Laser Ablation of Newly Diagnosed Malignant Gliomas: a Meta-Analysis

Ivan, Michael E. MD, MBS; Mohammadi, Alireza M. MD; De Deugd, Nicoleta BS; Reyes, Joshua; Rodriguez, Gregor BS; Shah, Ashish MD; Barnett, Gene H. MD; Komotar, Ricardo J. MD

doi: 10.1227/NEU.0000000000001446
Laser Interstitial Thermal Therapy (LITT) in Neurosurgery Supplement

BACKGROUND: Magnetic resonance-guided laser-interstitial thermotherapy (MR-LITT) is a minimally invasive technique that shows promise in neuro-oncology because of its superiority in delivering precise minimally invasive thermal energy with minimal collateral damage.

OBJECTIVE: In this analysis, we investigate initial data on the use of MR-LITT in the treatment of newly diagnosed high-grade gliomas.

METHODS: With the use of the PubMed, OVID, and Google-scholar database systems, a comprehensive search of the English literature was performed. Eighty-five articles were identified plus 1 that is pending publication. Four articles were accounted for in this review, including 25 patients with newly diagnosed high-grade gliomas who underwent MR-LITT treatment. We evaluated safety, progression-free survival, and overall survival.

RESULTS: Twenty-five patients with a mean age of 53.8 years underwent LITT treatments. On average, 82.9% of the pretreatment lesion volume was ablated. The average tumor volume treated was 16.5 cm3. The mean follow-up time was 7.6 months. Median overall survival was found to be 14.2 months (range 0.1-23 months). The median progression-free survival was 5.1 months (range 2.4-23 months); however, these data are limited by the relatively short follow-up of the patients reviewed and small sample size of only 25 patients. There was 1 (3.4%) major perioperative complication, which was a central nervous system infection.

CONCLUSION: MR-LITT is a promising technology for the treatment of small, yet difficult-to-treat newly diagnosed high-grade gliomas. This study demonstrates that MR-LITT is safe, and future randomized studies are needed to evaluate its role as a treatment adjunct for newly diagnosed high-grade gliomas.

ABBREVIATIONS: BBB, blood-brain barrier

HGG, high-grade glioma

LITT, laser-interstitial thermal therapy

WHO, World Health Organization

*Department of Neurological Surgery, Sylvester Comprehensive Cancer Center, The University of Miami Miller School of Medicine, Miami, Florida;

The Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Department of Neurological Surgery, Neurological and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio

Correspondence: Michael E. Ivan, MD, MBS, Department of Neurosurgery, Lois Pope Life Center, University of Miami, 1095 NW 14 Terrace, D4-6, 2nd Floor, Miami, FL 33136. E-mail:

Received January 15, 2016

Accepted September 02, 2016

Article Outline

For patients with operable, newly diagnosed high-grade glioma (HGG), defined as World Health Organization (WHO) Grade III to IV, although a diffuse disease,1 the first-line treatment is cytoreduction via maximal safe surgical excision followed by temozolomide chemotherapy and radiation therapy.2 However, the mean survival time is low (12-14 months) or up to 21.7 months if the patients have methylguanine methyltransferase promoter methylation and are treated with both temozolomide and radiation therapy.3 Although extent of tumor resection as low as 78% has been shown to improve overall survival compared with chemotherapy and radiation therapy alone,4 some patients do not qualify as surgical candidates because of their multiple comorbidities,5 the deep-seated location of their lesions, low functional scores, or inability to tolerate general anesthesia. Moreover, if the tumor is located within an eloquent area, total resection sometimes cannot be achieved without the risk of injuring the adjacent vital structures.6 When traditional craniotomy is deemed unsafe for the patient, the need for an alternative to open surgery becomes apparent. In these patients, laser-interstitial thermal therapy (LITT), a procedure for ablating tissue by heat generated through light absorption, is then considered.7-10 MR-LITT has shown promise over other minimally invasive techniques because of its superiority in delivering precise thermal energy in a highly controlled manner with minimal collateral damage.6,7,11-14

