Stereotactic Radiosurgery for Cranial and Spinal Hemangioblastomas: A Single-Institution Retrospective Series

BACKGROUND AND OBJECTIVES: Stereotactic radiosurgery (SRS) has been an attractive treatment modality for both cranial and spinal hemangioblastomas, especially for multiple lesions commonly associated with von Hippel-Lindau (VHL) disease. This study aims to provide the largest long-term analysis of treatment efficacy and adverse effects of SRS for cranial and spinal hemangioblastomas at a single institution. METHODS: We evaluated the clinical and radiological outcomes of patients with hemangioblastomas treated with CyberKnife SRS at our institute from 1998 to 2022. The follow-up data were available for 135 hemangioblastomas in 35 patients. Twenty-eight patients had 123 hemangioblastomas associated with VHL, and 7 had 12 sporadic hemangioblastomas. The median age was 36 years, and the median tumor volume accounted for 0.4 cc. The SRS was administered with the median single-fraction equivalent dose of 18 Gy to the 77% median isodose line. RESULTS: At a median follow-up of 57 months (range: 3-260), only 20 (16.2%) of the VHL-associated and 1 (8.3%) sporadic hemangioblastomas progressed. The 5-year local tumor control rate was 91.3% for all hemangioblastomas, 91.7% among the sporadic lesions, and 92.9% in patients with VHL. SRS improved tumor-associated symptoms of 98 (74.8%) of 131 symptomatic hemangioblastomas, including headache, neck pain, dizziness, visual disturbances, dysesthesia, ataxia, motor impairment, seizures, and dysphagia. Two patients developed radiation necrosis (5.7%), and 1 of them required surgical resection. CONCLUSION: SRS is a safe and effective treatment option for patients with hemangioblastomas in critical locations, such as the brainstem, cervicomedullary junction, and spinal cord, and in patients with multiple hemangioblastomas associated with VHL disease.


H
emangioblastomas are rare vascular neoplasms of the central nervous system. 1 Hemangioblastomas can occur either sporadically or as part of von Hippel-Lindau (VHL) disease.VHL is an autosomal dominant syndrome caused by mutations in the VHL tumor suppressor gene. 2 Patients with VHLassociated hemangioblastomas are typically younger and have a less favorable prognosis due to the development of multiple tumors. 3urgical resection is considered the preferred treatment option for symptomatic hemangioblastomas. 4However, complete resection of all tumors can be challenging, particularly in patients with VHL disease, who may develop multiple tumors. 5he morbidity of repeated surgeries prompted the consideration of radiation therapy as an alternative approach for residual, recurrent, or inoperable hemangioblastomas. 6Hemangioblastomas, due to their well-defined structure comprised lateresponding tissues, benefit from high-dose focused radiation treatment, such as stereotactic radiosurgery (SRS). 7RS precisely target tumors while sparing surrounding normal tissues, thereby reducing the occurrence of adverse radiation effects (ARE).This approach has been shown to improve local tumor control (LTC) and reduce the risk of long-term radiation toxicity.In addition, SRS provides the advantage of concurrently treating multiple, synchronous, or metachronous tumors. 8Following our previous study, 9 we now aim to present the largest single-institutional series of hemangioblastomas treated with SRS.

