Recent technological advancements in intraoperative imaging are shaping the way for a new era in brain tumor surgery. Magnetic resonance thermometry has provided intraoperative real-time imaging feedback for safe and effective application of laser interstitial thermal therapy (LITT) in neuro-oncology. Thermal ablation has also established itself as a surgical option in epilepsy surgery and is currently used in spine oncology with promising results. This article reviews the principles and rationale as well as the clinical application of LITT for brain tumors. It also discusses the technical nuances of the current commercially available systems.
Key points
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Recent technological advancements in intraoperative imaging are shaping the way for a new era in brain tumor surgery.
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Magnetic resonance thermometry has provided intraoperative real-time imaging feedback for safe and effective application of laser interstitial thermal therapy (LITT) in neuro-oncology.
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Thermal ablation has also established itself as a surgical option in epilepsy surgery and is currently used in spine oncology with promising results.
Introduction
LITT has emerged as a new treatment option for various conditions within the neurosurgery world, not only due to its minimal invasiveness but also because it has been shown safe and effective. In recent years, LITT has become a reality in neuro-oncology and epilepsy surgery and is emerging as an option in spine surgery and chronic pain syndromes.
Although introduced in 1983 by Bown, who demonstrated focal tissue photocoagulation in an experimental brain tumor model using an Nd:YAG laser, the clinical application of LITT was limited due to the inability to monitor and control laser-induced thermal damage to the target volume in a real-time fashion. The groundbreaking technological advancement, which allowed the widespread application of LITT in neurosurgery, was the development of MRI thermometry. MRI thermometry allows real-time image feedback of laser thermal energy delivery, making it possible to predict the thermal damage of a planned target in the brain. This article describes the application of LITT with a focus in neuro-oncology.
Introduction
LITT has emerged as a new treatment option for various conditions within the neurosurgery world, not only due to its minimal invasiveness but also because it has been shown safe and effective. In recent years, LITT has become a reality in neuro-oncology and epilepsy surgery and is emerging as an option in spine surgery and chronic pain syndromes.
Although introduced in 1983 by Bown, who demonstrated focal tissue photocoagulation in an experimental brain tumor model using an Nd:YAG laser, the clinical application of LITT was limited due to the inability to monitor and control laser-induced thermal damage to the target volume in a real-time fashion. The groundbreaking technological advancement, which allowed the widespread application of LITT in neurosurgery, was the development of MRI thermometry. MRI thermometry allows real-time image feedback of laser thermal energy delivery, making it possible to predict the thermal damage of a planned target in the brain. This article describes the application of LITT with a focus in neuro-oncology.
Principles and rationale of laser interstitial thermal therapy
LITT exerts its biological effect through thermal damage. Laser light photons are absorbed by neighboring tissue, which causes excitation and release of thermal energy that spreads to nearby structures by means of 2 phenomena, convection and conduction. Two factors are determinant of the degree of heat penetration into surrounding tissue: the physical properties of the tissue itself and the characteristics of the laser energy itself. In relation to the properties of the tissue, literature has shown that the amount of hemoglobin and water present in tissues are the main factors responsible for laser absorption. Regarding the energy used to produce the laser beam, the greatest degree of tissue penetration, in the range of 10 mm, is achieved with laser radiation with wavelengths in the near-infrared part of the spectrum.
