Advertisement

The effect of cochlear dose on hearing preservation after low dose stereotactic radiosurgery for vestibular schwannomas: a systematic review

Open AccessPublished:August 26, 2022DOI:https://doi.org/10.1016/j.adro.2022.101059

      Abstract

      Purpose

      Despite excellent tumour control after stereotactic radiosurgery (SRS) for vestibular schwannoma (VS), the hearing preservation rate remains unsatisfactorily low. Although many factors have been associated with hearing loss, the dose to cochlea has gained more interest in recent years. However, studies investigating the relation between cochlear dose and hearing outcomes have produced inconsistent results. The purpose of this work is to systematically review the literature and critically analyse the studies that investigated the correlation between cochlear dose and hearing loss.

      Methods and Materials

      A literature search of Ovid MEDLINE, Embase and Scopus was performed. Studies were included if the SRS dose used was 11-14 Gy and included adult patients with sporadic VS, initially serviceable hearing and at least 24 months of mean or median follow-up.

      Results

      Twenty-one cohort studies and one case-control study were eligible for inclusion, and none were considered to be truly prospective. There was substantial heterogeneity between studies in terms of baseline hearing status, cochlear dosimetry, definition and reporting of hearing outcome and duration of follow-up, limiting comparison between studies and precluding formal meta-analysis. Eleven studies showed a statistically significant correlation between cochlear dose and hearing outcome, but there was considerable variation in the reported cochlear dose parameter that predicted hearing outcome and if it was an independent predictor. The definition of hearing outcome and whether the outcome variable is continuous or dichotomous have a bearing on the reported correlation between cochlear dose and hearing outcome.

      Conclusions

      Whether cochlear dose is a predictor of hearing preservation after SRS for VS could not be unequivocally determined. Future studies should use consistent cochlear dosimetry and hearing outcomes for reliable assessment. In the meantime, based on currently available data, a practical approach will be to aim for a mean cochlear dose ˂ 4-6 Gy without compromising tumour dose.

      Keywords

      Introduction

      Stereotactic radiosurgery (SRS) is the mainstay of non-surgical treatment for vestibular schwannoma (VS). Leksell pioneered the SRS technique in the 1960s using a Cobalt 60 Gamma Unit, which became known as the Gamma Knife (GK).
      • Coughlin AR
      • Willman TJ
      • Gubbels SP.
      Systematic Review of Hearing Preservation After Radiotherapy for Vestibular Schwannoma.
      Nowadays, SRS can also be performed using linear accelerator (LINAC), CyberKnife or proton beam therapy units. Irrespective of the treatment device, the common attributes of SRS include stereotactic localisation of the tumour, delivery of a highly precise single dose of radiation and a steep dose fall-off beyond the target volume, reducing the dose to surrounding structures. For VS smaller than 3cm, SRS has become the preferred treatment due to the lower morbidity compared to surgical treatment and comparable long-term tumour control.
      • Pollock BE
      • Driscoll CL
      • Foote RL
      • et al.
      Patient outcomes after vestibular schwannoma management: a prospective comparison of microsurgical resection and stereotactic radiosurgery.
      • Frischer JM
      • Gruber E
      • Schöffmann V
      • et al.
      Long-term outcome after Gamma Knife radiosurgery for acoustic neuroma of all Koos grades: a single-center study.
      • Wolbers JG
      • Dallenga AHG
      • Mendez Romero A
      • et al.
      What intervention is best practice for vestibular schwannomas? A systematic review of controlled studies.
      The current standard for VS is to use a marginal tumour dose of 12-14Gy, lower than the doses used previously, to reduce treatment-related toxicity.
      • Tsao MN
      • Sahgal A
      • Xu W
      • et al.
      Stereotactic radiosurgery for vestibular schwannoma: International Stereotactic Radiosurgery Society (ISRS) Practice Guideline.
      • Goldbrunner R
      • Weller M
      • Regis J
      • et al.
      EANO guideline on the diagnosis and treatment of vestibular schwannoma.
      • Germano IM
      • Sheehan J
      • Parish J
      • et al.
      Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines on the Role of Radiosurgery and Radiation Therapy in the Management of Patients With Vestibular Schwannomas.
      While long-term tumour control is comparable to that with higher doses, the lower doses are associated with better preservation of facial nerve function
      • Combs SE
      • Engelhard C
      • Kopp C
      • et al.
      Long-term outcome after highly advanced single-dose or fractionated radiotherapy in patients with vestibular schwannomas - pooled results from 3 large German centers.
      ,
      • Yang I
      • Sughrue ME
      • Han SJ
      • et al.
      Facial nerve preservation after vestibular schwannoma Gamma Knife radiosurgery.
      and hearing.
      • Yang I
      • Aranda D
      • Han SJ
      • et al.
      Hearing preservation after stereotactic radiosurgery for vestibular schwannoma: a systematic review.
      ,
      • Kim JH
      • Jung HH
      • Chang JH
      • et al.
      Predictive Factors of Unfavorable Events After Gamma Knife Radiosurgery for Vestibular Schwannoma.
      Long-term hearing preservation, however, remains disappointingly low (23-64%).
      • Coughlin AR
      • Willman TJ
      • Gubbels SP.
      Systematic Review of Hearing Preservation After Radiotherapy for Vestibular Schwannoma.
      ,
      • Chopra R
      • Kondziolka D
      • Niranjan A
      • et al.
      Long-term follow-up of acoustic schwannoma radiosurgery with marginal tumor doses of 12 to 13 Gy.
      • 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.
      • Roos DE
      • Potter AE
      • Zacest AC.
      Hearing preservation after low dose linac radiosurgery for acoustic neuroma depends on initial hearing and time.
      • Tolisano AM
      • Hunter JB.
      Hearing Preservation in Stereotactic Radiosurgery for Vestibular Schwannoma.
      Although many mechanisms have been postulated, the pathogenesis of hearing loss is currently poorly understood.
      • Tolisano AM
      • Hunter JB.
      Hearing Preservation in Stereotactic Radiosurgery for Vestibular Schwannoma.
      • Thomas C
      • Di Maio S
      • Ma R
      • et al.
      Hearing preservation following fractionated stereotactic radiotherapy for vestibular schwannomas: Prognostic implications of cochlear dose.
      • Linskey ME.
      Hearing preservation in vestibular schwannoma stereotactic radiosurgery: what really matters?.
      However, in the past decade, radiation injury to the cochlea has been increasingly recognised as a possible cause of hearing loss and has been the subject of several studies.
      • Linskey ME.
      Hearing preservation in vestibular schwannoma stereotactic radiosurgery: what really matters?.
      • Wackym PA
      • Runge-Samuelson CL
      • Nash JJ
      • et al.
      Gamma knife surgery of vestibular schwannomas: Volumetric dosimetry correlations to hearing loss suggest stria vascularis devascularization as the mechanism of early hearing loss.
      • Ottaviani F
      • Neglia CB
      • Ventrella L
      • et al.
      Hearing loss and changes in transient evoked otoacoustic emissions after gamma knife radiosurgery for acoustic neurinomas.
      • Linskey ME
      • Johnstone PA
      • O'Leary M
      • et al.
      Radiation exposure of normal temporal bone structures during stereotactically guided gamma knife surgery for vestibular schwannomas.
      While some of these have reported an association between cochlear dose and hearing loss after SRS, others have not found a relation. Therefore, if and what cochlear dose constraints should be used to prevent hearing loss is currently ambiguous. Not surprisingly, there is little agreement in the current recommendations: the Congress of Neurological Surgeons consensus guidelines recommend keeping the dose to cochlea below 4Gy, Timmerman et al
      • Timmerman RD.
      An overview of hypofractionation and introduction to this issue of seminars in radiation oncology.
      suggest a dose limit of 12 Gy maximum point dose, the UK consensus guidelines suggest a mean dose of 4 Gy, but the QUANTEC review does not specify a dose constraint, instead recommending a prescription dose of 12 – 14 Gy.
      • Hanna GG
      • Murray L
      • Patel R
      • et al.
      UK Consensus on Normal Tissue Dose Constraints for Stereotactic Radiotherapy.
      • Carlson ML
      • Vivas EX
      • McCracken DJ
      • et al.
      Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines on Hearing Preservation Outcomes in Patients With Sporadic Vestibular Schwannomas.
      • Bhandare N
      • Jackson A
      • Eisbruch A
      • et al.
      Radiation therapy and hearing loss.
      This study systematically reviews the literature to identify studies that have assessed the relationship between cochlear dose and hearing outcome following SRS for VS. Our aim is to appraise the studies and critically analyse the methods used to assess the strength and significance of the correlation between cochlear dose and hearing loss. To our knowledge, this is the first systematic review of this subject.

