The management of neurosurgical disorders is changing. Many diseases that were traditionally treated with open surgical techniques are now managed with less invasive radiosurgical treatments. This is especially true of brain tumors, and in particular, metastatic intracranial disease. The majority of intracranial metastases are now treated with radiotherapy; craniotomy is reserved for single lesions, large symptomatic metastases, or lesions that have failed non-operative management. For both clinicians and patients, stereotactic radiosurgery (SRS) offers an attractive alternative to both open surgical approaches as well as large field radiation. The high, focal doses of radiation which can be delivered via SRS generally result in durable lesion control with minimal toxicity to surrounding tissues . However, as more patients are treated with SRS, clinicians are facing new challenges. Specifically, there are now an increasing number of patients with symptomatic regrowing lesions post-SRS . Clinically, this cohort encompasses a wide spectrum of pathological changes including a variable admixture of necrosis, inflammatory infiltrate, demyelination, reactive astrocytosis and recurrent tumor. Due to the large variability in their efficacy, treatment strategies for lesions regrowing after SRS vary widely and include changes in chemotherapeutic regimens, corticosteroids, further radiation, open surgical resection, hyperbaric oxygen, and anti-angiogenic medications. Over the past decade, laser interstitial thermal therapy (LITT) has been rejuvenated as a novel tool in the treatment of brain tumors . Here, we evaluate the published literature regarding the use of LITT for treatment of brain tumors, with specific attention to the use of LITT for post-SRS tumor recurrence and radiation necrosis. Additionally, we describe our own single institution experience treating these pathologies with two different commercially available LITT systems.
2 Materials and methods
We performed a PubMed search of the English literature (keywords: brain metastases, stereotactic radiosurgery, tumor regrowth, radiation necrosis, laser interstitial thermal therapy) and reviewed relevant papers. The literature search was supplemented by a review of the bibliographies of selected articles. We focused on papers which contained specific and unique reports of neoplasms treated with LITT. In addition, we reviewed our own series of patients with brain metastases and post-SRS regrowing lesions that were subsequently treated with LITT.
3.1 Review of the literature
3.1.1 LITT for central nervous system diseases
Mechanistically, LITT causes focal coagulation of the target lesion via delivery of interstitial heat. The effect of LITT on brain tissue has been well studied and is characterized by a region of cell death surrounded by a sharp ablation boundary zone. Microscopically, the zone immediately around the laser probe is marked by vaporized tissue, followed by a central zone of coagulative necrosis, then a peripheral zone of necrosis, interstitial fluid build-up, and finally perifocal edema .
The volume of cell death is predicted by the Arrhenius model where the thermal death time for tissues is calculated based on both the intensity of the laser and the duration of heat application. Different tissues are known to have differing sensitivities to this form of thermal injury based on variations in their content of substances such as water, fat, and hemoglobin. In general, neoplasms are sensitive at 40°C whereas normal tissues are sensitive at 44°C. This difference in tissue sensitivities can be exploited for the preferential destruction of tumor over normal brain .
LITT was first described by Bown  in 1983 for the treatment of malignancies. Subsequently, in 1990, Sugiyama et al.  reported using LITT for deep-seated brain tumors. Since then, there have been numerous publications regarding the feasibility of using LITT for a host of central nervous system (CNS) diseases, including gliomas, metastatic neoplasms, benign skull base tumors, and epilepsy [3, 8–21]. Of note, many of the early studies in this field employed carbon dioxide (CO2) and yttrium aluminum garnet (YAG) lasers; this allowed for effective delivery of heat to lesions ≤2 cm in size.
Perhaps the most important advance in the field of thermal ablation has been the ability to monitor temperature changes in real-time with magnetic resonance (MR) thermometry. First described by Jolesz et al.  in 1988, real-time MR thermometry allows the clinician to continuously and rapidly monitor temperatures within both the target lesion and the surrounding normal tissues. This feedback loop provides the clinician robust control over the delivery of heat. Current intracranial LITT devices employ a thin, fiber-optic diode laser design, with a cooled (gaseous or liquid) tip. These probes can pass easily through the brain via a small burr hole. The development of real-time MR thermometry and advancements in laser design has improved the safety profile of LITT. This, in concert with the increasing prevalence of intra-operative MRI suites has re-invigorated interest in this treatment modality.
