BACKGROUND:
Local management for vestibular schwannoma (VS) is associated with excellent local control with focus on preserving long-term serviceable hearing. Fractionated proton radiation therapy (FPRT) may be associated with greater hearing preservation because of unique dosimetric properties of proton radiotherapy.
OBJECTIVE:
To investigate hearing preservation rates of FPRT in adults with VS and secondarily assess local control and treatment-related toxicity.
METHODS:
A prospective, single-arm, phase 2 clinical trial was conducted of patients with VS from 2010 to 2019. All patients had serviceable hearing at baseline and received FPRT to a total dose of 50.4 to 54 Gy relative biological effectiveness (RBE) over 28 to 30 fractions. Serviceable hearing preservation was defined as a Gardner–Robertson score of 1 to 2, measured by a pure tone average (PTA) of ≤50 dB and a word recognition score (WRS) of ≥50%.
RESULTS:
Twenty patients had a median follow-up of 4.0 years (range 1.0-5.0 years). Local control at 4 years was 100%. Serviceable hearing preservation at 1 year was 53% (95% CI 29%-76%), and primary end point was not yet reached. Median PTA and median WRS both worsened 1 year after FPRT (P < .0001). WRS plateaued after 6 months, whereas PTA continued to worsen up to 1 year after FPRT. Median cochlea D90 was lower in patients with serviceable hearing at 1 year (40.6 Gy [RBE] vs 46.9 Gy [RBE]), trending toward Wilcoxon rank-sum test statistical significance (P = .0863). Treatment was well-tolerated, with one grade 1 cranial nerve V dysfunction and no grade 2+ cranial nerve dysfunction.
CONCLUSION:
FPRT for VS did not meet the goal of serviceable hearing preservation. Higher cochlea doses trended to worsening hearing preservation, suggesting that dose to cochlea correlates with hearing preservation independent of treatment modality.
KEY WORDS: Vestibular schwannoma, Fractionated proton radiation therapy
ABBREVIATIONS:
- ABR
auditory brainstem response
- CN
cranial nerve
- FPRT
fractionated proton radiation therapy
- GR
Gardner–Robertson
- KPS
Karnofsky Performance Status
- OAE
otoacoustic emissions
- PTA
pure tone average
- RBE
relative biological effectiveness
- RT
radiation therapy
- SRS
stereotactic radiosurgery
- VS
vestibular schwannoma
- WRS
word recognition score.
Vestibular schwannomas (VSs) are histologically benign tumors that represent 6% to 8% of intracranial neoplasms and arise from the vestibular branch of the eighth cranial nerve and originate near the medial aperture of the internal acoustic canal.1 Standard-of-care treatment for progressive or symptomatic lesions involves local management with either surgery or radiation therapy (RT). Surgical resection results in long-term control rates greater than 90% with postoperative loss of serviceable hearing at 15% to 73%.2-5 Nonoperative management with stereotactic radiosurgery (SRS) results in similar rates of local control to surgical series.6 Retrospective series of SRS for VS report long-term serviceable hearing loss of 22% to 29% beyond 5 years.7-9
Dosimetric studies have suggested that key determinants of hearing loss after RT are dose and volume to the cochlea, with less RT associated with improved hearing preservation rates.9-14 Fractionated stereotactic radiotherapy, delivered over several weeks, may spare cochlear function because of radiobiological recovery of normal tissue with fractionated treatments. Series have reported serviceable hearing rates of 54% to 84% at 5 years with high local control.8,12,15-22
Another potential strategy to spare the cochlea and preserve hearing is with fractionated proton RT (FPRT). The main advantage of protons is the finite radiation beam length ending within targets, eliminating downstream excess radiation dose to normal tissues beyond the target volume such as the cochlea and cranial nerves, which could result in improved hearing preservation.20,23,24 Because the cochlea is the primary organ involved with hearing, eliminating radiation damage risk should theoretically improve hearing preservation in patients treated for VS. A systematic review of series reporting patients treated with both proton SRS and FPRT noted crude hearing rates of 52%, with lower-than-expected serviceable hearing likely attributed to higher prescription dose, up to 54 to 60 Gy relative biological effectiveness (RBE).25 Two series from Loma Linda and the University of Florida published a series of FPRT for VS which reported serviceable hearing preservation of 64% at 4 years and 33% at 5.8 years, respectively.26,27
To date, no prospective studies of FPRT have been conducted, and the limited retrospective data available have not included vigorous analyses of hearing function.28,29 As such, given the known clinical advantages of fractionated stereotactic radiotherapy over SRS and the potential dosimetric advantages of proton therapy over photon therapy, we initiated a single-arm prospective case series to assess the utility of FPRT in the treatment of VS with a primary end point of hearing preservation. In this study, we report a preliminary analysis at 1 year of the first 20 patients accrued to this study.