LITT produces a sequence of biochemical events at the cellular level characterized by enzyme induction, denaturation of proteins, and breakdown of cellular membranes culminating with coagulation necrosis and blood vessel sclerosis. The end result of surgically applied laser technology can be photocoagulation, photovaporization, or photosensitization. LITT promotes photocoagulation, by providing a source of constant and continuous laser delivery to the target volume. Importantly, rapid increases in temperature should be avoided because they can result in tissue carbonization, which prevents adequate laser absorption. In addition, overheating can cause tissue vaporization, which could lead to increased intracranial pressure. When performing LITT, the aim is to precisely promote coagulation necrosis of the specific target without causing carbonization or vaporization of the treated area. Three zones of histologic changes around the laser probe have been described. The first zone is the area closest to the tip of the probe and represents the area of greatest tissue damage due to the highest degree of energy absorption. Coagulation necrosis occurs at temperatures in the range of 50°C to 100°C. Carbonization and vaporization are usually seen at temperatures above 100°C. The volume of tissue in the second or intermediate zone also undergoes thermal injury. Cells located at 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 3 zones of thermal damage may be displayed by the computer software as the thermal-damage-threshold (TDT) lines, through data acquired by MRI thermometry. This feature allows surgeons to customize the ablation based on the target volume, which ideally should be included in the first 2 zones.
As discussed previously, LITT is also affected by the optical properties of the targeted tissue. Studies focusing the optical properties of native and coagulated human brain tissue revealed that the deepest area of thermal coagulation and highest laser penetration were found in the wavelength range between 1000 nm and 1100 nm, which is in the near-infrared part of the electromagnetic spectrum. Furthermore, the depth of interstitial thermal damage and subsequent necrosis depends on the cooling conditions of the system, power density, and exposure time. Within the near-infrared part of the spectrum, the laser interaction with white matter and gray matter is different. Although gray matter shows a high level of laser absorption, white matter displays the lowest. The degree of laser penetration also varies depending on the tumor type. Research shows that tumors like glioblastomas (GBMs) and meningiomas exhibited the highest degree of laser absorption, whereas low-grade glioma displayed optical properties similar to gray matter. 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. Also, the extent of volume and surface area overlap between TDT lines and corticospinal tracts has been shown to correlate with postoperative motor deficits and needs to be considered during LITT procedure.
The game changer allowing the use of LITT for brain tumors was the capability to visualize real-time temperature changes in deep regions of the body, which was granted by MRI thermometry. Its principle relies on the temperature-dependent water proton resonance frequency (PRF). PRF image mapping is based on the premise that protons are displaced more efficiently within the magnetic field in the form of free water molecule (H 2 O) than in the form of hydrogen-bonded water molecules. Thus, as thermal energy is delivered during LITT and temperature increases, the number of hydrogen bonds decrease, resulting in an increased number of free H 2 O molecules and a lower PRF, which is then visualized with MRI thermometry coupled with advanced computer software in real-time fashion.
Technical nuances and commercially available systems
Lasers and Probes Used for Laser Interstitial Thermal Therapy
The 2 main types of lasers used for LITT are the continuous-wave Nd:YAG and diode lasers. Wavelengths in commercial systems range from 980 nm to 1064 nm and operate at a wide range of powers. Longer wavelength achieve higher tissue penetration especially in soft tissues with high blood whereas lower wavelengths are capable of producing lesions faster but typically with less penetration.
Laser Interstitial Thermal Therapy Probes
Laser thermal ablation probes consist of an optical fiber typically of a 600-μm diameter, of which the terminal approximately 1 cm is exposed, made of a heat-resistant material, such as quartz or sapphire. A cooling mechanism is required to avoid overheating, tissue carbonization, and optical fiber damage. The cooling mechanism uses a sheath that cools the optical fiber with a constant stream of fluid (water or saline) or cooled gas (liquid CO 2 ). The combination of the cooling mechanism and enclosing the optical fiber in a diffusion sheath further minimizes probe adherence to treated tissues and decreases the incidence of probe failure. The pattern of thermal energy deposition at the probe tip typically resembles a uniform ellipsoid along the axis of the probe. Advances in probe design, however, also led to the development of side-firing laser probes, which allow for further control of the energy deposition, which enables the treatment of lesions with complex shapes.