      Methods and Materials

      A literature search of MEDLINE (via Ovid), Embase (via Ovid) and Scopus databases was performed. The keywords used to develop the search strategy were acoustic neuroma, schwannoma, hearing preservation, cochlea and stereotactic radiosurgery. A search strategy was initially developed for Ovid MEDLINE (appendix 1) and then translated for Ovid Embase and Scopus databases. The Cochrane library was also searched for published reviews that may contain citations relevant to this review. The searches were filtered for articles in English and published after 2000. The study protocol was registered in XXXX (IDXXXX). In view of the publicly available literature under review, Research Ethics approval was deemed unnecessary.
      Publications were included if the study population comprised adults with sporadic VS with serviceable hearing (Gardner-Robertson Class [GRC] I-II or American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) class A and B), used contemporary radiosurgery doses (11–14 Gy), reported dose to the cochlea and analysed its relationship with hearing outcomes. Studies were excluded if the mean or median follow-up after radiosurgery was less than 24 months, if published only in abstract form, or if they included a substantial number of patients with NFII or having had prior radiotherapy treatment.
      Two reviewers independently examined the results of the searches. Bibliography search and citation tracking of relevant articles was used to identify other articles. Recent systematic reviews on hearing preservation after radiosurgery treatment were also examined for relevant citations. A predetermined data extraction form guided data extraction.
      The quality appraisal was performed using the Newcastle-Ottawa Scale which assesses observational studies in three categories (selection, comparability and outcome) to a maximum of nine stars.

      Wells GA, Shea B, O'Connell D et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. [cited 2021 Dec 12]. Available from: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.

      We used the following criteria (Appendix 2) for awarding stars for the comparability and outcome measures: one star if the study controlled for age, marginal dose and pre-treatment hearing status in the design or analysis and two stars if tumour volume and fundus distance or fundus involvement was also controlled; one star for the length of follow-up only if the follow-up of hearing outcome was longer than 36 months (mean or median).

      Results

      The database search yielded 2432 articles, and 6 additional articles were identified through bibliography search and citation tracking. The PRISMA flow diagram is shown in Figure 1. Twenty-two articles were judged to be relevant and included in this review: one retrospective case-control study and the rest retrospective cohort studies. Although three were stated to be prospective
      • Wackym PA
      • Runge-Samuelson CL
      • Nash JJ
      • et al.
      Gamma knife surgery of vestibular schwannomas: Volumetric dosimetry correlations to hearing loss suggest stria vascularis devascularization as the mechanism of early hearing loss.
      ,
      • Ottaviani F
      • Neglia CB
      • Ventrella L
      • et al.
      Hearing loss and changes in transient evoked otoacoustic emissions after gamma knife radiosurgery for acoustic neurinomas.
      ,
      • Paek SH
      • Chung HT
      • Jeong SS
      • et al.
      Hearing preservation after gamma knife stereotactic radiosurgery of vestibular schwannoma.
      , we instead categorized them as retrospective studies using prospective databases because it was not evident that patients were enrolled in prospective protocols specifically investigating the subject under review. The study characteristics are provided in Table 1. Two studies used LINAC SRS, all others Gamma Knife SRS. Only patients with serviceable hearing (GRC I and II or AAO-HNS Class A and B) were included in 8 studies (Table 1). In one, the population was exclusively GRC I; other studies included a mixed population of patients with serviceable and non-serviceable hearing. Two studies included patients treated with SRS or fractionated stereotactic radiotherapy(FSRT); only the analysis pertaining to the SRS subgroup was extracted from these studies.27, 28The cohort in the studies by Regis et al
      • Régis J
      • Tamura M
      • Delsanti C
      • et al.
      Hearing preservation in patients with unilateral vestibular schwannoma after gamma knife surgery.
      and Tamura et al
      • Tamura M
      • Carron R
      • Yomo S
      • et al.
      Hearing preservation after gamma knife radiosurgery for vestibular schwannomas presenting with high-level hearing.
      were drawn from the same patient population treated in their institution but varied in the inclusion criteria: GRC I and II versus GRC I only.
      Table 1Characteristics of included studies.
      Author yearStudy typeNo. of patients
      Number of patients in the analysis of predictive factors and hearing outcome
      Pre-treatment hearingDoseMachineFollow up(months)Hearing preservation (crude rate, unless specified)
      Ottaviani 200219Retrospective26Any12-14 GyGK
      Gamma Knife
      24 median-
      Paek 200526Retrospective25GRC
      Gardner-Robertson Class
      I-II
      11-14 GyGK49 median46% (5-yr, actuarial)
      Massager 200737Retrospective82GRC I-IV12 GyGK24 median56% (4-yr, actuarial)
      Lasak 200838Retrospective33Any12 or 13 GyGK24 median
      Regis 200829Retrospective184GRC I-II<13 GyGK84 mean60% (3-yr)
      Tamura 200930Retrospective74GRC I9 -13 GyGK48 median78.4% (3-yr)
      Wackym 201018Retrospective59
      7 patients had secondary GK SRS
      Any11.7-14 GyGK65.5 median-
      Yomo 201239Retrospective154Any9-14 GyGK52 mean58.1%
      Kim 2013
      • Kim YH
      • Kim DG
      • Han JH
      • et al.
      Hearing outcomes after stereotactic radiosurgery for unilateral intracanalicular vestibular schwannomas: Implication of transient volume expansion.
      Retrospective60GRC I-II11.5-13 GyGK61.5 mean55% (5-yr, actuarial)
      Baschnagel 201332Retrospective40GRC I-II12.5 or 13 GyGK34.5 median74% (3-yr, actuarial)
      Carlson 201313Retrospective44AAO-HNS
      American Academy of Otolaryngology-Head and Neck Surgery Class
      A and B
      12-13 GyGK111.6 median23% (10-yr, actuarial)
      Jacob 201441Retrospective59AAO-HNS A and B12 or 13 GyGK25.2 mean57% (3-yr, actuarial)
      Horiba 201634Retrospective49Any11-12 GyGK56 median57%
      Iorio-Morin 201633Retrospective41
      only Koos grade 4
      ,
      19% had prior resection
      Any11-13 GyGK47 median49% (5-yr, actuarial)
      Lin 201731Retrospective100AAO-HNS A and B12 or 13 GyGK78 median63%(5-yr)
      Pan 201735Retrospective64Any12 GyGK77.9 mean81.2%
      Schumacher 201740Retrospective18GRC I-IV11 GyGK42 median55%
      Park 201854Retrospective56Any10-13 GyGK24.4 mean-
      Chung 201827Retrospective

      Case-Control
      14GRC I-IV12 GyLINAC38.3 mean64% (5-yr, actuarial)
      Prabhuraj 201936Retrospective87GRC I-II11.5-14 GyGK30 mean62% (5-yr, actuarial)
      Patel 201928Retrospective43
      21% had prior resection
      Any12 GyLINAC25 median53%
      Bojrab 202148Retrospective106Any (PTA ≤ 90 dB)12.5 or 13 GyGK49.8 mean-
      a Number of patients in the analysis of predictive factors and hearing outcome
      b Gardner-Robertson Class
      c American Academy of Otolaryngology-Head and Neck Surgery Class
      d Gamma Knife
      e only Koos grade 4
      f 7 patients had secondary GK SRS
      g 19% had prior resection
      h 21% had prior resection
      The Newcastle-Ottawa Scale results for included studies are provided in Appendix 3. Scores ranged from 4-9 stars (median 5).

