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doi: 10.1227/NEU.0000000000000264
Research-Human-Clinical Studies: Editor's Choice

Stereotactic Radiosurgery for Neurofibromatosis 2—Associated Vestibular Schwannomas: Toward Dose Optimization for Tumor Control and Functional Outcomes

Mallory, Grant W. MD*; Pollock, Bruce E. MD*,‡; Foote, Robert L. MD; Carlson, Matthew L. MD§; Driscoll, Colin L. MD*,§; Link, Michael J. MD*,§

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Editor's Choice
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Author Information

*Departments of Neurologic Surgery,

Radiation Oncology, and

§Otolaryngology—Head and Neck Surgery, Mayo Clinic School of Medicine, Rochester, Minnesota

Correspondence: Michael J. Link, MD, Department of Neurologic Surgery, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail: link.michael@mayo.edu

Received August 11, 2013

Accepted November 25, 2013

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BACKGROUND: Management of neurofibromatosis type 2 (NF2)—associated vestibular schwannomas (VSs) remains controversial. Stereotactic radiosurgery (SRS) with conventional dosing is less effective for NF2-related VS compared with sporadic lesions.

OBJECTIVE: To evaluate optimal SRS dose parameters for NF2-related VS and to report long-term outcomes.

METHODS: A prospective database was reviewed and outcome measures, including radiographic progression, American Academy of Otolaryngology—Head and Neck Surgery hearing class, and facial nerve function, were analyzed. Progression-free survival was estimated with Kaplan-Meier methods. Associations between tumor progression and radiosurgical treatment parameters, tumor volume, and patient age were explored with the use of Cox proportional hazards regression.

RESULTS: Between 1990 and 2010, 26 patients with 32 NF2-related VSs underwent SRS. Median marginal dose and tumor volume were 14 Gy and 2.7 cm3, respectively. Twenty-seven tumors (84%) showed no growth (median follow-up, 7.6 years). Kaplan-Meier estimates for 5- and 10-year progression-free survival were 85% and 80%, respectively. Cox proportional hazards demonstrated a significant inverse association between higher marginal doses and tumor progression (hazard ratio, 0.49; 95% confidence interval, 0.17-0.92; P = .02). Audiometric data were available in 30 ears, with 12 having class A/B hearing before SRS. Only 3 maintained serviceable hearing at the last follow-up. Four underwent cochlear implantation. Initially, 3 achieved open-set speech recognition, although only 1 experienced long-term benefit. Facial nerve function remained stable in 50% of cases.

CONCLUSION: Higher marginal doses than commonly prescribed for sporadic VS were associated with improved tumor control in patients with NF2. Hearing outcomes were poor even when contemporary reduced marginal doses were used. However, SRS allows an anatomically preserved cochlear nerve and may permit hearing rehabilitation with cochlear implantation. Further consideration should be given to optimum dosing to achieve long-term control while maximizing functional outcomes.

ABBREVIATIONS: HB, House-Brackmann

NF2, neurofibromatosis type 2

SRS, stereotactic radiosurgery

VS, vestibular schwannoma

Neurofibromatosis type II (NF2) is an autosomal-dominant neurocutaneous syndrome resulting from a mutation in the NF2 gene on chromosome 22q12.1,2 Despite full penetrance, disease expressivity is extremely variable, with some patients presenting late in life with small bilateral eighth nerve schwannomas and others developing innumerable intracranial and spinal tumors before 20 years of age.3 Compared with sporadic tumors, NF2-related vestibular schwannomas (VSs) commonly develop at a younger age, behave more aggressively in terms of recurrence, and result in a greater number of associated cranial nerve deficits.3-5 Regardless of management, the majority of subjects with NF2 will ultimately acquire significant bilateral hearing loss. Options for aural rehabilitation include conventional hearing amplification, bone-anchored hearing aids for single-sided deafness, cochlear implantation for patients with nonaidable hearing and an anatomically preserved cochlear nerve, and auditory brainstem implantation when a functional cochlear nerve is no longer present.

Current treatment options for NF2 include observation, stereotactic radiosurgery (SRS) or fractionated radiotherapy, microsurgery, and more recently, bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor.6 Although radiosurgical outcomes after treatment of sporadic VSs have been studied extensively, there remains a paucity of literature on optimal dosing, long-term hearing preservation rates, and long-term tumor control among patients with NF2.7-11 Here, we review our experience managing NF2-related VSs over the last 2 decades to further define SRS outcomes and to provide recommendations regarding optimal dosing.

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Patient Selection

After Institutional Review Board approval (Institutional Review Board No. 13-004588) was granted, a prospectively maintained clinical database including all patients who underwent SRS for VS was reviewed, and all subjects fulfilling the Manchester (modified National Institutes of Health) diagnostic criteria for NF2 were identified.12 Additional patient data were then gathered, including baseline demographics, radiosurgical planning parameters, tumor characteristics, duration of follow-up, and pretreatment and posttreatment facial nerve function and hearing capacity. In accordance with Minnesota state statutes, all living patients consented to review of their medical records.