Magnetic resonance thermography and image acquisition
Various modalities, such as skin thermometers, infrared detectors, subcutaneous and interstitial probes, and thermographic cameras, have been used to measure the amount of heat energy deposited into the tissues during LITT with varied success. It was the introduction of magnetic resonance thermography, however, that led to a paradigm shift in the clinical utility of LITT. The ease of monitoring the extent of thermal deposition combined with minimally invasive nature of LITT made it a reasonable alternative in patients with deep-seated brain tumors. Magnetic resonance thermography is based on the PRF, which is temperature dependent and provides a visual information of the thermal deposition after LITT in 3-D space. With an increase in the temperature during laser therapy, there is an increase in the number of free water molecules secondary to disruption of hydrogen bonds. These free protons (hydrogen nuclei) align themselves in the presence of gradient field, thus producing real-time imaging, which can be analyzed by the software.
Preoperative images are typically acquired using 3T MRI (Siemens AG, Erlangen, Germany). The standard protocol for volumetric axial T1 Magnetization Prepared Rapid Acquisition Gradient Echo (MPRAGE) includes flip angle of 25°, repetition time/echo time 11/4.68, voxel size 1 mm 3 × 1 mm 3 × 1 mm 3 , imaging matrix 256 mm 3 × 256 mm 3 , and field of view of 256 mm 2 × 256 mm 2 . Extent of thermal ablation was defined by the M° vision software (Monteris Medical, Plymouth, Minnesota) as TDT lines. A yellow line surrounds the target volume that has received the thermal energy equivalent of 43°C for at least 2 minutes, a blue line surrounds the target volume that has been exposed to 43°C for at least 10 minutes, and a white line corresponds to tissue exposed to 43°C for 60 minutes. The tissues outside the yellow TDT line are considered to have no permanent damage; the tissue inside the blue line is considered to have severe damage; and the tissue within the white line has undergone coagulation necrosis.
Commercially available laser interstitial thermal therapy systems used in neurosurgery
Two of the most common commercially available LITT systems that have been used in neurosurgery include the NeuroBlate System (Monteris Medical, Plymouth, Minnesota) and the Visualase thermal therapy system (Medtronic, Minneapolis, Minnesota).
The Visualase thermal therapy system is an integrated, MRI-guided, minimally invasive laser ablation system. It consists of a 15-W 980-nm diode laser generator that supplies energy to a disposable 1.65-mm diameter outer cooling catheter, which contains a 1-cm long fiberoptic applicator with a light diffusing tip. Circulating sterile saline provides cooling to the probe tip and surrounding tissues. The probe delivers heat in an ellipsoid-cylindrical distribution. The system is connected to a computer workstation, which is subsequently connected to an MRI, which allows the display of real-time thermographic data at the treatment site. Thermal information produces color-coded thermal and damage images based on an Arrhenius rate process model. Limit temperatures can be designated as safety points on the pretreatment MRI and, if during treatment, an increase in temperature beyond the designated limit is detected at those points, the laser is automatically deactivated.
The NeuroBlate system uses a CO 2 gas-cooled directional laser probe. It uses a diode laser at 1064 nm, with a laser output of 12 W and both side-firing and diffuse-tip probes are available. The NeuroBlate directional laser is aimed for contoured ablation of targets whereas the diffusing laser probe is designed to provide fast volumetric ablation in a concentric fashion. The probes are available at diameters of 3.3 mm and 2.2 mm and are inserted using stereotactic guidance using one of several patient probe interfaces. The Mini-Bolt (Monteris) provides rigid skull fixation and allows a direct interface to the NeuroBlate laser probe. The AXiiiS device (Monteris) serves as a miniature stereotactic guidance frame and aligns to the target and provides the appropriate trajectory for probe insertion. The system is connected to a computer workstation that connects to the MRI, which provides real-time thermographic data. The NeuroBlate software displays the extent of heat deposition as TDT lines.
Clinical applications for laser interstitial thermal therapy
The clinical indications for LITT continue to expand as the technology advances and understanding of its potential grows. The potential applications range from treatment of neoplastic disease and management of radiation necrosis to its use in epilepsy and spine surgery. The indications and applications for LITT as well as future directions are reviewed.