      Cochlea contouring and dosimetry

      The cochlea contouring methods varied between studies: 3 used only CT scan, 4 used MRI and CT, and 4 relied only on MRI (Table 2). The method of contouring the cochlea was not stated in the rest of the studies. Four studies used cochlear dose constraints in treatment planning (Table 2): Lin et al
      • Lin RH
      • Wang TC
      • Lin CD
      • et al.
      Predictors of hearing outcomes following low-dose stereotactic radiosurgery in patients with vestibular schwannomas: A retrospective cohort review.
      and Baschnagel et al
      • Baschnagel AM
      • Chen PY
      • Bojrab D
      • et al.
      Hearing preservation in patients with vestibular schwannoma treated with Gamma Knife surgery.
      met their dose constraint (mean < 5 Gy) in the entire study population, Iorio-Morin et al
      • Iorio-Morin C
      • AlSubaie F
      • Mathieu D.
      Safety and Efficacy of Gamma Knife Radiosurgery for the Management of Koos Grade 4 Vestibular Schwannomas.
      met it (mean < 4 Gy) in 18 of the 68 patients, and the proportion of study population that met the constraint (maximum < 4 Gy) was not reported by Horiba et al.
      • Horiba A
      • Hayashi M
      • Chernov M
      • et al.
      Hearing preservation after low-dose gamma knife radiosurgery of vestibular schwannomas.
      The studies used various cochlear dose parameters to assess the relationship with the hearing outcomes (Table 2). Three studies did not specify the cochlear dose parameter but instead referred to it simply as “cochlear dose”.
      • Régis J
      • Tamura M
      • Delsanti C
      • et al.
      Hearing preservation in patients with unilateral vestibular schwannoma after gamma knife surgery.
      ,
      • Horiba A
      • Hayashi M
      • Chernov M
      • et al.
      Hearing preservation after low-dose gamma knife radiosurgery of vestibular schwannomas.
      ,
      • Pan SY
      • Liu SA
      • Sun MH
      • et al.
      Outcome of hearing preservation related to tumor morphologic analysis in acoustic neuromas treated by gamma knife radiosurgery.
      Only a point dose at the modiolus was calculated in one study.
      • 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.
      While most studies stated that volumetric cochlear dosimetry was performed, whether the maximum cochlear dose corresponded to a point or volume maximum was not always stated.
      Table 2Cochlear contouring and cochlear dosimetry in the included studies
      Author yearCochlea dose constraintCochlea contouringCochlear dose parameter assessedMaximum cochlear dose
      (Gy) (average, unless specified)Mean cochlear dose
      (Gy) (average, unless specified)
      Ottaviani 200219-ND
      Not described
      Maximum--
      Paek 200526-NDMaximum and minimum8.1
      -
      Massager 200737-CT and MRIMean, maximum and minimum8.52
      4.33
      Lasak 200838-MRIMean-5.2
      Regis 200829-NDCochlear dose--
      Tamura 200930-CTDose to modiolus, maximum--
      Wackym 201018-NDMaximum, volume receiving 100%, 75%, 50% and 25% of maximum, dose to modiolus and basal turn of the cochlea--
      Yomo 201239-CTMaximum--
      Kim 2013
      • Kim YH
      • Kim DG
      • Han JH
      • et al.
      Hearing outcomes after stereotactic radiosurgery for unilateral intracanalicular vestibular schwannomas: Implication of transient volume expansion.
      -MRIMean and maximum8.2
      4.2
      Baschnagel 201332Mean < 5 GyCT and MRIMaximum, minimum, mean, V3, V5, V8 and V106.9 (median)
      2.7 (median)
      Carlson 201313-NDPoint modiolus-5 (modiolus dose)
      Jacob 201441-CTMean, maximum, point modiolus11.8
      4.9
      Horiba 201634Maximum < 4 GyNDCochlear dose--
      Iorio-Morin 201633Mean < 4 GyMRIMean and maximum6.8 (median)
      4.3 (median)
      Lin 201731Mean < 5 GyNDMean, maximum and minimum5.9
      2.8
      Pan 201735-MRICochlear dose-3.3
      Schumacher 201740-NDMean and maximum12 (median)6 (median)
      Park 201854-NDMean8.9
      4.6
      Chung 201827-CT and MRIMean, maximum and minimum10.8
      8.3
      Prabhuraj 201936-NDMean5.9
      3.74
      Patel 201928-CT and MRIMean, maximum and minimum11.6
      8.2
      Bojrab 202148-NDMean and maximum5.9 (median)(median)
      a Not described