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Radiosurgical Planning and Indications for Treatment

All SRS was performed with the Leksell Gamma Unit (Elekta AB, Stockholm, Sweden). A model G Leksell stereotactic head frame was applied under local anesthesia. Axial and coronal postgadolinium T1-weighted (3-mm thickness, no skip) magnetic resonance images (MRI; 1990-1996) or high-resolution spoiled gradient recalled acquisition T1-weighted images (1-mm thickness; 1997-present) were obtained with a 1.5-T scanner (GE Healthcare Ltd, Little Chalfont, Buckinghamshire, United Kingdom). Since 2007, stereotactic noncontrast computed tomography of the temporal bone was also obtained and fused with the MRIs to optimize tumor targeting and to minimize radiation to normal adjacent structures, including the cochlea. Planning was performed on a computer workstation using the KULA dose planning system (1990-1995) or Leksell GammaPlan software (1995-present; Elekta AB, Stockholm, Sweden). Radiation was delivered initially with a model U (January 1990-December 1996), model B (January 1997-June 2001), model C (June 2001-October 2007), and most recently, Perfexion model (October 2007-present) Gamma Units.

Indications for SRS changed over the study period, reflecting evolving treatment paradigms. Initially, patients with NF2 received SRS for treatment of VSs when 1 or more of the following conditions were met: They were medically unfit for surgery; they refused microsurgery and the radiosurgical team agreed that SRS was an appropriate alternate treatment; the tumor was located in an only hearing ear and microsurgery was felt to carry an assured risk of ipsilateral deafness; or postoperative residual or recurrent tumor was present. Over time, the management strategy evolved to include initial observation for small nongrowing tumors, reserving treatment for patients with enlarging tumors and/or progressive hearing loss.

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Clinical Follow-up and Outcomes

The duration of follow-up was measured from the date of SRS to the most recent clinical evaluation. Patients were routinely seen every 6 months for the first year after treatment, annually for the next 3 years, and at least biennially thereafter; follow-up intervals were shortened in cases of new symptoms or radiographic evidence of progression. MRI scans were performed at each follow-up interval, and audiograms were obtained until the patient was determined to be functionally deaf. Tumors involving the cistern were measured using 2 orthogonal dimensions in the axial plane, excluding tumor within the internal auditory canal as outlined by the 1995 American Academy of Otolaryngology—Head and Neck Surgery consensus guidelines.13 Audiometric data were presented according to American Academy of Otolaryngology—Head and Neck Surgery guidelines, and facial nerve function was appraised by use of the House-Brackmann (HB) grading scale.13,14 Dosimetry analysis included marginal and maximum dose and treatment volume.

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Statistical Analysis

Tumor progression-free survival was estimated at 5 and 10 years after SRS with the Kaplan-Meier method. Tumor progression was defined as enlargement of at least 2 mm on 2 or more consecutive posttreatment imaging studies. Progression-free intervals were defined as the time from SRS treatment to tumor growth or last radiographic follow-up. Cox proportional hazards regression analysis was used to evaluate for associations between tumor progression and age, tumor volume, and marginal dosing. Hazard ratios are reported with 95% confidence intervals. Continuous variables are reported as median values. The Wilcoxon rank-sum test was used to compare median marginal doses in patients with worsened and stable facial nerve outcomes. Statistical analysis was performed with JMP software (SAS, Cary, North Carolina) with the assistance of a biomedical statistician. Statistical significance was defined as a value of P < .05.

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Baseline Treatment Data

Between 1990 and 2010, 26 patients (38% female) with NF2 underwent SRS for 32 presumed VSs at our institution. The median age at time of treatment was 37 years (range, 13-68 years), and the median duration of post-SRS follow-up was 7.6 years (range, 1-21.8 years). Five of the 26 patients were treated sequentially with SRS for bilateral VSs. The median time between treatments was 4.0 years (range, 1.7-7.0 years). Indications for treatment are shown in Table 1. The majority of patients had enlarging tumors (n = 24) and/or ipsilateral hearing loss (n = 25) at the time of treatment. As a result of the nature of our referral practice and the timeline of the study, exact growth rates could not be determined in all patients because many scans from outside centers were not available for direct comparison at the time of this analysis. The range of growth before treatment varied from 2 to 9 mm/y (median, 2 mm) in the largest posterior fossa dimension in those tumors in which it could be determined (n = 11). Five patients had undergone prior ipsilateral microsurgical resection and either had recurrent VS or developed new de novo tumors on remaining eighth nerve fibers that were subsequently treated with SRS. Six received SRS on the side of their only hearing ear. Tumor volume ranged from 0.4 to 11.2 cm3 (median, 2.7 cm3). The median posterior fossa diameter among tumors that enlarged was 15 mm (range, 6-40 mm). The median marginal and maximum doses were 14 Gy (range, 12-20 Gy) and 28 Gy (range, 24-40 Gy), respectively.

