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Radiation Therapy and Hearing Loss

      A review of literature on the development of sensorineural hearing loss after high-dose radiation therapy for head-and-neck tumors and stereotactic radiosurgery or fractionated stereotactic radiotherapy for the treatment of vestibular schwannoma is presented. Because of the small volume of the cochlea a dose–volume analysis is not feasible. Instead, the current literature on the effect of the mean dose received by the cochlea and other treatment- and patient-related factors on outcome are evaluated. Based on the data, a specific threshold dose to cochlea for sensorineural hearing loss cannot be determined; therefore, dose–prescription limits are suggested. A standard for evaluating radiation therapy–associated ototoxicity as well as a detailed approach for scoring toxicity is presented.

      1. Clinical Significance

      Radiation therapy (RT) may damage the cochlea and/or acoustic nerve, leading to sensorineural hearing loss (SNHL) (
      • Jereczek-Fossa B.A.
      • Zarowski A.
      • Milani F.
      • et al.
      Radiotherapy-induced ear toxicity.
      ,
      • Bhide S.A.
      • Harrington K.J.
      • Nutting C.M.
      Otological toxicity after postoperative radiotherapy for parotid tumours.
      ,
      • Raaijmakers E.
      • Engelen A.M.
      Is sensorineural hearing loss a possible side effect of nasopharyngeal and parotid irradiation? A systematic review of the literature.
      ,
      • Bhandare N.
      • Antonelli P.J.
      • Morris C.G.
      • et al.
      Ototoxicity after radiotherapy for head and neck tumors.
      ), with resultant long-lasting compromise in the quality of life. This report focuses on RT-induced SNHL in adults who have received fractionated RT, stereotactic radiosurgery (SRS), and fractionated stereotactic RT (FSRT) for head-and-neck cancers and vestibular schwannomas (VS).

