Laser interstitial thermal therapy (LITT) involves the introduction of a laser fiber probe to deliver thermal energy for the targeted ablation of diseased tissue. Thermal destruction of tissue is mediated via DNA damage, necrosis, protein denaturation, membrane dissolution, vessel sclerosis, and coagulative necrosis (Lagman et al., 2017). The goal of therapy is selective thermal injury through the maintenance of a sharp thermal border, as monitored via the parallel use of real-time magnetic resonance (MR) thermography and controlled with the use of actively cooled applicators (Medvid et al., 2015). In neurological applications, LITT involves the creation of a transcranial burr hole for the placement of the laser probe at the target brain tissue. Probe position, ablation time, and intensity are controlled under magnetic resonance imaging (MRI) guidance.
The majority of neurological LITT indications described in the literature involve the ablation of primary and metastatic brain tumors, epileptogenic foci, and radiation necrosis (RN) in surgically inaccessible or eloquent brain areas (Medvid et al., 2015). LITT may offer a minimally invasive treatment option for individuals with a high risk of morbidity with traditional surgical approaches. The most common complications following LITT are transient and permanent weakness, cerebral edema, hemorrhage, seizures, and hyponatremia (Holste and Orringer, 2020). Delayed neurological deficits due to brain edema are temporary and typically resolve after corticosteroid therapy. Contraindications to MRI are also applicable to the administration of LITT.
REFRACTORY EPILEPSY
Epilepsy is one of the most common neurological disorders in the United States and has a prevalence of approximately 3 million adults. Epilepsy is diagnosed when an individual has unprovoked seizures. Primary seizure disorders include multiple subtypes that are recognizable by the degree and type of impairment of consciousness and motor capacity. Seizure disorders may be secondary to brain tumors or other space-occupying intracranial lesions such as congenital malformations, stroke, genetic syndromes, brain trauma, and cerebral infections. Mesial temporal lobe epilepsy (mTLE), also known as complex partial seizures, is a focal epilepsy syndrome. The epileptogenic foci may present in the hippocampus, amygdala, or parahippocampal gyrus. The most common nontraumatic or noninfectious etiology of mTLE is hippocampal sclerosis. The associated neuronal loss is a partial explanation for the difficulties in achieving satisfactory seizure control with antiepileptic medication. Approximately one third of individuals with epilepsy do not achieve adequate seizure control with antiepileptic drugs. Management generally involves antiepileptic drugs (AEDs), but for approximately 30% of individuals, seizures are uncontrolled by medical therapy. For individuals with focal seizure disorders, more invasive interventions such as open surgical procedures (e.g., open craniotomy with resection), stereotactic radiosurgery (SRS), or neurostimulation might be warranted.
LITT is an alternative treatment option that is less invasive and may therefore reduce the potential for adverse events (AEs). LITT is a focused thermal therapy technique to ablate epileptogenic foci when seizures have become drug-resistant or medication-related AEs are intolerable, and to potentially avoid complications associated with alternative surgical interventions. The treatment of refractory epilepsy with LITT may require more than one treatment session to reduce or eliminate seizures. The population of interest is individuals with drug-resistant or medication-intolerant epilepsy, defined as failure to achieve sustained seizure freedom despite adequate trials of two or more appropriately chosen and tolerated antiseizure medications, as specified by the International League Against Epilepsy (ILAE) Commission on Therapeutic Strategies consensus definition for drug-resistant epilepsy (Kwan et al., 2010). Outcomes of interest are symptom improvement, change in disease status, quality of life, hospitalizations, medication use, treatment-related morbidity, and disease-specific survival.
REVIEW OF EVIDENCE
Systematic Reviews
Ekman et al. (2024) performed a systematic review and meta-analysis of MR-guided LITT compared to temporal lobe resection in individuals with drug-resistant mTLE. Only cohort studies with a follow-up of at least 24 months were considered for inclusion (randomized trials were excluded). Of the 55 studies in the review, 14 studies assessed MR-guided LITT (n=534) and 41 studies assessed temporal lobe resection (n=4606). The primary outcome (seizure freedom, defined as the proportion of individuals achieving Engel I status) was reported in six of the MR-guided LITT studies. A random-effects model found that the proportion of individuals with seizure freedom after MR-guided LITT was 57.1% (95% confidence interval [CI], 51.2%–62.7%) versus 72.5% (95% CI, 65.6%–78.5%) after temporal lobe resection (P<0.01). The overall rate of complications was 6.5% (95% CI, 3.3%–12.3%) after MR-guided LITT and 11.4% (95% CI, 7.4%–17.2%) after temporal lobe resection (P=0.15). There was no difference in major complications (2.7% vs. 2.0%, respectively; P=0.54) but minor complications were more common with temporal lobe resection (9.9%) than with MR-guided LITT (4.1%; P=0.04).
Hect et al. (2023) conducted a systematic review of MR-guided LITT corpus callosum ablation for drug-resistant epilepsy. Sixteen observational reports were included (N=85 individuals). Seizure freedom at 6 months was evaluable in 53 individuals and occurred at a rate of 18.87%. The rate of freedom from atonic seizures postoperatively was 46.28%. Overall, the rate in average number of seizures per day decreased by 80.12%. The complication rate was 12.94% and permanent neurologic deficits occurred in 4.71% of individuals. The authors concluded that most individuals experienced a meaningful decrease in seizure frequency with an acceptable rate of complications.
