Minimally Invasive Targeted Therapy for Glioblastoma: Laser Interstitial Thermal Therapy

Introduction

Laser interstitial thermal therapy (LITT) is a minimally invasive treatment modality for brain tumors and other central nervous system (CNS) disorders, first introduced by Bown in 1983, which has been revived over the last 2 decades because of recent technological advancements in laser technology and MRI thermography. At that time, the main limitations of this surgical technique were the inability to monitor or predict the extent of ablation with real-time imaging feedback and the lack of an effective cooling system that could prevent overheating followed by tissue carbonization and optical fiber damage. These pitfalls have now been overcome and LITT is an US Food and Drug Administration–cleared treatment option for ablating CNS tissue such as recurrent glioblastoma, and is emerging as a surgical option for upfront treatment of selected patients with malignant gliomas, brain metastatic disease that failed radiosurgery and some forms of epilepsy. LITT is ideally suited, but not limited, to patients with tumors located in deep-seated, hard-to-access areas who could develop significant postoperative neurologic deficits after traditional surgical resection leading to poor performance status. The basic biological effect of LITT is thermal damage. Laser near-infrared photons are absorbed by the surrounding tissue, causing excitation and release of thermal energy. Ultimately, a cascade of events leads to cell breakdown and coagulative necrosis of the target volume. As clinicians move toward a more individualized approach in cancer care based on the biomolecular profile of different types of tumors, neurosurgeons also offer surgical individualized options for each patient based on their clinical history, performance status, tumor characteristics (size, location), and complication profile of different surgical approaches.

Physical and biological basis for the use of laser therapy in the ablation of glioblastoma

LITT exerts its biological effect by inducing thermal damage of the targeted tumor. Laser electromagnetic photons are emitted by the laser source and absorbed by surrounding tissue, causing excitation and release of thermal energy, which is transformed to heat and distributed to nearby structures via convection and conduction. The degree of direct heat penetration into surrounding tissue is determined by the properties of the tissue and the wavelength and power density delivered by the laser. Previous studies have shown that the main determinants of laser absorption by tissues are the water and hemoglobin content present. In terms of depth, the greatest degree of tissue penetration, which is several millimeters, is observed with laser radiation at wavelengths in the near-infrared part of the spectrum (1000–1100 nm). In addition, the depth of interstitial thermal damage and subsequent necrosis depends on the cooling conditions, power density, and exposure time. It is also known that the results obtained after laser interaction with white and gray matter are different. Although white matter displays the lowest level of laser penetration, gray matter shows a higher level of laser absorption. Eggert and Blazek were able to show that, within the near-infrared spectral range, glioblastomas and meningioma had the highest degree of laser absorption, whereas low-grade gliomas had optical properties similar to gray matter. LITT triggers a cascade of cellular events that include enzyme induction, denaturation of proteins, cellular membrane breakdown, coagulation necrosis, and blood vessel sclerosis. Two phenomena should ideally be avoided when applying LITT: tissue carbonization and vaporization. Rapid increases in temperature can result in tissue carbonization, preventing adequate laser absorption. Overheating can also cause tissue vaporization, which, if sufficiently severe, could lead to increased intracranial pressure with potentially disastrous consequences. A goal of LITT is to achieve coagulation necrosis of the target volume without provoking carbonization or vaporization of the treated area. Coagulation necrosis occurs at temperatures in the range of 50°C to100°C. Carbonization and vaporization are usually seen at temperatures greater than 100°C.

MRI thermography provides real-time thermal data allowing surgeons to monitor the extent of ablation in an effective and safe manner. Its principle relies on the temperature-dependent water proton resonance frequency (PRF). PRF image mapping is based on the fact that protons are displaced more efficiently within the magnetic field in the form of free water molecules (H ₂ O) than in the form of hydrogen bonded water molecules. As thermal energy is delivered during LITT and temperature increases, the number of hydrogen bonds decreases, resulting in an increased number of free H ₂ O molecules and a lower PRF, which can be visualized with MRI thermometry coupled with advanced computer software in real-time fashion.

Three zones of specific histologic changes around the laser probe are observed during LITT. The first zone is the area closest to the tip of the probe and represents the area of greatest tissue damage caused by the highest degree of thermal energy absorption. The second or intermediate zone also undergoes thermal injury. Tissue cells located in the third and most marginal zone, although damaged by thermal energy, are still viable. True coagulation necrosis is observed in the first 2 zones. The NeuroBlate System (Monteris Medical Corporation, Plymouth, MN) displays the 3 zones of thermal damage in the computer software as the thermal-damage-threshold lines (TDT lines), through real-time imaging data acquired by MRI thermography. This distinctive characteristic of the NeuroBlate System gives surgeons the capability of performing an effective and complete ablation of the tumor by including the target volume in the first 2 zones (TDT lines). Optimal laser ablation is achieved when a sharp border of thermal injury is observed at the brain-tumor interface characterizing a selective procedure with preservation of the normal brain tissue surrounding the tumor.