      2. Endpoints

      SNHL is traditionally defined as a clinically significant increase in bone conduction threshold (BCT) at the key human speech frequencies (0.5–4.0 kHz), as seen in pure-tone audiometry. However, reports of SNHL after fractionated RT vary in terms of: (a) the frequencies evaluated (e.g., 2 or 4 kHz alone (
      • Pan C.C.
      • Eisbruch A.
      • Lee J.S.
      • et al.
      Prospective study of inner ear radiation dose and hearing loss in head-and-neck cancer patients.
      ,
      • Chen W.C.
      • Jackson A.
      • Budnick A.S.
      • et al.
      Sensorineural hearing loss in combined modality treatment of nasopharyngeal carcinoma.
      ) and/or pure tone average [PTA] of frequencies between 0.5–3.0 kHz) (
      • Kwong D.L.
      • Wei W.I.
      • Sham J.S.
      • et al.
      Sensorineural hearing loss in patients treated for nasopharyngeal carcinoma: A prospective study of the effect of radiation and cisplatin treatment.
      ,
      • Oh Y.T.
      • Kim C.H.
      • Choi J.H.
      • et al.
      Sensory neural hearing loss after concurrent cisplatin and radiation therapy for nasopharyngeal carcinoma.
      ,
      • Committee on Hearing and Equilibrium
      Committee on Hearing and Equilibrium guidelines for the evaluation of hearing preservation in acoustic neuroma (vestibular schwannoma). American Academy of Otolaryngology-Head and Neck Surgery Foundation, Inc.
      ); (b) the control/standard used for comparison (e.g., pre-RT BCT of same ear (
      • Honore H.B.
      • Bentzen S.M.
      • Moller K.
      • et al.
      Sensori-neural hearing loss after radiotherapy for nasopharyngeal carcinoma: Individualized risk estimation.
      ) or post-RT BCT of the contralateral ear (
      • Pan C.C.
      • Eisbruch A.
      • Lee J.S.
      • et al.
      Prospective study of inner ear radiation dose and hearing loss in head-and-neck cancer patients.
      ), or age-specific standard (
      • Bhandare N.
      • Antonelli P.J.
      • Morris C.G.
      • et al.
      Ototoxicity after radiotherapy for head and neck tumors.
      )); and (c) the change in BCT (ΔBCT) that is defined as clinically significant (e.g., 20 dB (
      • Pan C.C.
      • Eisbruch A.
      • Lee J.S.
      • et al.
      Prospective study of inner ear radiation dose and hearing loss in head-and-neck cancer patients.
      ,
      • Chen W.C.
      • Jackson A.
      • Budnick A.S.
      • et al.
      Sensorineural hearing loss in combined modality treatment of nasopharyngeal carcinoma.
      ), 15 dB (
      • Kwong D.L.
      • Wei W.I.
      • Sham J.S.
      • et al.
      Sensorineural hearing loss in patients treated for nasopharyngeal carcinoma: A prospective study of the effect of radiation and cisplatin treatment.
      ,
      • Oh Y.T.
      • Kim C.H.
      • Choi J.H.
      • et al.
      Sensory neural hearing loss after concurrent cisplatin and radiation therapy for nasopharyngeal carcinoma.
      ), 10 dB (
      • Pan C.C.
      • Eisbruch A.
      • Lee J.S.
      • et al.
      Prospective study of inner ear radiation dose and hearing loss in head-and-neck cancer patients.
      )). The degree of hearing loss after RT for head-and-neck cancer is worse at higher frequencies, as presented in Figures 1a–c (
      • Pan C.C.
      • Eisbruch A.
      • Lee J.S.
      • et al.
      Prospective study of inner ear radiation dose and hearing loss in head-and-neck cancer patients.
      ,
      • Chen W.C.
      • Jackson A.
      • Budnick A.S.
      • et al.
      Sensorineural hearing loss in combined modality treatment of nasopharyngeal carcinoma.
      ,
      • Kwong D.L.
      • Wei W.I.
      • Sham J.S.
      • et al.
      Sensorineural hearing loss in patients treated for nasopharyngeal carcinoma: A prospective study of the effect of radiation and cisplatin treatment.
      ,
      • Oh Y.T.
      • Kim C.H.
      • Choi J.H.
      • et al.
      Sensory neural hearing loss after concurrent cisplatin and radiation therapy for nasopharyngeal carcinoma.
      ,
      • Honore H.B.
      • Bentzen S.M.
      • Moller K.
      • et al.
      Sensori-neural hearing loss after radiotherapy for nasopharyngeal carcinoma: Individualized risk estimation.
      ,
      • Ho W.K.
      • Wei W.I.
      • Kwong D.L.
      • et al.
      Long-term sensorineural hearing deficit following radiotherapy in patients suffering from nasopharyngeal carcinoma: A prospective study.
      ,
      • van der Putten L.
      • de Bree R.
      • Plukker J.T.
      • et al.
      Permanent unilateral hearing loss after radiotherapy for parotid gland tumors.
      ). Although early changes in hearing can be reversible, persistent hearing loss (HL) continues to increase with time (
      • Ho W.K.
      • Wei W.I.
      • Kwong D.L.
      • et al.
      Long-term sensorineural hearing deficit following radiotherapy in patients suffering from nasopharyngeal carcinoma: A prospective study.
      ). Selected studies on SNHL after head-and-neck radiation therapy are shown in Table 1.
      Figure thumbnail gr1
      Fig. 1Mean dose response for sensorineural hearing loss (SNHL) at (a): 4 kHz; (b): 0.5–2 kHz; and (c): all frequencies (0.25–12 kHz). Data from: Figure 3 of Chen et al.
      (
      • Chen W.C.
      • Jackson A.
      • Budnick A.S.
      • et al.
      Sensorineural hearing loss in combined modality treatment of nasopharyngeal carcinoma.
      )
      (retrospective study; SNHL defined as a ≥20-dB increase in the bone-conduction threshold at ≥1 year; patients received concurrent and adjuvant cisplatin chemotherapy); Figure 1 of Honore et al.
      (
      • Honore H.B.
      • Bentzen S.M.
      • Moller K.
      • et al.
      Sensori-neural hearing loss after radiotherapy for nasopharyngeal carcinoma: Individualized risk estimation.
      )
      (retrospective study; SNHL defined as 20-dB increase in the bone-conduction threshold at ∼0.5–6.5 years); of Pan et al.
      (
      • Pan C.C.
      • Eisbruch A.
      • Lee J.S.
      • et al.
      Prospective study of inner ear radiation dose and hearing loss in head-and-neck cancer patients.
      )
      (prospective study; SNHL defined as a 20-dB difference between bone-conduction thresholds for ipsilateral and contralateral ears at 1 year; doses are ipsilateral-ear mean doses minus contralateral-ear mean doses); of Oh et al.
      (
      • Oh Y.T.
      • Kim C.H.
      • Choi J.H.
      • et al.
      Sensory neural hearing loss after concurrent cisplatin and radiation therapy for nasopharyngeal carcinoma.
      )
      (prospective study; SNHL defined as a 15-dB increase in the bone-conduction threshold at 1 year; patients received neoadjuvant and concurrent cisplatin chemotherapy); Table 1, Table 2 of Kwong et al.
      (
      • Kwong D.L.
      • Wei W.I.
      • Sham J.S.
      • et al.
      Sensorineural hearing loss in patients treated for nasopharyngeal carcinoma: A prospective study of the effect of radiation and cisplatin treatment.
      )
      (prospective study; SNHL defined as a 15-dB increase in the bone-conduction threshold at 1 year; patients received neoadjuvant and concurrent chemotherapy; ears received the full prescription dose; prescriptions were converted to biologically effective dose in 2 Gy fractions using α/β = 3 Gy); of van der Putten et al.
      (
      • van der Putten L.
      • de Bree R.