Barot et al. (2022) published a systematic review and meta-analysis of LITT treatment outcomes among individuals with drug-resistant epilepsy of varying etiologies. Twenty-eight studies representing 559 individuals were identified. The overall prevalence of Engel class I outcomes was 56% (95% CI, 52%–60%). Highest seizure freedom rates were observed among individuals with hypothalamic hamartomas (67%; 95% CI, 57%–76%). Comparable seizure freedom rates were observed between individuals with mTLE (56%; 95% CI, 50%–61%) and extratemporal epilepsy (50%; 95% CI, 40%–59%). The overall rate of adverse events was 19% (95% CI, 0.14%–25%), of which visual field defects were most common.
Marathe et al. (2021) conducted a systematic review and meta-analysis comparing open surgical resection, SRS, LITT, and radiofrequency ablation (RFA) in drug-resistant mTLE. Forty-one publications were included in the analysis, including 19 studies on open surgery, 11 on LITT, four on radiofrequency, and seven on radiosurgery. The pooled seizure-free rate per person-year was 0.72 (95% CI, 0.66–0.79) with trans-sylvian selective amygdalohippocampectomy (sAHE), 0.70 (95% CI, 0.64–0.77) with anterior temporal lobe (ATL) resection, 0.60 (95% CI, 0.49–0.73) with transcortical sAHE, 0.59 (95% CI, 0.53–0.65) with LITT, 0.50 (95% CI, 0.34–0.73) with SRS, and 0.38 (95% CI, 0.14–1.00) with RFA.
Kohlhase et al. (2021) performed a systematic review and meta-analysis to compare outcomes and complications from MR-guided LITT, RFA, and conventional open surgery (i.e., ATL or sAHE) in individuals with drug-refractory mTLE. Forty-three studies were identified (13 LITT; six RFA; 24 conventional surgery) between 1995 and 2018. Meta-analytic estimates for the proportion of individuals achieving Engel I outcomes were 34% (95% CI, 15%–61%), 57% (95% CI, 53%–61%), 65% (95% CI, 58%–72%) and 69% (95% CI, 62%–75%) for RFA, LITT, sAHE, and ATL, respectively. No significant difference in outcome was noted between LITT and RFA (P=0.098), whereas significantly better outcomes were observed following conventional surgery with both sAHE (P=0.0247) and ATL (P=0.0113) compared to LITT. In a subgroup analysis of individuals with follow-up duration of 60 months or more, both ATL (P=0.009) and sAHE (P=0.043) resulted in significantly higher rates of Engel I outcomes compared to LITT. Among individuals treated with LITT, significantly better outcomes were observed in individuals with mTLE and hippocampal sclerosis (P=0.0035). Overall complication rates were 14.1%, 17.5%, 31.3%, and 18.2% for LITT, RFA, ATL, and sAHE, respectively, with corresponding major complication rates of 3.8%, 3.7%, 10.9%, and 7.4%. However, meta-analysis revealed no significant differences concerning overall and major complication rates between procedures.
Brotis et al. (2021) conducted a meta-analysis to estimate the efficacy of LITT for mTLE. Sixteen retrospective case series published between 2012 and 2019 representing 575 individuals (range, 1–231) were identified. Overall, seizure freedom was achieved in 54.7% (95% CI, 50.6%–58.8%; I2=18.7%) of individuals undergoing LITT with a median follow-up duration of 18 months (interquartile range [IQR], 12–26 months). Sensitivity analyses yielded similar results. Four studies representing 150 individuals indicated that the prevalence of Engel Class IA outcomes decreased with time, estimated at 64.2%, 46.9%, and 42.4% at 12-, 24-, and 36-month follow-up, respectively. The overall quality of evidence was regarded as "very low" according to GRADE recommendations, with only four studies including more than 20 individuals. The authors concluded that while mTLE resective surgeries are invasive and irreversible, they offer better seizure control rates, with previously reported seizure-free rates ranging from ranging from 60% to 90% for mTLE.
Grewal et al. (2019) published a systematic review and meta-analysis comparing MR-guided LITT versus SRS for medically intractable temporal lobe epilepsy (TLE). No comparative studies of LITT versus SRS were available. The authors performed an indirect meta-analysis of data from the included studies regardless of comparator to generate pooled incidence for each intervention. Nineteen studies published between 2008 and 2018 representing 404 individuals (range, 5–58) were identified, including nine retrospective studies on LITT (n=239). The overall seizure freedom rate was not found to be significantly different between LITT (50%; 95% CI, 44%–56%) and SRS (42%; 95% CI, 27%–59%; P=0.39), nor was it significantly different for individuals with lesional conditions (62% [95% CI, 48%–74%] vs. 50% [95% CI, 37%–64%]; P=0.23). While LITT was associated with a significantly lower procedural complication rate (20% vs. 26%; P=0.06), reoperation rates were not significantly different (15% vs. 27%; P=0.31). No overall estimate of study quality or individual study ratings were provided; however, all studies were retrospective in nature, with the exception of a single randomized controlled trial (RCT) among the SRS studies.