3.1.2 Clinical experience with MR thermometry-guided LITT
Laser thermal therapy has been successfully used to treat de novo malignancies throughout the body, including the breast, liver, and lung [23–26]. Since 2008, the results of 63 brain tumor patients (in 6 centers) treated with MR-guided LITT (MRgLITT) have been reported in the literature. The indications for using LITT in these cases were summarized into four categories by Jethwa et al.  and include:
High-risk for traditional craniotomy (i.e., due to medical comorbidities)
With the exception of one center in the United States that has published their preliminary experiences in treating newly diagnosed glioblastoma multiforme with LITT , the literature since 2008 has shown that LITT is being trialed predominantly for patients with brain tumors in whom medical and radiation management has failed and traditional open surgical approaches have been deemed too morbid [8, 9, 11–13, 27]. In the past 18 months, two groups have published more extensive experiences using LITT to treat a variety of intracranial malignancies, including regrowing lesions post-SRS, glioblastoma, hemangioblastoma, ependymoma, meningioma, and chordoma [11, 27]. These studies highlight the versatility of LITT as a surgical tool and confirm an acceptable safety profile. Major complications included fatal meningitis, hematoma requiring evacuation, refractory edema requiring hemicraniectomy, inaccurate laser placement requiring conversion to open resection, and pituitary injury. Importantly, in both series, complications decreased with user experience.
Hereinafter, we review the role of LITT in the treatment of intracranial metastatic disease, with specific attention to regrowing lesions post-SRS.
3.1.3 Regrowing metastatic lesions: recurrent tumor and radiation necrosis
Longitudinal studies have demonstrated that approximately one-third of all SRS-treated brain metastases will undergo an increase in lesion size . Histologically, these regrowing lesions represent a mixed group and include both recurrent tumors and radiation necrosis. Although the majority of these volumetric increases are asymptomatic, a small fraction of patients will require further treatment to achieve symptom relief. Recently, several groups have published their initial experiences using LITT for the management of post-SRS regrowing lesions, including both recurrent tumors and radiation necrosis [9, 11–13, 28].
In 2008, Carpentier et al.  published the first report of patients treated with real-time MRgLITT. This group included 4 patients with a total of 6 lesions. Biopsy was not performed, however, all lesions were assumed to represent tumor regrowth based on imaging characteristics. On average, 7.5–15 W was administered over 0.5–3.0 min for maximum ablation dimensions of 11.8–27.0 mm. Overall, patients in this series tolerated the procedure well with no peri-operative complications and minimal hospital stay. Of note, peripheral recurrence was noted in 3 lesions at 3 months; however, these lesions were only partially treated due to safety concerns. A follow-up study by the same group included 7 patients with 15 radioresistant metastatic lesions . In all patients, the procedure was well-tolerated with discharge home within 24 h. Moreover, follow-up imaging up to 30 months post-procedure was negative for tumor recurrence within the ablation zones.
Our group has recently published our initial experience in treating radiation necrosis with LITT . A cohort of 6 patients with biopsy proven, steroid-refractory radiation necrosis underwent LITT. A total of 690–6978 J was delivered achieving ablation dimensions of 7–30 mm. There were no peri-procedural complications and all patients were discharged home within 48 h of surgery. The most notable clinical result post-LITT was the rapid resolution of perilesional edema on the second week post-procedure magnetic resonance imaging (MRI) allowing all patients to be weaned-off steroids by 1 month post-LITT. In 5 out of 6 patients, there was durable lesion control for their entire follow-up period with median overall survival of the group being 7.5 months .
Other groups have also reported similar results. Jethwa et al.  published their series of 20 patients with brain tumors treated with LITT, 4 of which were recurrent metastases. Rahmathulla et al. , Hawasli et al. , and Fabiano et al.  have each published a single case demonstrating the efficacy of LITT for treatment of metastatic lesions regrowing after radiosurgery, further validating the clinical utility of this approach.
These initial case series have also helped to define the expected MRI changes following LITT. Immediately after completion of LITT, treated lesions often contain blood products within the treatment bed, a thin rim of contrast enhancement around the thermocoagulated region, and restricted diffusion within the lesion . In each series, the authors note a transient increase in lesion volume immediately post-ablation (within the first 24 h). This appears to peak at the first week, followed by a steady decline in lesion volume to a new baseline at 3 months. As discussed above, compared to pre-operative images, the amount of cerebral edema seen on transverse (or spin-spin) relaxation time (T2) or fluid-attenuated inversion recovery (FLAIR) sequences is typically dramatically decreased by 2 weeks post-LITT and also continues to steadily decline thereafter. At 1 month post-LITT, lesion sizes begin to decrease below pre-treatment volumes [3, 28].
3.2 Case examples
To further illustrate the above concepts, we present clinical data from several patients treated with intracranial LITT at our institution subsequent to our recent publication. In each case, the patient underwent treatment using NeuroBlate™ (Monteris Medical Inc., Manitoba, Canada).