      • Plukker J.T.
      • et al.
      Permanent unilateral hearing loss after radiotherapy for parotid gland tumors.
      )
      (retrospective study; SNHL defined as a 15-dB increase in the average of all pure-tone thresholds at 2–17 years).
      Table 1Selected studies for SNHL after head-and-neck radiation therapy
      Influence of variables on the outcome
      AuthorNumber of patients in studyMean cochlear dose (Gy)/Rx dose (Gy)Dose per fraction (Gy)Chemoradiation (cisplatin based)Chemo-radiationAgePost-RT SOMGenderTime to hearing testPre-RT hearing levelStandard used for comparisonEndpoint for SNHL (shift in BCT)/frequencies (kHz) tested
      Prospective
      Grau et al., 1999
      • Grau C.
      • Overgaard J.
      Postirradiation sensorineural hearing loss: A common but ignored late radiation complication.
      22NS/60–682–2.81No, RT aloneNo
      Dose and age component of HL separated.
      NoNoSame earNominal shifts in BCT (in dB) reported/ 0.5, 1.0, 2.0, 4.0
      Kwong et al., 1996
      • Kwong D.L.
      • Wei W.I.
      • Sham J.S.
      • et al.
      Sensorineural hearing loss in patients treated for nasopharyngeal carcinoma: A prospective study of the effect of radiation and cisplatin treatment.
      132NS/71.3–852–3.5/2
      Total doses calculated as BED in 2 Gy fractions, with α/β = 3 Gy.
      Yes
      The primary endpoint of a prospective clinical trial.
      , neoadjuvant
      NoYes
      Older age found significant.
      YesYes
      Rate of HL male > female.
      YesNoSame ear15/avg. of 0.5, 1, 2 15; 4
      Ho et al., 1999
      • Ho W.K.
      • Wei W.I.
      • Kwong D.L.
      • et al.
      Long-term sensorineural hearing deficit following radiotherapy in patients suffering from nasopharyngeal carcinoma: A prospective study.
      29470–91
      Total doses calculated as BED in 2 Gy fractions, with α/β = 3 Gy.
      /59.9–70
      2–3.5/2
      Total doses calculated as BED in 2 Gy fractions, with α/β = 3 Gy.
      Yes
      The primary endpoint of a prospective clinical trial.
      , neoadjuvant
      NoYesYesNoSame ear10/avg. of (0.5, 1, 2) 10; 4
      Data for these endpoints reconstructed from figures for this paper.
      Oh et al., 2004
      • Oh Y.T.
      • Kim C.H.
      • Choi J.H.
      • et al.
      Sensory neural hearing loss after concurrent cisplatin and radiation therapy for nasopharyngeal carcinoma.
      3254.3–81.4/702Yes
      The primary endpoint of a prospective clinical trial.
      , neoadjuvant and concurrent
      NoYes
      The primary endpoint of a prospective clinical trial.
      Younger age found significant.
      YesYes
      Rate of HL male > female.
      YesSame ear15/avg. of (0.5, 1, 2) 15; 4
      Pan et al., 2005
      • Pan C.C.
      • Eisbruch A.
      • Lee J.S.
      • et al.
      Prospective study of inner ear radiation dose and hearing loss in head-and-neck cancer patients.
      22Ipsi:
      The primary endpoint of a prospective clinical trial.
      14.1–68.8 Contra:
      The primary endpoint of a prospective clinical trial.
      0.5–31.3/40–70
      NSRT alone
      • Low W.K.
      • Toh S.T.
      • Wee J.
      • et al.
      Sensorineural hearing loss after radiotherapy and chemoradiotherapy: A single, blinded, randomized study.
      Concurrent chemo.
      • Bhandare N.
      • Antonelli P.J.
      • Morris C.G.
      • et al.
      Ototoxicity after radiotherapy for head and neck tumors.
      YesNoNoYes
      Better pre-RT hearing associated with worse post RT HL.
      Contralateral ear20/0.25, 0.5, 1, 2
      Data for these endpoints reconstructed from figures for this paper.
      , 4
      Data for these endpoints reconstructed from figures for this paper.
      , 8
      Low et al., 2006
      • Low W.K.
      • Toh S.T.
      • Wee J.
      • et al.
      Sensorineural hearing loss after radiotherapy and chemoradiotherapy: A single, blinded, randomized study.
      115NS/702Yes
      The primary endpoint of a prospective clinical trial.
      , concurrent and adjuvant
      Yes (4 kHz)Same earNominal shifts in BCT (in dB) reported/4, avg. of (0.5, 1.0, 2.0)
      Retrospective
      Honore et al., 2002
      • Honore H.B.
      • Bentzen S.M.
      • Moller K.
      • et al.
      Sensori-neural hearing loss after radiotherapy for nasopharyngeal carcinoma: Individualized risk estimation.
      207.1–68/ 50–682–4.3No, RT aloneYesNoYes
      Better pre-RT hearing associated with worse post RT HL.
      Same ear15/0.5, 1, 2, 4 20; 4
      Data for these endpoints reconstructed from figures for this paper.
      Chen et al., 2006
      • Chen W.C.
      • Jackson A.
      • Budnick A.S.
      • et al.
      Sensorineural hearing loss in combined modality treatment of nasopharyngeal carcinoma.
      2228.4–701.6–2.34Yes, concurrent and adjuvantYes (4 kHz)NoNoYesNoSame ear20/0.5, 1, 2
      Data for these endpoints reconstructed from figures for this paper.
      , 3, 4
      Data for these endpoints reconstructed from figures for this paper.
      Van der Putten et al.,2006
      • van der Putten L.
      • de Bree R.
      • Plukker J.T.
      • et al.
      Permanent unilateral hearing loss after radiotherapy for parotid gland tumors.
      5229.2–77.3/50–701.8–3.0No, RT aloneContralateral15/0.25–12 for ≥3 of these frequencies
      Abbreviations: NS = not specified; AS = absolute shift in the hearing threshold reported; SOM = serous otitis media; RT = radiation therapy; CT = bone conduction threshold; db = decibels; SNHL = sensorineural hearing loss; Rx = prescription.
      Dose and age component of HL separated.
      Total doses calculated as BED in 2 Gy fractions, with α/β = 3 Gy.
      The primary endpoint of a prospective clinical trial.
      § Older age found significant.
      || Rate of HL male > female.
      Data for these endpoints reconstructed from figures for this paper.
      ∗∗ Younger age found significant.
      †† Better pre-RT hearing associated with worse post RT HL.
      Hearing status after SRS for VS is evaluated using the Gardner-Robertson hearing grade (GRHG) scale, which includes both PTA and speech discrimination scores (SDS) (
      • Niranjan A.
      • Lunsford L.D.
      • Flickinger J.C.
      • et al.
      Dose reduction improves hearing preservation rates after intracanalicular acoustic tumor radiosurgery.
      ). HL after SRS for VS is commonly presented as pre-RT to post-RT variation in GRHG as: (a) pretreatment hearing preservation (HP) in terms of (i) serviceable hearing (SH), as hearing that is useful with or without a hearing aid, or (ii) measurable hearing (MH), as any hearing with detectable audiometric responses; and (b) improvement or loss in hearing expressed as change in GRHG. Selected studies on the treatment of vestibular schwannomas are shown in Table 2.
      Table 2Selected studies on the treatment of vestibular schwannomas
      Author and yearNo. of patients in studyMarginal tumor dose (Gy)
      Single fraction unless otherwise stated.
      Follow-upTumor control (%)Hearing status (%)
      SRS
      Hirsch et al., 1988
      • Hirsch A.
      • Noren G.
      Audiological findings after stereotactic radiosurgery in acoustic neurinomas.
      12618–25Mean 4.7 y86HP: 26
      Noren et al., 1993
      • Noren G.
      • Greitz D.
      • Hirsch A.
      • et al.
      Gamma knife surgery in acoustic tumors.
      Total: 254 NF2: 6118–20

