Radiological and clinical outcomes of stereotactic radiosurgery for gangliogliomas: an international multicenter study

Georgios MantziarisDepartment of Neurological Surgery, University of Virginia, Charlottesville, Virginia;

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Joshua DiamondDepartment of Neurological Surgery, University of Virginia, Charlottesville, Virginia;

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Stylianos PikisDepartment of Neurological Surgery, University of Virginia, Charlottesville, Virginia;

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Farid M. El HefnawiDepartment of Neurosurgery, Cleveland Clinic, Cleveland, Ohio;

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Ghusn Al SideiriDepartment of Neurosurgery, Cleveland Clinic, Cleveland, Ohio;

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François-Louis CoupéDepartment of Neurosurgery, Université de Sherbrooke, Centre de recherche du CHUS, Sherbrooke, Quebec, Canada;

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David MathieuDepartment of Neurosurgery, Université de Sherbrooke, Centre de recherche du CHUS, Sherbrooke, Quebec, Canada;

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Cheng-Chia LeeDepartment of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan;

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Jaromir MayDepartment of Stereotactic and Radiation Neurosurgery, Na Homolce Hospital, Prague, Czech Republic;

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Roman LiščákDepartment of Stereotactic and Radiation Neurosurgery, Na Homolce Hospital, Prague, Czech Republic;

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Selcuk PekerDepartment of Neurosurgery, Koc University School of Medicine, Istanbul, Turkey; and

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Yavuz SamanciDepartment of Neurosurgery, Koc University School of Medicine, Istanbul, Turkey; and

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Ajay NiranjanDepartment of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

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L. Dade LunsfordDepartment of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

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Jason P. SheehanDepartment of Neurological Surgery, University of Virginia, Charlottesville, Virginia;

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OBJECTIVE

The optimal treatment for recurrent and residual gangliogliomas remains unclear. The aim of this study was to evaluate the safety and efficacy of stereotactic radiosurgery (SRS) in the management of patients with recurrent or residual intracranial ganglioglioma.

METHODS

This retrospective multicenter study involved patients managed with SRS for ganglioglioma. The study endpoints included local tumor control and tumor- or SRS-related neurological morbidity following treatment. Factors associated with tumor progression and neurological morbidity were also analyzed.

RESULTS

The cohort included 20 patients (11 males [55%]) with a median age of 24.5 (IQR 14) years who had been managed with SRS for ganglioglioma. Five-year radiological progression-free survival was 85.6%. After SRS, 2 patients (10%) experienced transient neurological deterioration. At a median clinical follow-up of 88.5 (IQR 112.5) months, 1 patient (5%) experienced seizure worsening and 1 (5%) required further resection of the tumor because of radiological progression. No mortality was noted in this series.

CONCLUSIONS

SRS appears to be a safe and effective treatment option for surgically inaccessible, recurrent, and residual gangliogliomas. In this series, the 5-year progression-free survival rate after SRS was 85.6%. Gross-total resection remains the primary treatment of choice for patients with newly diagnosed or recurrent ganglioglioma. SRS may be considered for patients unfit for surgery and those with surgically inaccessible newly diagnosed, residual, and recurrent lesions.

ABBREVIATIONS

CNS = central nervous system; GKRS = Gamma Knife radiosurgery; GTR = gross-total resection; IRRF = International Radiosurgery Research Foundation; SRS = stereotactic radiosurgery; STR = subtotal resection.

OBJECTIVE

The optimal treatment for recurrent and residual gangliogliomas remains unclear. The aim of this study was to evaluate the safety and efficacy of stereotactic radiosurgery (SRS) in the management of patients with recurrent or residual intracranial ganglioglioma.

METHODS

This retrospective multicenter study involved patients managed with SRS for ganglioglioma. The study endpoints included local tumor control and tumor- or SRS-related neurological morbidity following treatment. Factors associated with tumor progression and neurological morbidity were also analyzed.

RESULTS

The cohort included 20 patients (11 males [55%]) with a median age of 24.5 (IQR 14) years who had been managed with SRS for ganglioglioma. Five-year radiological progression-free survival was 85.6%. After SRS, 2 patients (10%) experienced transient neurological deterioration. At a median clinical follow-up of 88.5 (IQR 112.5) months, 1 patient (5%) experienced seizure worsening and 1 (5%) required further resection of the tumor because of radiological progression. No mortality was noted in this series.