LITT has been used since the 1980s; however, only recently has it regained popularity as a minimally invasive surgical option for difficult-to-treat tumors owing to the progress made in design and functionality of the laser probe and real-time thermal imaging with MRI. The systems available for performing the LITT procedure are Visualase Thermal Therapy System (Visualase; Medtronic, Minneapolis, Minnesota) and the NeuroBlate System (Monteris Medical, Kalamazoo, Michigan). Placing the laser probe under stereotactic guidance and local anesthesia is possible with both systems, with the surgeon controlling the depth and rotation of the laser probe.15 Precise monitoring of the ablation of the lesion, also useful in protecting adjacent eloquent areas of the brain, is possible with Magnetic Resonance Thermal Imaging.

Previous studies in recurrent HGGs have found that the LITT technique may have advantages over repeat craniotomies because of its minimally invasive nature of access, which improves patient healing, decreases morbidity and mortality, and provides the benefit of uninterrupted chemotherapy treatment.16 Furthermore, because it is based on thermal destruction of the tumor, LITT is not constrained by a maximum dose limit and may be used multiple times. Similar results were reported by Carpentier et al17 in a study on patients with metastatic brain tumors in which median survival time was reported to be 17 months, compared with 7 months, the median prognosis survival prediction.17

Finally, because adjuvant treatment of HGGs with chemotherapy is difficult because of the selective permeability of the blood-brain barrier (BBB) in preclinical animal studies as well as in patient studies, thermotherapy has been shown to improve the delivery of therapeutic agents18,19 and was further considered as a means of manipulation of BBB in patients with brain neoplasms. Schwarzmaier et al20 hypothesized that a possible explanation for the better clinical outcome of their patients could be attributed to the disruption of the BBB following the LITT therapy.

Despite given these benefits of using thermotherapy as a means of treating brain neoplasms, to date there is no article that solely investigates the LITT procedure for patients with newly diagnosed gliomas. In the present study, we aim to review the results reported in the published literature for HGGs treated with LITT, and explore whether this procedure is safe for newly diagnosed gliomas and could potentially improve the progression-free and overall survival in patients treated with LITT as an initial treatment.

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Using the PubMed, OVID, and Googlescholar database systems, a literature search was conducted using the key words “Laser Interstitial Thermal Therapy” AND “tumor” or “neoplasm” or “glioma” or “glioblastoma.” The filters were set to 15 years, accounting for the years between 2001 and 2016 inclusively. After including articles found in reference lists and excluding duplicate articles, a total of 85 articles were screened. Criteria for inclusion were limited to articles containing upfront treatment of intracranial HGGs using stereotactic laser ablation on human subjects. Retrospective studies, prospective analyses, and case series were included in the review, but commentaries, editorials, and reviews without any clinical data were excluded. Articles were also excluded if at least 1 of the data parameter outcomes (complications, overall survival, or progression-free survival) was not reported. None of the articles were found to be duplicates. The last PubMed search was conducted on June 27, 2016. A flow diagram in Figure 1 shows the number of articles found, screened, and included in the analysis. In addition, unpublished data were included that have been submitted and are in review (Ivan et al, unpublished data, September 2016).

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Data Extraction

The 3 articles included in the review were carefully analyzed to identify all relevant patient data. In addition, 1 article by a coauthor that is under review was included in the analysis. Factors considered relevant to the review included patient demographics, tumor size, location of the tumor, system used for ablation, and the patient outcomes from the procedure. These factors were then divided and presented with demographics and perioperative information. None of the studies reported were randomized controlled studies, and therefore, bias cannot be completely excluded in the data reported or extracted.

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Data Analysis

An analysis of progression-free survival and overall survival after LITT was performed by using JMP software (SAS Institute Inc, Cary, North Carolina). Confounding factors were carefully inspected; however, because of the limited amount of data available, no significant correlations could be determined. Data for all patients available in the literature were presented when possible.