      10–15
      1–17 yUnilateral:94

      NF2: 84
      HP: 22

      Moderate HD: 55

      Severe HD: 23
      Foote et al.,
      1995
      • Foote R.L.
      • Coffey R.J.
      • Swanson J.W.
      • et al.
      Stereotactic radiosurgery using the gamma knife for acoustic neuromas.
      3616–202.5–36 mo100HP (SH): 10 at 1 y

      42 ± 17 at 2 y
      Flickinger et al., 1996
      • Flickinger J.C.
      • Kondziolka D.
      • Pollock B.E.
      • et al.
      Evolution in technique for vestibular schwannoma radiosurgery and effect on outcome.
      273 CT: 118, MRI: 15512–2096.48HL, MRI: 32 ± 7 at 3 y

      HL, CT: 61 ± 7 at 3 y
      Kondziolka et al., 1998
      • Kondziolka D.
      • Lunsford L.D.
      • McLaughlin M.R.
      • et al.
      Long-term outcomes after radiosurgery for acoustic neuromas.
      16212–20

      Mean: 16.6
      6–102 mo (60% >5 y)94HP (SH): 47

      HP (MH): 51
      Lunsford et al., 1998
      • Lunsford L.D.
      • Kondziolka D.
      • Flickinger J.C.
      • et al.
      Acoustic neuroma management: Evolution and revolution.
      402Earlier in series: 17

      Later in the series: 12–14
      Mean: 36 mo93HP: 39 at 5 y

      HP: 68 at last 5 y
      Flickinger et al., 2001
      • Flickinger J.C.
      • Kondziolka D.
      • Niranjan A.
      • et al.
      Results of acoustic neuroma radiosurgery: An analysis of 5 years' experience using current methods.
      19011–18

      Median: 13
      Median: 30 mo Max: 80 mo91 at 5 yHP:74

      HI:7
      FSRT/HP-FSRT
      Andrews et al., 2001
      • Andrews D.W.
      • Suarez O.
      • Goldman H.W.
      • et al.
      Stereotactic radiosurgery and fractionated stereotactic radiotherapy for the treatment of acoustic schwannomas: Comparative observations of 125 patients treated at one institution.
      GK-SRS: 64 (NF2: 5)

      FSRT: 46 (NF2: 10)
      GK-SRS:12

      SRT: 50 (2 Gy/fx)
      GK-SRS: 119 ± 67 weeks

      SRT: 115 ± 96 weeks
      GK-SRS: 98

      SRT: 97
      HP, GK: 33

      HP, SRT: 81
      Williams et al., 2002
      • Williams J.A.
      Fractionated stereotactic radiotherapy for acoustic neuromas.
      125Tumors <3 cm: 25/5 fx

      Tumors ≥3 cm: 30/10 fx
      1.0–5.7 y

      Median: 1.8 y
      100HP: 46

      HL: 36

      HI: 18
      Meijer et al., 2003
      • Meijer O.W.
      • Vandertop W.P.
      • Baayen J.C.
      • et al.
      Single-fraction vs. fractionated linac-based stereotactic radiosurgery for vestibular schwannoma: A single-institution study.
      Total: 37