The Canadian Agency for Drugs and Technologies in Health published a rapid response report examining the clinical effectiveness of LITT for epilepsy and/or brain tumors in June 2019. In this report, outcomes of interest were seizure freedom, disease progression and overall survival, quality of life, hospitalization, and adverse events. Evidence of limited quality and quantity suggested that LITT provides no advantage over SRS in inducing seizure freedom in individuals with drug-resistant, medically intractable TLE. Relative to individuals who were treated with SRS and craniotomy, individuals treated with LITT appeared to experience fewer adverse events and complications. No comparative evidence on disease progression, overall survival, hospitalization, or quality of life was found. None of the studies reported on the incidence of epileptic episodes, postoperative pain, use of medication, or hospital readmissions.
Xue et al. (2018) reported postoperative outcomes for MR-guided LITT in the treatment of drug-resistant epilepsy. Sixteen nonrandomized studies published between 2014 and 2018 representing 269 individuals (range, 5–30) were included in the meta-analysis. The prevalence of Engel Class I, II, III, and IV outcomes was 61%, 12%, 16%, and 15%, respectively. The prevalence of postoperative complications was 24% (95% CI, 16%–32%).
Hoppe and Helmstaedter (2020) reported postoperative outcomes for pediatric individuals (age <18 years) treated with LITT for drug-resistant epilepsy. Twenty-five case series representing 179 individuals were included in the review, with the majority of cases attributed to hypothalamic hamartomas (64.2%). Among published cases, the overall complication rate was 23.5% with a 3.4% rate of severe complications. Engel I seizure-free outcomes were achieved by 57.5% of individuals across studies, including individuals with short follow-up (e.g., 1 month) and repeat treatments. No studies reported on cognitive outcomes on the basis of standardized psychometric measures.
Comparative Observational Studies
Hale et al. (2019) reported postsurgical outcomes in 26 pediatric individuals with insular epilepsy treated with LITT (n=14) or open resection (n=12). Mean follow-up was 2.43 years. Engel Class I outcomes were achieved in 43% of individuals treated with LITT compared to 50% who underwent open insular resection at 1 year postsurgery. Postoperative complications occurred in six individuals treated with LITT and seven individuals treated with resection, all of which resolved within 3 to 4 months.
Petito et al. (2018) published a retrospective, single center analysis of 100 consecutive neurosurgeries performed between 2013 and 2015 in individuals with drug-resistant epilepsy, representing 33 LITT procedures and 21 open resections with mean follow-up durations of 21.7 and 21.3 months, respectively. A discrete lesion was radiographically identified in 85% of individuals treated with LITT and 65% of individuals treated with resection. The mean postoperative hospital length of stay was significantly shorter for LITT compared to resection (1.18 vs. 3.43 days; P=0.0002). Individuals treated with resection were significantly younger, with a mean age of 35.4 years (P=0.001). At 12 months, seizure freedom was achieved in 56.3% (95% CI, 39.3%–71.8%) and 60% (95% CI, 38.7%–78.12%) of individuals treated with LITT and resection, respectively (P=0.79). Among individuals with focal lesions, the seizure freedom outcomes were not significantly different between groups (=0.21). For nonlesional individuals, LITT treatment trended towards a better outcome, but did not achieve statistical significance (P=0.05).
Single-Arm Studies
Esmaeili et al. (2023) conducted a prospective observational study of consecutive LITT-treated individuals with drug-resistant epilepsy between 2013 and 2021. The primary outcome was sudden unexpected death in epilepsy (SUDEP). There were four SUDEP cases among 135 individuals over a median duration of 3.5 years (range, 0.1–9.0) for an estimated SUDEP incidence of eight per 1000 person-years. Among a historical control group, the incidence of SUDEP was estimated to be two per 1000 person-years in individuals who underwent resection surgery and 6.1 per 1000 years in individuals who did not receive surgical intervention but were candidates. Thus, LITT-treated individuals had significantly higher SUDEP incidence compared with surgery (P=0.02) but similar rates compared with those without intervention (P=0.55).
Kanner et al. (2022) conducted a retrospective review of long-term seizure and psychiatric outcomes among individuals who underwent LITT for drug-resistant mTLE between 2013 and 2019 at a single academic center. Forty-eight individuals (mean age, 43 years) were identified with a mean follow-up duration of 50 ± 20.7 months (range, 18–81). Engel class I outcomes were achieved in 29 (60.4%) subjects and 11 (22.9%) reported one to three seizures per year. The seizure-freedom rate was 77.8% among individuals with 24-month follow-up that decreased to 50% among individuals with more than 61 months of follow-up data. Seizure freedom was associated with mesial temporal sclerosis, no pre-treatment focal to bilateral tonic-clonic seizures, and no psychopathology in the last follow-up year. Mood and/or anxiety orders were identified in 30 (62.5%) of individuals pre-surgery, of which 19 (62%) remitted following LITT.
Landazuri et al. (2020) reported 1-year outcomes following LITT of epileptogenic foci with the NeuroBlate system in individuals with drug-resistant epilepsy. Engel Class I outcomes were achieved in 27 of 42 (64.3%; 95% CI, 48.0%–78.5%) individuals at 1 year. No significant difference was observed in individuals with mTLE (70.8%) versus other etiologies. Five adverse events were reported, with one categorized as serious. Median baseline Quality of Life in Epilepsy questionnaire (QOLIE-31) score was 51.7 (range, 8.7–77.3). Median scores increased by 14.1 points reflecting a 72.4% improvement (95% CI, 52.8%–87.3%) in quality of life measures. However, the total score change was not statistically significant (P=0.2173). Seizure worry and social functioning subscores were considered statistically significant (P=0.0219 and P=0.0175, respectively). The authors noted that the primary success of LITT remains in well-localized lesions/localizations, such as those seen in mTLE/MTS, cortical dysplasia, and hypothalamic hamartoma.