Patients
From 1998 to 2022, we treated 166 hemangioblastomas in 46 patients using CyberKnife SRS.Patients were selected based on a minimum followup period of 3 months, yielding 135 lesions in 35 patients eligible for inclusion.There were 7 patients (4 male and 3 female patients) with 12 sporadic hemangioblastomas (Group 1) and 28 patients (13 male and 15 female patients) with 123 hemangioblastomas associated with VHL (Group 2).The diagnosis of VHL disease was established through genetic testing of the VHL gene.Our cohort included patients with both cystic and solid hemangioblastomas, while the exploration of patient outcomes will be the focus of our forthcoming study.The related clinical information is maintained in a database approved by the Institution Review Board.Informed consent was obtained from all subjects involved in the study.
Recurrence was defined as the regrowth of a previously treated lesion in the same location, requiring further intervention.Radiation necrosis (RN) was defined as radiographic death of healthy tissues surrounding a tumor after radiation.
The detailed demographics and characteristics of our cohort are presented in Table 1.The cohort consists of 17 male and 18 female patients with a median age of 36 years (range: 18-82) at the time of SRS, 48 years (range: 30-82) in Group 1, and 36 years (range: 18-70) in Group 2 (P < .001).Overall, 29 patients underwent surgery before SRS, with 5 patients in Group 1 and 24 patients in Group 2 (P < .001).Two individuals in Group 1 and 4 patients in Group 2 received SRS as primary treatment based on radiographic diagnosis.None of the patients received previous treatment with belzutifan.Of the 35 patients, 9 (25.7%)experienced tumor progression.Specifically, 8 (28.6%) patients had VHL-associated hemangioblastomas, while 1 (14.3%)patient had sporadic hemangioblastomas.One (3.6%) patient with VHL underwent subsequent surgery, while another patient with VHL deceased.The remaining patients (20%) who experienced tumor progression received subsequent treatment with SRS.

Biologically Effective Dose and Single-Fraction Equivalent Dose
The biologically effective dose (BED) delivered to each lesion was calculated with the linear-quadratic model. 10The α/β ratio was used to model the repair capability of a certain type of cell.An α/β ratio of 3 Gy was used for benign histology. 11The BED was converted to SFED for further comparison using the linear-quadratic model. 12The median BED was 126 Gy (range: 66.7-330), and the median SFED was 18 Gy (range: 12.7-30) for the treated lesions in the entire cohort (Table 1).BED and SFED were not significantly different between the groups.

Follow-up
Patients received clinical evaluation and MRI follow-up twice a year for the first 2 years after SRS and annually thereafter.The tumor volume was measured in axial, sagittal, and coronal planes and calculated by multiplying the dimensions and dividing the resulting number by 2. The statistical analysis was conducted by means of Kaplan-Meier analysis as well as univariate and multivariate analyses.The graphical representations were generated using standard statistical software (IBM SPSS Statistics 29.0) and Origin 2023.The manuscript underwent revision in accordance with the CONSORT guidelines, as endorsed by the EQUATOR Network.

Data Availability
Authors can confirm that all relevant data are included in the article.Data set(s) derived from public resources and made available with the article (references).

Patient Survival
After excluding patients lost to follow-up, 135 lesions were eligible for inclusion in 35 patients.In this article, 34 patients (97.1%) were alive and 1 VHL patient (2.9%) with bilateral cerebellar hemangioblastomas had passed away due to distant progression of an untreated left lesion after CyberKnife SRS and resection of the right lesion.The median follow-up after SRS treatment was 57 months (range: 3-260) (Table 1).The 5-year overall survival (OS) rate from the initial diagnosis was 99.3% (Table 2).

Symptomatic Outcome
Clinical evaluation was available for 32 patients with 131 symptomatic hemangioblastomas.A total of 98 (74.8%) lesions in 31 (96.9%)patients demonstrated symptomatic improvements after SRS treatment (Table 2).In Group 1, motor impairment and dysesthesia exhibited a greater degree of improvement (Figure 2A).Conversely, in Group 2, weight loss, motor impairment, visual disturbances, and dizziness were all observed to show significant improvements (Figure 2B).Only 12 (9.2%)hemangioblastomas in 6 (18.8%) patients with VHL disease displayed a deterioration in clinical symptoms, such as motor impairment, visual disturbances, dysesthesia, neck pain, and headache (P = .004)(Figure 2B).In addition, ARE led to the emergence of new symptoms exclusively in patients with VHL, such as dizziness, visual disturbances, and dysesthesia (P = .01)(Table 2).
Most symptoms of cranial hemangioblastomas remained stable (Figure 2C).Conversely, symptoms arising from spinal hemangioblastomas exhibited significant improvements (Figure 2D).Moreover, it was observed that lesions located in critical areas exhibited remarkable clinical outcomes, as all the symptoms initially presented were improved (Figure 2E and 2F).