      SRS:12

      HPFSRT: 25
      SRS: 10–12

      HPFSRT: 20–25
      12–61 mo

      Mean: 25 mo
      HP: 91
      Combs et al., 2005
      • Combs S.E.
      • Volk S.
      • Schulz-Ertner D.
      • et al.
      Management of acoustic neuromas with fractionated stereotactic radiotherapy (FSRT): Long-term results in 106 patients treated in a single institution.
      106FSRT: 57.6 (1.8 Gy/fx)3–172 mo94.3 at 3 y, 93 at 5 yHP: 94 at 5 y
      Abbreviations: SRS = stereotactic radiosurgery; SOM = Serous Otitis Media; HL = hearing loss; MRI = magnetic resonance imaging; BCT = bone conduction threshold; CT = computed tomography; SRT = stereotactic radiotherapy; NF2: neurofibromatosis type 2; FSRT = fractionated SRT; HPFSRT = hypofractionated SRT; HPRT = hypofractionation trial; GRHG = Gardener- Robertson Hearing Grade; HG = hearing grade; HP = hearing preservation corresponding either to serviceable hearing (SH; GRHG-I, II) or measurable hearing (MH; GRHG: III, IV); HD = hearing deterioration; HI = hearing improvement; NR = not reported; UH = useful hearing; GK = gamma knife; fx = fraction; y = year; mo = months.
      Single fraction unless otherwise stated.
      Acute SNHL has been reported after SRS (
      • Pollack A.G.
      • Marymont M.H.
      • Kalapurakal J.A.
      • et al.
      Acute neurological complications following gamma knife surgery for vestibular schwannoma. Case report.
      ), but not after fractionated RT. Hearing impairment has been reported within 3 to 24 months after single-fraction SRS (
      • Niranjan A.
      • Lunsford L.D.
      • Flickinger J.C.
      • et al.
      Dose reduction improves hearing preservation rates after intracanalicular acoustic tumor radiosurgery.
      ,
      • Subach B.R.
      • Kondziolka D.
      • Lunsford L.D.
      • et al.
      Stereotactic radiosurgery in the management of acoustic neuromas associated with neurofibromatosis Type 2.
      ), with a median time to onset of 4 months (
      • Subach B.R.
      • Kondziolka D.
      • Lunsford L.D.
      • et al.
      Stereotactic radiosurgery in the management of acoustic neuromas associated with neurofibromatosis Type 2.
      ,
      • Linskey M.E.
      • Lunsford L.D.
      • Flickinger J.C.
      Tumor control after stereotactic radiosurgery in neurofibromatosis patients with bilateral acoustic tumors.
      ). Although it can occur as early as 3 months after completing fractionated RT, the median latency is 1.5–2.0 years (
      • Honore H.B.
      • Bentzen S.M.
      • Moller K.
      • et al.
      Sensori-neural hearing loss after radiotherapy for nasopharyngeal carcinoma: Individualized risk estimation.
      ,
      • Ho W.K.
      • Wei W.I.
      • Kwong D.L.
      • et al.
      Long-term sensorineural hearing deficit following radiotherapy in patients suffering from nasopharyngeal carcinoma: A prospective study.
      ).

      3. Challenges Defining Volumes

      Computed tomography (CT)-magnetic resonance imaging fusion is helpful in defining the inner ear. Its small size and location (embedded deep in the temporal bone) make it challenging to delineate on CT scans and requires the appropriate bone window, level, and image thickness (preferably ≤1.0 mm). The cochlea is a conical structure with its base resting anterior to the internal auditory canal and its apex pointed anteriorly, inferiorly, and laterally, toward the carotid artery. The vestibule is located posterior to the cochlea and lateral to the internal auditory canal. The internal auditory canal is a readily apparent landmark for identification of the cochlea and vestibule on CT (Figure 2). The volume of cochlea can be defined on axial CT images as the net volume defined by the bony labyrinth. In adults, the reported average volume of the cochlea using CT varies from 0.13 mL (range, 0.11–0.15 mL) (
      • Pacholke H.D.
      • Amdur R.J.
      • Schmalfuss I.M.
      • et al.
      Contouring the middle and inner ear on radiotherapy planning scans.
      ) to 0.56 mL (range, 0.15–0.91 mL) (
      • Pan C.C.
      • Eisbruch A.
      • Lee J.S.
      • et al.
      Prospective study of inner ear radiation dose and hearing loss in head-and-neck cancer patients.
      ).
      Figure thumbnail gr2
      Fig. 2Axial computed tomography image through the skull base. EAC = external acoustic canal; C = cochlea; V = vestibule; IAC = internal auditory canal.