Neoplastic Disease
The use of LITT in the treatment of neoplastic disease is perhaps most widely accepted for tumors that are otherwise not candidates for surgical resection. These include tumors in deep or eloquent regions as well as recurrent lesions not amenable for further surgery. In this article, the most common neoplasms treated by LITT are discussed, including high-grade gliomas, metastases, and radiation necrosis in the post-treatment setting.
High-Grade Gliomas
GBM continues to be a challenging and often devastating disease owing in part to its resistance to traditional therapies, localization to eloquent cortices, and high rate of infiltration into surrounding tissue. These factors result in a dismal 5-year survival rate of less than 17%. In patients with recurrent GBM, the outcome is even bleaker, with a median survival of 3 months to 5 months. Although surgical re-resection has been shown to offer some improvement in these cases, it is often not possible due to tumor and patient characteristics. Chang and colleagues performed a study involving a prospective database and noted an increase in the rate of perioperative complications after a second craniotomy compared with the first. These results have been confirmed in more recent studies demonstrating that the modest improvement in postoperative survival declines with recurrent surgeries, with a marked corresponding increase in overall complication rate from 12.8% after the first surgery to 27% after the second surgery. The increased risk associated with re-resection along with lack of survival improvement with chemotherapy and radiotherapy in cases of recurrence, creates an urgent need for alternatives to surgery. It is in this setting that LITT therapy becomes a particularly appealing alternative.
Although initial studies of LITT for GBM demonstrated adverse overheating at the entry site, the advent of cooled tips has largely overcome these issues resulting in the ability to use higher-power lasers without the adverse overheating and carbonization. LITT has also been increasingly used for the treatment of irregular and heterogeneous high-grade gliomas due to the increase in conformal ability with the use of multiple fibers and trajectories. These advances in LITT technology have expanded the treatment possibilities for intracranial lesions generally, and high-grade gliomas in particular.
The efficacy of LITT therapy in patients with recurrent high-grade glioma has been studied by several investigators. Studies have reported an estimated median survival ranging from 10 months to 20.9 months when LITT is used in conjunction with standard therapy. Although these studies demonstrated a modest improvement in survival, the investigators also reported high rates of tumor recurrence in this patient population, making the decision to use LITT as a secondary therapy dependent on therapeutic goals and patient status.
Sloan and colleagues reported the first-in-human phase I clinical trial using the NeuroBlate system for recurrent GBM. This prospective, multicenter study focused on evaluating the safety of this technology in a dose-escalation trial using 3 thermal dose levels for patients with recurrent GBM who were not candidates for resection. The investigators reported preliminary results from 10 patients resulting in a median survival of 316 days and a 6-month progression-free survival of greater than 30%, nearly doubling prior outcomes with recurrent GBM. Low-dose therapy did not seem to result in clinical improvement, which was seen only at the intermediate and high doses, and dose did not seem to correlate with rate of adverse events. The adverse effects reported included transient deficits in 2 patients, postoperative edema managed with steroids, and 2 cases of intracerebral hemorrhage resulting in neurologic worsening. Although the potential complications are not insignificant, the patients treated had developed recurrence despite multiple prior therapies, making it a particularly high-risk patient population with few options. Overall, this treatment seems a viable alternative for a patient population with few other therapeutic options. The safety profile may be improved by continued improvement in the analysis of traversing neurovascular structures, including the use of pretreatment fiber tracking and vascular studies to avoid neurologic deficit and hemorrhage, respectively.
Also, Leuthardt and colleagues have shown that hyperthermia induces disruption of peritumoral blood-brain barrier beginning 1 week to 2 weeks after ablation for up to 4 weeks to 6 weeks, thus providing an opportunity to deliver otherwise blood-brain barrier impermeable chemotherapeutic agents. This finding opens up the horizon of yet another exciting application of LITT in future studies. Fig. 1 shows LITT application for high-grade glioma.