Spinal Hemangioblastomas
We observed 42 spinal cases in 18 patients within our entire cohort.The treated median volume was 0.42 cc, and it received a median marginal dose of 20 Gy, corresponding to 80% of the isodose line.The median SFED used was 16 Gy.The 5-year LTC rate of the spinal lesions was 97.4%, which was significantly higher than that of cranial lesions (87.8%) (P < .05)(Table 2, Figure 2C and 2D).Furthermore, the final OS at the latest follow-up was 146.8 months in the spinal lesions, which was significantly shorter than that of cranial lesions (185.6 month) (P < .05)(Table 2).After SRS treatment, clinical symptoms improved in 52.5% of patients with spinal hemangioblastomas.Only 1 patient with spinal hemangioblastoma developed radiation-induced edema (RIE) after SRS treatment, which was successfully managed with steroid treatment.

Radiation-Induced Adverse Events
ARE were observed in 4 patients in the entire cohort.RIE occurred in 3 (8.6%)patients with 8 (5.9%) hemangioblastomas.Two patients (5.7%) and 7 lesions (5.2%) were found to have developed RN.One patient had both RIE and RN.
Lesions experiencing RIE or RN were all VHL-associated and symptomatic.Patients with edema exhibited new-onset headaches, worsening neck and/or chest pain, and extremity weakness or numbness in a dermatomal distribution.One patient with RN reported worsening speech.Steroid treatment was used for all ARE cases, with surgical resection needed for 1 patient with RN.The radiosurgical plan did not differ from that of other lesions.However, multiple SRS treatments were often required for patients with VHL due to their long-standing history, resulting in significant overlap of irradiation zones.

DISCUSSION
Hemangioblastomas can exhibit growth features that can lead to neurological deficits, morbidity, or mortality. 14In our series, 1 patient with VHL-associated cerebellar hemangioblastomas passed away due to progression of an untreated cerebellar lesion, representing 2.9% of the entire cohort.Patients with VHL-associated hemangioblastomas have a higher mortality rate compared with those with sporadic hemangioblastomas. 15,16This study suggests that patients with VHL-related hemangioblastomas require more active monitoring and early intervention.
Our series demonstrates an improved LTC compared with our prior institutional experiences. 9We previously reported 5-year LTC of 82%, while our current data demonstrated 5-year LTC of 91.3% for all hemangioblastomas.Despite lacking statistical significance, the positive outcome seems promising for future improvements in SRS.
For neurological outcomes, 32 patients with 131 lesions (91.4% and 97%, respectively) had clinical symptoms before CyberKnife SRS.SRS resulted in symptomatic improvement in 74.9% of the lesions in 96.9% of the patients.Although SRS usually stabilizes tumor size without shrinkage, patients typically experience clinical improvement.Gradual tumor regression was more frequent in follow-up exceeding 3 years, consistent with previous findings. 15n Hippel-Lindau Disease The median volume of sporadic hemangioblastomas was 4.7 cc (Group 1), which was significantly greater than that of VHLassociated lesions (0.4 cc, Group 2) (Table 1).Patients in Group 2 were significantly younger compared with the patients of Group 1, potentially due to the more frequent MRI monitoring of VHL-associated tumors.The LTC rate did not differ significantly between these groups after 5 years (Table 2).However, there was a noteworthy decrease in the LTC rate in Group 2, resulting in substantial discrepancies during the final follow-up evaluation.Moreover, symptomatic worsening and new symptoms were observed exclusively in Group 2, likely due to multiple treatment courses (Table 2, Figure 2).In univariate and multivariate analyses, younger patients with VHL who received SRS treatment with lower SFED within a shorter interval of time had better long-term LTC rates (Table 3).