      Hearing outcomes

      Studies differed in terms of the number and nature of hearing outcomes used, how the hearing loss or deterioration was defined, and the ways the outcome variable was handled (continuous vs dichotomous) (Table 3).
      Table 3Cochlear dose correlation with hearing outcomes in the included studies - studies ordered based on method of hearing outcome assessment
      Author, yearHearing outcomePredictive factors analysedCochlear dose predicted hearing outcome (dose parameter)Cochlea dose threshold
      Univariate analysisMultivariate analysis
      Hearing outcome – Loss of baseline GRC
      Gardner-Robertson Class
      (dichotomous outcome)
      Chung 201827Stable vs decreased hearing at last follow-upPatient, tumour and dosimetric-Yes (minimum)Cochlear minimum dose of > 6 Gy was associated with higher risk for hearing deterioration
      Massager 200737Hearing preservation (same or improved GRC)NoneYes(mean)-Median mean dose to cochlear volume: 3.7 Gy (hearing preserved) vs 5.33 Gy (hearing deteriorated)
      Hearing outcome – loss of serviceable hearing (dichotomous outcome)
      Lin 201731Hearing preservation (AAO-HNS
      American Academy of Otolaryngology-Head and Neck Surgery Class
      A / B)
      Patient, tumour and dosimetricYes(mean) -only predictor-Mean dose of < 4 Gy favourable predictor of hearing outcome
      Regis 200829Loss of functional hearing (GRC I / II)Patient, tumour and dosimetric-Yes-
      Prabhuraj 201936Hearing preservation (GRC I / II) at 24 monthsPatient and tumourYes (mean)No-
      Pan 201735Preservation of serviceable hearing (< 50 dB and ≥ 50% SD)Tumour and dosimetricYesNo-
      Iorio-Morin 201633Preservation of serviceable hearing (GRC I / II)Tumour and treatment-relatedNo--
      Horiba 201634Preservation of serviceable hearing (GRC I / II)Patient, tumour and dosimetricNo--
      Hearing outcome – loss of baseline GRC and loss of serviceable hearing (dichotomous outcome)
      Tamura 200930Preservation of GRC I and functional hearing preservation (GRC I/ II)Patient, tumour and dosimetric-Yes (maximum), for GRC I preservation90.9 % functional hearing preservation - for maximum cochlear dose of < 4 Gy
      Baschnagel 201332Serviceable hearing (GRC I / II) and maintain GRCPatient, tumour and dosimetricYes (mean and % vol. ≥ 3 Gy)NoMean cochlear dose of < 3 Gy associated with better serviceable hearing preservation (trend towards statistical significance). 2-yr Hearing preservation - 91% (mean dose < 3 Gy) vs 59% (mean dose ≥ 3 Gy)
      Patel 201928Loss of baseline GRC and loss of serviceable hearing at 1year and last follow-upPatient and tumour
      SRS and FSRT groups combined to analyse tumour and patient-related factors
      Yes (minimum, mean and maximum) -only predictors-Mean and minimum correlated with both outcomes, maximum only with loss of GRC. Minimum dose was the most robust predictor. Hearing preservation: 94% (minimum < 5Gy) vs 13% (minimum ≥ 5Gy)
      Schumacher 201740Loss of baseline GRC and loss of serviceable hearingPatient, tumour and dosimetric-Yes (mean and maximum)Mean dose correlated with both outcomes, maximum only with loss of GRC.Serviceable hearing preservation: 100% (mean <6 Gy) vs 13% (mean ≥ 6 Gy). GRC preservation: 89% (maximum dose < 12 Gy) vs 20% maximum dose ≥ 12 Gy)
      Hearing outcome – change in PTA (Continuous outcome)
      Lasak 200838Change in PTA
      Pure tone average
      and SDS
      Speech discrimination score
      NoneYes (mean)-Only minimum SDS after SRS correlated with mean cochlear dose At 12 months, change in PTA was significantly worse for mean cochlear dose ≥ 4.75 Gy
      Wackym 201018Change in PTA3
      PTA3 – 500, 1000 and 200Hz
      , PTA4
      PTA4 – 500,1000,2000 and 3000 Hz
      , PTA-HF
      PTA-HF – 4000, 6000 and 8000 Hz
      and speech recognition during first 12 months
      NoneYes (maximum)-Cochlear dose > 4 Gy correlated with change in PTA3
      Yomo 201239Annual rate of PTA decrease (dB/yr)Patient and tumour-Yes (maximum)Maximum cochlear dose ≤ 4 Gy was statistically significant predictive factor. Hearing decrease:3.14 dB/yr (maximum dose ≤ 4 Gy) vs 4.43 dB/yr (maximum dose > 4 Gy)
      Ottaviani 2002192-year decrease in LTA
      low tone average
      , PTA and HTA
      high-tone average
      NoneYes (maximum – correlated only with HTA)--
      Hearing outcome – change in PTA (dichotomous outcome)
      Park 201854PTA increase ≥ 15 dBPatient, tumour and dosimetricYesNo-
      Paek 200526PTA increase ≥ 20 dBDose to cochlear nerve and cochlear nucleusNo--
      Hearing outcome – time to hearing loss (continuous outcome variable)
      Carlson 201313Time to non-serviceable hearingPatient, tumour and dosimetricno--
      Jacob 201441Time to non-serviceable hearingPatient, tumour and dosimetricYes (mean)No3-yr serviceable hearing preservation: 76% (mean dose < 5 Gy) vs 37% (mean dose ≥ 5 Gy)
      Hearing outcome – loss of serviceable hearing and change in PTA (dichotomous outcome variable)
      Kim 2013
      • Kim YH
      • Kim DG
      • Han JH
      • et al.
      Hearing outcomes after stereotactic radiosurgery for unilateral intracanalicular vestibular schwannomas: Implication of transient volume expansion.
      Preservation of serviceable hearing (GRC I / II) and hearing deterioration (PTA increase ≥ 20)Patient, tumour and dosimetricYes (mean)No-
      Bojrab 202148Maintenance of AAO-HNS A/B and hearing preservation (PTA increase ≤ 20 dB)Tumour and dosimetric factorsNo--
      a Gardner-Robertson Class
      b American Academy of Otolaryngology-Head and Neck Surgery Class
      c Pure tone average
      d Speech discrimination score
      e PTA3 – 500, 1000 and 200Hz
      f PTA4 – 500,1000,2000 and 3000 Hz
      g PTA-HF – 4000, 6000 and 8000 Hz
      h low tone average
      i high-tone average
      j SRS and FSRT groups combined to analyse tumour and patient-related factors
      The different hearing outcomes and definitions used were:
      • Loss of serviceable hearing (GRC III and IV or AAO-HNS Class C and D) – dichotomous variable, mostly used in studies that included or analysed only patients with serviceable hearing
      • Increase or loss of baseline GRC or AAO-HNS Class – dichotomous variable, used in studies including patients with GRC I only or GRC I-IV
      • Change or rate of change in pure tone audiometry (PTA) (difference between pre- and post-SRS PTA) after SRS, without defining a PTA threshold for clinically significant hearing loss or deterioration – continuous variable, used mostly in studies including patients with any hearing level
      • Hearing deterioration, defined as the difference between pre- and post-SRS PTA of greater than or equal to 15 dB or 20 dB – dichotomous variable
      • Time to non-serviceable hearing – continuous variable.

      Follow up and timing of hearing outcome assessment

      Although we included only studies with median or mean follow-up of at least 24 months, in some studies, the hearing outcomes were assessed within a much shorter duration after treatment despite having a longer follow-up period (Table 1). Ottaviani et al
      • Ottaviani F
      • Neglia CB
      • Ventrella L
      • et al.
      Hearing loss and changes in transient evoked otoacoustic emissions after gamma knife radiosurgery for acoustic neurinomas.
      and Wackym et al
      • Wackym PA
      • Runge-Samuelson CL
      • Nash JJ
      • et al.
      Gamma knife surgery of vestibular schwannomas: Volumetric dosimetry correlations to hearing loss suggest stria vascularis devascularization as the mechanism of early hearing loss.
      assessed PTA change at 24 months and 12 months, respectively. Patel et al
      • 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.
      assessed the loss of baseline GRC and serviceable hearing at 12 months and last follow-up, while Prabhuraj et al
      • Prabhuraj AR
      • Yeole U
      • Arimappamagan A
      • et al.
      Effect of Gamma Knife Radiosurgery on Vestibular Schwannoma with Serviceable Hearing: A Single-Center Indian Study.
      evaluated serviceable hearing preservation at 24 months. The median or mean follow up was more than 36 months in 8 studies and more than 60 months in 6 studies.

      Relationship betweehn cochlear dose and hearing preservation

      Eleven studies reported that the cochlear dose predicted hearing outcome (Table 3). Only a narrative synthesis of the results was possible due to considerable variation in the hearing outcome and the correlating cochlear dose parameter in the studies. Among these eleven studies, not all investigated if the cochlear dose was an independent predictor of hearing outcome. Wackym et al
      • Wackym PA
      • Runge-Samuelson CL
      • Nash JJ
      • et al.
      Gamma knife surgery of vestibular schwannomas: Volumetric dosimetry correlations to hearing loss suggest stria vascularis devascularization as the mechanism of early hearing loss.
      , Ottaviani et al
      • Ottaviani F
      • Neglia CB
      • Ventrella L
      • et al.
      Hearing loss and changes in transient evoked otoacoustic emissions after gamma knife radiosurgery for acoustic neurinomas.
      , Massager et al
      • Massager N
      • Nissim O
      • Delbrouck C
      • et al.
      Irradiation of cochlear structures during vestibular schwannoma radiosurgery and associated hearing outcome.
      and Lasak et al
      • Lasak JM
      • Klish D
      • Kryzer TC
      • et al.
      Gamma knife radiosurgery for vestibular schwannoma: Early hearing outcomes and evaluation of the cochlear dose.
      did not include any other predictive factor apart from cochlear dose in their analysis. Other studies assessed various predictive factors but with remarkable variation in their choice of factors (Table 3). Six studies were able to show a correlation between cochlear dose and hearing outcome only in the univariate analysis and not in the multivariate analysis.
      In terms of the cochlear dose parameter correlation with hearing outcome, mean dose significantly correlated with hearing preservation in 3 studies,
      • Lin RH
      • Wang TC
      • Lin CD
      • et al.
      Predictors of hearing outcomes following low-dose stereotactic radiosurgery in patients with vestibular schwannomas: A retrospective cohort review.
      ,
      • Massager N
      • Nissim O
      • Delbrouck C
      • et al.
      Irradiation of cochlear structures during vestibular schwannoma radiosurgery and associated hearing outcome.
      ,
      • Lasak JM
      • Klish D
      • Kryzer TC
      • et al.
      Gamma knife radiosurgery for vestibular schwannoma: Early hearing outcomes and evaluation of the cochlear dose.
      maximum dose in four,
      • Wackym PA
      • Runge-Samuelson CL
      • Nash JJ
      • et al.
      Gamma knife surgery of vestibular schwannomas: Volumetric dosimetry correlations to hearing loss suggest stria vascularis devascularization as the mechanism of early hearing loss.
      ,
      • Ottaviani F
      • Neglia CB
      • Ventrella L
      • et al.
      Hearing loss and changes in transient evoked otoacoustic emissions after gamma knife radiosurgery for acoustic neurinomas.
      ,
      • Tamura M
      • Carron R
      • Yomo S
      • et al.
      Hearing preservation after gamma knife radiosurgery for vestibular schwannomas presenting with high-level hearing.
      ,
      • Yomo S
      • Carron R
      • Thomassin JM
      • et al.
      Longitudinal analysis of hearing before and after radiosurgery for vestibular schwannoma.
      , mean and maximum dose in one
      • Schumacher AJ
      • Lall RR
      • Lall RR
      • et al.
      Low-Dose Gamma Knife Radiosurgery for Vestibular Schwannomas: Tumor Control and Cranial Nerve Function Preservation after 11 Gy.
      while minimum dose was found to be the best predictor of hearing preservation in 2 studies.
      • 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.
      ,
      • 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.
      All four studies that used the change in PTA as a continuous outcome variable showed that cochlear dose correlated with hearing outcome (Table 3). However, among these, the study by Lasak et al
      • Lasak JM
      • Klish D
      • Kryzer TC
      • et al.
      Gamma knife radiosurgery for vestibular schwannoma: Early hearing outcomes and evaluation of the cochlear dose.
      showed a correlation only between mean cochlear dose and post-treatment speech discrimination score (SDS) but not with PTA, Ottaviani et al.
      • Ottaviani F
      • Neglia CB
      • Ventrella L
      • et al.
      Hearing loss and changes in transient evoked otoacoustic emissions after gamma knife radiosurgery for acoustic neurinomas.
      showed correlation only between cochlear dose and high tone audiometry and Wackym et al
      • Wackym PA
      • Runge-Samuelson CL
      • Nash JJ
      • et al.
      Gamma knife surgery of vestibular schwannomas: Volumetric dosimetry correlations to hearing loss suggest stria vascularis devascularization as the mechanism of early hearing loss.
      assessed change in PTA only during the first 12 months after SRS. All but one study that used loss of baseline hearing class as the hearing outcome showed a significant relationship between cochlear dose and hearing outcome (Table 3). On the other hand, only 4 out of 12 studies using loss of functional or serviceable hearing as the outcome revealed a significant relationship (Table 3).