CONCLUSIONS

SRS appears to be a safe and effective treatment option for surgically inaccessible, recurrent, and residual gangliogliomas. In this series, the 5-year progression-free survival rate after SRS was 85.6%. Gross-total resection remains the primary treatment of choice for patients with newly diagnosed or recurrent ganglioglioma. SRS may be considered for patients unfit for surgery and those with surgically inaccessible newly diagnosed, residual, and recurrent lesions.

Gangliogliomas are rare central nervous system (CNS) tumors of glioneuronal histopathology. They account for less than 1% of all CNS tumors1–3 and are usually benign (WHO grade I), although atypical (WHO grade II) and anaplastic (WHO grade III) gangliogliomas can occur.2,3 These neoplasms most commonly affect children and young adults, are usually located in the temporal lobe, and constitute the most common cause of tumor-related temporal lobe epilepsy.3

Gross-total resection (GTR) usually provides long-term tumor control and is the treatment of choice for newly diagnosed and recurrent lesions.3 When GTR is not feasible, observation or adjuvant radiation as a management option is typically used,3–5 although the need for adjuvant radiation treatment has been debated.3 In this study, we discuss the role of adjuvant stereotactic radiosurgery (SRS) for the treatment of residual and recurrent gangliogliomas.2,6–8

Methods

Study Population and Inclusion Criteria

This study included patients managed with SRS for an intracranial ganglioglioma at seven centers participating through the International Radiosurgery Research Foundation (IRRF). All participating centers obtained institutional review board approval for the study and for sharing the de-identified data with the IRRF coordinating office. Data were verified for completeness by the IRRF coordinator at each center.

Study inclusion criteria were tissue diagnosis of ganglioglioma and at least one clinical and radiological follow-up. Collected data included patient demographics and pertinent history such as age at ganglioglioma diagnosis and at SRS, indication for SRS (i.e., adjuvant or at recurrence), neurological function at SRS and the last follow-up, radiological features of the tumor (i.e., solid, cystic, or mixed) prior to SRS and at the last follow-up, procedural details (e.g., margin dose, maximum dose, and isocenter number), and post-SRS treatments.

Study Endpoints

The primary safety endpoint was defined as the absence of SRS-related mortality and morbidity at the last follow-up. The primary effectiveness endpoint was radiological tumor stability or regression after SRS. The secondary endpoint was the incidence of treatment-related morbidity following SRS.

Tumor response was defined as either an increase (i.e., progression) or a decrease (i.e., regression) in tumor volume at the last follow-up by > 20% of the baseline volume. Tumor stability was defined as variation in tumor volume within 20% of its baseline volume at the last radiological follow-up.

Stereotactic Radiosurgical Technique and Follow-Up

The stereotactic frame (Leksell frame, Elekta Instruments AB) was placed with the patient under monitored anesthesia and in a sitting position. Patients whose age was < 18 years underwent frame placement while under general anesthesia. Following frame placement, a stereotactic head CT scan and/or brain MR image were obtained.

A dose plan was formulated by the local treating team to safely deliver an effective radiation dose to the target tumor while maximizing dose falloff outside the tumor volume. Typically, the procedural target volume included both the solid and cystic components of the tumor.

After SRS, patients were followed up with clinical and radiological assessments according to local institutional protocols.

Statistical Analysis

All statistical analyses were performed using R programming (R Foundation for Statistical Computing) in RStudio (RStudio Team 2020). A p value < 0.05 was considered statistically significant. Predictors of tumor progression by > 20% and new post-SRS symptoms were evaluated using Cox regression analysis considering patient age, sex, tumor volume, and marginal SRS dose. The Kaplan-Meier method was used to perform time-dependent analysis for progression-free survival.

Results

Patient Characteristics

A total of 20 SRS-treated patients (11 males [55%]) with a median age of 24.5 (IQR 14) years were included in the study. At the time of SRS, 8 patients (40%) were asymptomatic, 5 (25%) were managed medically for seizures, 5 (25%) complained of headaches or dizziness, 2 (10%) had cerebellar symptoms, 1 (5%) had facial hypesthesia, and 1 (5%) had visual field deficits (Table 1). The median Karnofsky Performance Status at the time of SRS was 90 (IQR 10).

TABLE 1.