Wu et al. (2019) published the results of a multicenter, retrospective cohort study of 234 individuals with drug-resistant mTLE who underwent LITT between 2011 and 2017. At both 1 and 2 years after LITT, 58% of individuals achieved Engel I outcomes. Engel I outcomes were associated with ablations involving more anterior medial, and inferior temporal lobe structures, which tended to involve greater amygdalar volume. Presence or absence of hippocampal sclerosis did not have a significant effect on seizure outcomes. Overall, Engel I or II outcomes were achieved by 76.9% of individuals at the time of last follow-up. Forty-two complications were observed in 35 individuals, of which 34 persisted at last follow-up.
MALIGNANT BRAIN TUMORS
Glioblastoma (GBM) is the most prevalent primary malignant intracranial tumor, representing as much as 16% of primary brain tumors. In the United States, the annual incidence rate of GBM ranges from 0.59 to 3.69 cases per 100,000. GBM is a fast-growing aggressive glioma that develops from glial cells in the brain. The overall prognosis is poor and even with the best standard of care, the median survival for adults with GBM ranges from 11 to 15 months and 5 to 7 months for recurrent disease. The current standard care for newly diagnosed GBM is surgery, followed by chemotherapy with temozolomide (TMZ) in combination with radiation therapy, and then ongoing maintenance treatment with TMZ. Virtually all individuals with newly diagnosed GBM relapse, for which the treatment options are very limited.
Metastatic brain neoplasms (also referred to as brain metastases) are tumors caused by cancer cells that spread from another part of the body to the brain and are associated with substantial morbidity, mortality, and treatment burden. Median survival for individuals with brain metastasis ranges from a few months to a few years, making timely treatment critical. However, the rate of local recurrence of a surgically resected brain metastasis is estimated to be as high as 85%. Standard treatment of initial brain metastasis includes medical management of symptoms (e.g., headache, edema, seizures), surgery, radiotherapy, and/or SRS. Chemotherapy is not considered an efficacious brain metastasis treatment option. For recurrent lesions, there is no specific prescribed regimen; treatment often depends on the size, number, and location of the recurrent brain metastasis and location of the tumor of origin.
Primary intracranial malignant tumors include gliomas, astrocytomas, malignant meningiomas, and primitive neuroectodermal tumors (i.e., medulloblastoma, pineoblastoma). Treatment of primary brain tumors such as gliomas is more challenging, due to their generally larger size and infiltrative borders. Intracranial metastases tend to have a smaller spherical size and noninfiltrative borders. Brain metastases occur frequently, seen in 25% to 30% of all individuals with cancer, particularly in those with cancer of the lung, breast, colon, kidney, and melanoma.
LITT is an alternative treatment option that is less invasive and may therefore reduce the potential for AEs. LITT is a focused thermal therapy technique used to ablate malignant brain tumors and to avoid potential complications associated with alternative surgical interventions. The following therapies are currently being used to treat malignant metastatic brain tumors in select treatment settings: open surgical resection (e.g., craniotomy), SRS, radiotherapy (including whole-brain radiotherapy [WBRT]), and systemic therapies (e.g., chemotherapy). The population of interest is individuals with malignant brain tumors that are inaccessible surgically or located in proximity to eloquent or radiosensitive areas. LITT is typically used when surgery is contraindicated due to a high risk of procedural morbidity and/or presence of comorbidities that preclude candidacy for open surgery. LITT may be preferred by individuals desiring a less-invasive surgical alternative and its use has been explored in first-line, adjunct, and salvage settings. Primary outcomes of interest are overall survival (OS) and progression-free survival (PFS). Additional outcomes include local disease control, symptom improvement, functional outcomes, change in disease status, quality of life, and treatment-related morbidity.
REVIEW OF EVIDENCE
Systematic Reviews
Pandey et al. (2024) conducted a meta-analysis of 22 noncomparative studies (N=206, range, 2–29) that reported use of LITT for primary brain tumors (glioblastoma [n=185] and IDH-mutated astrocytoma [n=21]). Among individuals with glioblastoma, OS was 9.3 months (range, 7.1–11.4) and PFS was 4.8 months (range, 2.0–7.9). Neurologic complications occurred in 10.3% and non-neurologic complications occurred in 4.8% of individuals with glioblastoma. Among individuals with astrocytoma, OS and PFS could not be determined due to a lack of data. Neurologic complications occurred in 33% and non-neurologic complications occurred in 8.3% of individuals with astrocytoma.
Zhao et al. (2024) performed a systematic review and meta-analysis of eight noncomparative studies (N=128, range 3–60) in individuals with recurrent glioblastoma multiforme (rGBM). At 6 months, PFS was 25% (95% CI, 15%–37%; I2=53%) and OS was 92% (95% CI, 83%–100%; I2=0%). At 12 months, PFS was 9% (95% CI, 4%–15%; I2=24%) and OS was 42% (95% CI, 13%–73%; I2=67%). Complication rates were low overall and most complications were mild to moderate in severity. The authors stated that "[f]urther well-designed clinical trials are needed to expand the application of LITT in glioma treatment."
