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

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

plications 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

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

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

to 68.9 cm<sup>3</sup>

. Postoperatively, serious com-

of pre-treatment tumor volumes was from 0.37 cm<sup>3</sup>

194 Glioma - Contemporary Diagnostic and Therapeutic Approaches

is similar to open craniotomy procedures [56, 57].

**3.2. Laser ablation near eloquent areas**

critical subcortical fiber tracts.

**3.3. Advantages of LITT**

tolerate a large craniotomy.

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 tumor in the immediate post-procedure period.

### **3.5. Sensitization to radiation**

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 thermotherapy affects tumor cells that results in enhanced sensitivity to radiation [8]. Glioma stem cell (GSC) cultures and mice bearing glioma xenographs were first exposed to 42°C for 1 h followed by radiation. When compared to radiation or hyperthermia alone, glioma stem cells are most significantly affected when both modalities are used in combination. Exposure of GSC to heat and radiation reduced stem cell survival, proliferation, and DNA repair, as well as promoted cell death. On the molecular level, there was significantly less AKT phosphorylation in cells exposed to hyperthermia and radiation, and rescuing AKT phosphorylation levels reversed negative effects of heat and radiation maintaining viability of tumor stem cells. Furthermore, exposing the mice bearing glioma xenographs to hyperthermia and radiation consistently reduced tumor size in these animals, and significantly increased their survival compared to animals exposed to either hyperthermia or radiation alone. These results add further evidence that the addition of hyperthermia to the standard radiation treatment may have a significant additive effect with respect to tumor control that is mediated by altering phosphorylation levels of PI3K-AKT pathway. Thus, early radiation therapy after laser ablation procedure may have additive effect on controlling tumor growth and affecting glioma cell viability. Further studies are needed to explore the clinical potential of this combined treatment.

> **Figure 1.** Representative axial T1-weighted MRI images obtained post gadolinium contrast administration. (A) Preoperative; (B) at 24 h post laser ablation; (C) at 3 months; (D) at 1 year; and (E) at 6 years post laser ablation; (F) a

Laser Interstitial Thermal Therapy in Glioblastoma http://dx.doi.org/10.5772/intechopen.77078 197

**Figure 2.** Representative MRI images of the right temporal lesion of patient 2. Axial T1-weighted MR images following contrast administration. The patient originally presented with a right mesial homogenously enhancing lesion (A). Immediately following laser ablation the characteristics of the lesion changed with markedly less contrast uptake (B). In the subsequent months, the lesion has continued to involute and significantly decreased in size at 3 months (C), and

almost disappeared completely at 2.5 years (D).

corresponding T2 weighted axial slice demonstrating very limited amount of edema surrounding the lesion.