Table 1
Table 1
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Tumor Control

At a median follow-up of 7.6 years (range, 1.3-21.7 years), 27 tumors (84%) were either smaller (n = 19, 59%) or unchanged in size (n = 8, 25%). The median reduction in posterior fossa tumor diameter was 5 mm (range, 2-15 mm) in tumors that decreased in size (Figure 1). Tumor enlargement was seen in 16% (n = 5) of tumors at a median follow-up interval of 8.8 years (range, 4.8-12.3 years; Figure 2). Two patients with tumor progression underwent microsurgical resection with pathological confirmation of schwannoma, and the remaining 3 patients continue to be followed up despite definite enlargement. Kaplan-Meier estimates for 5- and 10-year progression-free survival were 85% and 80%, respectively (Figure 3). Cox proportional hazards regression demonstrated a significant inverse association between radiation dose and tumor progression (hazard ratio, 0.49; 95% confidence interval, 0.17-0.92; P = .02). The median marginal dose of tumors that became smaller (n = 19) was 15.5 Gy (range, 12-20 Gy), whereas the median marginal dose for VSs that enlarged after SRS (n = 5) was 13 Gy (range, 12-14 Gy). No statistically significant associations were found between tumor size (hazard ratio, 1.0; 95% confidence interval, 0.91-1.05; P > .05) and patient age (hazard ratio, 0.98; 95% confidence interval, 0.99-1.0; P > .05), although this analysis was limited by small sample size.

Figure 1
Figure 1
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Figure 2
Figure 2
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Figure 3
Figure 3
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Audiological and Facial Outcomes

A total of 30 ears had documented pretreatment and posttreatment audiometric data and were included in the analysis. Twelve had serviceable hearing (American Academy of Otolaryngology—Head and Neck Surgery class A or B) before SRS (Table 2), and 6 patients had serviceable hearing only in the ipsilateral ear at the time of SRS treatment. At the last follow-up, 3 maintained serviceable hearing. The remaining 9 cases progressed to either class C (n = 3) or class D (n = 6) hearing. The median post-SRS follow-up in those who maintained serviceable hearing was 2.0 years (range, 1.7-4.0 years) compared with 14.1 years (range, 1.3-21.8 years) in those who progressed to nonserviceable hearing. Kaplan-Meier estimates for median time to progression to nonserviceable hearing was 75 months (Figure 4). The time to progression to nonserviceable hearing in patients (n = 2) receiving <16 Gy was 54 months compared with 44.5 months in subjects (n = 7) receiving ≥16 Gy. Of the 6 patients with an only hearing ear treated, 2 progressed to class C hearing and 4 progressed to class D hearing.

Table 2
Table 2
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Figure 4
Figure 4
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Four subjects underwent cochlear implantation at various time points after SRS, as previously reported.15 Three of the 4 initially enjoyed open-set speech recognition and were daily users of their devices. One patient who was treated with a marginal dose of 13 Gy experienced progressive tumor growth and underwent microsurgical resection 2.5 years later, necessitating device explantation and placement of an auditory brainstem implant. Despite progressive tumor enlargement, this patient reported excellent device performance (95% Hearing in Noise test; 46% monosyllabic word score) until the day of device removal. A second patient with severe phenotype NF2 who received a marginal dose of 20 Gy nearly 2 decades earlier initially received excellent benefit but experienced performance deterioration 1 year after surgery. In the first year after cochlear implantation, she enjoyed open-set speech recognition but was unable to complete formal audiometric testing secondary to her poor physical condition. It remains unknown whether the performance decline was related to delayed radiation injury, undiagnosed device malfunction, or increasing tumor burden. The third patient was treated with a marginal dose of 15 Gy and continues to be a high performer (95% AzBio sentences; 86% Consonant Nucleus Consonant monosyllabic word score), with nearly 5 years of clinical follow-up. The single patient who failed to gain any benefit from cochlear implantation had a 15-year history of profound deafness before implantation.

Detailed facial nerve outcome data were available in 25 of 32 VSs (78%). The median pretreatment and posttreatment HB grades were 1 and 3. Of the 25 patients who had complete facial outcome data, 22 had HB 1 or 2 function before SRS. Eleven of the 22 (50%) had no deterioration in facial function, remaining in HB grade 1, whereas 4 (18%) had a deterioration of 1 to 2 grades, and 7 (32%) deteriorated ≥3 grades (Table 3). Three patients with worsening function had preexisting facial weakness (HB grade 2), only 1 of whom had undergone prior resection, raising the possibility that the other 2 patients may have been harboring ipsilateral facial nerve schwannomas in addition to or rather than VS. Two additional patients experienced decline in facial function after microsurgical resection for radiosurgical failure. Thus, worsening facial function was directly attributable to SRS in 6 cases, whereas the remaining 5 cases had additional confounding factors (2 with mild pre-existing facial weakness despite no prior treatment, 1 having undergone prior tumor resection, and 2 having facial weakness after resection of an enlarging tumor after failed SRS). Three patients with severe pre-SRS facial weakness (2 HB grade 5 and 1 HB grade 6) had no change in facial function after treatment and were excluded from analysis. No difference was found between median marginal doses in those with declining facial function compared with those with stable function (16 vs 13.5 Gy; P = .38).

