Hello, my name is Dr. Andrew Sloan from University Hospitals of Cleveland in the Seidman Cancer Center. Today, I'm going to talk to you about laser interstitial thermotherapy for gliomas. Here are my disclosures. I'm going to begin by giving a little bit of background on gliomas and the history of LIT. Then I'm going to talk about some of the initial studies and the clinical results. Finally, I'm going to talk about new directions and sum up with conclusions about LIT and the indications. By way of background, I think we all know that prognosis of LIT, I'm sorry, prognosis of gliomas remains dismal. LIT is a minimally invasive technique which has been used for tumor ablation for decades. However, several technical challenges have limited widespread adoption. Chief among these are the inability to precisely and non-invasively monitor and control the dose of thermal energy delivered. Laser interstitial thermotherapy, which is also sometimes called stereotactic laser ablation or SLA, has a number of advantages compared to conventional surgery. It's minimally invasive. It gives the surgeon the ability to reach difficult to access tumors. It's feasible to use in patients with relative contraindications for surgery and has a potential to combine with other types of therapies, which we'll talk about later. Now, heat can damage all cells, but it's critical in LIT that we try to keep the temperature between 43 and 55 degrees centigrade. At this temperature, we induce apoptosis, necrosis, and melt lipid bilayers, which can damage tumor. However, we try to keep the temperature 57 degrees or below. At 57 degrees or higher, one can induce coagulation, vaporization, and carbonization. This can create intracranial gas or inflammatory response, which can then lead to increased intracranial pressure in the fixed space of the skull, which is obviously undesirable. Heat is measured and tracked using the Arrhenius thermodynamic theory. In general, we think of heat in terms of the equivalence of 43 degrees by X number of minutes, and we'll discuss this a bit later. The use of heat to treat tumors has a very long history. Radiofrequency has been used for liver, kidney, uterine, and prostate for years. Radioactive energy has been used for brain, prostate, and liver disease. Ultrasound has been used for brain, uterus, tissues. Cryotherapy has been used for treatment of breast and prostate cancer. And LIT, as we currently understand it, has a long and successful history for liver metastasis, as well as thyroid cancer and lung cancer, as well as others. Leonardo and Schwarzmeier did pioneering work in GBM in the early parts of the century, but they found it worked in some cases, but not so well in others. In general, it was very hard to predict outcome. There are three recent advances that are really responsible for the increased application of LIT in our current day. First among these are cooled probes. This allows one to deliver heat, I'm sorry, to control the heat to only the desired region and not heat the entire brain. The second is non-invasive real-time thermography. As you can see, this is stable at a number of different temperatures with minimal shift. The third is the prediction of thermal damage thresholds. This is critically important because as the surgeon moves the laser probe back and forth and left and right in a larger tumor, the tissues that have been previously heated cool. And the thermography shows the current temperature and not the previous temperature. However, the surgeon needs to have some way to monitor the damage that has been induced in a cumulative fashion to avoid going back and re-treating areas that have already been treated, which could be dangerous. Thermal damage threshold allows the software to track the tissue damage that's already been induced, which enables the surgeon to see where the areas have been treated and what areas have not been treated and to fine tune the treatment accordingly. This is a cartoon. There are two commercially available platforms used for LIT. The first is the visualized platform manufactured by Medtronic. This uses a 980 nanometer diode laser probe on a fiber optic catheter. It's surrounded by coaxial cooling catheter, which circulates cold saline. This creates an elliptoid diffusion pattern. The software allows the surgeon to identify targets and set temperature limits so that the laser automatically shuts off when the temperatures reach this limit in a particular area. The Monteros platform uses a neodymium YAG laser that emits energy at 1064 nanometers at 12 watts. It is CO2 cooled and has two types of probes, a side-fired probe, which is used for sculpting, and a diffusion-tipped probe, which is faster and used to treat larger volumes in a symmetrical fashion. There's also a robotic probe driver that can be driven from the console so that the surgeon does not have to go to the MRI to adjust the position. Finally, software and hardware displays TDTs, or thermodamage thresholds, which is how the surgeon tracks the damage that's been done. Both catheters have to be inserted through the skull. Because the Monteros uses a robotic platform, it has to fix onto this small titanium bolt, which is screwed in through an incision into the skull. The Monteros platform has a servo driver that you can see here that is controlled by the surgeon remotely so the surgeon does not have to go into the MRI. This allows the bolt to move in and out, or left and right in the case of the directional probe. The visualized probe is manually inserted and pulled in and out by the surgeon in the OR, and because it is a symmetrical diffusion-tipped probe, there's no directionality or tilting. The first studies of LIT4-GBM using thermometry were done using the visualized platform by Carpentier and published in 2012. He treated four patients, two with corpus callosum lesions, one with a frontal lesion, and one with a temporal lesion. All these volumes were between 0.4 and 8.9 centimeters, and he had two complications. We published the first-in-man studies of the Monteros platform right before it was FDA-approved in 2013. This used a multi-center prospective phase one design with a K-in-a-row modified dose escalation design. The idea here is we started with a low dose, illustrated in yellow, which is the thermal dose equivalent of 43 degrees at two minutes, and we treated only recurrent GBM. The importance of the yellow line is that everything outside the yellow line essentially gets complete recovery. At the highest dose, at which we treated five patients, and which is equivalent to roughly 60 minutes at 43 degrees, everything inside the white line is completely destroyed and necrotic. The blue line is essentially integral and in between the white and the yellow line and represents roughly 10 minutes at 43 degrees. Since we weren't sure what dose would be most appropriate, we treated three patients at the yellow line, two at the blue, and five at the white line. Here are the characteristics of the patients that were treated. There were mild complications between day one and day 14 at the two lower doses. However, in the