METHODS
Patients and Eligibility Criteria
This study was a single-arm phase II trial of adult patients aged 18 years or older with vestibular schwannoma and an indication for RT from 2010 to 2019 at a single academic institution. Subjects were required to have subjectively useful hearing in the ipsilateral ear without previous surgery. Other criteria included no prior RT, life expectancy greater than 5 years, and Karnofsky Performance Status (KPS) ≥60. All patients were given information sheets regarding the study protocol, and both verbal and written informed consents were obtained at the time of recruitment. Ethics approval was obtained from the local institutional review board. This trial is registered under the ClinicalTrials.gov identifier NCT01199978.
Assessment and Treatment
Patients underwent a pretreatment MRI, audiological evaluation, and history and physical examination within 3 months before the start of RT. Audiological studies included pure tone average (PTA), word recognition score (WRS), auditory brainstem response (ABR), otoacoustic emissions (OAE), and tympanometry. Toxicity during treatment was evaluated and recorded with the revised National Cancer Institute (NCI) common terminology criteria for adverse events (v4.0). Symptoms during treatment were managed according to the standard of care. Dose modifications were at the discretion of the physician.
Treatment planning was performed using the fused gadolinium-enhanced MRI sequences and a planning computed tomography scan. RT was delivered to a total dose of 50.4 to 54 Gy RBE in 28 to 30 fractions of 1.8 Gy (RBE) each. FPRT was planned with a passive scattering technique, using at least 3 fields positioned to avoid end-of-range into the brainstem (Figure 1). Patient immobilization included a rigid, frameless mask with a dental mold implant. Planning target volume received at least 90% of prescribed dose, and dose constraints stipulated avoiding hotspot to the brainstem and dose as low as reasonably achievable to critical organs at risk, including the cochlea. No dose restriction was formally placed on the cochlea (Supplemental Methods, http://links.lww.com/NEU/B523).
FIGURE 1.
Fractionated proton therapy plan for vestibular schwannoma with 3 noncoplanar fields. Dose distribution is visualized from a 3-field plan, revealing the 95%, 50%, and 20% isodose lines. Planning target volume, brainstem, and cochlea are outlined, showing excellent conformity of the Planning Target Volume and significant overlap of the adjacent cochlea.
Follow-up
Follow-up after completion of RT was at 6 months and then annually through 5 years. Each follow-up assessment included an interval history, physical examination, MRI, and audiological studies.
Outcome Measures
The primary end point of this study was rate of ipsilateral serviceable hearing after treatment. Serviceable hearing was defined as a Gardner–Robertson (GR) score 1 to 2, measured as PTA ≤50 dB and WRS ≥50%. Other validated definitions of serviceable hearing were investigated, including change in PTA of <12 dB from baseline and change in WRS outside a binomial distribution of baseline PTA.30,31 This study aimed to demonstrate improvement in the rate of serviceable hearing compared with a historical rate of approximately 65% at 5 years in patients treated with photon RT. Secondary end points include additional audiometric outcomes, local control, dosimetric parameters, and the incidence of second tumors. This report represents the preliminary analysis of the first 20 patients accrued to this study.
Statistical Analysis
This study was designed as a single-arm superiority study, with primary end point of at least 80% serviceable hearing preservation in the affected side at 5 years compared with historical control of 65%. Accrual goal was set at 30 patients to have 76% power to detect the 15% difference with a type 1 error rate of 12%. This is the preliminary analysis of the first 20 patients accrued and followed for >12 months. Changes in hearing outcomes from baseline to 12 months posttreatment were compared using the McNemar test and Wilcoxon signed-rank test. The Fisher exact test and Wilcoxon rank-sum test were used to compare patient and treatment characteristics between patients with and without serviceable hearing at 12 months. All P-values are based on a 2-sided hypothesis without adjustment for multiple comparisons. Analyses were performed in SAS 9.4 (SAS Institute Inc) and R 4.0.3 (The R Foundation).
RESULTS
Patient Characteristics
Twenty patients were enrolled and followed prospectively for a median follow-up of 4.0 years (range 1.0-5.0). Nineteen patients (95%) had hearing evaluations at baseline and at 12 months after treatment. The median age was 64 years, 14 patients were female (70%), and 17 patients were White (85%) (Table 1). All patients had KPS ≥70, no patients had a known history of neurofibromatosis 2, and no patients had prior surgical intervention. Median tumor volume was 0.81 cm3, and median longest diameter was 1.63 cm. The first 4 patients (20%) were treated to 54 Gy (RBE), and the remaining 16 patients (80%) were treated to 50.4 Gy (RBE). No patients experienced progression of disease at the last follow-up.
TABLE 1.