Table 3
Table 3
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Natural History of NF2-Associated VS: Tumor Growth and Hearing

Compared with sporadic VS, the natural history of NF2-associated VS is poorly understood. Slattery et al16 followed up 84 VSs in 54 patients with NF2 and found an annual growth rate of 1.3 mm/y. Only 13% of tumors demonstrated growth over a follow-up period of 9 months to 4 years, which is less than what has been reported among sporadic tumors.17 More recently, the assumption of linear growth has been questioned. Dirks et al18 followed up 18 NF2-related VSs for a mean period of 9.5 years and found that all tumors demonstrated variable patterns and rates of growth, with approximately half exhibiting “saltatory” progression with intermittent quiescence between episodes of growth. No difference in growth pattern has been shown with respect to molecular mutations. Age has been variably reported to be both a positive and a negative predictor of growth, but generally, patients who present with larger tumors at a younger age are thought to harbor a more aggressive form of NF2.19-21

The natural history of hearing loss in untreated tumors is equally unpredictable. Fisher et al22 evaluated 52 patients with NF2 harboring 104 VSs and found that although larger tumors tended toward poorer hearing, there was no statistical association between amount of growth and magnitude of hearing loss on either side. Masuda et al23 followed up 63 subjects with NF2 (108 tumors) and found that 73% had no significant change in their baseline hearing over a 2-year period. Peyre and colleagues24 examined 92 NF2-related VSs (46 patients) for a mean of 6 years and found that 85% of patients had at least 1 ear with serviceable hearing at presentation, with 74% maintaining such status at the last follow-up. Similar to the above-mentioned studies, we found no statistical correlation between tumor growth and preservation of serviceable hearing.

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Results With SRS: Tumor Control and Hearing Preservation

In reviewing our experience, we found that 84% of NF2-associated VSs demonstrated growth arrest or tumor regression after SRS at a median follow-up of 7.6 years for the entire series. Although the present series is limited by small numbers, a notable association was found between marginal dose and tumor control. Specifically, the median marginal dose for tumors decreasing in size after SRS was 15.5 Gy compared with 13 Gy for tumors that enlarged after treatment. Despite favorable tumor control, only 25% of ears presenting with useful pretreatment hearing maintained class A or B hearing. The median follow-up in this small group of patients was only 2.0 years, so it is still very possible that they will go on to have further hearing deterioration over the next decade. This would match the long-term pattern of hearing deterioration among radiosurgically treated sporadic tumors.25

Previous series have reported variable outcomes, depending on the definition of tumor control and length of follow-up (Table 4).7-11 In an early review from the University of Pittsburgh, Subach et al9 defined radiosurgical failure as the need for surgical intervention and reported an overall 98% control rate at a median follow-up of 36 months; 6 of 14 patients (43%) maintained serviceable hearing. Using the same definition of need for surgery, the tumor control rate in the present series would translate to 94%. However, we feel that this is not an accurate definition because some patients may be managed conservatively despite growth and others may undergo surgery for intractable symptoms. A later article from Pittsburgh found a 5-year tumor control rate of 85%, with 48% of patients having preserved hearing.11 Sharma et al7 reported an overall control rate of 88% in 36 tumors, 18 of which were treated after microsurgical resection; hearing was preserved in 67% of ears at a mean follow-up of 26 months. Rowe et al,10 from Sheffield, evaluated 122 NF2-related VSs (96 patients) and estimated that at 8 years after treatment, 50% of VSs lacked discernible growth. Phi et al8 reported an actuarial tumor control rate of 66% and hearing preservation rate of 33% at 5 years. Thus, our data corroborate earlier studies suggesting that SRS provides tumor control in approximately 80% of NF2-associated VSs at 5 years; however, hearing preservation can be expected in <40% of treated tumors.

Table 4
Table 4
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Although the present study found a significant trend toward improved tumor control with higher marginal doses, little can be discerned from prior studies either to refute or to support this finding. Unfortunately, there is a paucity of literature reporting higher marginal doses in NF2-associated VSs because, almost uniformly, centers reduced marginal doses for all VSs, sporadic and syndromic, in the early 1990s. This report is unique in that regard in that we examined the effect of dose on radiographic tumor response and continued to use a marginal dose >14 Gy until approximately 1996. Meta-analysis is difficult because in prior reports the treatment protocol varied over time and there is no way to sort out how many patients in a series received higher vs contemporary marginal dosing.10,26,27

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Auditory Rehabilitation With Cochlear Implantation

