Long-term clinical outcomes of stereotactic radiotherapy for bilateral vestibular schwannomas in neurofibromatosis type 2 patients

The evidence for treating patients with neurofibromatosis 2-related vestibular schwannoma (VS-NF2) using hypofractionated stereotactic radiation therapy (HSRT) is limited. This study aimed to investigate clinical outcomes in patients with VS-NF2 treated with Robotic HSRT. We retrospectively analyzed 25 NF2 patients with 48 VSs who were treated using Robotic HSRT at Ramathibodi Hospital from January 2009 to January 2020. Median follow-up was 98 months (range, 24–155 months). Median tumor volume was 2.3 cm3 (range, 0.4–28.3 cm3). Median prescribed dose was 18 Gy (range, 18–25 Gy) in three fractions (range, 3–5). The 5- and 10-year local control rates were 87% and 80%, respectively. The 5- and 10-year hearing preservation rates were 59% and 35%, respectively. Three patients developed new symptoms associated with transient volume expansion after treatment: hydrocephalus in one, facial weakness in one, and ataxia in one. No patient developed worsening of trigeminal nerve function. No histologically confirmed of radiation induced malignancy was reported in the study. Robotic HSRT demonstrated excellent long-term tumor control with a low non-auditory complication rate in patients with VS-NF2. However, preservation of hearing remains a major concern.


Introduction
Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disorder caused by mutations in the NF2 gene [1,2].Bilateral vestibular schwannomas (VSs) are a hallmark, but NF2 is also associated with other benign schwannomas as well as meningiomas and ependymomas.Patients with NF2-related VS (VS-NF2) commonly present with progressive hearing loss and deafness.There are several different

Patients
This retrospective study examined consecutive patients diagnosed with NF2 who harbored unilateral or bilateral VSs treated using Robotic HSRT at Ramathibodi Hospital, Mahidol University in Bangkok, Thailand from January 2009 to January 2020.Patients with VS-NF2 are managed in our institution using a team-based approach.Treatment decisions are mainly based on symptoms and Koos classification [8].
For Asymptomatic Koos I tumors, observation is generally recommended.Symptomatic patient with Koos grade I-III tumors are typically treated with HSRT.Koos grade IV tumors are typically resected with or without postoperative HSRT.However, some patients with Koo grade IV tumors and contraindications for surgery may be treated using HSRT.All patients provided informed consent for treatment.The study was approved by the institutional review board of Ramathibodi Hospital.

HSRT
HSRT was delivered using a Robotic radiosurgery; CyberKnife G4 system (Accuray, Inc., Sunnyvale, CA, USA), which uses a 6 MV light-weight linear accelerator that is mounted on an articulated robotic arm.Multiplan Treatment Planning Software (Accuray, Inc.) was used for inverse treatment planning.Real-time 6D skull tracking was applied for image-guidance to visualize and engage the intracranial lesion.A thermoplastic facemask was individually constructed for patients to wear while lying in the supine position.Computed tomography simulation was performed with the mask applied using 1.25 mm slice thickness.Simulation images and gadolinium-enhanced magnetic resonance images were transferred to the treatment planning workstation.Gross tumor volume (GTV) and critical structures were delineated at the workstation.No additional margin was added to the GTV to obtain the clinical target volume (CTV) and planning target volume (PTV).
HSRT was delivered in three to five fractions.Total dose ranged from 18 to 25 Gy and was prescribed to the periphery of the lesion.Prescribed isodoses were selected individually for each patient to cover more than 95% of the GTV Selection of total tumor dose, number of fractions, and prescribed isodose varied among patients according to tumor size and treating physician preference.Treatment planning (Fig. 1) was determined and finalized by a radiosurgery team comprising neurosurgeons, radiation oncologists, and medical physicists.