Patient and Tumor Characteristics
| Patient and tumor characteristics (n = 20) | |
|---|---|
| Age, years, median (range) | 64 (48-70) |
| Sex, n (%) | |
| Female | 14 (70) |
| Male | 6 (30) |
| Race, n (%) | |
| White | 17 (85) |
| Non-White | 3 (15) |
| KPS, n (%) | |
| KPS 70-100 | 20 (100) |
| NF2, n (%) | 0 (0) |
| Affected ear, n (%) | |
| Right | 9 (45) |
| Left | 11 (55) |
| Tumor size | |
| Volume, cm3, median (IQR) | 0.81 (0.54-1.95) |
| Longest diameter, cm, median (IQR) | 1.63 (1.30-1.86) |
| Radiation dose | |
| 50.4 Gy (RBE) | 16 (80) |
| 54.0 Gy (RBE) | 4 (20) |
IQR, interquartile range; KPS, Karnofsky Performance Status; NF2, neurofibromatosis 2; RBE, relative biological effectiveness.
Hearing Outcomes
Audiometric assessments are listed in Table 2. All patients had serviceable hearing at baseline, with 16 patients having GR score 1 and 4 patients having GR score 2. Six months after treatment, 14 of 20 patients (70%) had preserved serviceable hearing. Twelve months after treatment, 19 of 20 patients had evaluable audiometric testing (Figure 2). Of these, 10 of 19 patients (53%, 95% CI 29%-76%) maintained serviceable hearing, which was a statistically significant decrease in serviceable hearing from baseline (P = .0039). Six of 15 patients (40%) with GR 1 score at baseline developed unserviceable hearing, and 3 of 4 patients (75%) with GR 2 score at baseline developed unserviceable hearing at 12 months. Other measures of serviceable hearing loss were not associated with primary end point, including change in PTA >12 dB from baseline (P = .07) and change in WRS outside binomial distribution of baseline WRS (P = .63).
TABLE 2.
Baseline, 6-Month, and 12-Month Hearing Performance
| Hearing outcome | Pretreatment (n = 20) |
6 mo after treatment (n = 20) | 12 mo after treatment (n = 19) | P-value (baseline vs 12 mo) |
|---|---|---|---|---|
| Ipsilateral GR score (n) | ||||
| 1—Good to excellent | 16 | 5 | 5 | |
| 2—Serviceable | 4 | 9 | 5 | |
| 3—Nonserviceable | 0 | 6 | 9 | |
| 4—Poor | 0 | 0 | 0 | |
| 5—None/deaf | 0 | 0 | 0 | |
| Serviceable hearing (GR score = 1 or 2), n (%) | 20 (100) | 14 (70%) | 10 (53%) | .0039 |
| Ipsilateral GR score, median (IQR) | 1.0 (1.0-1.0) | 2.0 (1.5-3.0) | 2.0 (1.0-3.0) | .0002 |
| Functional hearing tests | ||||
| Ipsilateral PTA, median (IQR) | 42 (34-49) | 56 (44-61) | 62 (53-71) | <.0001 |
| Adjusted ipsilateral PTAa, median (IQR) | 56 (46-64) | 61 (63-71) | ||
| Contralateral PTA, median (IQR) | 15 (10-26) | 17 (11-27) | 13 (9-30) | .6427 |
| Word recognition score, median (IQR) | 85 (70-94) | 59 (22-70) | 48 (8-70) | <.0001 |
| Ipsilateral ABR, median (IQR) | 7.2 (6.7-8.0) | 7.5 (6.9-8.0) | 7.7 (7.2-10) | .0730 |
| Ipsilateral OAE absent, n (%) | 12 (60) | 18 (90) | 18 (100)b | .0156 |
| Tympanometry test normal, n (%) | 20 (100) | 20 (100) | 18 (100)b |
ABR, auditory brainstem response; GR, Gardner–Robertson; IQR, interquartile range; OAE, otoacoustic emissions; PTA, pure tone average.
Adjusted ipsilateral PTA = ipsilateral PTA—(contralateral PTA pretreatment—contralateral PTA after 6 or 12 mo).
18 of 19 patients completed OAE and tympanometry test at the 12-mo follow-up.
FIGURE 2.
Hearing outcomes over time. A, Serviceable hearing before and after RT, B, distribution of ipsilateral PTA before and after RT, and C, distribution of the ipsilateral word recognition score before and after RT. Box plots depict the horizontal line representing median values, and lower and upper boundaries indicated the 25th and 75th percentiles, respectively, with outliers representing minimum and maximum values. PTA, pure tone average; RT, radiation therapy.