      Cochlear dose threshold for hearing preservation

      Eleven studies provided a cochlear dose threshold or cut-off for better preservation of hearing (Table 3 and Figure 2). Since the cochlear dose threshold for better function or serviceable hearing preservation can be obtained only if functional or serviceable hearing preservation was the outcome, this information was obtainable from only four studies. Patel et al
      • 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.
      showed that hearing preservation was 94% if a cochlear minimum dose cut-off of 5 Gy was met and 13% if not met. Lin et al
      • Lin RH
      • Wang TC
      • Lin CD
      • et al.
      Predictors of hearing outcomes following low-dose stereotactic radiosurgery in patients with vestibular schwannomas: A retrospective cohort review.
      suggested that a mean cochlear dose ˂ 4 Gy predicted better hearing preservation. Schumacher et al
      • Schumacher AJ
      • Lall RR
      • Lall RR
      • et al.
      Low-Dose Gamma Knife Radiosurgery for Vestibular Schwannomas: Tumor Control and Cranial Nerve Function Preservation after 11 Gy.
      showed serviceable hearing preservation was 100% for a mean cochlear dose ˂ 6 Gy compared to 13% for > 6 Gy. Tamura et al
      • Tamura M
      • Carron R
      • Yomo S
      • et al.
      Hearing preservation after gamma knife radiosurgery for vestibular schwannomas presenting with high-level hearing.
      also showed that functional hearing preservation was 90% when the maximum dose was ˂ 4 Gy.
      Figure 2
      Figure 2Cochlear threshold doses from individual studies with the hearing outcomes. - Indicates studies that showed correlation between cochlear dose and hearing outcome in multivariate analysis, other studies showed correlation only in univariate analysis or did not perform multivariate analysis. The study by Schumacher et al is represented twice to show the cochlear threshold doses corresponding to different hearing outcomes.
      Two studies that did not show a significant correlation in the multivariate analysis also described hearing preservation in relation to cochlear dose. Baschnagel et al
      • Baschnagel AM
      • Chen PY
      • Bojrab D
      • et al.
      Hearing preservation in patients with vestibular schwannoma treated with Gamma Knife surgery.
      showed that no patient with a mean cochlear dose ˂ 2 Gy lost serviceable hearing, and when the mean dose was ˂ 3 Gy, the chance of maintaining serviceable hearing at 2 years was 91%. However, mean cochlear dose showed only a trend towards statistical significance as an independent predictor. In the study by Jacob et al
      • Jacob JT
      • Carlson ML
      • Schiefer TK
      • et al.
      Significance of cochlear dose in the radiosurgical treatment of vestibular schwannoma: Controversies and unanswered questions.
      , which used the time to non-serviceable hearing loss as the outcome, the 3-year serviceable hearing preservation was 76% for a mean dose ˂ 5 Gy, whereas it was 37% for mean dose ≥ 5 Gy.
      In the studies using change in PTA as the hearing outcome, Wachym et al
      • Wackym PA
      • Runge-Samuelson CL
      • Nash JJ
      • et al.
      Gamma knife surgery of vestibular schwannomas: Volumetric dosimetry correlations to hearing loss suggest stria vascularis devascularization as the mechanism of early hearing loss.
      showed that a maximum cochlear dose > 4 Gy correlated with change in PTA during first 12 months after SRS. Similarly, Yomo et al
      • Yomo S
      • Carron R
      • Thomassin JM
      • et al.
      Longitudinal analysis of hearing before and after radiosurgery for vestibular schwannoma.
      showed that a cochlear dose ≤ 4 Gy was associated with a lower rate of change in PTA than > 4 Gy (3.14 dB/yr vs 4.43 dB/yr). Mean cochlear dose of ≥ 4.75 Gy was associated with significantly worse PTA at 12 months, in Lasak et al's
      • Lasak JM
      • Klish D
      • Kryzer TC
      • et al.
      Gamma knife radiosurgery for vestibular schwannoma: Early hearing outcomes and evaluation of the cochlear dose.
      study, but the correlation was not significant in stepwise regression analysis.
      Taking only studies that used any change in baseline hearing class as the hearing outcome, Chung et al
      • 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.
      reported that a minimum cochlear dose of > 6 Gy was associated with a higher risk for hearing deterioration and Massager et al
      • Massager N
      • Nissim O
      • Delbrouck C
      • et al.
      Irradiation of cochlear structures during vestibular schwannoma radiosurgery and associated hearing outcome.
      showed the median mean dose to cochlea was 3.7 Gy for the group that maintained baseline GRC and 5.33 Gy for those that lost GRC.

      Discussion

      This appears to be the first systematic literature review on cochlear dose in relation to hearing preservation after SRS for VS. It has revealed that all of the existing data are retrospective (albeit some obtained from prospective databases), with considerable heterogeneity in definitions and reporting of outcomes, precluding formal meta-analysis and definitive recommendations. We highlight and discuss some of the important study variables that affected interpretation.