      4. Review of Dose–Volume Data

       Standard fractionated RT for head-and-neck cancer

      A dose–volume analysis is impractical for the cochlea due to its small volume and the limitations associated with its delineation. Several studies have attempted to relate mean or median cochlear dose to persistent hearing loss (
      • Chen W.C.
      • Jackson A.
      • Budnick A.S.
      • et al.
      Sensorineural hearing loss in combined modality treatment of nasopharyngeal carcinoma.
      ,
      • Honore H.B.
      • Bentzen S.M.
      • Moller K.
      • et al.
      Sensori-neural hearing loss after radiotherapy for nasopharyngeal carcinoma: Individualized risk estimation.
      ,
      • Low W.K.
      • Toh S.T.
      • Wee J.
      • et al.
      Sensorineural hearing loss after radiotherapy and chemoradiotherapy: A single, blinded, randomized study.
      ).
      Pan (
      • Pan C.C.
      • Eisbruch A.
      • Lee J.S.
      • et al.
      Prospective study of inner ear radiation dose and hearing loss in head-and-neck cancer patients.
      ) prospectively studied BCTs in 31 patients 1–36 months after unilateral RT with standard fractionation using changes seen in the contralateral ear as standard (0.25-8 kHz). ΔBCTs >10 dB were rarely seen unless the corresponding difference in mean cochlear dose was ≥45 Gy. The doses to the contralateral cochlea varied between 0.5 and 31.3 Gy (mean, 4.2 Gy).
      Honore (
      • Honore H.B.
      • Bentzen S.M.
      • Moller K.
      • et al.
      Sensori-neural hearing loss after radiotherapy for nasopharyngeal carcinoma: Individualized risk estimation.
      ) retrospectively estimated mean cochlear doses in 20 patients with head-and-neck cancer (1.8–4.3 Gy/fraction) and observed ΔBCT 7–79 months post-RT. Doses were reconstructed from patient-specific CT scans or proxy phantoms. A dose-response relationship was observed for ΔBCT >15 dB at 4 kHz, but not at other frequencies.
      Chen (
      • Chen W.C.
      • Jackson A.
      • Budnick A.S.
      • et al.
      Sensorineural hearing loss in combined modality treatment of nasopharyngeal carcinoma.
      ) retrospectively studied 22 patients treated with RT for nasopharyngeal cancer (with fraction sizes from 1.6–2.3 Gy and concurrent/adjuvant chemotherapy) and studied ΔBCT 12–79 months post-RT. A significant increase in hearing loss (ΔBCT of ≥20 dB at one frequency or ≥10 dB at two consecutive frequencies) was observed for all frequencies (0.5–4 kHz) when the mean dose received by the cochlea was >48 Gy.
      Van der Putten (
      • van der Putten L.
      • de Bree R.
      • Plukker J.T.
      • et al.
      Permanent unilateral hearing loss after radiotherapy for parotid gland tumors.
      ) retrospectively evaluated ΔBCT 2–7 years after RT in 21 patients with unilateral parotid tumors (fraction sizes 1.8–3.0 Gy). Using the contralateral ear as a control, SNHL (ΔBCT >15 db difference in ≥three frequencies between 0.25–12 kHz) was seen when mean doses received by the cochlea were >50 Gy.
      Oh (
      • Oh Y.T.
      • Kim C.H.
      • Choi J.H.
      • et al.
      Sensory neural hearing loss after concurrent cisplatin and radiation therapy for nasopharyngeal carcinoma.
      ) prospectively studied ΔBCTs (0.25–4 kHz) 3–12 months post-RT in 25 patients with nasopharyngeal cancer (fraction size 2 Gy). In this study, the inner ear doses were high (63–70 Gy), and hearing loss (ΔBCT ≥15 db from baseline) was associated with total dose received by the inner ear.

       SRS for vestibular schwannomas

       Volume–length effect

      A dose–volume analysis is not feasible because of the small nerve diameter, lack of visibility on CT, and variable thickness. Nevertheless, the location and length of the cochlear nerve involved with tumor and the prescription/marginal tumor dose reflect the dose received by the cochlear nerve (
      • Linskey M.E.
      • Lunsford L.D.
      • Flickinger J.C.
      Tumor control after stereotactic radiosurgery in neurofibromatosis patients with bilateral acoustic tumors.
      ,
      • Flickinger J.C.
      • Kondziolka D.
      • Lunsford L.D.
      Dose and diameter relationships for facial, trigeminal, and acoustic neuropathies following acoustic neuroma radiosurgery.
      ). For example, the cochlear nerve may receive less radiation if it lies on the tumor surface vs. if it passes through the core. SRS was found to be more likely to preserve hearing in patients with small VS (<3 cm) vs. larger lesions (
      • Pollock B.E.
      • Lunsford L.D.
      • Kondziolka D.
      • et al.
      Outcome analysis of acoustic neuroma management: A comparison of microsurgery and stereotactic radiosurgery.
      ). When SRS is used to treat intracanalicular VS with an irradiated nerve length of 4–12 mm, neither the tumor position in the canal (lateral vs. medial) nor the length of the nerve correlated with long-term hearing preservation. However, the marginal/prescription dose to the tumor was significant as was the dose extending beyond the tumor volume inside the canal was the most important factor responsible for cochlear nerve injury in SRS patients (
      • Niranjan A.
      • Lunsford L.D.
      • Flickinger J.C.
      • et al.
      Dose reduction improves hearing preservation rates after intracanalicular acoustic tumor radiosurgery.
      ). Intracanalicular tumor volume (<100 mm3 vs. ≥100 mm3) and intracanalicular integrated dose (dose × volume) are also thought to influence hearing loss (
      • Massager N.
      • Nissim O.
      • Delbrouck C.
      • et al.
      Role of intracanalicular volumetric and dosimetric parameters on hearing preservation after vestibular schwannoma radiosurgery.
      ).

       Total dose effect

      In one SRS study, patients receiving a mean maximum cochlear nucleus dose in the brain stem of 6.9 Gy and mean cochlear dose of 9.1 Gy retained useful hearing, whereas those in patients with hearing declines received 11.1 Gy and 7.8 Gy (
      • Paek S.H.
      • Chung H.T.
      • Jeong S.S.
      • et al.
      Hearing preservation after gamma knife stereotactic radiosurgery of vestibular schwannoma.
      ). In another study, serviceable hearing was preserved in 100% of the patients receiving marginal tumor doses ≤14 Gy but dropped to 20% in those receiving >14 Gy (
      • Niranjan A.
      • Lunsford L.D.
      • Flickinger J.C.
      • et al.
      Dose reduction improves hearing preservation rates after intracanalicular acoustic tumor radiosurgery.
      ). Other studies noted increased hearing preservation with marginal tumor doses of 10–16 (vs. 25) Gy (
      • Andrews D.W.
      • Suarez O.
      • Goldman H.W.
      • et al.
      Stereotactic radiosurgery and fractionated stereotactic radiotherapy for the treatment of acoustic schwannomas: Comparative observations of 125 patients treated at one institution.
      ), and 12–14 (vs. 16–20) Gy (
      • Combs S.E.
      • Volk S.
      • Schulz-Ertner D.
      • et al.
      Management of acoustic neuromas with fractionated stereotactic radiotherapy (FSRT): Long-term results in 106 patients treated in a single institution.
      ,

      Williams J. Fractionated radiotherapy for acoustic neuromas. Congress of Neurological Surgeons: 50th Annual Meeting 2000. San Antonio, TX: 155.