The individual components of the GR score (PTA and WRS) both worsened 12 months after treatment (Figures 2 and 3). An ipsilateral PTA score worsened over 12 months, with the median PTA score increased from 42 dB at baseline to 62 dB at 12 months (P < .0001). Ipsilateral WRS worsened over 12 months, with median WRS score decreasing from 85% to 48% (P < .0001). The contralateral PTA score did not worsen over 12 months (P = .6427) (Supplemental Figure, http://links.lww.com/NEU/B525). An adjusted PTA score was calculated by ipsilateral PTA at 12 months minus the difference in contralateral PTA score from baseline to 12 months, and this score was very similar to the original ipsilateral PTA score.
FIGURE 3.
Individual and median hearing outcomes, A, ipsilateral Gardner–Robertson scores before and after RT, B, ipsilateral PTA before and after RT, and C, ipsilateral word recognition score before and after RT. PTA, pure tone average; RT, radiation therapy.
Ipsilateral ABR showed a worsening trend from baseline to 1 year after treatment (P = .0730), whereas tympanometry was normal in all patients at baseline and remained normal at the 1-year test. OAE was absent in 60% of patients at baseline and absent in 100% at 1 year after treatment, which was statistically significant (P = .0156).
Dosimetric Analysis
Median radiation dose to 90% of the cochlea (D90) was 40.6 Gy (RBE) for patients with serviceable hearing at 1 year compared with 46.9 Gy (RBE) for patients without serviceable hearing (P = .0863) (Table 3). Median cochlea D50 and D5 were 46.2 Gy (RBE) and 49.7 Gy (RBE) for patients with serviceable hearing compared with 49.2 Gy (RBE) and 50.7 Gy (RBE) for patients without serviceable hearing at 12 months, respectively; neither was significantly different. Median cochlea Dmax was 50.1 Gy (RBE) for patients with serviceable hearing compared with 50.7 Gy (RBE) for patients without serviceable hearing at 12 months and was not statistically different. Cochlea V90, Dmean, and Dmin were also not significantly associated with hearing after FPRT.
TABLE 3.
Univariate Analysis of Risk Factors
| Risk factor, median (IQR) | Serviceable hearing at 12 mo | Unserviceable hearing at 12 mo | P-value (baseline vs 12 mo) |
|---|---|---|---|
| Dosimetric characteristics | |||
| Cochlea D90 (Gy [RBE]) | 40.6 (35.6-45.4) | 46.9 (44.1-48.2) | .0863 |
| Cochlea D50 (Gy [RBE]) | 46.2 (43.7-48.4) | 49.2 (47.5-49.6) | .2053 |
| Cochlea D5 (Gy [RBE]) | 49.7 (48.8-50.7) | 50.7 (50.5-51.3) | .1411 |
| Cochlea Dmax (Gy [RBE]) | 50.1 (49.5-51.5) | 51.3 (50.8-51.8) | .1768 |
| Cochlea V90 (%) | 65.3 (22.6-91.0) | 95.8 (71.0-98.0) | .2205 |
| Cochlea Dmean (Gy [RBE]) | 45.7 (42.6-48.1) | 48.8 (46.4-49.2) | .1530 |
| Cochlea Dmin (Gy [RBE]) | 34.4 (25.9-42.5) | 41.2 (39.4-43.2) | .1259 |
| Tumor size (cm) | 1.53 (1.30-1.80) | 1.80 (1.38-2.70) | .2524 |
| Total RT dose (Gy [RBE]) | 50.4 (50.4-50.4) | 50.4 (50.4-50.4) | .6514 |
| Age (y) | 65 (57-68) | 65 (60-67) | .9679 |
| Affected ear | — | — | .8724 |
IQR, interquartile range; RBE, relative biological effectiveness.
Univariate Analysis
Several patient and tumor factors were investigated as potential risk factors of worsening serviceable hearing over time. Tumor size, tumor volume, total RT dose, age, and affected ear and baseline ipsilateral OAE were not statistically associated with serviceable hearing at 12 months.
Toxicity
Acute toxicity was defined as any event occurring during treatment and up to 90 days after treatment with any attribution to RT (Supplemental Table 1, http://links.lww.com/NEU/B526). One grade 3 event was reported of vertigo, in the context of a viral syndrome. Three grade 2 events were reported: 2 patients experienced fatigue and 1 patient experienced hearing impairment. The most common grade 1 acute toxicity was fatigue (70%), followed by headache (30%).
Few toxicities were reported at 12 months after the completion of radiation treatment (Supplemental Table 2, http://links.lww.com/NEU/B527). One G3 event (hearing impairment) was reported. Nine G2 events were reported, most common was hearing impairment (n = 7). One patient reported cranial nerve (CN) V symptoms at the 12-month follow-up, noted as G1 facial pain; no G2-5 CN V symptoms were reported.