five patients at the higher doses, there was two patients who had some permanent damage at day 84. One of this was a patient with a pseudoaneurysm, and in retrospect, we feel that the laser was actually resting on a vessel and had weakened the wall. The median survival in this trial was 338 days, roughly 11.2 months, which was higher than the 90 to 150 day survival that we expected in the setting of recurrent GBM. The median free survival was about 30% at six months, again, higher than the expected survival, about 15% in the historical literature. In terms of the volume of tumor treated, we felt that we treated on average of about 78% of the tumor, plus or minus 12%. This is significantly lower than we typically treat in terms of volume treated with radiosurgery or brachytherapy. However, it's equivalent to previous described goals for treatment of newly diagnosed GBM published by Seneye et al in 2011. One of the reasons for the low amount of tumor treated was that the FDA, as part of the first in man trial, only allowed us to do a single trajectory. There were also technical limitations limited to the permissible aim of the trajectories and our dependence on an axis or a navigus arm, as well as limitations of coil design that limited and restricted our treatments. These are, again, survival slides. Here you see the 316 day median survival of all the patients combined. As you can see, the patients at the white line, which is the higher dose of 43 degrees by 60 minutes, did somewhat better. However, this was also the dose at which several patients had permanent damage. In terms of imaging, it's clear that there's typically increased swelling for about as early as 24 to 48 hours post-op and can typically increase for up to three to four months. After that, it begins to shrink and sometimes lesions actually go away after about three years. In some of the early studies, there are 13 studies, most of which were single institution studies and typically treated gliomas, but also other tumors and tumors in a variety of regions of the brain, making it very difficult to come up with conclusions. The LAYS study, which is recently coming out, is a study from 14 different institutions that describes the treatment of 68 GBMs and 29 other gliomas for 97 gliomas altogether. We looked at how these... It's a retrospective study, and what we found was the superficial lesions were primarily those in recurrent gliomas, whereas the deep lesions were typically those in newly diagnosed gliomas. Other types of gliomas were treated in a variety of different ways. In terms of ICU stays, recurrent gliomas, possibly because they were more superficial, actually had less ICU stay than newly diagnosed gliomas, and this approached statistically significant. Days to ambulation, length of hospital stay, AEs, perioperative complications, and procedural success did not vary between newly diagnosed or recurrent GBM or other gliomas. Similarly, there was no difference in neurologic impairment at 90 days in this series. One year overall survival was essentially about 50% in both newly diagnosed and recurrent GBMs. A subsequent study that was recently published earlier this month, known as LANTERN, was a prospective study of LIT for a number of intracranial lesions. This also looked at quality of life, which did not vary significantly depending on the time or the type of lesion. One interesting finding reported by Mohamedy et al. is that when they looked at the patients who had the most successful LIT, 11 of the 12 had tumor volumes of 10 cubic centimeters or less, and the 12th had a volume of about 12 cubic centimeters. 10 cubic centimeters is equivalent to a sphere with a radius of about 1.3 or a diameter of 2.6 centimeters, so essentially these are fairly small lesions. Larger lesions generally do not do as well. Why is that? Part of it is that it's probably harder to treat larger lesions to the yellow or blue TDT, which we think is essential. Also when one treats any lesion to the yellow or blue TDT, one creates swelling and the level of swelling is obviously worse for larger tumors with larger volumes. This can do more damage. There may also be damage to fiber tracts due to our inability to track TDT. A number of early studies have found difficulty and problems treating large volumes because of mass effect. This has been treated with steroids or mannitol and occasionally for craniotomy for decompression. However, some of these studies suggested that the consistency of the previously treated tumor using LIT was soft and suckable, and so we began to ask, could we combine LIT plus a trans-sulcal or trans-tubular approach in the same operation? The goal here was not gross total resection, but debulking to avoid complication of post-op edema. We published a series of 10 cases using this approach, using trans-tubular approaches to decompress the tumor after LIT to avoid post-op swelling. This was successful in terms of being able to treat large tumors, several as high as 50 or 70 cubic centimeters, without the need for craniotomy or adverse post-op swelling. The outcomes were fairly good with progression-free survival of 280 degrees and overall survival of 482 degrees in the setting of recurrent GBM. Here's an example of a thalamic tumor. As you can see in A, there's some deposition of tissue damage initially post-op, and by 48 hours, there's this eggshell appearance that's classic. By several months later, this begins to dissolve, and there's minimal mass effect, and the patient is now tumor-free here at about three years. There are some challenges with the literature on LIT. It is primarily retrospective. It describes a variety of tumor types and locations. There are very few prospective trials and very few clinical trials. The differences between treatment parameters and outcomes include definitive outcome analysis. So LIT may have a role in the treatment of glioma and other malignant brain tumors, as well as radiation necrosis, particularly those under 10 cubic centimeters. Future directions will focus on better software with faster TDT, incorporation of DTI for fiber tracking, and ways to visualize fiber tracks in vessels and predict treatment plans and trajectories for more successful and more rapid treatment. New coils will be easier to use, and new studies, some of which are currently underway, will allow us to combine LIT with other types of treatment, such as focused resection, immunotherapy, or chemotherapy and radiotherapy. In summary, LIT is a promising and emergent modality for the treatment of gliomas, brain mets, and radiation necrosis, particularly those under 10 cubic centimeters. It's minimally invasive, allows us to reach deep lesions, and is associated with short hospital and ICU stays. Many of these initial challenges have been overcome. Standardized indications and techniques in larger studies will be required in order to move the field forward. Thank you very much for your attention. I'd be happy to take any questions by email. Thank you.

laser interstitial thermotherapy

gliomas

minimally invasive technique

tumor ablation

temperature control