      ).

      5. Factors Affecting Risk

       Treatment-related factors

      • (1)
        The mean total dose to the cochlea during fractionated RT, or to the eighth cranial nerve in SRS for VS, is a dominant factor in post-RT hearing status (see Review of Dose–volume Data).
      • (2)
        The effect of dose per fraction (≤ or >2.0 Gy) has not been thoroughly described.
      • (3)
        The one study comparing once-daily vs. twice-daily fractionation observed no effect (
        • Bhandare N.
        • Antonelli P.J.
        • Morris C.G.
        • et al.
        Ototoxicity after radiotherapy for head and neck tumors.
        ). Some studies suggest that the patients treated for VS with FSRT have a better chance of maintaining serviceable hearing when compared with those treated by SRS (
        • Andrews D.W.
        • Suarez O.
        • Goldman H.W.
        • et al.
        Stereotactic radiosurgery and fractionated stereotactic radiotherapy for the treatment of acoustic schwannomas: Comparative observations of 125 patients treated at one institution.
        ,
        • Combs S.E.
        • Volk S.
        • Schulz-Ertner D.
        • et al.
        Management of acoustic neuromas with fractionated stereotactic radiotherapy (FSRT): Long-term results in 106 patients treated in a single institution.
        ,

        Williams J. Fractionated radiotherapy for acoustic neuromas. Congress of Neurological Surgeons: 50th Annual Meeting 2000. San Antonio, TX: 155.

        ). Hypofractionated RT with four fractions of 5 Gy, or five fractions of 4 Gy, may have less toxicity than SRS in fractions of 10–12 Gy (
        • Meijer O.W.
        • Vandertop W.P.
        • Baayen J.C.
        • et al.
        Single-fraction vs. fractionated linac-based stereotactic radiosurgery for vestibular schwannoma: A single-institution study.
        ).
      • (4)
        The possible synergistic toxicity of chemotherapy combined with RT has been studied prospectively (
        • Pan C.C.
        • Eisbruch A.
        • Lee J.S.
        • et al.
        Prospective study of inner ear radiation dose and hearing loss in head-and-neck cancer patients.
        ,
        • Kwong D.L.
        • Wei W.I.
        • Sham J.S.
        • et al.
        Sensorineural hearing loss in patients treated for nasopharyngeal carcinoma: A prospective study of the effect of radiation and cisplatin treatment.
        ,
        • Oh Y.T.
        • Kim C.H.
        • Choi J.H.
        • et al.
        Sensory neural hearing loss after concurrent cisplatin and radiation therapy for nasopharyngeal carcinoma.
        ,
        • Ho W.K.
        • Wei W.I.
        • Kwong D.L.
        • et al.
        Long-term sensorineural hearing deficit following radiotherapy in patients suffering from nasopharyngeal carcinoma: A prospective study.
        ,
        • Low W.K.
        • Toh S.T.
        • Wee J.
        • et al.
        Sensorineural hearing loss after radiotherapy and chemoradiotherapy: A single, blinded, randomized study.
        ), and retrospectively (
        • Bhandare N.
        • Antonelli P.J.
        • Morris C.G.
        • et al.
        Ototoxicity after radiotherapy for head and neck tumors.
        ,
        • Chen W.C.
        • Jackson A.
        • Budnick A.S.
        • et al.
        Sensorineural hearing loss in combined modality treatment of nasopharyngeal carcinoma.
        ,
        • Honore H.B.
        • Bentzen S.M.
        • Moller K.
        • et al.
        Sensori-neural hearing loss after radiotherapy for nasopharyngeal carcinoma: Individualized risk estimation.
        ,
        • van der Putten L.
        • de Bree R.
        • Plukker J.T.
        • et al.
        Permanent unilateral hearing loss after radiotherapy for parotid gland tumors.
        ). Cisplatin is known to cause hearing loss (
        • Combs S.E.
        • Volk S.
        • Schulz-Ertner D.
        • et al.
        Management of acoustic neuromas with fractionated stereotactic radiotherapy (FSRT): Long-term results in 106 patients treated in a single institution.
        ). Increased toxicity has been observed in patients treated with both adjuvant and concurrent cisplatin-RT (
        • Bhandare N.
        • Antonelli P.J.
        • Morris C.G.
        • et al.
        Ototoxicity after radiotherapy for head and neck tumors.
        ,
        • Chen W.C.
        • Jackson A.
        • Budnick A.S.
        • et al.
        Sensorineural hearing loss in combined modality treatment of nasopharyngeal carcinoma.
        ,
        • Low W.K.
        • Toh S.T.
        • Wee J.
        • et al.
        Sensorineural hearing loss after radiotherapy and chemoradiotherapy: A single, blinded, randomized study.
        ). Low (
        • Low W.K.
        • Toh S.T.
        • Wee J.
        • et al.
        Sensorineural hearing loss after radiotherapy and chemoradiotherapy: A single, blinded, randomized study.
        ) reported results at 1 and 2 years after RT delivered with concurrent and adjuvant cisplatin and found significant increases both in BCT at 4 kHz and in BCTs averaged over 0.5, 1, and 2 kHz. Conversely, no such increase has been seen in patients treated with neoadjuvant cisplatin followed by RT (i.e., without concurrent cisplatin/RT) (
        • Kwong D.L.
        • Wei W.I.
        • Sham J.S.
        • et al.
        Sensorineural hearing loss in patients treated for nasopharyngeal carcinoma: A prospective study of the effect of radiation and cisplatin treatment.
        ,
        • Oh Y.T.
        • Kim C.H.
        • Choi J.H.
        • et al.
        Sensory neural hearing loss after concurrent cisplatin and radiation therapy for nasopharyngeal carcinoma.
        ,
        • Ho W.K.
        • Wei W.I.
        • Kwong D.L.
        • et al.
        Long-term sensorineural hearing deficit following radiotherapy in patients suffering from nasopharyngeal carcinoma: A prospective study.
        ).