      Cochlear contouring and dosimetry

      The cochlear contouring was not consistent between studies, differing by the imaging modality used and whether the whole cochlea was contoured or not. Kulkarni et al
      • Kulkarni BSN
      • Bajwa H
      • Chandrashekhar M
      • et al.
      CT- and MRI-based gross target volume comparison in vestibular schwannomas.
      found that cochlear volume based on MRI (T2-weighted) was larger than CT. However, despite the poor correlation in cochlear volume between CT and MRI contouring, Faramand et al
      • Faramand AM
      • Kano H
      • Johnson S
      • et al.
      CT versus MR Imaging in Estimating Cochlear Radiation Dose during Gamma Knife Surgery for Vestibular Schwannomas.
      did not find any significant dosimetric disagreement, perhaps due to the small volume of the cochlea. Hence, we believe that CT or MRI may be acceptable as long as the whole cochlea is contoured. However, CT bone window may be preferable for contouring due to the superior resolution of the bony anatomy of the cochlea and because MRI can be affected by distortion, particularly when dealing with small structures like the cochlea.
      • Jacob JT
      • Carlson ML
      • Schiefer TK
      • et al.
      Significance of cochlear dose in the radiosurgical treatment of vestibular schwannoma: Controversies and unanswered questions.
      ,
      • Pacholke HD
      • Amdur RJ
      • Schmalfuss IM
      • et al.
      Contouring the middle and inner ear on radiotherapy planning scans.
      Using only the modiolus dose is not favoured as many structures within the cochlea, namely stria vascularis and basal turn of the cochlea, are possible targets of radiation damage.
      • Wackym PA
      • Runge-Samuelson CL
      • Nash JJ
      • et al.
      Gamma knife surgery of vestibular schwannomas: Volumetric dosimetry correlations to hearing loss suggest stria vascularis devascularization as the mechanism of early hearing loss.
      ,
      • Watanabe S
      • Yamamoto M
      • Kawabe T
      • et al.
      Stereotactic radiosurgery for vestibular schwannomas: average 10-year follow-up results focusing on long-term hearing preservation.
      Therefore, cochlear dosimetry should be based on the whole volume to best represent the dose received by the cochlea.
      • Jacob JT
      • Carlson ML
      • Schiefer TK
      • et al.
      Significance of cochlear dose in the radiosurgical treatment of vestibular schwannoma: Controversies and unanswered questions.
      The discrepancy in the cochlear dose parameters reported to correlate with hearing outcome and the variation in dose threshold for better hearing preservation (a mean dose of 3-6 Gy, a maximum dose of 4-12 Gy and a minimum dose of 5-6 Gy) also impaired comparison between studies. In principle, comparison between different dose parameters is possible as there seems to be an inherent relationship between various cochlear dose parameters. Ma et al
      • Ma L
      • Braunstein SE
      • Theodosopoulos PV
      • et al.
      Inherent functional dependence among cochlear dose surrogates for stereotactic radiosurgery of vestibular schwannomas.
      investigated the relationship between maximum point dose to cochlea and cochlear mean dose, modiolus dose, dose to 0.01, 0.02 and 0.03mL, showing a strong correlation between these parameters: the cochlear mean dose and modiolus dose were one-half of the maximum point dose and similar to the dose to 0.03mL of the cochlea. However, in practice, we could not undertake such any comparisons between studies since they did not mention if the maximum dose corresponded to point or volume maximum.

      Hearing outcome assessment

      Functional or serviceable hearing loss as outcome

      Using functional or serviceable hearing loss as the outcome measure has its advantages. Firstly, it is a standardised and clinically useful endpoint that allows easy comparison between studies. Secondly, by correlating cochlear dose with this endpoint, it would be possible to determine a cochlear dose threshold that could be employed in treatment planning for better preservation of serviceable hearing. But it has disadvantages that hinder the assessment of correlation between cochlear dose and hearing outcome.
      The first disadvantage is due to the use of a cut-off (50 dB and 50% SDS) to define serviceable hearing loss. The time point when serviceable hearing will be lost depends on pre-treatment PTA and the rate of hearing loss. The average PTA loss after SRS has been reported to be around 4-7 dB/year in the first 24-36 months after treatment and at a slower rate thereafter.
      • Yomo S
      • Carron R
      • Thomassin JM
      • et al.
      Longitudinal analysis of hearing before and after radiosurgery for vestibular schwannoma.
      ,
      • Boari N
      • Bailo M
      • Gagliardi F
      • et al.
      Gamma Knife radiosurgery for vestibular schwannoma: clinical results at long-term follow-up in a series of 379 patients.
      Hence, a lower pre-treatment PTA will mean that it will take longer to reach the threshold of serviceable hearing loss; in other words, patients with GRC I may have a longer duration of serviceable hearing than GRC II.
      • Bojrab 2nd, DI
      • Fritz CG
      • Lin KF
      • et al.
      A Protective Cap: Fundal Fluid Cap Facilitates a Reduction in Inner Ear Radiation Dose in the Radiosurgical Treatment of Vestibular Schwannoma.
      This time lag created by using an arbitrary cut-off can deceptively associate pre-treatment PTA or GRC with the hearing outcome, especially if the follow-up period is not long enough. Linge et al
      • 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.
      demonstrated this problem in their study, which analysed the hearing outcome in three different ways: functional hearing loss, loss of baseline GRC, and PTA increase per month. The pre-treatment PTA and V90 of the cochlea were associated with hearing outcomes if the endpoint was functional hearing loss (GRC I and II) or loss of baseline GRC. However, the pre-treatment PTA was not associated with hearing outcome when rate of change of PTA was used as the endpoint, but V90 of the cochlea remained significant. Similarly, if the time to serviceable hearing loss is used as the hearing outcome measure, then one would anticipate pre-treatment PTA will be a strong prognostic factor. This is evident in the study by Jacob et al,
      • Jacob JT
      • Carlson ML
      • Schiefer TK
      • et al.
      Significance of cochlear dose in the radiosurgical treatment of vestibular schwannoma: Controversies and unanswered questions.
      which used the time to serviceable hearing loss as the outcome. This study showed that the cochlear dose was a significant predictor of hearing outcome but lost significance when multivariate analysis adjusted for pre-treatment PTA.
      The second disadvantage emerges due to the grouping of PTA data into classes (GR I and II or AAO-HNS A and B) to define serviceable hearing, frequently employed in studies that use serviceable hearing loss as the outcome. The grouping of PTA data into hearing classes results in loss of granularity of the data and is less sensitive to changes in PTA, compared to using difference in PTA as a continuous outcome.
      • 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.
      The above factors suggest that pre-treatment PTA or hearing class (GRC I) may appear to be stronger predictive factors than the cochlear dose if functional hearing preservation or the time to serviceable hearing loss is used as the endpoint. Perhaps, this explains why a much lower proportion of studies that used functional or serviceable hearing loss, and neither of the two studies that used the time to serviceable hearing loss as the outcome, were able to show that cochlear dose was an independent predictor of hearing loss compared to studies that used loss of hearing class or only change in PTA as endpoints.

      Loss of baseline GRC as hearing outcome

      Five of the six studies using this outcome showed that cochlear dose was a predictive factor, notwithstanding the differences in their patient populations. Except for Tamura et al,
      • Tamura M
      • Carron R
      • Yomo S
      • et al.
      Hearing preservation after gamma knife radiosurgery for vestibular schwannomas presenting with high-level hearing.
      who included only patients in GRC I, others had patients with GRC I-IV. It must be noted that Massager et al
      • Massager N
      • Nissim O
      • Delbrouck C
      • et al.
      Irradiation of cochlear structures during vestibular schwannoma radiosurgery and associated hearing outcome.
      did not assess other predictive factors of hearing loss; hence it is not clear if cochlear dose was an independent prognostic factor. Allowing for the heterogeneity between these studies, why a substantially higher proportion using loss of baseline GRC showed correlation, compared to studies using serviceable hearing loss as the outcome, is unclear. It may be that the sensitivity of the outcome to change in hearing increases when the endpoint is defined as an improvement in hearing class by just one level only.