Assessment of treatment response and toxicity
Patients were followed clinically and with magnetic resonance imaging (MRI) to evaluate treatment outcomes.Hearing function was evaluated using patient-reported hearing ability and audiometric testing.Hearing function was classified using the Gardner-Roberson (GR) system [9]; class I and II hearing was defined as serviceable.Trigeminal and facial nerve function were assessed using the Barrow Numbness Index and House-Brackman score [10], respectively.New trigeminal or facial nerve symptoms or worsening of pre-existing ones were defined as nonauditory complications.
MRI was performed annually or biannually for the first 5 years, and then every 2 to 3 years thereafter.Radiologic response was reported using the standard RECIST criteria [11].Local control was defined as the absence of radiologic tumor progression.Transient volume expansion (TVE) was defined as the eventual shrinkage of the tumor after transient enlargement.If the surgery was performed in the course of the enlargement, it was defined as tumor progression.Hearing preservation was defined as the presence of serviceable hearing (GR class I or II) at last follow up.

Statistical analysis
Categorical data are expressed as numbers with and percentage.Continuous data are expressed as medians with range.Survival was determined using the Kaplan-Meier method.Univariate and multivariate survival analysis were performed using the log-rank test and Cox proportional hazard regression, respectively.Variables in the analysis included age at diagnosis (both continuous and categorical: </=18 vs. > 18 year).Gender, Koos grade (Koos 1-2 vs. Koos 3-4), previous surgical (yes vs. no).Statistical analyses were performed using STATA software (17.0,StataCorp, Coollege station, TX, USA).

Tumor response and local control
Median clinical follow-up was 98 months (range; 24-155).TVE occurred after treatment in 13 tumors (27%) in 13 patients.These tumors appeared eventual shrinkage of the tumor after transient enlargement with the median time of 12 months (range 5-30).Three of these patients developed new symptoms in conjunction with TVE, including one with hearing decrease and facial weakness that improved with dexamethasone treatment.With the median imaging F/U of 65 months (range, 24-90), the tumor response was classified as stable in 30 (63%), PR in 11 (23%), and PD in 7 (14%).
In six patients with seven tumors classified as PD, two developed symptoms in conjunction with TVE; the other four had progressive tumors.Four of these six required surgical intervention, including tumor resection in three (two with a progressive tumor and one with TVE) and ventriculoperitoneal shunt placement in one patient who developed hydrocephalus because of TVE.The two other patients with progressive tumors did not undergo surgery because of extensive simultaneous bilateral tumor progression and poor performance status.One died because of the tumor and the other was still alive at last follow-up.The 5-and 10-year local control rates for the entire cohort were 87% and 80%, respectively (Fig. 2A).The median time to progression was 42 months (range, 10-83).In the univariable analysis, Koos grading (Fig. 2C) and patient's age (Fig. 2D) correlated significantly with local control.In multivariable analysis using the Cox proportional hazards model, patient's age > 18 year was the only factor significantly associated with better local control (supplementary Table 1).Figure 3 presented case of bilateral VS treated with HSRT and showed different response in each tumor.

Hearing preservation
Median auditory F/U time was 76 months (range; 24-150).Seventeen patients with 18 tumors had serviceable hearing in the affected ear before treatment: GR class I in 13 (72%) and class II in 5 (28%).One patient with bilateral VSs presented with GR class 1 hearing on both sides and maintained serviceable hearing in both throughout follow-up of 146 months.Nine patients (53%) developed worsening of hearing in the treated ear.The 5-and 10-year hearing preservation rates were 59% and 35%, respectively (Fig. 2B).Median time to hearing deterioration was 59 months (range, 5-146).Serviceable hearing was maintained in 62% of patients with GR class I hearing before treatment; in patients with class II hearing, serviceable hearing was maintained in only 20%.In univariable and multivariable analysis, no factor was significantly associated with hearing preservation (Supplementary Table 2).

Non-auditory complications
No patient developed new or worsening facial numbness after HSRT.Histologically confirmed of radiation-induced malignancy was no reported in the study.