Baseline characteristics of 20 patients with ganglioglioma

CharacteristicValue
Male sex11 (55%)
Median KPS at SRS (IQR)90 (10)
Median age at SRS in yrs (IQR)24.5 (14)
Pre-SRS symptom
 None8 (40%)
 Headache/dizziness5 (25%)
 Seizures5 (25%)
 Nausea/vomiting2 (10%)
 Visual deficits1 (5%)
 Sensory deficits1 (5%)
Prior surgery
 GTR 6 (30%)
 STR 8 (40%)
 Biopsy6 (30%)
Prior adjuvant treatment
 None18 (90%)
 External beam radiotherapy2 (10%)
 Chemotherapy1 (5%)

KPS = Karnofsky Performance Status.

Prior to SRS, 6 patients (30%) underwent GTR, 8 (40%) subtotal resection (STR), and 6 (30%) biopsy. The median time from resection to SRS was 9 (IQR 23.3) months. Two patients (10%) had been previously treated with conventional radiotherapy and 1 (5%) with chemotherapy.

Indications for SRS were disease recurrence following GTR in 6 patients (30%), surgically inaccessible lesions biopsied in 6 patients (30%), and treatment following STR in 8 patients (40%) either at ganglioglioma progression (6/8) or as an adjuvant treatment without documented tumor progression (2/8; Tables 1 and 2).

TABLE 2.

Individual patient and tumor characteristics

Case No.SexLesion LocationPrior ResectionPrior Chemo/RTWHO Grade/BRAF V600ETime to SRS (mos) Reason for SRSPrescription Dose in Gy (fractions)Radiological OutcomeClinical OutcomePost-SRS TxFU (mos)
1FTemporal lobeSTRI6RP17ProgressedStable12
2FTemporal lobeGTRI26CP24ProgressedStableResection36
3FLateral ventricleGTRChemo/RTI/+11RP15StableStable15
4MParietal/occipital lobeGTRI/+53RP15StableImproved6
5FParietal/occipital lobeSTRI134RP20RegressedStable12
6MOccipital lobeSTRRTI56RP18RegressedStable84
7FTemporal lobeSTRI2ADJ28RegressedImproved156
8FFrontal lobeBiopsyI2LI15RegressedSeizures worsened156
9MParietal lobeSTRI15ADJ4.5 (×5)RegressedImproved19
10MParietal lobeBiopsyI3LI5.5 (×5)RegressedImproved96
11MThird ventricleGTRII47RP16RegressedTransient headache158
12MParietal lobeSTRI26CP14RegressedImproved216
13MOccipital lobeGTRI25RP12RegressedImproved132
14FTemporal lobeSTRI10RP13RegressedImproved95
15MTemporal lobeSTRI8RP11StableImproved25
16FBrainstemBiopsyI8LI12RegressedTransient motor weakness26
17MTemporal lobeBiopsyI1LI12StableImproved93
18MFrontal lobeGTRI6RP14RegressedStable53
19FCerebellumBiopsyI1LI12RegressedImproved148
20MHypothalamusBiopsyI0LI13RegressedStable120

+ = yes; ADJ = adjuvant treatment; chemo = chemotherapy; CP = clinical progression; FU = follow-up; LI = location inaccessible; RP = radiographic progression; RT = radiation therapy; Tx = treatment.

Tumor and Treatment Parameters

The median tumor volume at the time of SRS was 4.1 (IQR 5.6) cm3. Nineteen patients (95%) harbored WHO grade I gangliogliomas, and 1 patient (5%) had a WHO grade II tumor (Table 3). Immunohistochemistry reports were available in 2 patients, both of whom tested positive for the BRAF V600E mutation.

TABLE 3.

Tumor and SRS treatment characteristics

CharacteristicValue
Median tumor vol at SRS in cm3 (IQR) 4.1 (5.6)
Cystic component present9 (45%)
WHO grade
 I19 (95%)
 II1 (5%)
Tumor location
 Temporal lobe6 (30%)
 Frontal lobe2 (10%)
 Parietal lobe5 (25%)
 Occipital lobe4 (20%)
 Brainstem 1 (5%)
 Cerebellum1 (5%)
 Hypothalamus1 (5%)
 Ventricular system2 (10%)
SRS treatment parameters
 Median margin dose in Gy (IQR)15 (5.8)
 Median max dose in Gy (IQR)30 (14.4)
Hypofractionated treatments2 (10%)

SRS was performed using the Gamma Knife (Elekta AB). Treatment was delivered in a single fraction in 18 patients (90%), while the remaining 2 (10%) underwent hypofractionated radiosurgery involving a 5-fraction approach. The median margin dose was 15 (IQR 5.8) Gy.