Spinal Hemangioblastomas
The LTC rate of spinal lesions was significantly higher than that of cranial tumors (Figure 3A and 3B) (P < .05)with complete or partial improvement of all symptoms initially presented (Table 2, Figure 2C and 2D).Furthermore, both univariate and multivariate analyses revealed that hemangioblastomas located in the spinal regions were associated with an improved LTC (Table 3, Figure 3C  and 3D).Despite the decline in LTC observed during the latest follow-up, spinal hemangioblastoma demonstrated superior tumor control compared with cranial lesions (Table 2).
Despite spinal lesions exhibiting a higher LTC rate compared with cranial lesions, they display significantly shorter OS rates.Therefore, it is imperative to develop customized treatment schedules based on tumor characteristics to achieve effective treatment while minimizing the risk of ARE or radiation-induced myelopathy in spinal regions.Although we were successful in preventing severe ARE among our patients, it remains crucial to conduct further investigations into treatment plans to refine the optimal dose, fractionation scheme, and organ-at-risk constraints specifically for spinal tumors.8][29][30][31][32][33][34][35][36][37][38][39][40] Our series showed no mortality in spinal hemangioblastomas, and only 1 patient developed RIE after SRS.In total, 92.9% of lesions were associated with VHL disease.These findings strongly support the use of SRS as a safe and highly effective treatment option for patients with spinal hemangioblastomas, especially in cases with multiple lesions.

Hemangioblastomas in Critical Location
Hemangioblastomas located in the brainstem or cervicomedullary junction were considered to have a surgically unfavorable location due to their proximity to critical neurovascular structures. 13In our study, 88% of hemangioblastomas in critical areas demonstrated a significant improvement in the initial symptoms after SRS treatment (Figure 2F) with 100% LTC and OS rates at 5 years, and no occurrence of new symptoms or ARE (Table 2).Although OS remained at 100% during the most recent follow-up evaluation, the LTC rate exhibited a decrease to 66.7% (Table 2).Based on our treatment plans and findings, SRS emerges as an excellent treatment option for hemangioblastomas located in critical areas.However, further research is warranted to validate these findings and establish their broader applicability.

Complications
Preexisting peritumoral edema may render a patient unsuitable for SRS, as treatment may exacerbate neurological symptoms.ARE in our series was predominantly related to multiple treatments with overlapping radiation fields resulting in cumulative radiation doses and was associated with VHL.

Limitations
Limitations of our study include its retrospective nature, potential for incomplete data and selection bias, and the need for long-term follow-up to assess safety and efficacy of SRS.Caution should be exercised when interpreting prognostic factors and comparing SRS with surgery.Moreover, despite the initial superiority in OS and LTC rates at 5 years, a subsequent decrease was observed in these rates over the long term, underscoring the need for further advancements in treatment.The association between lower SFED and better LTC requires further validation with larger samples.Furthermore, SRS may not yield desirable outcomes in patients with asymptomatic hemangioblastomas.In cases of symptomatic tumors accompanied by cysts or edema, caution is warranted due to the heightened risk of ARE and poor LTC, as demonstrated in our forthcoming study.

CONCLUSION
This study is the largest long-term analysis of hemangioblastomas treated with SRS.SRS is a valuable treatment option for both sporadic and VHL-associated hemangioblastomas, providing excellent LTC, preventing further growth, and managing symptoms.SRS is a promising alternative for patients with multiple hemangioblastomas associated with VHL disease or in challenging surgical regions.