Auditory rehabilitation in NF2 remains a challenging problem. Traditionally, auditory brainstem implantation has been used in patients with advanced hearing loss with mixed success.28 Recently, however, cochlear implantation has been used in a growing number of cases and offers an attractive alternative in select patients, with advantages including superior auditory performance and less invasive surgery. Although the literature suggests that most patients with NF2 who undergo SRS or microsurgery will ultimately lose serviceable hearing, SRS fortuitously spares an anatomically intact cochlear nerve even when functional hearing is lost. In a recent review, the authors found that 80% of patients with NF2 who underwent cochlear implantation after SRS or radiotherapy experienced open-set speech recognition. Among the 26 patients in the present study, 4 subjects underwent cochlear implantation as previously reported.15 Three of the 4 initially enjoyed open-set speech recognition and were high-functioning daily users of their devices. The single patient who had no initial response from cochlear implantation had a 15-year history of profound deafness before implantation. Similarly, the patient who had deterioration 1 year after cochlear implantation underwent SRS treatment (20 Gy) nearly 2 decades earlier. The poor outcomes in these 2 patients may be explained by prolonged auditory deprivation (>10 years), which is a well-established predictor of poor postoperative performance after cochlear implantation.29 Although the outcomes in the subset of patients who underwent cochlear implantation are not ideal, their initial response is encouraging, considering the very limited benefit most NF2 patients with auditory brainstem implant experience.

Given the extreme phenotypic variability of NF2, treatment should be individualized to optimally balance neurological function with tumor control. The literature suggests that initial conservative observation with serial MRI best maximizes auditory longevity compared with upfront surgery or SRS. Even at a reduced marginal dose, most patients with NF2 experience accelerated hearing loss after SRS compared with natural history and at the potential expense of tumor control.8,24 With these considerations in mind, we propose a treatment paradigm using a higher marginal dose of 15 to 16 Gy for NF2-associated VS when SRS is chosen as treatment. We anticipate this will maximize tumor control and still allow meaningful auditory rehabilitation with cochlear implantation if useful hearing is lost in follow-up. It is worth emphasizing that for patients with small to medium-sized tumors and serviceable hearing, we generally advocate a period of initial observation until definite growth and/or significant hearing loss occurs given the variable natural history. In those patients with enlarging tumors or worsening symptoms, we advocate for active treatment and counsel regarding the risks and benefits of both SRS and microsurgery. Results from clinical trials using bevacizumab or other chemotherapeutic agents will undoubtedly further modify the role of surgery and SRS in the management of these tumors.

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Optimal SRS Dosing and Facial Nerve Outcome

The unknown tradeoff of the proposed strategy to increase marginal dose is facial nerve outcomes. From prior series evaluating sporadic VS, we have learned that marginal doses of 12 to 13 Gy reduce the risk of facial neuropathy without apparent compromise in tumor control.30,31 Additionally, NF2-associated tumors appear to have worse facial outcomes than sporadic tumors. Although the present series found no significant correlation with marginal dose and facial outcomes in NF2 tumors, this should be interpreted with caution given the small sample size. Of the 11 patients who had worsening function in the present series, the median treatment dose was 16 Gy. Rowe and colleagues10 found that patients treated with a lower marginal dose (mean, 13.4 Gy) experienced worsening facial function only 8% of the time, whereas those treated with a dose >17 Gy developed facial weakness in a third of cases. Mathieu et al11 reported that 16.2% of patients developed lasting facial weakness after a mean marginal dose of 14 Gy. These data confirm a trend toward poorer facial nerve function with higher marginal doses; however, as alluded to earlier, facial nerve outcomes in NF2 are often confounded by adjunctive surgery and difficulty in discerning which patients with presumed VSs may also harbor facial schwannomas (Figure 5). Furthermore, early series commonly used higher doses with less sophisticated treatment planning, which may have resulted in significantly higher levels of radiation exposure to the facial nerve compared with the current versions of GammaPlan.

Figure 5
Figure 5
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Study Limitations and Future Direction

We wish to acknowledge several limitations of the present study. First, given the long time span of the study, determination of preoperative growth rates for patients who were treated early in the series was difficult secondary to a higher likelihood of proactive treatment without initial observation and incomplete MRI data available for review. Thus, the study cohort may have comprised both patients with rapidly growing and those with quiescent tumors, which limits the conclusions that can be made when comparing the results of the natural history against radiosurgical treatment. Second, the average age of the cohort is higher compared with the age of patients followed up in several NF2 natural history studies. It is possible that patients diagnosed at a later age might harbor a less aggressive phenotype of NF2.19-21 Third, the small sample size limited statistical inference. Although higher dosing was found to be associated with improved tumor control, tumor volume and age were not found to be statistically associated with tumor growth in the present series, which may reflect lack of statistical power.8,11 Although the rate of facial neuropathy is relatively high in this cohort, this finding is significantly confounded by incomplete facial outcome data in some patients, prior and/or subsequent surgery, and presumably a subset of patients with facial nerve schwannomas given the presence of preoperative weakness. Finally, when considering higher dosing paradigms, there is a theoretical concern for secondary malignancy, particularly given the genetic predisposition of NF2 patients.32,33 However, current data suggest that this risk is very low; the largest series (n = 118) with >900 patient-years of follow-up noted only 2 malignances (1.7%).34

Future study is needed to further characterize optimal SRS dosing for treatment of NF2-associated VS. Given the rarity of disease and heterogeneous treatment protocols between institutions, a prospective data registry will likely be needed to improve statistical power and to standardize patient follow-up, particularly with regard to hearing outcomes. Although the initial results of cochlear implantation are promising, aural rehabilitation in NF2 remains a challenging problem.