DISCUSSION
This preliminary report demonstrates fractionated proton therapy for vestibular schwannoma results in excellent local control but did not meet the goal of serviceable hearing preservation, although hearing loss was not worse than historical controls at 12 months. We demonstrated 12-month local control of 100% with low rate of acute and late adverse events and 12-month serviceable hearing preservation of 53% (95% CI 29%-76%). Only 2 series have reported hearing outcomes for FPRT for VS: Loma Linda and the University of Florida reported institutional experiences of serviceable hearing preservation of 64% at 4 years and 33% at 5.8 years, respectively.26,27 This is the first published prospective trial on fractionated proton therapy for vestibular schwannoma and one of the first studies to report comprehensive audiometric results at multiple time points in patients receiving RT for vestibular schwannoma.
Our primary end point of serviceable hearing was defined as preservation of a GR score 1 to 2. As presented in Table 2 and Figure 3, both the PTA and WRS scores deteriorated over time, suggesting each component contributing to hearing loss after FPRT. Figure 2B demonstrates that WRS score sharply decreases after FPRT, whereas that PTA score gradually decreases up to 1 year after FPRT. The primary mechanism of radiation damage of nonproliferating organs is through late-term fibrosis and vascular damage. This suggests that patients treated with FPRT who develop generalized cochlear damage from radiation present with initial worsening WRS followed by worsening PTA (Supplemental Discussion, http://links.lww.com/NEU/B528).32,33
Several studies have demonstrated higher radiation dose to the cochlea (reported as several measures, including D90, Dmean, Dmin, and V90) to be associated with worse hearing preservation.12,20,34-39 In our series, D90 had a trend toward worse hearing outcomes (median 40.6 Gy [RBE] vs 46.9 Gy [RBE], P = .0863) and both groups with and without serviceable hearing at 12 months had relatively higher doses to the cochlea compared with other fractionated RT studies. This suggests that hearing preservation is less affected by avoidance of dose outside of the Bragg peak distribution, and anatomic relationship of tumor and cochlea may be more relevant to hearing than advantage of treatment modality.
The European Particle Therapy Network consensus recommends total average dose to the cochlea by fractionated radiotherapy be limited to 45 Gy (lower than median Dmean in this study), and other series have recommended more conservative doses.12,20,34,39-41 In the setting of excellent local control in our study, future studies may investigate further preservation of cochlear dose for improved hearing outcomes.
The WRS/PTA and ABR/OAE dynamics after FPRT seem to suggest a sequential mechanism of radiation impact on hearing loss. We find that RT likely affects hearing function by regional damage to the cochlea without impact on neural pathways, which correlates with the initial loss of WRS hearing capacity before eventual PTA audibility function. The benefit of proton therapy is the rapid radiation dose fall off distal to and lateral to the irradiated target; FPRT does not seem to have as much dosimetric advantage when the cochlea is immediately adjacent and sometimes directly abutting the tumor.
There may be a few reasons for why hearing preservation at 12 months in our study was not improved compared with historical controls and prior fractionated proton therapy series. First, the limited sample size may introduce bias of results compared with larger studies. Second, differing prescription doses could have affected hearing outcome. The series from Loma Linda reported decreased 4-year hearing preservation rates for patients treated with FPRT to 54 Gy (RBE) compared with patients treated to 50.4 Gy (RBE) (44% vs 64%), although not statistically significant.26,29 The first 4 patients in our series were treated to 54 Gy (RBE), whereas the remaining were treated to 50.4 Gy (RBE), although the hearing preservation rates between the 2 radiation doses were not statistically significant. Finally, at a median follow-up of 4 years, hearing loss tended to plateau at 1 year, earlier than other long-term series.42-44 Proton therapy may have a greater biological effect on normal tissues, which could contribute to greater hearing loss earlier than anticipated.
Our study showed that fractionated proton therapy for vestibular schwannoma was very well-tolerated. One patient reported CN V dysfunction (G1 facial pain), and no patients reported G2-5 CN V dysfunction at the 12-month follow-up. Aside from hearing loss, there were few other toxicities with 10% G2 toxicity (1 patient with tinnitus and 1 patient with vertigo) and no G3+ toxicity.
Limitations
Limitations of our series include the small sample size of a 20-patient series at a single institution that may not translate to a more diverse patient population. Our series also reports short-term results with a minimum 1-year follow-up and median 4.0-year follow-up, with several series noting continued events at long-term outcomes beyond 5 to 10 years. Future studies should investigate the role of proton beam RT with attention to cochlear dose sparing.
CONCLUSION
FPRT for vestibular schwannoma results in excellent local control but did not meet the goal of serviceable hearing preservation. Audiometric dynamics after FPRT suggest that radiation-associated hearing dysfunction is manifested as early worsening and plateau of WRS, followed by gradual worsening of PTA. Radiation dose to the cochlea likely correlates with long-term hearing preservation such that greater attempt to minimize radiation dose to the cochlea may achieve better long-term hearing function.