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Study Characteristics

An initial search of the literature screening for articles that included LITT for HGGs returned 6 articles, including 3 reviews and 3 clinical series. Only the 3 clinical series, which included patient data, and 1 series pending review were included in this review and are presented in Table 1. A total of 29 patients were presented in the clinical series; however, 4 patients' data overlapped in 2 articles, reducing the number of the present review to 25 patients.

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Patient Characteristics

Only patients with a WHO grade of III or IV were considered in the review, including 1 anaplastic oligodendroglioma, 3 anaplastic astrocytomas, and 21 glioblastomas. Lesion location was reported as 1 basal ganglia, 7 frontal lobe, 1 corpus callosum, 3 temporal lobe, 1 parietal lobe, 1 insular, 1 midbrain, and the remaining 10 in the thalamus. The mean patient age was 53.8 (range, 19-81). The Neuroblate system was used for 19 patients, and the Visulase Thermal Therapy was used for 6 patients (Table 2). The literature for LITT performed on newly diagnosed HGGs is still very sparse and data for patient outcomes are not reported in a systematic way or with complete follow-up, making analysis difficult.

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LITT Treatment

Outcome data were available for a total of 25 MR-LITT ablations on 25 patients. Tumor size was available on 22 patients and extent of ablation was available on 9 patients. The mean target volume was found to be 16.5 cm3 (range, 1.5-70 cm3) for the 22 patients with data. Using the Neuroblate system's intraoperative thermometry at 43°C or the Visualase approximation of ablation line, an average extent of ablation of 82.9% (range, 46.5%-100%) was measured. Clinical notes were included for case 4 indicating that the patient had had a prior aborted awake craniotomy; however, this case was still considered as newly diagnosed treatment because no prior treatment was performed. No correlation between percent ablated or tumor volume can be made with these limited data. After MR-LITT was performed, all patients received chemotherapy and radiation per standard of care.

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LITT Safety and Clinical Status Postablation

Our results are limited by the complication data only being available in 13 of 25 patients. No intraoperative mortality was noted, nor did any intraoperative complications occur in this series of 25 patients. Postoperative complications are listed in Table 3. Two serious postoperative complications were noted. The first included a postoperative central nervous system infection that led to death. Another early complication was noted in a patient that developed significant postoperative ablation edema, after a 70 cm3 lesion was ablated in 3 sessions; this patient needed a hemicraniotomy. Since this incident, the group no longer offers ablation to patients with such large lesions. Additional complications included postoperative hyponatremia in 1 patient, postoperative deep vein thrombosis in 1 patient, and transient aphasia that recovered in 24 hours in 1 patient. No patients experienced permanent neurological side effects from the ablative procedure. Although the most common side effect presented in the literature for postoperative LITT patients is transient neurological deficit from edema, we only noted 1 case in this series.

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LITT Outcomes: Overall Analysis

All patients in this review were followed with serial MRI scans as well as follow-up visits. Data collected were used to determine time to progression and overall survival, which is presented in Table 3. The follow-up time varied greatly, from 0.1 to 18.6 months, with the mean of 7.6 months. Twelve patients are still being followed or were lost to follow-up. Figure 2 depicts the survival analysis for this cohort. The median overall survival time was 14.2 months (range, 0.1-23 months). Figure 3 shows the average progression-free survival at 5.1 months (range 2.4-23 months). The 75% confidence interval for these curves is noted in Figures 2 and 3.

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Current Therapies and Outcomes for Glioblastomas and Other HGGs

Overall survival for HGG does depend on various preoperative predictors but overall can average between 8.5 and 14.5 months.21-26 In this review we demonstrate that MR-LITT can provide comparable outcomes to those who undergo open surgery or biopsy before chemotherapy and radiation for selected patients. The overall survival of the patients who received MR-LITT in this review was 14.2 months.

MR-LITT has also shown adequate overall survival times in patients with recurrent HGGs and specifically recurrent glioblastomas.13,19,21,27-29 Results from a recent systematic review of LITT in recurrent gliomas demonstrated an overall median survival from LITT procedure of 9.9 months, and a median progression-free survival of 4.5 months in recurrent gliomas. Further investigation into MR-LITT using both newly diagnosed and recurrent HGGs is warranted.