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Although clearly the trend in SRS for sporadic VS has been dose de-escalation to minimize hearing loss and to eliminate the risk of facial weakness, we propose a different paradigm for NF2-associated tumors. The best evidence shows that NF2-associated VSs respond less well to lower contemporary marginal SRS doses; therefore, consideration should be given to increasing the marginal dose to 15 to 16 Gy to improve tumor control. Although this may theoretically accelerate loss of any residual hearing, we did not encounter a difference in the time to nonuseful hearing (54 vs 44.5 months) in patients treated at higher doses compared with those treated with more contemporary dosing. Most important, SRS offers the potential for cochlear implant salvage in patients with advanced binaural hearing loss. Further study is needed to determine the probability of adverse facial nerve outcomes with increasing marginal doses because the risk of facial neuropathy appears to be higher in NF2 compared with sporadic VS after SRS.

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Internal departmental funding was used without commercial sponsorship or support. Institutional Review Board approval: 13-004588. The authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article.

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1. Rouleau GA, Merel P, Lutchman M, et al.. Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2. Nature. 1993;363(6429):515–521.

2. Trofatter JA, MacCollin MM, Rutter JL, et al.. A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell. 1993;75(4):826.

3. Asthagiri AR, Parry DM, Butman JA, et al.. Neurofibromatosis type 2. Lancet. 2009;373(9679):1974–1986.

4. Mautner VF, Lindenau M, Baser ME, et al.. The neuroimaging and clinical spectrum of neurofibromatosis 2. Neurosurgery. 1996;38(5):880–885; discussion 885-886.

5. Samii M, Matthies C, Tatagiba M. Management of vestibular schwannomas (acoustic neuromas): auditory and facial nerve function after resection of 120 vestibular schwannomas in patients with neurofibromatosis 2. Neurosurgery. 1997;40(4):696–705; discussion 705-706.

6. Plotkin SR, Stemmer-Rachamimov AO, Barker FG II, et al.. Hearing improvement after bevacizumab in patients with neurofibromatosis type 2. N Engl J Med. 2009;361(4):358–367.

7. Sharma MS, Singh R, Kale SS, Agrawal D, Sharma BS, Mahapatra AK. Tumor control and hearing preservation after Gamma Knife radiosurgery for vestibular schwannomas in neurofibromatosis type 2. J Neuro Oncol. 2010;98(2):265–270.

8. Phi JH, Kim DG, Chung HT, Lee J, Paek SH, Jung HW. Radiosurgical treatment of vestibular schwannomas in patients with neurofibromatosis type 2: tumor control and hearing preservation. Cancer. 2009;115(2):390–398.

9. Subach BR, Kondziolka D, Lunsford LD, Bissonette DJ, Flickinger JC, Maitz AH. Stereotactic radiosurgery in the management of acoustic neuromas associated with neurofibromatosis type 2. J Neurosurg. 1999;90(5):815–822.

10. Rowe JG, Radatz MW, Walton L, Soanes T, Rodgers J, Kemeny AA. Clinical experience with gamma knife stereotactic radiosurgery in the management of vestibular schwannomas secondary to type 2 neurofibromatosis. J Neurol Neurosurg Psychiatry. 2003;74(9):1288–1293.

11. Mathieu D, Kondziolka D, Flickinger JC, et al.. Stereotactic radiosurgery for vestibular schwannomas in patients with neurofibromatosis type 2: an analysis of tumor control, complications, and hearing preservation rates. Neurosurgery. 2007;60(3):460–468; discussion 468-470.

12. Baser ME, Friedman JM, Wallace AJ, Ramsden RT, Joe H, Evans DG. Evaluation of clinical diagnostic criteria for neurofibromatosis 2. Neurology. 2002;59(6):1759–1765.

13. Committee on hearing and equilibrium guidelines for the evaluation of hearing preservation in acoustic neuroma (vestibular schwannoma): American Academy of Otolaryngology—Head and Neck Surgery Foundation, Inc. Otolaryngol Head Neck Surg. 1995;113(3):179–180.

14. House JW, Brackmann DE. Facial nerve grading system. Otolaryngol Head Neck Surg. 1985;93(2):146–147.

15. Carlson ML, Breen JT, Driscoll CL, et al.. Cochlear implantation in patients with neurofibromatosis type 2: variables affecting auditory performance. Otol Neurotol. 2012;33(5):853–862.