Discussion
Management of VS-NF2 remains challenging because these tumors are frequently bilateral and they occur in young patients.Moreover, the risks of malignant transformation and radiation-induced tumors are a particular concern in young patients [12,13].Based on the European Association of Neuro-Oncology guidelines for treatment of patients with VS-NF2 [14], observation with surveillance imaging every 6 to 12 months is recommended for asymptomatic small tumors.Surgical decompression is mandatory for large tumors compressing the brainstem.For tumors that are incompletely resected to preserve hearing and/or facial nerve function, the residual may be treated using SRS.SRS may also be used to treat smaller tumors to preserve hearing and facial nerve function.Bevacizumab is also recommended in NF2 patients because of its effects on hearing and VS growth [3].Although treatment of sporadic VSs using HSRT has been previously reported [15], the role of HSRT for treating VS-NF2 is unclear.To the best of our knowledge, this is the first study to report long-term clinical outcomes of HSRT treatment of VS-NF2.
In previous studies of SRS in VS-NF2, 10-year local control rates varied between 41% and 87% [7,[16][17][18][19][20][21][22][23].The large difference in rates might be due to inter-study differences in design, definition of tumor control, and length of follow-up.Local control at 10 years in our study was 80%, which is comparable with the above rates and the 88% rate reported in a meta-analysis of SRS for NF2-VS [22].Based on our results, HSRT appears to provide excellent tumor control comparable with that of SRS.Table 2. Summarized studies of Linac-based stereotactic RT for VS-NF2.Although various factors have been associated with tumor control, such as age, previous surgery and tumor volume [7,26,27], independent factors have not been definitively established.We graded tumor bulkiness using the Koos classification and found that Koos grade III/IV was the factor significantly associated with tumor progression, which agrees with two previous reports [20,26].In contrast, another previous study reported no correlation between tumor size and outcome [20].However, tumor size cutoffs varied between studies, which makes interpretation and comparison of studies difficult.Future studies are warranted to better define tumors that are appropriate to treat using SRS or HSRT.Younger patient age was also revealed to be a predictor of poor tumor control in this and previous studies [27,28].With specific NF2 gene mutations in young age, the disease's severity and prognosis as a whole are known to worsen.These genotype-phenotype relationships may have an impact on treatment outcomes [2,29].18-21, 23, 26].The reasons these rates are so low in NF2 patients are multifactorial and remain unclear.
Fractionation has been employed in many CNS tumor for a long time because it's potential to spare normal tissues while also eradicating tumor cells [30,31].Stereotactic radiosurgery (SRS) is the unique technique for administering high-precision radiation in a single high dose.The possibilities for stereotactic radiation therapy (SRT), which using hypofraction (2-5 fractions) or up to 5-6 weeks of Thirteen tumors (27%) transiently enlarged after treatment and then stabilized or decreased in size.This TVE is common in benign tumors treated using SRS/SRT.All patients in our study who experienced TVE did not require surgical intervention.
Hearing preservation is a critical challenge in NF2 patients with VSs.In previous SRS studies, the 5-year serviceable hearing preservation rates ranged from 10 to 50%; at 10 years, the rates decreased to between 25% and 30% [7, rates of tumor control of > 97%, however SRT patients had a rate of hearing preservation that was 2.5 times greater.Contrarily, Lo et al. [37] observed the hearing preservation steadily declined over time during the long term auditory F/U, even with a fractionated schedule.In addition, SRS was associated with higher rates of trigeminal nerve dysfunction.The conflicts of the studies may be caused by the relatively small numbers of NF2 patients and retrospective nature of investigations.A large sample size with a welldesigned study concentrating on NF2 patients would be helpful to identify the role of SRT in NF2 patients.
Our 5-and 10-year hearing preservation rates were 59% and 35%, respectively, which are similar to those in the SRS studies.HSRT therefore did not improve hearing preservation as we had anticipated.Based on previous studies including our study, most RT modalities seem to be rarely effective to revert the natural course of hearing dysfunction conventional fraction, were expanded with the advent of advanced customized Gamma-Knife and Linear accelerators.SRS uses high ablative single doses, whereas SRT is based on the well-known radiobiological effects of multiple fractions comprising lower doses per fraction up to a required much higher total dose that ought to lead to differential sparing of healthy normal brain parenchyma, cranial nerve and brainstem tissue [31][32][33].Although fractionation is theoretically better for decreased rates of cranial nerve toxicity, notably of the cochlear nerves, this has not been clearly approve yet.Based on earlier investigations of vestibular schwannomas, comparable high tumor control rates between SRS and SRT were consistently reported; however, it was found that there was disagreement regarding cranial nerve toxicity, particularly with the rate of hearing preservation across different studies [4,6,[34][35][36][37].For the example, Andrew et al. [4] observed that both SRS and SRT had high  Trigeminal and facial neuropathy are also concerning potential complications of SRS in patients with VS-NF2; reported rates of facial neuropathy range from 16 to 50% [19,27].Such high rates may be due to the less sophisticated treatment plans and higher SRS doses used in the old era of SRS treatment.Recent advances in radiosurgery technique along with the use of lower SRS doses and fractionation has reduced these rates to between zero and 5% [21,22,26].No patient in our study experienced facial or trigeminal neuropathy as a complication.
Despite their efficacy and low complication rate, SRS and HSRT have not been widely used to treat patients with VS-NF2, probably because of concerns about malignant transformation and radiation-induced tumors.The true incidence rates of these potential complications are unknown and reported rates vary.No patient in our study developed a secondary tumor or experienced malignant transformation, which is consistent with previous reports [7,16,[19][20][21][22][23][24]26].However, a recent study of NF2 patients in the UK reported a 6% long-term risk of malignancy/malignant progression in those treated with radiation; in contrast, the risk was < 1% in non-irradiated patients [38].The study concluded that radiation therapy should not be the first-line option for treating benign tumors in NF2 patients.Nonetheless, radiation therapy will still have a role, especially for inoperable tumors and in older patients and those with comorbidities.