Clinical Outcomes

At a median clinical follow-up of 88.5 (IQR 112.5) months, 10 patients (55%) reported improvement in their neurological symptoms following SRS; resolution of headache was noted in 5 patients (25%), decrease in seizure frequency requiring less or no antiepileptic medication in 4 patients (20%), and partial improvement of ataxia in 1 patient (5%).

Transient and permanent neurological deterioration following SRS were noted in 2 (10%) and 1 (5%) patient, respectively. One patient experienced worsening seizures and required additional antiepileptic medications. One patient had transient weakness worsening after Gamma Knife radiosurgery (GKRS) for a left medullary lesion, and 1 patient harboring a WHO grade II ganglioglioma experienced transient increased headache post-GKRS. Both patients had T2-weighted hyperintensities at the treatment site after GKRS and required a short course of oral corticosteroid treatment (Radiation Therapy Oncology Group [RTOG] grade 2 early radiation morbidity). One patient (5%) underwent resection for asymptomatic cystic tumor progression. The pathology of the tumor remained consistent with WHO grade I ganglioglioma, and following surgical excision, the patient remained asymptomatic under antiepileptic medication. Further information on the long-term outcomes of the second patient with the asymptomatic radiological progression is not available.

Radiological Outcomes

At a median radiological follow-up of 68 (IQR 131.8) months, the primary study endpoint of tumor control was reached by 18 patients (90%), including 1 (5%) harboring a WHO grade II ganglioglioma (Fig. 1, Tables 2 and 3). At the last radiological follow-up, 14 gangliogliomas (70%) had regressed and 4 (20%) had remained stable. Radiological progression was noted in 2 patients (10%), 1 (5%) of whom was managed with resection 36 months after SRS treatment. Univariate and multivariate analysis did not reveal any significant factors associated with tumor progression.

FIG. 1.
FIG. 1.

Left: Procedural axial contrast-enhanced T1-weighted MR image significant for a third ventricle, WHO grade II ganglioglioma with overlying prescription (16 Gy) and isodose (12 Gy) lines. Right: Axial contrast-enhanced T1-weighted MR image demonstrating tumor regression at the last radiological follow-up (13 years). Figure is available in color online only.

Discussion

SRS appears to be a safe and effective management option for patients with ganglioglioma. In our study, which included 20 patients treated with SRS for ganglioglioma, 5-year radiological progression-free survival was 85.6% (Fig. 2). At a median clinical follow-up of 88.5 (IQR 112.5) months, 3 patients (15%) experienced neurological deterioration. No risk factors associated with post-SRS radiological progression and clinical deterioration were identified in the patient analysis.

FIG. 2.
FIG. 2.

Kaplan-Meier plot demonstrating radiological progression-free survival following SRS treatment with a 5-year radiological progression-free survival of 85.6%.

GTR is associated with high rates of long-lasting tumor control and is the initial management of choice for patients with ganglioglioma. In a single-center retrospective study of the radiological and clinical outcomes of 184 patients surgically managed for ganglioglioma, GTR was achieved in 146 patients (79%). The 7.5-year recurrence-free survival rate after GTR was 99%, significantly higher than after STR (92%).3 Tumor location significantly influences management of the disease,9 hindering GTR when the tumor involves eloquent areas or is close to critical structures.10

The role of adjuvant radiotherapy in the management of residual low-grade and anaplastic gangliogliomas is unclear. Although adjuvant radiotherapy provides higher local control rates,11 the low radiological progression rates of residual disease3,10 and concerns about malignant transformation of gangliogliomas following radiotherapy2,12,13 have promoted an active surveillance approach.14 Adverse radiation effects, including vasculopathy and neurocognitive and endocrinological complications, usually make radiotherapy undesirable in the pediatric and young adult population.15

The efficacy of systemic chemotherapy as an adjuvant therapy following STR or in recurrence is also unclear.16 Standard chemotherapy regimens have shown limited benefit in extending progression-free survival17 but may be beneficial in delaying radiotherapy in the pediatric population.14,18 BRAF V600E mutations have been detected in approximately 50% of gangliogliomas19,20 and are associated with poor outcomes following conventional radiation treatment and chemotherapy, suggesting that BRAF V600E–mutated gangliogliomas may constitute a different tumor type.19,21 Positive responses following targeted monotherapy or combination therapies with BRAF inhibitors have been reported in case reports on adult and pediatric patients with low-grade and anaplastic gangliogliomas.18,22–25 The results of several ongoing clinical studies are pending (NCT01748149, NCT02684058, and NCT02124772).