16. Slattery WH III, Fisher LM, Iqbal Z, Oppenhiemer M. Vestibular schwannoma growth rates in neurofibromatosis type 2 natural history consortium subjects. Otol Neurotol. 2004;25(5):811–817.

17. Stangerup SE, Caye-Thomasen P, Tos M, Thomsen J. The natural history of vestibular schwannoma. Otol Neurotol. 2006;27(4):547–552.

18. Dirks MS, Butman JA, Kim HJ, et al.. Long-term natural history of neurofibromatosis type 2-associated intracranial tumors. J Neurosurg. 2012;117(1):109–117.

19. Abaza MM, Makariou E, Armstrong M, Lalwani AK. Growth rate characteristics of acoustic neuromas associated with neurofibromatosis type 2. Laryngoscope. 1996;106(6):694–699.

20. Baser ME, Makariou EV, Parry DM. Predictors of vestibular schwannoma growth in patients with neurofibromatosis type 2. J Neurosurg. 2002;96(2):217–222.

21. Mautner VF, Baser ME, Thakkar SD, Feigen UM, Friedman JM, Kluwe L. Vestibular schwannoma growth in patients with neurofibromatosis type 2: a longitudinal study. J Neurosurg. 2002;96(5):223–228.

22. Fisher LM, Doherty JK, Lev MH, Slattery WH. Concordance of bilateral vestibular schwannoma growth and hearing changes in neurofibromatosis 2: neurofibromatosis 2 natural history consortium. Otol Neurotol. 2009;30(6):835–841.

23. Masuda A, Fisher LM, Oppenheimer ML, Iqbal Z, Slattery WH. Hearing changes after diagnosis in neurofibromatosis type 2. Otol Neurotol. 2004;25(2):150–154.

24. Peyre M, Goutagny S, Bah A, et al.. Conservative management of bilateral vestibular schwannomas in neurofibromatosis type 2 patients: hearing and tumor growth results. Neurosurgery. 2013;72(6):907–913; discussion 914; quiz 914.

25. Carlson ML, Jacob JT, Pollock BE, et al.. Long-term hearing outcomes following stereotactic radiosurgery for vestibular schwannoma: patterns of hearing loss and variables influencing audiometric decline. J Neurosurg. 2013;118(3):579–587.

26. Linskey ME, Lunsford LD, Flickinger JC. Tumor control after stereotactic radiosurgery in neurofibromatosis patients with bilateral acoustic tumors. Neurosurgery. 1992;31(5):829–838; discussion 838-839.

27. Kida Y, Kobayashi T, Tanaka T, Mori Y. Radiosurgery for bilateral neurinomas associated with neurofibromatosis type 2. Surg Neurol. 2000;53(4):383–389; discussion 389-390.

28. Schwartz MS, Otto SR, Brackmann DE, Hitselberger WE, Shannon RV. Use of a multichannel auditory brainstem implant for neurofibromatosis type 2. Stereotact Funct Neurosurg. 2003;81(1-4):110–114.

29. Waltzman SB, Fisher SG, Niparko JK, Cohen NL. Predictors of postoperative performance with cochlear implants. Ann Otol Rhinol Laryngol Suppl. 1995;165:15–18.

30. Foote KD, Friedman WA, Buatti JM, Meeks SL, Bova FJ, Kubilis PS. Analysis of risk factors associated with radiosurgery for vestibular schwannoma. J Neurosurg. 2001;95(3):440–449.

31. Chopra R, Kondziolka D, Niranjan A, Lunsford LD, Flickinger JC. Long-term follow-up of acoustic schwannoma radiosurgery with marginal tumor doses of 12 to 13 Gy. Int J Radiat Oncol Biol Phys. 2007;68(3):845–851.

32. Carlson ML, Babovic-Vuksanovic D, Messiaen L, Scheithauer BW, Neff BA, Link MJ. Radiation-induced rhabdomyosarcoma of the brainstem in a patient with neurofibromatosis type 2. J Neurosurg. 2010;112(1):81–87.

33. Demetriades AK, Saunders N, Rose P, et al.. Malignant transformation of acoustic neuroma/vestibular schwannoma 10 years after gamma knife stereotactic radiosurgery. Skull Base. 2010;20(5):381–387.

34. Rowe J, Grainger A, Walton L, Radatz M, Kemeny A. Safety of radiosurgery applied to conditions with abnormal tumor suppressor genes. Neurosurgery. 2007;60(5):860–864.