3.2.1 Patient #1
The first patient is a 75-year-old male with metastatic melanoma whose metastasis was initially successfully treated with SRS (20 Gy to the 50% isodose line) (Figure 1A and B). Eight months post-SRS, while being treated with vemurafenib, the patient developed significant confusion and a right homonymous hemianopsia (Figure 1C and D). Intra-operative stereotactic biopsy was consistent with radiation necrosis. Single trajectory LITT was performed (Figure 2); 28.77 kJ was delivered over 34 min and 19 s. Immediate post-op images show the classic intralesional hemorrhage on the susceptibility-weighted imaging (SWI) sequence and a thin rim of enhancement demonstrating the area of thermal injury (Figure 1E and F). The 2-week post-LITT MRI demonstrates a significant decrease in perilesional edema (Figure 1G and H). The patient was discharged home on post-operative day 1, weaned off steroids within 2 weeks post-procedure, and has returned to a normal neurological examination.
3.2.2 Patient #2
The second patient is a 61-year-old female with metastatic human epidermal growth factor receptor 2 (HER2/neu)-positive breast cancer who underwent SRS to 3 intracranial metastases with good result (Figure 3A–D). The largest lesion, located in the right occipital lobe, was treated with 20 Gy to the 50% isodose line. Ten and a half months post-SRS, this lesion regrew radiographically, causing the patient to develop progressively worsening headaches and visual field loss (Figure 3E and F). Biopsy tissue was consistent with radiation necrosis. Single trajectory LITT was again performed taking visual pathway fibers into account during trajectory planning (Figure 4A). In total, 4.81 kJ was delivered over 5 min and 1 s. The patient was discharged home on post-operative day 1, weaned off of steroids by 2 weeks post-procedure, recovered her full visual fields in 6 weeks, and has returned to work (Figure 4B and C).
3.2.3 Patient #3
The third patient is a 46-year-old female with metastatic non-small cell lung cancer who was found to have a deep right frontal lesion, adjacent to the corticospinal tract, causing hemiparesis. For this, she was treated with SRS (20 Gy to the 45% isodose line) and had an excellent radiographic response at 6 weeks (Figure 5A and B). Subsequently, at approximately 8 months post-SRS, the patient re-presented with a left hemiparesis and the lesion was noted to be regrowing on MRI (Figure 5C and D). Due to persistence of symptoms despite corticosteroids, concern for tumor recurrence, and deep lesion location adjacent to eloquent structures, LITT was offered. Biopsy confirmed tumor recurrence and single trajectory LITT was performed. In total, 8.34 kJ was delivered over 7 min and 28 s. During LITT administration, >95% of the lesion volume was ablated; however, a small portion of the superior aspect of the lesion remained untreated (Figure 6C). The reason for this remains unclear. Despite good laser positioning, accurate MR thermometry, prolonged laser application, and reasonable heat propagation throughout all other regions of the tumor, the superior aspect of the lesion would not pick up heat. The mechanisms for this phenomenon are poorly understood; future laboratory investigations may provide meaningful insights.
The patient had an excellent initial response to LITT, marked by both clinical and radiographic improvements (Figure 5E and F). However, at 6 months post-LITT, the patient was noted to have tumor regrowth at the superior, untreated aspect of the lesion, highlighting both the advantages and limitations of this system (Figure 6A and B).
3.2.4 Patient #4
The last patient is a 45-year-old male with known BRAF-mutant metastatic melanoma with multiple brain metastases. The left frontal lesion was treated with SRS (20 Gy to the 50% isodose line). After an initial excellent systemic response to vemurafenib, the patient was switched to definitive anti-PD-1 (programmed cell death 1) treatment. Approximately 6 months post-SRS (and 3 months after starting anti-PD-1), the patient was noted to have a regrowing lesion on MRI, concerning for radiation necrosis (Figure 7A and B). Due to the radiographically significant mass effect and perilesional edema, LITT was performed. Biopsy was consistent with radiation necrosis. Single trajectory LITT was subsequently performed with good lesional coverage (Figure 7C and D). In total, 6.99 kJ was delivered over 6 min and 29 s. Follow-up imaging over the next 2 years demonstrates excellent radiographic control (Figure 7E and F).
3.3 Comparison of available systems
At present, there are two commercially available systems for the administration of intracranial LITT in the United States: Visualase (Visualase, Inc; Houston, TX, USA) and NeuroBlate™ (formerly known as AutoLITT; Monteris Medical, Inc; Manitoba, Canada). We have been fortunate to trial both systems at our institution and a few points are worth noting:
Wavelength: The Visualase system employs a 980-nm diode laser, while the Monteris system employs a 1064-nm diode laser.
Cooling: The Visualase laser is saline-cooled while the Monteris laser is CO2-cooled.