SRS has been utilized in the treatment of patients with gangliogliomas after STR or at recurrence following GTR. However, data on the safety and effectiveness of SRS in the management of residual and recurrent gangliogliomas are mostly limited to those in small case series,6 studies evaluating multiple radiotherapy and radiosurgical modalities,2,7,8 or radiosurgical series with diverse neuroepithelial histopathology.26 The present study represents the largest series focusing exclusively on post-SRS radiological and clinical outcomes of ganglioglioma patients.

According to our results, SRS appears to afford a tumor control rate comparable to the 75%–90%7,11 tumor control rate reported using radiotherapy, with a lower rate of adverse radiation events. In addition, because of the different radiobiological effect2,6 and the low risk of radiation-induced malignancy,27 SRS may be a more beneficial management option than classic radiotherapy for patients with gangliogliomas.

The natural history of supratentorial gangliogliomas is frequently complicated by epilepsy; thus, control of epileptic seizures constitutes an important clinical outcome in ganglioglioma management. Currently, there is conflicting evidence concerning the effect of GTR compared to STR in epileptic seizure control.8,28,29 However, symptomatic relief of epilepsy (Engel class I) has been reported at a rate between 76% and 88% following resection.6 In our series, 3 of 5 patients with epileptic activity at SRS experienced favorable clinical outcomes. Therefore, we believe that SRS represents an attractive treatment option for patients with epilepsy refractory to medical management who are not good candidates for GTR.

Study Limitations

Limitations of our study include the bias inherent to its retrospective design, the lack of a centralized radiological review leading to interrater and intrarater variability, and the nonstandardized follow-up protocols among the participating centers. Because of the small sample size, our analysis of factors that could be associated with tumor progression and patient outcomes, such as extent of resection as well as radiosurgical and tumor parameters, could not be fully realized.

Conclusions

GTR remains the optimal management choice for ganglioglioma. SRS may be recommended as an adjuvant treatment after partial resection, at progression, and at recurrence following GTR. In our study, 5-year radiological progression-free survival was 85.6% and only 1 patient experienced worsening seizures. Further well-designed studies are necessary to establish the role of SRS in the management of gangliogliomas.

Disclosures

Dr. Lunsford is a shareholder in Elekta AB, the manufacturer of some radiosurgical devices, and a member of the data safety monitoring board of Insightec. Dr. Liščák is a consultant for Elekta AB.

Author Contributions

Conception and design: Sheehan. Acquisition of data: Mantziaris, Diamond, Pikis, El Hefnawi, Al Sideiri, Coupé, Mathieu, Lee, May, Liščák, Peker, Samanci, Niranjan, Lunsford. Analysis and interpretation of data: Sheehan, Mantziaris, Diamond, Pikis. Drafting the article: Mantziaris, Diamond, Pikis. Critically revising the article: Sheehan, Mantziaris, Diamond, Pikis, El Hefnawi, Al Sideiri, Coupé, Mathieu, Lee, May, Peker, Samanci, Niranjan, Lunsford. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Sheehan. Statistical analysis: Mantziaris, Diamond, Liščák. Study supervision: Sheehan.

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Illustration from Xu et al. (pp 1418–1430). With permission from Juan Carlos Fernandez-Miranda and The Neurosurgical Atlas by Aaron Cohen-Gadol.

  • View in gallery
    FIG. 1.

    Left: Procedural axial contrast-enhanced T1-weighted MR image significant for a third ventricle, WHO grade II ganglioglioma with overlying prescription (16 Gy) and isodose (12 Gy) lines. Right: Axial contrast-enhanced T1-weighted MR image demonstrating tumor regression at the last radiological follow-up (13 years). Figure is available in color online only.

  • View in gallery
    FIG. 2.

    Kaplan-Meier plot demonstrating radiological progression-free survival following SRS treatment with a 5-year radiological progression-free survival of 85.6%.

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