, obviating the need of waiting at least 2–3 weeks for the tissues to heal before restarting chemotherapy of radiation. In fact, there is evidence that LITT may open up the blood-brain barrier in the vicinity of treatment area, thus enhancing delivery of

Laser Interstitial Thermal Therapy in Glioblastoma http://dx.doi.org/10.5772/intechopen.77078 195

The blood-brain barrier (BBB) is one of the main challenges for chemotherapy delivery to brain tumors. Various methods have been attempted to bypass or disrupt the blood-brain barrier, including convection-enhanced delivery of implanted catheters into the tumor, intraarterial mannitol injections, or focused ultrasound to temporally disrupt the blood-brain barrier. Recently, laser interstitial thermal therapy was implicated in disrupting the integrity of tumor endothelial cells post-treatment. The core of the lesion that is produced after laser ablation is coagulum that consists of a permanently damaged tissue, whereas at the periphery where the temperature reaches 40°C and is insufficient to result in cell death, however it does lead to physiological temporary disruption in cellular function resulting in transient disruption of the BBB. Imaging of the lesion after laser ablation therapy displays an area of peripheral contrast enhancement that was speculated to represent disruption of the blood-brain barrier. This was demonstrated in a rodent model where there was extravasation of Evans blue dye that was injected intravenously at the periphery of the lesion post ablation [59].

Recently, advanced MRI imaging was used to demonstrate the presence of blood-brain barrier disruption [7]. Dynamic contrast-enhanced MRI was used in 14 patients to determine transfer coefficients (Ktrans) as a measure of permeability at the periphery of the lesion produced by laser ablation. In all patients, Ktrans coefficient peaked after the procedure, and then declined gradually over the next 4 weeks. The authors also used brain specific enolase (BSE) serum levels as a marker of BBB breakdown, and those levels peaked at about 3 weeks, followed by gradual decline and normalization at 6 weeks. This data suggests that there is some breakdown of the blood-brain barrier in the first few weeks following laser ablation of primary brain tumors, and that this may facilitate chemotherapy delivery to residual infiltrated

Radiation is one of the non-surgical modalities that has significant impact on survival in glioblastoma patients, yet the control rates remain poor despite maximal therapy. Several studies have demonstrated the synergistic effect of hyperthermia in sensitizing tumor tissues to radiation and improved tumor control [60–62]. A recent study investigated the mechanism by which

chemotherapeutics in that time range [7].

tumor in the immediate post-procedure period.

**3.5. Sensitization to radiation**

**3.4. LITT and blood-brain barrier**

### **3.2. Laser ablation near eloquent areas**

The most common complication reported after laser ablation is a temporary or permanent neurological deficit, such as hemiparesis or aphasia. The reported complication rates range from 0 to 29.4% for transient and 0–10% for permanent postoperative neurological deficits. In many instances it is the damage to subcortical tracts that results in a new deficit. Recently, diffusion weighted imaging (DTI) with fiber-tracking algorithms started to be increasingly used in tumor resection surgery to avoid injury to eloquent white matter tracts. A recent study investigated the role of integration of DTI fiber tracts in laser thermal therapy. Using the NeuroBlate System, Sharma et al. looked that the extent of the overlap of the thermal damage threshold lines with the cortical fibers that would result in a postoperative motor deficit [58]. Retrospective analysis of 80 patients who underwent LITT for tumor near a critical area was performed. Fourteen patients (17.5%) had developed a new postoperative deficit that was temporary in 3 patients and permanent in 11. When looking at the average volume or surface overlap between treated area and the corticospinal fibers, there was a significant difference between the group that developed a postoperative deficit and the group that did not. Therefore, even a minimal overlap between the treated area enclosed within thermal damage treatment lines and the descending motor fibers can cause a postoperative neurological deficit after laser ablation. Addition of DTI tractography to treatment plans of lesions located in proximity to eloquent areas can help avoid fiber damage and thus preserve neurological functioning of the patient and is routinely used in our ablations near critical subcortical fiber tracts.

### **3.3. Advantages of LITT**

There are a number of characteristics of LITT that lead to its recent popularity and investigation for multiple applications in neurosurgery. The main one is the ability to produce a lesion in a location that is difficult to access with open surgery. It is a minimally invasive technique that requires a very small incision and subsequently a very short period of healing. Given the minimally invasive nature of the procedure, the operation can be done under local anesthesia in a cooperative patient. This allows treatment of lesions in patients that cannot otherwise tolerate a large craniotomy.

Furthermore, LITT is a thermal ablating technique, which means that at the time of tumor recurrence the procedure can be repeated. That is not always the case with ionizing radiation, for example, since there is cumulative accumulation of radiation dose that limits the number of treatments that can be safely offered. The procedure also offers the advantage of obtaining a tissue specimen, when combined with needle biopsy, for updated pathology and biomarkers to follow tumor evolution and response to therapy. Finally, the minimally invasive nature of the procedure allows continued use of adjuvant treatments around the time of the surgery, or very shortly thereafter, obviating the need of waiting at least 2–3 weeks for the tissues to heal before restarting chemotherapy of radiation. In fact, there is evidence that LITT may open up the blood-brain barrier in the vicinity of treatment area, thus enhancing delivery of chemotherapeutics in that time range [7].