Stereotactic procedure: Both lasers can be inserted stereotactically via drill (<5 mm) or burr hole.
Insertion system: The Visualase insertion system is considerably less bulky than the Monteris system. This translates to an ability to freely target lesions in both the supra- and infratentorial compartments with the Visualase system, while currently only supratentorial lesions can be treated with the Monteris system. However, the Monteris insertion system is noted, both anecdotally and in the literature, to be highly accurate with a lower incidence of poor laser placement than the Visualase system.
Ablation: The Visualase laser appears to exhibit faster heat propagation than the Monteris laser; with Visualase treatment temperatures rising into the 80–90°C range versus only 50–60°C with Monteris treatments. This is due to intrinsic physical differences in the two lasers as well as the controls applied to each laser’s energy delivery system. The Visualase laser system has the ability to set variable power settings and fires continuously in an omnidirectional pattern; the Monteris laser is unidirectional, emits a beam 90° orthogonal to the probe and fires intermittently at 12 W in 2.2-s bursts with a built-in 1.7-s delay between each burst of firing. Clinically, this translates to a more time-efficient treatment with the Visualase system with less ability to clearly define the anatomical boundaries of the treatment, versus a slower, but much more controlled treatment with the Monteris system allowing contouring of the lesion around critical neurological structures.
Treatment planning system: The Monteris system has a 3-D treatment planning capability that is not available in the Visualase system.
Robotics: The Monteris system has the advantage of having the first intra-operative robotic catheter positioning device which allows the surgeon to change the rotation and depth of the laser fiber remotely from the control room once it is placed in its starting position within the lesion. This increases the amount of surgeon control during the treatment while also streamlining some of the workflow issues unique to LITT.
The management of patients with intracranial metastases and regrowing lesions post-SRS is challenging. Increasing numbers of intracranial metastases are being treated with SRS and these patients are living longer due to improvements in systemic therapy. As such, clinicians are presented with regrowing post-SRS lesions at a steadily increasing frequency. Management of these patients is often presumptive and based primarily on radiographic interpretations of the underlying pathology. This has obvious limitations; the appropriate treatment for recurrent tumor is quite different from that of radiation necrosis.
LITT represents a promising modality for treatment of this group of patients. In a single session, a patient may undergo stereotactic biopsy to confirm pathology, and then receive definitive treatment with LITT regardless of the pathology. A number of early studies have demonstrated reasonable clinical and radiographic durability with this approach. Based on these initial reports, it appears that this strategy is best suited for patients with either: (1) small, deep-seated lesions that are refractory to traditional approaches, or (2) patients with medically refractory but surgically accessible lesions, who are too ill for conventional open surgery.
Previous attempts at intracranial laser thermocoagulation were hindered by a lack of real-time thermometry; estimates of laser-tissue interactions were purely theoretical. The development of MR thermometry in concert with the intra-operative MRI suites has increased the safety and practicality of this technique. Additionally, advancements in laser design, as compared to previous YAG lasers, have resulted in elimination of char, faster treatment times, and sharper thermal gradients. This has further increased the safety and efficiency of LITT and made it well-suited to widespread clinical investigation.
What remains unclear is how laser type and energy delivery rate affect clinical outcome. From the literature and the few representative cases shown here, it appears that recurrent tumor requires much more comprehensive lesional coverage by LITT than radiation necrosis. An ideal laser system then would be one that could rapidly deliver thermal therapy in the setting of radiation necrosis to limit the treatment time for the patient, but could also carefully contour out a regrowing tumor to ensure 100% coverage while preserving normal, functional brain. Further research is required to determine the ideal laser settings and thermal death time estimates that would enable these goals to be achieved.
As an increasing number of patients present with regrowing lesions post-SRS, clinicians are facing new challenges. Although the majority of these lesions will respond to traditional therapies, a small fraction will remain refractory to these approaches. LITT is a new tool in the neurosurgical armamentarium which demonstrates early promise in the treatment of these lesions. To gain widespread acceptance, this technology will require further streamlining and improved operative efficiency. Future studies are needed to better define ideal laser settings, as well as to determine optimal imaging sequences on MRI to assist in understanding post-treatment changes for different disease types. If control-matched, multi-institutional clinical studies confirm utility in salvage tumor scenarios, it is feasible that LITT may also play a role in the de novo treatment of intracranial lesions. As a minimally invasive tool, future investigations should focus on the completion of larger scale clinical trials to conclusively answer outstanding questions regarding cost, clinical efficacy, and impact on quality of life in comparison with standard therapeutic options.
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About the article
Published Online: 2014-02-03
Published in Print: 2014-04-01
Conflict of interest statement: The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified. There are no financial disclosures to note.