Conclusion
HSRT is effective for tumor control in patients with VS-NF2 and associated with a low non-auditory complication rate; however, hearing preservation, radiation-induced tumors, and malignant transformation remain concerns.HSRT should be recommended for growing tumors in older patients, patients with comorbidities, and those with inoperable tumors.HSRT should not be recommended in patients with VS-NF2 if hearing preservation is a goal.Although development of radiation-induced tumor and malignant transformation did not occur in our study, they are known risks that must be clearly disclosed to patients prior to HSRT.

Fig. 2
Fig. 2 Kaplan-Meier survival curves of tumor control (A) and hearing preservation rate (B) in all patient.Kaplan Meier plot comparing local control in patients who had Koos grade 1-2 vs. grade 3-4 (C) and age < 18 year vs. > 18 year (D)

Fig. 3 Table 2
Fig. 3 Bilateral vestibular schwannomas are shown (A) before, (B) 6 months after, and (C) 12 months after hypofractionated stereotactic radiotherapy.The tumors showed different responses.The tumor on the right appeared more bulbous initially with an altered enhancement pattern; then it decreased to the pretreatment volume, suggestive of transient volume expansion.In contrast, the one on the left continuously enlarged and required resection.Postoperative imaging is shown in panel (D) Sequential follow-up scans (E and F) showed bilateral tumor regression over time

Table 1
Patient, tumor, and treatment characteristics FundingThe authors declare that no funds, grants or other support were received during the preparation of this manuscript.in NF2 patient.Our policy generally avoided using HSRT in patients with VS-NF2 who have serviceable hearing.On the other hand, HSRT should considered in VS-NF2 without serviceable hearing.