Acknowledgments
The authors acknowledge Chris F. Halpin, PhD, for his consultation and aid to this project.
Footnotes
This abstract was accepted as a Quick Pitch presentation to the American Society for Radiation Oncology (ASTRO) 2021 Annual Conference on October 24, 2021, in Chicago, IL.
Supplemental digital content is available for this article at neurosurgery-online.com.
CNS Journal Club Podcast and CME Exams available at cns.org/podcasts.
The CNS Spotlight gallery is available at cns.org/spotlight.
Funding
This work received funding from any of the following organizations: National Institutes of Health (NIH), Wellcome Trust, Howard Hughes Medical Institute (HHMI), and other foundation(s) requiring open access. This work was also supported by C06 CA059267 NCI Federal Share of program income for Proton Radiation Research.
Disclosures
The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. Dr Pike reported consulting agreements with Blackstone investments, Third Rock Ventures, Galera Therapeutics, Dynamo Therapeutics, Myst Therapeutics, Monte Rosa Therapeutics, and Teladoc Inc, as well as equity/ownership with Schrodinger, Novavax, and Clovis oncology. Dr Shih reports UpToDate (writer) and The Radiosurgery Society (board).
Supplemental Digital Content
Supplemental Methods. Further description of patient selection and treatment planning, including methodology of RT dose prescription and planning technique and immobilization.
Supplemental Figure. Ipsilateral and contralateral PTA scores before and after radiation therapy.
Supplemental Table 1. Acute toxicity (CTCAE v4.0), events up to and including 90 days after treatment.
Supplemental Table 2. Delayed toxicity (CTCAE v4.0), events at 12 months after treatment.
Supplemental Discussion. Further discussion of otoacoustic emission results and their significance with RT damage, as well as discussion of end-of-range uncertainty with proton beam.
REFERENCES
- 1.Stangerup S-E, Tos M, Thomsen J, Caye-Thomasen P. True incidence of vestibular schwannoma? Neurosurgery. 2010;67(5):1335-1340; discussion 1340. [DOI] [PubMed] [Google Scholar]
- 2.Brackmann DE, Owens RM, Friedman RA, et al. Prognostic factors for hearing preservation in vestibular schwannoma surgery. Am J Otol. 2000;21(3):417-424. [DOI] [PubMed] [Google Scholar]
- 3.Betchen SA, Walsh J, Post KD. Long-term hearing preservation after surgery for vestibular schwannoma. J Neurosurg. 2005;102(1):6-9. [DOI] [PubMed] [Google Scholar]
- 4.Barker FG, Carter BS, Ojemann RG, Jyung RW, Poe DS, McKenna MJ. Surgical excision of acoustic neuroma: patient outcome and provider caseload. Laryngoscope. 2003;113(8):1332-1343. [DOI] [PubMed] [Google Scholar]
- 5.Ahsan SF, Huq F, Seidman M, Taylor A. Long-term hearing preservation after resection of vestibular schwannoma: a systematic review and meta-analysis. Otol Neurotol. 2017;38(10):1505-1511. [DOI] [PubMed] [Google Scholar]
- 6.Persson O, Bartek J, Shalom NB, Wangerid T, Jakola AS, Förander P. Stereotactic radiosurgery vs. fractionated radiotherapy for tumor control in vestibular schwannoma patients: a systematic review. Acta Neurochir (Wien). 2017;159(6):1013-1021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Maniakas A, Saliba I. Microsurgery versus stereotactic radiation for small vestibular schwannomas: a meta-analysis of patients with more than 5 years’ follow-up. Otol Neurotol. 2012;33(9):1611-1620. [DOI] [PubMed] [Google Scholar]
- 8.Kopp C, Fauser C, Müller A, et al. Stereotactic fractionated radiotherapy and LINAC radiosurgery in the treatment of vestibular schwannoma-report about both stereotactic methods from a single institution. Int J Radiat Oncol Biol Phys. 2011;80(5):1485-1491. [DOI] [PubMed] [Google Scholar]
- 9.Tamura M, Carron R, Yomo S, et al. Hearing preservation after gamma knife radiosurgery for vestibular schwannomas presenting with high-level hearing. Neurosurgery. 2009;64(2):289-296; discussion 296. [DOI] [PubMed] [Google Scholar]
- 10.Massager N, Nissim O, Delbrouck C, et al. Irradiation of cochlear structures during vestibular schwannoma radiosurgery and associated hearing outcome. J Neurosurg. 2007;107(4):733-739. [DOI] [PubMed] [Google Scholar]