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The authors present a series of 32 vestibular schwannomas in 26 patients with neurofibromatosis type 2 (NF2) treated with Gamma Knife radiosurgery over a 20-year period. They posit that tumor control is enhanced by using a higher marginal dose. According to their data, this is not at the expense of hearing preservation, because even with lower marginal doses, hearing preservation is very poor. The small sample size limits conclusions about facial nerve outcome, although about half of all patients suffer a decline in facial nerve function. I should note that, in the series as a whole, tumor control is < 85%. Because NF2 is rare and the phenotypic characteristics are so variable from patient to patient, any series, be it microsurgical, radiosurgical, or natural history, has its limitations. Each treatment option always has its advantages and significant disadvantages. Unfortunately, although it has shown promise, this is true for bevacizumab as well. The results presented in this article would be considered poor for sporadic tumors, but they may be quite acceptable for NF2 tumors. Patients considering radiosurgery should be counseled as such. At the very least, radiosurgery should not be held out as a hearing preservation treatment for NF2 patients. The authors note that they reserve radiosurgical treatment for patients who show evidence of tumor progression, which, in my opinion, is proper management. Although radiosurgical treatment may preserve the option of cochlear implantation for auditory rehabilitation, this strategy can be considered a success in only 1 of their patients (of 4 implanted and of 21 who were treated without prior surgery). This option is, however, at the cost of an opportunity for auditory brainstem implantation placement. The authors characterize auditory brainstem implantation benefit as “very limited.” I would strongly disagree with that sentiment. Although auditory brainstem implantation benefit is highly variable, the most recent series show significant benefit, with up to more than one third of patients obtaining open-set speech recognition.1

Marc S. Schwartz

Los Angeles, California

1. Matthies C, Brill S, Kaga K, et al.. Auditory brainstem implantation improves speech recognition in neurofibromatosis type II patients. ORL J Otorhinolaryngol Relat Spec. 2013;75(5):282–295. PubMed | CrossRef Cited Here... |

The authors provide a small clinical series of vestibular schwannomas in the setting of neurofibromatosis type 2 after stereotactic radiosurgery. The findings are consistent with other reports. In the majority of patients, tumor growth control is obtained with low overall risk. Over time, hearing function deteriorated in most patients with their median 14-Gy dose. Bevacizumab has been shown to be effective at least in the short term when it is administered. It is clear that new concepts for longer-term hearing preservation should be pursued, including combined medical therapy and radiosurgery to modulate effects or augmentation strategies such as those discussed here with cochlear implants.

Douglas Kondziolka

New York, New York

The optimal management of vestibular schwannomas (VSs) in neurofibromatosis type 2 (NF2) remains a controversial issue in neurosurgery, especially with the development of new treatment options such as bevacizumab and considering ongoing clinical trials (Lapatinib, everolimus, and new).

This report of 32 VSs in 26 patients with NF2 treated with Gamma Knife is an interesting contribution to the literature and reveals the successful results and limitations of radiosurgery to treat these aggressive tumors.

As mentioned by the authors, determination of preoperative growth rates for patients who were treated early in the series was difficult because of a higher likelihood of proactive treatment without initial observation and incomplete magnetic resonance imaging data available for review. Thus, the study cohort may include quiescent tumors, which is plausible considering that the mean age of the patients was higher compared with the mean age of patients in several reported NF2 surgical and natural history studies. Because old NF2 patients usually present with a mild phenotype, this inclusion bias seriously limits the significance of this study and its use to create a therapeutic flow chart. I found that the rate of facial neuropathy is high and the hearing preservation rate is low in this cohort, indicating that radiosurgery with a median marginal dose at 14 Gy should not be considered a hearing preservation treatment for NF2 patients. In this series, secondary cochlear implantation could be considered a success in only 1 case. At our institution, we consider Gamma Knife to be an option only in growing small to moderate-sized tumors in older patients. We strongly recommend the evaluation of VSs by serial volumetric magnetic resonance imaging and the determination of the tumor growth pattern of each tumor in each patient before choosing the best therapeutic option. Surgical or radiosurgical treatment of nongrowing tumors should be avoided because of the secondary effects on facial function and hearing. Cochlear implantation is indicated in cases of nongrowing VSs, and auditory brainstem implantation is considered after removal of the second growing VS after medical (bevacizumab or inclusion in clinical trial) therapeutic failure.

Michel Kalamarides

Paris, France

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CME Questions:

1. When a patient with neurofibromatosis type II (NF-2) presents with a small vestibular schwannoma with serviceable hearing, what is the most effective treatment strategy to maximize auditory longevity?

A. Microsurgery

B. Stereotactic radiosurgery (SRS)

C. Fractionated radiotherapy

D. Observation until tumor progression

E. Bevacizumab

2. What is the accepted marginal dose for NF-2 associated vestibular schwannoma radiosurgery to minimize the incidence of facial nerve dysfunction while still providing tumor control?

A. 10-11 Gy

B. 12-13 Gy

C. 14-15 Gy

D. 16-17 Gy

E. 18-19 Gy

3. A 35-year-old NF-2 patient with a 1.5 cm vestibular schwannoma is undergoing stereotactic radiosurgery (SRS). What variable contributes most to improved tumor control?

A. Marginal dose

B. Rate of tumor growth

C. Tumor size

D. Patient age

E. Gardner-Robertson (GR) hearing grade


Acoustic neuroma; Cochlear implantation; Gamma Knife; Neurofibromatosis type 2; Stereotactic radiosurgery; Vestibular schwannoma

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