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Advantages of MR-LITT

In our experience, we have found multiple advantages of using MR-LITT as a minimally invasive approach in the treatment of HGGs.13,16,28-32 MR-LITT has the ability to reach tumors that are located deep in the brain with minimal manipulation of the overlying tissue. This allows tumors in locations such as the basal ganglia to be treated with MR-LITT when otherwise they would only be biopsied.33 The procedure is very minimally invasive requiring only a small 3-mm skin incision and insertion of a small laser probe. Therefore, there is minimal tissue disruption, which decreases the decadron needed postoperatively and shortens the hospital stay to only 1 to 2 days.33 The lessened invasiveness also allows patients with significant comorbidities to undergo MR-LITT who might otherwise not tolerate a large cranial surgery. If the tumor progresses after MR-LITT, the patient may receive additional treatments of MR-LITT because there is no risk of cumulative ionizing radiation damage.33 In addition, if needed, a biopsy of the lesion can be obtained at the time of ablation, which allows for additional tissue sampling for pathological and genomic testing. Radiation treatment does not allow for these unless a separate biopsy procedure is performed. Finally, we have noticed that, because of the small incision and minimal tissue manipulation, patients can begin their adjuvant chemotherapy sooner than if waiting the typical 3 weeks postoperatively when receiving chemotherapy after an open craniotomy.33 Further investigation is needed to determine the optimal timing of chemotherapy and radiation in concordance with MR-LITT, because breakdown of the BBB following MR-LITT could provide an improvement in drug diffusion into the tumor.20

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Our Experience Using MR-LITT for Gliomas

In all cases, we report no complications during the procedure itself, and the use of MR-LITT as a minimally invasive technique thus continues to demonstrate safety. This has been well described in literature previously.12,13,34 The most common postoperative complication noted in the literature is transient neurological deficit,28 but we only noted 1 episode of this complication.

Current literature discusses the need to completely ablate tumors >95% of the tumor volume without overablation and extension to nearby healthy tissues to achieve the best local recurrence rates while minimizing injury to the local structures.16,28 In our series, there are too few data points to analyze; however, our experience supports that increased extent of ablation will offer prolonged tumor control in other tumor types. This further supports the overarching concept in tumor surgery that achieving a maximal safe reduction of tumor burden is the goal.

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This review focuses on the subgroup of patients with HGG that were treated with LITT as a first option, in lieu of craniotomy resection. The documentation on these patients is very limited. Many of the patients have a short follow-up period and this series contains a small sample size. Therefore, an estimated overall survival and progression-free survival should be viewed as only preliminary data. Likewise, with such a small cohort and confounding factors such as the fatal central nervous system infection of case 5, the ability to fully understand the impact of the use of LITT compared with classical resection is limited. In addition, molecular profiling, Karnofsky Performance Scale, and treatment type specifics were not available on this group of patients, which can lead to variable results. Ultimately, however, MR-LITT continues to prove to be a safe technique for providing tumor ablation in select patients with minimal side effects. Furthermore, randomized controlled studies need to be completed to draw statistically significant conclusions. None of the studies reported were randomized controlled studies, and, therefore, bias cannot be completely excluded in these reports.

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MR-LITT continues to be explored as a minimally invasive option for cytoreduction of difficult-to-treat HGGs. In our review, we show the safety of MR-LITT for the primary treatment of HGGs, which offers several advantages over open surgical treatment. MR-LITT is a promising technology for the treatment of newly diagnosed HGGs in select patients; however further randomized studies are needed to evaluate MR-LITT's role as a standard treatment adjunct in this patient population.

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Michael Ivan and Ricardo Komotar are paid consultants of Medtronic. Alireza Mohammadi and Gene Barnett are paid consultants of Monteris Medical. The other authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. Please note the use of Laser Ablation is only Food and Drug Administration Approved for the ablation of soft tissue.

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Brain tumors; Laser-interstitial thermotherapy; Glioblastoma; Glioma; Minimally invasive neurosurgery

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