      Change in PTA as outcome

      Using the change in PTA as the hearing outcome may appear to be a better strategy due to the above-discussed issues with using serviceable hearing loss as the outcome. Moreover, by using change in PTA, studies can use a larger patient population (not limited to GRC I and II or AAO-HNS Class A and B), and as a result, may have a better chance of showing significant correlation.
      • Bojrab 2nd, DI
      • Fritz CG
      • Lin KF
      • et al.
      A Protective Cap: Fundal Fluid Cap Facilitates a Reduction in Inner Ear Radiation Dose in the Radiosurgical Treatment of Vestibular Schwannoma.
      Change or rate of change of PTA is also a continuous variable. Although debatable, the hearing outcome as a continuous rather than dichotomous variable may be more suitable for the statistical analysis of the correlation between hearing outcome and cochlear dose. Brown et al's
      • Brown M
      • Ruckenstein M
      • Bigelow D
      • et al.
      Predictors of hearing loss after gamma knife radiosurgery for vestibular schwannomas: age, cochlear dose, and tumor coverage.
      study is a case in point. They analysed the correlation between cochlear dose and hearing outcome as a continuous variable (difference in PTA) and dichotomous variable (change in PTA of < 20 dB or ≥ 20 dB) and showed that cochlear dose (volume receiving > 5.3 Gy) correlated only with the difference in PTA as a continuous outcome.
      However, using change in PTA, too, has its disadvantages. Firstly, as a hearing outcome, difference in PTA is not as clinically applicable as preservation of serviceable hearing and will not be well suited to assess the cochlear dose threshold for hearing preservation. Moreover, what PTA difference (10 dB, 15 dB or 20 dB) represents a clinically significant loss is unclear. Secondly, the time-dependent nonlinearity of PTA can pose problems. As previously mentioned, the rate of change of PTA is faster in the first 24-36 months after treatment, followed by a longer period of many years with a slower rate of change.
      • Lin RH
      • Wang TC
      • Lin CD
      • et al.
      Predictors of hearing outcomes following low-dose stereotactic radiosurgery in patients with vestibular schwannomas: A retrospective cohort review.
      ,
      • Yomo S
      • Carron R
      • Thomassin JM
      • et al.
      Longitudinal analysis of hearing before and after radiosurgery for vestibular schwannoma.
      ,
      • Boari N
      • Bailo M
      • Gagliardi F
      • et al.
      Gamma Knife radiosurgery for vestibular schwannoma: clinical results at long-term follow-up in a series of 379 patients.
      Not only can this cause problems with statistical analysis, but studies with different duration of follow-up can end up showing different results – studies with short follow-up are more likely to show significant correlation. Of the 4 studies that showed a correlation between cochlear dose and difference in PTA, three studies assessed PTA difference only up to 24 months; whether the correlation would remain true on longer follow-up is uncertain. However, one could argue that hearing loss due to cochlear irradiation should manifest within the first few years after SRS when the acute decline in PTA is demonstrated.
      • Hasegawa T
      • Kato T
      • Yamamoto T
      • et al.
      Long-term hearing outcomes after gamma knife surgery in patients with vestibular schwannoma with hearing preservation: evaluation in 92 patients with serial audiograms.

      Study limitations

      It is generally agreed that hearing loss after SRS for VS is a complex process and there are possibly multiple factors that determine hearing preservation. However, by focusing only on the cochlear dose we have not considered other factors that may also need to be considered. We identified studies by scrutinising their title and abstract for the mention of cochlear dose. Hence, there is potential for selection bias by not including studies that did not mention cochlear dose because of lack of correlation. By excluding studies that used doses higher than 14 Gy, we may have overlooked useful information that could have been obtained from such studies possibly demonstrating cochlear dose to be a predictive factor. It should also be noted that the tool we used for appraising study quality has been subject to criticism in relation to scoring consistency.
      • Hartling L
      • Milne A
      • Hamm MP
      • et al.
      Testing the Newcastle Ottawa Scale showed low reliability between individual reviewers.

      Conclusions

      Despite accumulating evidence, it is still ambiguous if cochlear dose is an independent predictor of hearing preservation after SRS for VS. Without consistency between studies in relation to cochlear dosimetry and hearing outcomes, the cochlear dose tolerance is uncertain. However, based on currently available data, a practical approach will be to aim for a mean cochlear dose ˂ 4-6 Gy without compromising tumour dose. We recommend future studies to report all cochlear dose parameters and multiple endpoints, such as the change in PTA, functional hearing preservation and the preservation of baseline hearing class.

      Uncited References

      [
      • Park MJ
      • Park HJ
      • Chung JW
      • et al.
      Factors affecting hearing deterioration in vestibular schwannoma patients treated with gamma knife radiosurgery: the Asan Medical Center experience.
      ]

      Declaration of Competing Interest

      None

      Funding

      None
      Research data are stored in an institutional repository and will be shared upon request to the corresponding author.

      Appendix. Supplementary materials

      References

        • Coughlin AR
        • Willman TJ
        • Gubbels SP.
        Systematic Review of Hearing Preservation After Radiotherapy for Vestibular Schwannoma.
        Otol Neurotol. 2018; 39: 273-283
        • Pollock BE
        • Driscoll CL
        • Foote RL
        • et al.
        Patient outcomes after vestibular schwannoma management: a prospective comparison of microsurgical resection and stereotactic radiosurgery.
        Neurosurgery. 2006; 59: 77-85
        • Frischer JM
        • Gruber E
        • Schöffmann V
        • et al.
        Long-term outcome after Gamma Knife radiosurgery for acoustic neuroma of all Koos grades: a single-center study.
        J Neurosurg. 2019; 130: 388-397
        • Wolbers JG
        • Dallenga AHG
        • Mendez Romero A
        • et al.
        What intervention is best practice for vestibular schwannomas? A systematic review of controlled studies.
        BMJ Open. 2013; 3e001345
        • Tsao MN
        • Sahgal A
        • Xu W
        • et al.
        Stereotactic radiosurgery for vestibular schwannoma: International Stereotactic Radiosurgery Society (ISRS) Practice Guideline.
        J Radiosurg SBRT. 2017; 5: 5-24
        • Goldbrunner R
        • Weller M
        • Regis J
        • et al.
        EANO guideline on the diagnosis and treatment of vestibular schwannoma.
        Neuro Oncol. 2020; 22: 31-45
        • Germano IM
        • Sheehan J
        • Parish J
        • et al.
        Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines on the Role of Radiosurgery and Radiation Therapy in the Management of Patients With Vestibular Schwannomas.
        Neurosurgery. 2018; 82: E49-e51
        • Combs SE
        • Engelhard C
        • Kopp C
        • et al.
        Long-term outcome after highly advanced single-dose or fractionated radiotherapy in patients with vestibular schwannomas - pooled results from 3 large German centers.
        Radiother Oncol. 2015; 114: 378-383
        • Yang I
        • Sughrue ME
        • Han SJ
        • et al.
        Facial nerve preservation after vestibular schwannoma Gamma Knife radiosurgery.
        J Neurooncol. 2009; 93: 41-48
        • Yang I
        • Aranda D
        • Han SJ
        • et al.
        Hearing preservation after stereotactic radiosurgery for vestibular schwannoma: a systematic review.
        J Clin Neurosci. 2009; 16: 742-747
        • Kim JH
        • Jung HH
        • Chang JH
        • et al.
        Predictive Factors of Unfavorable Events After Gamma Knife Radiosurgery for Vestibular Schwannoma.
        World Neurosurg. 2017; 107: 175-184
        • Chopra R
        • Kondziolka D
        • Niranjan A
        • et al.
        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: 845-851
        • 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: 579-587
        • Roos DE
        • Potter AE
        • Zacest AC.
        Hearing preservation after low dose linac radiosurgery for acoustic neuroma depends on initial hearing and time.
        Radiother Oncol. 2011; 101: 420-424
        • Tolisano AM
        • Hunter JB.
        Hearing Preservation in Stereotactic Radiosurgery for Vestibular Schwannoma.
        J Neurol Surg B. 2019; 80: 156-164
        • 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: 917-926
        • Linskey ME.
        Hearing preservation in vestibular schwannoma stereotactic radiosurgery: what really matters?.
        J Neurosurg. 2008; 109 (Suppl): 129-136
        • Wackym PA
        • Runge-Samuelson CL
        • Nash JJ
        • et al.
        Gamma knife surgery of vestibular schwannomas: Volumetric dosimetry correlations to hearing loss suggest stria vascularis devascularization as the mechanism of early hearing loss.
        Otol Neurotol. 2010; 31: 1480-1487
        • Ottaviani F
        • Neglia CB
        • Ventrella L
        • et al.
        Hearing loss and changes in transient evoked otoacoustic emissions after gamma knife radiosurgery for acoustic neurinomas.
        Arch Otolaryngol Head Neck Surg. 2002; 128: 1308-1312
        • Linskey ME
        • Johnstone PA
        • O'Leary M
        • et al.
        Radiation exposure of normal temporal bone structures during stereotactically guided gamma knife surgery for vestibular schwannomas.
        J Neurosurg. 2003; 98: 800-806
        • Timmerman RD.
        An overview of hypofractionation and introduction to this issue of seminars in radiation oncology.
        Semin Radiat Oncol. 2008; 18: 215-222
        • Hanna GG
        • Murray L
        • Patel R
        • et al.
        UK Consensus on Normal Tissue Dose Constraints for Stereotactic Radiotherapy.
        Clin Oncol (R Coll Radiol). 2018; 30: 5-14
        • Carlson ML
        • Vivas EX
        • McCracken DJ
        • et al.
        Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines on Hearing Preservation Outcomes in Patients With Sporadic Vestibular Schwannomas.
        Neurosurgery. 2018; 82: E35-e39
        • Bhandare N
        • Jackson A
        • Eisbruch A
        • et al.
        Radiation therapy and hearing loss.
        Int J Radiat Oncol Biol Phys. 2010; 76: S50-S57
      1. Wells GA, Shea B, O'Connell D et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. [cited 2021 Dec 12]. Available from: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.