Alkazemi et al. (2023) published a systematic review of comparative and descriptive studies (excluding case reports) assessing the evidence for LITT in primary and metastatic brain tumors. Forty-five studies (N=826, range 2–91) were included. Lesions were categorized as high-grade gliomas (n=361), low-grade gliomas (n=116), metastatic brain tumors (n=337), or nonglial tumors (n=15). The majority of studies offered LITT in individuals with inaccessible or deep tumors (n=12), after failed radiosurgery (n=9), or were nonspecific (n=12). One-year PFS was 19.6% (95% CI, 11.3%–29.0%; I2=0%) in high-grade gliomas, 16.9% (95% CI, 11.6%–24.0%; I2=0%) in grade 4 astrocytomas, and 51.2% (95% CI, 36.7%–65.5%; I2=0%) in brain metastases. One-year OS was 43.0% (95% CI, 36.0%–50.0%; I2=7.6%) in high-grade glioma, 45.9% (95% CI, 37.9%–54%; I2=0%) in grade 4 astrocytomas, 93.0% (95% CI, 42.3%–100%; I2=not applicable) in low-grade gliomas, and 56.3% (95% CI, 47.0%–65.3%; I2=not applicable) in brain metastases. Major procedure-related AEs were 30% (95% CI, 27%–40%) with a 16% incidence (95% CI, 12%–22%) of major or minor neurological deficits.
Chen et al. (2021) published a systematic review and meta-analysis of retrospective studies and case series investigating the efficacy of LITT for brain metastases with in-field recurrence or RN following treatment with SRS. A meta-analysis of 14 studies (470 individuals [range, 7–92] with 542 lesions) was performed. The overall 12-month local control rate ranged between 56.0% and 84.7% with a pooled rate of 69.0% (95% CI, 60.0%–76.7%; I2=50.584%; P=0.048) and pooled OS of 17.15 months (95% CI, 13.27–24.8). Among 153 recurrent brain metastatic lesions across five studies, the 12-month local control rate was 59.9% (95% CI, 47.9%–70.9%). Among 75 RN lesions across four studies, the 12-month local control rate was 76.3% (95% CI, 65.0%–84.8%). Thus, LITT provided more favorable local control efficacy in individuals with RN compared to those with brain metastasis recurrence. No significant difference in median OS at 1 year was determined between the RN and brain metastasis groups (66.5% vs. 66.8%; P=0.978). Survival outcomes were not stratified by pathology and safety outcomes were not reported. Compared to previously reported estimates for surgical resection with a local control rate ranging from 62% to 93% and a median OS of 8.7 months, the authors concluded that LITT demonstrates comparable local control but a more satisfactory survival benefit.
de Franca et al. (2020) published a systematic review and meta-analysis of LITT as a therapy for brain tumors compared to SRS based on 25 studies. The selected studies included a RCT evaluating SRS, prospective cohort studies, and retrospective studies. Individual populations included individuals with brain metastasis (n=12 [LITT], n=1555 [SRS]) and rGBM (n=27 [LITT], n=232 [SRS]) . A significant improvement in median OS was observed in individuals treated with LITT compared to SRS among individuals with brain metastasis (12.8 vs. 9.8 months; P<0.02) and was associated with a 15% reduction in risk of AEs overall. The authors concluded that "there is no evidence that LITT can be used as a treatment of choice when compared to SRS," but use of LITT may have a role in lowering the risk of AEs. The analysis was limited by inclusion of heterogeneous populations, the small number of individuals treated with LITT (n=39), and a lack of reporting on prior treatments. In particular, individuals treated with SRS varied in their degree of radiosensitivity and prior radiation exposure, which may have influenced the higher rate of AEs observed in this group.
Barnett et al. (2016) conducted a systematic review and meta-analysis comparing LITT (eight studies; 79 individuals) to open craniotomy (12 studies; 1036 individuals) for the treatment of high-grade gliomas in or near areas of eloquence, with a focus on AEs. Proportions of major complications occurred in 5.7% (95% CI, 1.8%–11.6%) and 13.8% (95% CI, 10.3%–17.9%) of individuals treated via LITT and craniotomy, respectively.
Randomized Controlled Trials
In 2026, Neutel et al. published the results of an RCT that was terminated early. Given that an adequately powered trial required 238 participants, yet only 26 were included in the intent-to-treat analysis, this analysis fails to provide additional evidence for the safety and effectiveness of LITT beyond that of which has already been characterized.
Comparative Observational Studies
Grabowski et al. (2022) published a multicenter, retrospective study of individuals undergoing treatment for biopsy-proven brain metastasis recurrence after stereotactic radiotherapy (SRT). Individuals were stratified into three groups: planned LITT plus SRT (n=21), LITT alone (n=25), or repeat SRT alone (n=9). Mean age was 60 years (range, 37–86) and median follow-up duration was 7.3 months (range, 1.0–30.5). No individuals in the LITT plus SRT group received prior surgery or WBRT, compared to 20% and 28% treated with LITT alone and 11% and 56% treated with SRT alone (P=0.05 and 0.01, respectively). Median time to index lesion progression for LITT plus SRT, LITT alone, and repeat SRT alone was 29.8, 7.5, and 3.7 months, respectively (P=0.022). A univariate analysis found a significantly increased risk of tumor progression among individuals receiving prior surgery (hazard ratio [HR], 5.33; 95% CI, 1.41–16.93; P=0.0007).