- 11.Hayden Gephart MG, Hansasuta A, Balise RR, et al. Cochlea radiation dose correlates with hearing loss after stereotactic radiosurgery of vestibular schwannoma. World Neurosurg. 2013;80(3-4):359-363. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Thomas C, Di Maio S, Ma R, et al. Hearing preservation following fractionated stereotactic radiotherapy for vestibular schwannomas: prognostic implications of cochlear dose. J Neurosurg. 2007;107(5):917-926. [DOI] [PubMed] [Google Scholar]
- 13.Timmer FCA, Hanssens PEJ, van Haren AEP, et al. Gamma knife radiosurgery for vestibular schwannomas: results of hearing preservation in relation to the cochlear radiation dose. Laryngoscope. 2009;119(6):1076-1081. [DOI] [PubMed] [Google Scholar]
- 14.Régis J, Tamura M, Delsanti C, Roche P-H, Pellet W, Thomassin J-M. Hearing preservation in patients with unilateral vestibular schwannoma after gamma knife surgery In: Regis J, Roche P-H, eds. Modern Management of Acoustic Neuroma. Prog Neurol Surg. 2008;21:142-151. [DOI] [PubMed] [Google Scholar]
- 15.Muzevic D, Legcevic J, Splavski B, Cayé-Thomasen P. Stereotactic radiotherapy for vestibular schwannoma. Cochrane Database Syst Rev. 2014;12(12):CD009897. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Chan AW, Black P, Ojemann RG, et al. Stereotactic radiotherapy for vestibular schwannomas: favorable outcome with minimal toxicity. Neurosurgery. 2005;57(1):60-70; discussion 60-70. [DOI] [PubMed] [Google Scholar]
- 17.Andrews DW, Suarez O, Goldman HW, et al. Stereotactic radiosurgery and fractionated stereotactic radiotherapy for the treatment of acoustic schwannomas: comparative observations of 125 patients treated at one institution. Int J Radiat Oncol Biol Phys. 2001;50(5):1265-1278. [DOI] [PubMed] [Google Scholar]
- 18.Litre F, Rousseaux P, Jovenin N, et al. Fractionated stereotactic radiotherapy for acoustic neuromas: a prospective monocenter study of about 158 cases. Radiother Oncol. 2013;106(2):169-174. [DOI] [PubMed] [Google Scholar]
- 19.Maire J-P, Huchet A, Milbeo Y, et al. Twenty years’ experience in the treatment of acoustic neuromas with fractionated radiotherapy: a review of 45 cases. Int J Radiat Oncol Biol Phys. 2006;66(1):170-178. [DOI] [PubMed] [Google Scholar]
- 20.Rasmussen R, Claesson M, Stangerup S-E, et al. Fractionated stereotactic radiotherapy of vestibular schwannomas accelerates hearing loss. Int J Radiat Oncol Biol Phys. 2012;83(5):e607-e611. [DOI] [PubMed] [Google Scholar]
- 21.Aoyama H, Onodera S, Takeichi N, et al. Symptomatic outcomes in relation to tumor expansion after fractionated stereotactic radiation therapy for vestibular schwannomas: single-institutional long-term experience. Int J Radiat Oncol Biol Phys. 2013;85(2):329-334. [DOI] [PubMed] [Google Scholar]
- 22.Kapoor S, Batra S, Carson K, et al. Long-term outcomes of vestibular schwannomas treated with fractionated stereotactic radiotherapy: an institutional experience. Int J Radiat Oncol Biol Phys. 2011;81(3):647-653. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Phillips MH, Frankel KA, Lyman JT, Fabrikant JI, Levy RP. Comparison of different radiation types and irradiation geometries in stereotactic radiosurgery. Int J Radiat Oncol Biol Phys. 1990;18(1):211-220. [DOI] [PubMed] [Google Scholar]
- 24.Verhey LJ, Smith V, Serago CF. Comparison of radiosurgery treatment modalities based on physical dose distributions. Int J Radiat Oncol Biol Phys. 1998;40(2):497-505. [DOI] [PubMed] [Google Scholar]
- 25.Koetsier KS, Hensen EF, Wiggenraad R, et al. Clinical outcomes and toxicity of proton radiotherapy for vestibular schwannomas: a systematic review. J Radiat Oncol. 2019;8(4):357-368. [Google Scholar]
- 26.Barnes CJ, Bush DA, Grove RI, Loredo LN, Slater JD. Fractionated proton beam therapy for acoustic neuromas: tumor control and hearing preservation. Int J Part Ther. 2018;4(4):28-36. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Zhu S, Rotondo R, Mendenhall WM, et al. Long-term outcomes of fractionated stereotactic proton therapy for vestibular schwannoma: a case series. Int J Part Ther. 2018;4(4):37-46. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Vernimmen FJAI, Mohamed Z, Slabbert JP, Wilson J. Long-term results of stereotactic proton beam radiotherapy for acoustic neuromas. Radiother Oncol. 2009;90(2):208-212. [DOI] [PubMed] [Google Scholar]