        • Paek SH
        • Chung HT
        • Jeong SS
        • et al.
        Hearing preservation after gamma knife stereotactic radiosurgery of vestibular schwannoma.
        Cancer. 2005; 104: 580-590
        • 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. 2018; 79: 335-342
        • 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: 329-337
        • Régis J
        • Tamura M
        • Delsanti C
        • et al.
        Hearing preservation in patients with unilateral vestibular schwannoma after gamma knife surgery.
        Prog Neurol Surg. 2008; 21: 142-151
        • 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: 289-296
        • Lin RH
        • Wang TC
        • Lin CD
        • et al.
        Predictors of hearing outcomes following low-dose stereotactic radiosurgery in patients with vestibular schwannomas: A retrospective cohort review.
        Clin Neurol Neurosurg. 2017; 162: 16-21
        • Baschnagel AM
        • Chen PY
        • Bojrab D
        • et al.
        Hearing preservation in patients with vestibular schwannoma treated with Gamma Knife surgery.
        J Neurosurg. 2013; 118: 571-578
        • Iorio-Morin C
        • AlSubaie F
        • Mathieu D.
        Safety and Efficacy of Gamma Knife Radiosurgery for the Management of Koos Grade 4 Vestibular Schwannomas.
        Neurosurgery. 2016; 78: 521-530
        • Horiba A
        • Hayashi M
        • Chernov M
        • et al.
        Hearing preservation after low-dose gamma knife radiosurgery of vestibular schwannomas.
        Neurol Med Chir. 2016; 56: 186-192
        • Pan SY
        • Liu SA
        • Sun MH
        • et al.
        Outcome of hearing preservation related to tumor morphologic analysis in acoustic neuromas treated by gamma knife radiosurgery.
        Radiat Oncol. 2017; 12: 134
        • Prabhuraj AR
        • Yeole U
        • Arimappamagan A
        • et al.
        Effect of Gamma Knife Radiosurgery on Vestibular Schwannoma with Serviceable Hearing: A Single-Center Indian Study.
        World Neurosurg. 2019; 127: e114-e123
        • Massager N
        • Nissim O
        • Delbrouck C
        • et al.
        Irradiation of cochlear structures during vestibular schwannoma radiosurgery and associated hearing outcome.
        J Neurosurg. 2007; 107: 733-739
        • Lasak JM
        • Klish D
        • Kryzer TC
        • et al.
        Gamma knife radiosurgery for vestibular schwannoma: Early hearing outcomes and evaluation of the cochlear dose.
        Otol Neurotol. 2008; 29: 1179-1186
        • Yomo S
        • Carron R
        • Thomassin JM
        • et al.
        Longitudinal analysis of hearing before and after radiosurgery for vestibular schwannoma.
        J Neurosurg. 2012; 117: 877-885
        • Schumacher AJ
        • Lall RR
        • Lall RR
        • et al.
        Low-Dose Gamma Knife Radiosurgery for Vestibular Schwannomas: Tumor Control and Cranial Nerve Function Preservation after 11 Gy.
        J Neurol Surg B. 2017; 78: 2-10
        • Jacob JT
        • Carlson ML
        • Schiefer TK
        • et al.
        Significance of cochlear dose in the radiosurgical treatment of vestibular schwannoma: Controversies and unanswered questions.
        Neurosurgery. 2014; 74: 466-474
        • Kulkarni BSN
        • Bajwa H
        • Chandrashekhar M
        • et al.
        CT- and MRI-based gross target volume comparison in vestibular schwannomas.
        Rep Pract Oncol Radiother. 2017; 22: 201-208
        • Faramand AM
        • Kano H
        • Johnson S
        • et al.
        CT versus MR Imaging in Estimating Cochlear Radiation Dose during Gamma Knife Surgery for Vestibular Schwannomas.
        AJNR Am J Neuroradiol. 2018; 39: 1907-1911
        • Pacholke HD
        • Amdur RJ
        • Schmalfuss IM
        • et al.
        Contouring the middle and inner ear on radiotherapy planning scans.
        Am J Clin Oncol. 2005; 28: 143-147
        • Watanabe S
        • Yamamoto M
        • Kawabe T
        • et al.
        Stereotactic radiosurgery for vestibular schwannomas: average 10-year follow-up results focusing on long-term hearing preservation.
        J Neurosurg. 2016; 125: 64-72
        • Ma L
        • Braunstein SE
        • Theodosopoulos PV
        • et al.
        Inherent functional dependence among cochlear dose surrogates for stereotactic radiosurgery of vestibular schwannomas.
        Pract Radiat Oncol. 2017; 7: e1-e7
        • Boari N
        • Bailo M
        • Gagliardi F
        • et al.
        Gamma Knife radiosurgery for vestibular schwannoma: clinical results at long-term follow-up in a series of 379 patients.
        J Neurosurg. 2014; 121: 123-142
        • Bojrab 2nd, DI
        • Fritz CG
        • Lin KF
        • et al.
        A Protective Cap: Fundal Fluid Cap Facilitates a Reduction in Inner Ear Radiation Dose in the Radiosurgical Treatment of Vestibular Schwannoma.
        Otol Neurotol. 2021; 42: 294-299
        • 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: 253
        • Brown M
        • Ruckenstein M
        • Bigelow D
        • et al.
        Predictors of hearing loss after gamma knife radiosurgery for vestibular schwannomas: age, cochlear dose, and tumor coverage.
        Neurosurgery. 2011; 69: 605-613
        • Hasegawa T
        • Kato T
        • Yamamoto T
        • et al.
        Long-term hearing outcomes after gamma knife surgery in patients with vestibular schwannoma with hearing preservation: evaluation in 92 patients with serial audiograms.
        J Neurooncol. 2018; 138: 283-290
        • Hartling L
        • Milne A
        • Hamm MP
        • et al.
        Testing the Newcastle Ottawa Scale showed low reliability between individual reviewers.
        J Clin Epidemiol. 2013; 66: 982-993
        • Kim YH
        • Kim DG
        • Han JH
        • et al.
        Hearing outcomes after stereotactic radiosurgery for unilateral intracanalicular vestibular schwannomas: Implication of transient volume expansion.
        Int J Radiat Oncol Biol Phys. 2013; 85: 61-67
        • Park MJ
        • Park HJ
        • Chung JW
        • et al.
        Factors affecting hearing deterioration in vestibular schwannoma patients treated with gamma knife radiosurgery: the Asan Medical Center experience.
        Acta Oto-Laryngologica. 2018; 138: 96-104