Fadel et al. (2022) retrospectively reviewed an institutional database to identify individuals with unifocal, lobar, surgically accessible recurrent glioblastoma who were treated with LITT or resection between 2013 and 2020. Of 744 individuals identified, a LITT cohort of 17 individuals was compared with 23 surgical individuals. Baseline characteristics were similar between groups except for average lesion size, which was smaller in individuals treated with LITT (4.37 cm3 vs. 7.54 cm3; P=0.017). Overall survival (14.1 vs. 13.8 months; P=0.578) and PFS (3.7 vs. 3.3 months; P=0.004) were not significantly different between groups. Significantly shorter hospital stays were observed in individuals treated with LITT (2.2 vs. 3.0 days; P=0.004).
Mohammadi et al. (2019) conducted a multicenter retrospective review of survival outcomes in individuals with deep seated newly diagnosed glioblastoma treated with upfront MR-guided LITT prior to chemotherapy/radiotherapy (n=24; median age, 54 years; 50% male; 71% <70 years) compared to a matched cohort of biopsy-only individuals (n=24; median age, 64 years; 58% male; 75% <70 years). Individuals were matched based on age, gender, tumor location (deep vs. lobar), and tumor volume. Median follow-up was 9.3 months (range, 2–43 months) and 14.7 months (range, 2–41 months) in LITT and biopsy-only cohorts, respectively. Overall median estimates of OS and PFS in the LITT cohort was 14.4 and 4.3 months compared to 15.8 and 5.9 months for the biopsy-only cohort. Age less than 70 years and tumor volume less than 11 cm3 were identified as favorable prognostic factors for OS.
Single-Arm Studies
The Laser Ablation of Abnormal Neurological Tissue Using Robotic NeuroBlate System (LAANTERN) registry is an ongoing industry-sponsored, multicenter, multinational prospective registry of the NeuroBlate device enrolling individuals with primary and metastatic brain tumors, epileptic foci, and movement disorders (NCT02392078). Rennert et al. (2020) reported procedural safety outcomes for the first 100 individuals enrolled in the LAANTERN registry. Kim et al. (2020) reported 12-month survival and quality of life outcomes among 223 individuals enrolled in the LAANTERN registry with primary (n=131) or metastatic (n=92) brain tumors who received treatment with the NeuroBlate device. The majority of individuals with primary tumors had high-grade glioma (n=90) and individuals with metastatic disease had recurrent tumors (n=43) or radionecrosis (n=34). The 1-year estimated OS rate was 73% (95% CI, 65.3%–79.2%), which was not found to be significantly different between primary or metastatic tumors (74.6% vs. 70.7%, respectively). Quality of life assessments with the Functional Assessment of Cancer Therapy - Brain (FACT-Br) questionnaire did not meet the criteria for a clinically meaningful change (>10%) and EQ-5D questionnaires indicated an overall decline of 0.1 points from baseline. In 2022, de Groot et al. published a subgroup analysis of LAANTERN registry data focusing on new (n=29) and recurrent (n=60) cases of IDH wild-type glioblastoma. Median OS was 9.73 months (95% CI, 5.16–15.91) for newly diagnosed individuals and 8.97 months (95% CI, 6.94–12.36) for recurrent individuals. Median OS in newly diagnosed individuals receiving post-LITT chemotherapy/radiation therapy was 16.14 months (95% CI, 6.11 to not reached).
RADIATION NECROSIS
Radiation therapy is intended to destroy or slow the growth of cancer cells by causing damage at the cellular level. RN, also known as radionecrosis, is an inflammatory reaction that can occur as a side effect at the site of radiation, leading to cell death. The tissue in a tumor bed is especially susceptible to RN because of swelling and blood vessel deprivation. Symptomatic RN of brain tissue is a fairly uncommon but serious complication of radiation therapy for brain metastases.
Treatment-induced brain tissue necrosis (also referred to as cranial RN or radionecrosis) is a serious delayed complication of cranial irradiation that typically develops after 1 to 3 years. RN is more likely to occur with high-dose fractionation and potentially with concurrent chemotherapy or use of radiosensitizers. The risk of RN following SRS has been reported to be higher, with a steep dose-response relationship. Differentiating RN from recurrent brain tumors via imaging can be difficult, as conventional structural MRI may reveal features that overlap with the typical radiographic appearance of high-grade primary or metastatic brain tumors. Biopsy may be required for a definitive diagnosis of RN, particularly among individuals who are symptomatic or with worsening radiographic findings over time. Symptoms of RN are dependent on the location of the lesion and may include focal neurologic deficits or more generalized signs and symptoms of increased intracranial pressure. Seizures are observed in approximately 20% of individuals.
The current standard care for the treatment of asymptomatic brain RN is observation with serial neuroimaging. For individuals with symptoms, corticosteroids are typically the first-line therapy, with additional conservative treatment options including bevacizumab, anticoagulants, pentoxifylline, high-dose vitamin E, and hyperbaric oxygen therapy. For individuals who remain symptomatic after conservative treatment, the standard treatment is surgical resection (craniotomy), although not all RN lesions are surgically accessible and some individuals are not good candidates for surgery. For such individuals, LITT is a minimally invasive surgical option.