COMMENTS
T he effectiveness of radiosurgery for hemangioblastomas has been well-documented, with reported tumor control rates comparable to or even exceeding those of surgery.CyberKnife provides high accuracy in targeting and can be applied also to spinal cord lesions.Furthermore, this platform provides the benefit of multifraction dose delivery with potential, but substantially unexplored benefits.The authors report the largest long-term analysis of cranial and spinal hemangioblastomas treated with SRS based on a single-institution experience.The study provides relevant and unique information, but leaves some questions still open.
The 5-year local control (ie, >90%) is impressive.Nevertheless, a subsequent decline was observed over the long term, underscoring the need for further advancements in treatment.Overall, radiation-induced toxicities were limited to around 5%, that is more than acceptable as compared to surgical morbidity.Another fundamental question is the optimal dose-response rate for those lesions.The authors used a single fraction in the majority of the cases and median (single-fraction equivalent) marginal dose of 18 Gy for cerebellar/brainstem and 16 Gy for spinal cord lesions.This is a relevant practical information for clinicians involved in radiosurgery.We need however further information regarding the best dose/fraction scheme based on the combination of site and volume of the lesion.Also, the authors identified an association between lower dose and better local control, which appears to be counterintuitive.For this, further validation with larger and multicentric studies are needed.
While radiosurgery offers numerous advantages, not all cases are suitable for this treatment approach.Tumor size, location, and proximity to critical structures must be evaluated to determine the optimal treatment strategy for each patient.Authors correctly recommend that for symptomatic tumors accompanied by cysts or edema, caution should be taken due to the increased risk of toxicity and poor local control.
In conclusion, radiosurgery confirms to be a valuable tool in the management of hemangioblastomas, holding great promise in improving patient outcomes and quality of life especially in patients with VHL requiring multiple lifelong treatments.Cautions are, however, necessary for larger and critically located lesions whose long-term outcome requires more data.

FIGURE 1 .
FIGURE 1. Summary of patient outcome according to Kaplan-Meier method with the number of lesions at risk; local tumor control rate of A, sporadic vs VHL-associated hemangioblastomas (P = .8),hemangioblastomas in B, cranial vs spinal (P = .038),and C, noncritical vs critical locations (P = .32).VHL, von Hippel-Lindau.

FIGURE 2 .
FIGURE 2. Summary of clinical presentations at baseline and the symptomatic development after treatment with CyberKnife stereotactic radiosurgery in 3 categories: improved (blue), stable (gray), and worsened (red) in patients with A, sporadic hemangioblastomas, B, VHL disease, C, cranial hemangioblastomas, D, spinal hemangioblastomas, E, hemangioblastomas in noncritical location, and F, hemangioblastomas in critical location.VHL, von Hippel-Lindau.

FIGURE 3 .
FIGURE 3. CyberKnife treatment plan at baseline A + C and the radiographic studies at the latest follow-up B + D in axial panel of patients with a cranial A + B and a spinal C + D hemangioblastomas.A, A 45-yearold female patient with a history of VHL disease and multiple hemangioblastomas located in the right cerebellum, presented with headaches, dizziness, and dysesthesia in her right arm and face before the CyberKnife SRS treatment.A marginal dose of 16 Gy was delivered with the maximum dose of 21.92 Gy in a single fraction to 73% of the isodose line.The treatment has resulted in a significant size reduction of the tumors and an improvement of headaches and dysesthesia in her right arm.B, The 21-month follow-up MRI demonstrated a decrease of the right cerebellar hemangioblastoma in size after SRS treatment.C, A 38-year-old female patient with VHL with an intramedullary spinal hemangioblastoma at the T4 level presented with hypoesthesia and motor impairment in her right hand before CyberKnife SRS treatment.A marginal dose of 21 Gy was delivered with the maximum dose of 25.93 Gy in 3 fractions to 81% of the isodose line.The treatment has successfully reduced the size of tumor significantly and improved pre-SRS symptoms.D, The 15-month follow-up MRI demonstrated interval decrease in size of T4-5 spinal cord hemangioblastoma after SRS treatment.The diameter of the syringomyelia and spinal cord edema has also decreased.SRS, stereotactic radiosurgery; VHL, von Hippel-Lindau.

TABLE 1
NEUROSURGERY VOLUME 94 | NUMBER 3 | MARCH 2024 | 633 STEREOTACTIC RADIOSURGERY FOR HEMANGIOBLASTOMAS © Congress of Neurological Surgeons 2023.Unauthorized reproduction of this article is prohibited.

TABLE 2 .
Summary of Patient Outcomes FU, follow-up; LTC, local tumor control; NS, new symptoms; OS, overall survival; SI, symptomatic improvement; SW, symptomatic worsening; VHL, von Hippel-Lindau disease; y, years.a P values were calculated using log-rank test.Bold entries indicate vairables of significance (P <.05).b Critical locations include brainstem and cervicomedullary junction.