- 29.Bush DA, McAllister CJ, Loredo LN, Johnson WD, Slater JM, Slater JD. Fractionated proton beam radiotherapy for acoustic neuroma. Neurosurgery. 2002;50(2):270-273; discussion 273-275. [DOI] [PubMed] [Google Scholar]
- 30.Blakeley JO, Ye X, Duda DG, et al. Efficacy and biomarker study of bevacizumab for hearing loss resulting from neurofibromatosis type 2-associated vestibular schwannomas. J Clin Oncol. 2016;34(14):1669-1675. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Halpin C, Rauch SD. Using audiometric thresholds and word recognition in a treatment study. Otol Neurotol. 2006;27(1):110-116. [DOI] [PubMed] [Google Scholar]
- 32.de Jong MA, Luder A, Gross M. Main aspects of peripheral and central hearing system involvement in unexplained HIV-related hearing complaints. Front Neurol. 2019;10:845. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Xiong B, Liu Z, Liu Q, et al. Missed hearing loss in tinnitus patients with normal audiograms. Hear Res. 2019;384:107826. [DOI] [PubMed] [Google Scholar]
- 34.Patel KS, Ng E, Kaur T, et al. Increased cochlear radiation dose predicts delayed hearing loss following both stereotactic radiosurgery and fractionated stereotactic radiotherapy for vestibular schwannoma. J Neurooncol. 2019;145(2):329-337. [DOI] [PubMed] [Google Scholar]
- 35.Woods K, Lee P, Kaprealian T, Yang I, Sheng K. Cochlea-sparing acoustic neuroma treatment with 4π radiation therapy. Adv Radiat Oncol. 2018;3(2):100-107. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.van Linge A, van Os R, Hoekstra N, et al. Progression of hearing loss after LINAC-based stereotactic radiotherapy for vestibular schwannoma is associated with cochlear dose, not with pre-treatment hearing level. Radiat Oncol. 2018;13(1):253. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Zach L, Stall B, Ning H, et al. A dosimetric comparison of four treatment planning methods for high grade glioma. Radiat Oncol. 2009;4(1):45. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.St Clair WH, Adams JA, Bues M, et al. Advantage of protons compared to conventional X-ray or IMRT in the treatment of a pediatric patient with medulloblastoma. Int J Radiat Oncol Biol Phys. 2004;58(3):727-734. [DOI] [PubMed] [Google Scholar]
- 39.Pan CC, Eisbruch A, Lee JS, Snorrason RM, Ten Haken RK, Kileny PR. Prospective study of inner ear radiation dose and hearing loss in head-and-neck cancer patients. Int J Radiat Oncol Biol Phys. 2005;61(5):1393-1402. [DOI] [PubMed] [Google Scholar]
- 40.Lambrecht M, Eekers DBP, Alapetite C, et al. Radiation dose constraints for organs at risk in neuro-oncology; the European Particle Therapy Network consensus. Radiother Oncol. 2018;128(1):26-36. [DOI] [PubMed] [Google Scholar]
- 41.Chung LK, Ung N, Sheppard JP, et al. Impact of cochlear dose on hearing preservation following stereotactic radiosurgery and fractionated stereotactic radiotherapy for the treatment of vestibular schwannoma. J Neurol Surg B Skull Base. 2018;79(4):335-342. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Coughlin AR, Willman TJ, Gubbels SP. Systematic review of hearing preservation after radiotherapy for vestibular schwannoma. Otol Neurotol. 2018;39(3):273-283. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Santa Maria PL, Shi Y, Gurgel RK, et al. Long-term hearing outcomes following stereotactic radiosurgery in vestibular schwannoma patients-A retrospective cohort study. Neurosurgery. 2019;85(4):550-559. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Patel MA, Marciscano AE, Hu C, et al. Long-term treatment response and patient outcomes for vestibular schwannoma patients treated with hypofractionated stereotactic radiotherapy. Front Oncol. 2017;7:200. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplemental Methods. Further description of patient selection and treatment planning, including methodology of RT dose prescription and planning technique and immobilization.
Supplemental Figure. Ipsilateral and contralateral PTA scores before and after radiation therapy.
Supplemental Table 1. Acute toxicity (CTCAE v4.0), events up to and including 90 days after treatment.
Supplemental Table 2. Delayed toxicity (CTCAE v4.0), events at 12 months after treatment.
Supplemental Discussion. Further discussion of otoacoustic emission results and their significance with RT damage, as well as discussion of end-of-range uncertainty with proton beam.