The purpose of LITT is to use a focused thermal therapy technique to ablate regions of cerebral RN in symptomatic individuals with an insufficient or intolerable response to medications, and to potentially avoid complications associated with alternative surgical interventions. The population of interest is individuals with symptomatic cranial RN with insufficient response or intolerance to medication management. LITT is typically used when open surgery is contraindicated due to high risk of procedural morbidity and/or presence of comorbidities that precludes candidacy for open surgery. Outcomes of interest are symptom improvement, medication use, quality of life, treatment-related morbidity, OS, and PFS.
REVIEW OF EVIDENCE
Systematic Reviews
Gecici et al. (2024) conducted a systematic review and meta-analysis of 24 studies (N=547) that compared bevacizumab and LITT in individuals with RN. Most of the included studies were retrospective. Symptomatic improvement or stability occurred in 87.7% and 71.2% of individuals, respectively (P=0.020). Radiologic improvement or stability occurred in 86.2% and 64.7%, respectively (P=0.27). Steroid discontinuation occurred in 45% and 62.4%, respectively (P=0.90). Heterogeneity for all comparisons was high (I2>70%). Adverse event rates were similar between groups (11.2% vs. 14.9%; P=0.66).
Vellayappan et al. (2024) conducted a systematic review of treatments for RN in individuals who had previously undergone SRS. The review was conducted on behalf of the International Stereotactic Radiosurgery Society. Of the 21 included studies, only five included LITT (n=151); one LITT study was prospective and the rest were retrospective. The pooled radiologic improvement/stability rate was 88% (95% CI, 82%–93%) with LITT compared to 94% with bevacizumab. Symptom improvement was only reported in two studies and could not be pooled for analysis. Toxicity results were not consistently reported and no conclusions could be made.
The meta-analysis published by Chen et al. (2021) included 168 (35.7%) individuals with RN who received LITT following prior treatment with SRS. The local control rate for individuals with RN at 6 and 12 months was 83.1% (95% CI, 68.4%–91.8%) and 66.8% (95% CI, 49.1%–80.8%), respectively, and was more satisfactory compared to individuals with recurrent brain metastasis. Overall survival was 83.1% versus 69.2% at 6 months and 66.8% versus 66.5% at 12 months for RN and recurrent brain metastasis groups, respectively. Preablation biopsy, which can accurately diagnose RN, was not routinely performed in all analyzed studies, highlighting a major limitation of this meta-analysis given that it can be quite challenging to accurately distinguish RN from brain metastases based on radiographic evidence alone.
Palmisciano et al. (2021) published a systematic review and meta-analysis of bevacizumab versus LITT for the treatment of RN in individuals with brain metastases previously treated with radiotherapy. Eighteen studies were included for analysis, including 143 individuals treated with bevacizumab and 148 treated with LITT. Compared to LITT, a higher proportion of individuals treated with bevacizumab experienced symptomatic improvement (73.3% vs. 60.8%) and ability to wean off steroids (66.7% vs. 44.1%), but these differences were not significantly different between groups (P=0.187; I2=54.8% and P=0.614; I2=25.5%, respectively). At 18 months, median OS was significantly higher for individuals treated with LITT (46.4% vs. 25%; P=0.038; I2=73.7%). Rates of AEs were similar between bevacizumab (14.7%) and LITT (12.2%) cohorts.
Comparative Observational Studies
Sankey et al. (2022) published a multicenter, retrospective study of SRS-treated individuals with brain metastases who developed biopsy-proven RN who were treated with LITT (n=57) or medical management (n=15). Median follow-up was 10.0 months (range, 4.2–25.1 months). There was no significant difference in median OS (15.2 vs. 11.6 months; P=0.60) or freedom from local progression (13.6 vs. 7.06 months; P=0.40) in LITT or medical management cohorts, respectively. Individuals were able to discontinue steroid therapy earlier in the LITT cohort at a median of 37 versus 245 days (P<0.001).
Sujijantarat et al. (2020) conducted a retrospective chart review comparing outcomes for individuals with biopsy-confirmed RN treated with LITT (n=25) or bevacizumab (n=13) at a single center between 2011 and 2018. The LITT group had a significantly longer OS compared to bevacizumab (median, 24.8 vs. 15.2 months; P=0.003). Time to local recurrence was not statistically significant between groups (P=0.091), but trended longer in the LITT cohort. Among 13 individuals with pre-treatment symptoms in the LITT group, nine (69%) achieved symptom relief. Among 11 individuals with pre-treatment symptoms in the bevacizumab group, four (36%) achieved symptom relief. No significant difference was noted between groups for the ability to wean off concurrent steroids. Given that only 50% of lesions treated with LITT were symptomatic compared to 80% of lesions treated with bevacizumab, the authors suggest that LITT treatment may be more successful before RN lesions become symptomatic.
Hong et al. (2019) conducted a single-center retrospective chart review of individuals treated with LITT or craniotomy for previously irradiated brain metastasis, including 42 individuals with recurrent brain tumors and 33 individuals with RN. Among the 33 individuals with RN, 15 received craniotomy and 18 received LITT, of which 20% and 38.9% received adjuvant postoperative bevacizumab, respectively. No significant differences for mean length of hospital stay, symptom improvement, ability to wean off steroids, or rate of perioperative complications were observed between LITT and craniotomy groups. Overall PFS for individuals with RN was 73.2% and 86.7% at 24 months for individuals treated with LITT and craniotomy, respectively. Overall survival for individuals with RN at 24 months was 64.6% for those receiving craniotomy and 63.2% for those receiving LITT.
Single-Arm Studies
The LAASR study by Ahluwalia et al. (2019) included 19 individuals with biopsy-confirmed RN who received LITT following prior treatment with SRS for brain tumors. PFS and OS were 100% and 91%, respectively, at 12 weeks, and 100% and 82.1%, respectively, at 26 weeks. PFS was significantly higher at 12 weeks for individuals with RN compared to individuals with recurrent tumors (P=0.016) but was not significantly different at 12 weeks (P=0.166). Similar trends were seen for OS in individuals with RN at 12 weeks (P=0.02) and 26 weeks (P=0.09). Thirty percent of subjects were able to stop or reduce steroid usage by 12 weeks after surgery. For individuals with RN, regardless of whether a lesion was totally or subtotally ablated, LITT resulted in close to 100% lesion control and greater than 80% survival at 6 months. No significant differences in Karnofsky performance status, quality of life, or neurocognitive scores were detected between subgroups.
PRACTICE GUIDELINES AND POSITION STATEMENTS
AMERICAN ASSOCIATION OF NEUROLOGICAL SURGEONS (AANS) AND CONGRESS OF NEUROLOGICAL SURGEONS (CNS)
In September 2021, the AANS and CNS Joint Section on Tumors issued a position statement regarding the use of LITT for brain tumors and RN. The statement concludes that "LITT is an appealing option because it offers a method of minimally invasive, targeted thermal ablation of a lesion with minimal damage to healthy tissue. There is a growing body of evidence to demonstrate that LITT is an effective and well tolerated cytoreductive option for treatment of [newly diagnosed glioblastoma multiforme (GBM), recurrent GBM, and primary or recurrent brain metastases.] Intracranial LITT is also an effective option for addressing radiation necrosis with an overall reduction in steroid dependence for these individuals. Especially in instances where the therapeutic window is narrowed such that craniotomy is not a viable option, LITT can play an important role in treatment for glioma or metastatic brain cancer."
AMERICAN SOCIETY OF CLINICAL ONCOLOGY (ASCO)
In 2021, the ASCO issued a joint evidence-based guideline on the treatment of brain metastases with the Society for Neuro-Oncology (SNO) and the American Society for Radiation Oncology (ASTRO) (Vogelbaum et al., 2022). The guideline stated that "no recommendation can be made for or against laser interstitial thermal therapy (Type: informal consensus; Evidence quality: low; Strength of recommendation: none)."
AMERICAN SOCIETY FOR STEREOTACTIC AND FUNCTIONAL NEUROSURGERY (ASSFN)
In September 2021, the ASSFN issued a position statement on the use of LITT in drug-resistant epilepsy (Wu et al., 2021). The statement recommends consideration of MR-guided LITT (MRgLITT) as a treatment option when all of the following criteria are met:
- "Failure to respond to, or intolerance of, at least 2 appropriately chosen medications at appropriate doses for disabling, localization-related epilepsy AND
- Well-defined epileptogenic foci or critical pathways of seizure propagation accessible by MRgLITT."
CONGRESS OF NEUROLOGICAL SURGEONS (CNS)
The CNS guidelines for the treatment of adults with metastatic brain tumors (Elder et al., 2019) state that "there is insufficient evidence to make a recommendation regarding the routine use of laser interstitial thermal therapy (LITT), aside from use as part of approved clinical trials."
INTERNATIONAL STEREOTACTIC RADIOSURGERY SOCIETY
In 2024, the International Stereotactic Radiosurgery Society published recommendations for managing RN after stereotactic radiosurgery (Vellayappan et al., 2024). Individuals with corticosteroid-refractory symptoms can be considered for LITT based on low-quality evidence (weak recommendation). The suggested management flowchart includes LITT as a treatment option for individuals with refractory symptoms after noninvasive therapy such as bevacizumab or hyperbaric oxygen therapy, and as first-line or second-line therapy for individuals with more severe symptoms who require invasive treatment.
NATIONAL COMPREHENSIVE CANCER NETWORK (NCCN)
The NCCN clinical practice guidelines for central nervous system cancers ( v.2.2026) states that MRgLITT "may be considered for patients who are poor surgical candidates (craniotomy or resection). Potential indications include relapsed brain metastases, radiation necrosis, glioblastoma, and other gliomas." (Category 2B) The guidelines additionally state that LITT "can be considered on a case-by-case basis for treatment of radiation necrosis in patients with a history of RT [radiation therapy] for primary brain tumor or metastatic disease. Consultation with neurosurgeons trained in LITT should be done when the procedure is considered."
NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE (NICE)
In 2020, NICE published an interventional procedures guidance on the use of MR-guided LITT for drug-resistant epilepsy. NICE states the following:
- "Evidence on the safety of MRI-guided laser interstitial thermal therapy for drug-resistant epilepsy shows there are serious but well-recognised safety concerns. Evidence on its efficacy is limited in quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research."
- "Further research could be in the form of randomised controlled trials, large case series or collaborative registries. It should report details of patient selection, including the size and site of the lesions being created, patient-reported outcomes and long-term follow up, particularly neurodevelopmental outcomes in children."