       Patient-related factors

      • (1)
        The rate of post-RT SNHL appears to increase with age (>50) (
        • Bhandare N.
        • Antonelli P.J.
        • Morris C.G.
        • et al.
        Ototoxicity after radiotherapy for head and neck tumors.
        ,
        • Pan C.C.
        • Eisbruch A.
        • Lee J.S.
        • et al.
        Prospective study of inner ear radiation dose and hearing loss in head-and-neck cancer patients.
        ,
        • Kwong D.L.
        • Wei W.I.
        • Sham J.S.
        • et al.
        Sensorineural hearing loss in patients treated for nasopharyngeal carcinoma: A prospective study of the effect of radiation and cisplatin treatment.
        ,
        • Honore H.B.
        • Bentzen S.M.
        • Moller K.
        • et al.
        Sensori-neural hearing loss after radiotherapy for nasopharyngeal carcinoma: Individualized risk estimation.
        ,
        • Ho W.K.
        • Wei W.I.
        • Kwong D.L.
        • et al.
        Long-term sensorineural hearing deficit following radiotherapy in patients suffering from nasopharyngeal carcinoma: A prospective study.
        ,
        • Moretti J.A.
        Sensori-neural hearing loss following radiotherapy to the nasopharynx.
        ). Grau (
        • Grau C.
        • Overgaard J.
        Postirradiation sensorineural hearing loss: A common but ignored late radiation complication.
        ) found a significant relationship between higher patient age and increased risk of hearing loss, but, when corrected for dose, the correlation disappeared. Higher rates of post-RT SNHL have been reported in males compared with females (
        • Kwong D.L.
        • Wei W.I.
        • Sham J.S.
        • et al.
        Sensorineural hearing loss in patients treated for nasopharyngeal carcinoma: A prospective study of the effect of radiation and cisplatin treatment.
        ,
        • Ho W.K.
        • Wei W.I.
        • Kwong D.L.
        • et al.
        Long-term sensorineural hearing deficit following radiotherapy in patients suffering from nasopharyngeal carcinoma: A prospective study.
        ). Other studies have not observed any difference in the incidence of SNHL between sexes or races (
        • Bhandare N.
        • Antonelli P.J.
        • Morris C.G.
        • et al.
        Ototoxicity after radiotherapy for head and neck tumors.
        ).
      • (2)
        Greater post-RT hearing losses (i.e., greater thresholds) have been associated with better pre-RT hearing (i.e., lower thresholds) (
        • Pan C.C.
        • Eisbruch A.
        • Lee J.S.
        • et al.
        Prospective study of inner ear radiation dose and hearing loss in head-and-neck cancer patients.
        ,
        • Honore H.B.
        • Bentzen S.M.
        • Moller K.
        • et al.
        Sensori-neural hearing loss after radiotherapy for nasopharyngeal carcinoma: Individualized risk estimation.
        ).
      • (3)
        Post-RT otitis media has been associated with an increased risk of SNHL (
        • Bhandare N.
        • Antonelli P.J.
        • Morris C.G.
        • et al.
        Ototoxicity after radiotherapy for head and neck tumors.
        ,
        • Kwong D.L.
        • Wei W.I.
        • Sham J.S.
        • et al.
        Sensorineural hearing loss in patients treated for nasopharyngeal carcinoma: A prospective study of the effect of radiation and cisplatin treatment.
        ,
        • Ho W.K.
        • Wei W.I.
        • Kwong D.L.
        • et al.
        Long-term sensorineural hearing deficit following radiotherapy in patients suffering from nasopharyngeal carcinoma: A prospective study.
        ).
      • (4)
        Compared with sporadic VS, VS secondary to neurofibromatosis (NF2) after SRS or FSRT exhibits lower hearing preservation and increased hearing deterioration (
        • Andrews D.W.
        • Suarez O.
        • Goldman H.W.
        • et al.
        Stereotactic radiosurgery and fractionated stereotactic radiotherapy for the treatment of acoustic schwannomas: Comparative observations of 125 patients treated at one institution.
        ,
        • Flickinger J.C.
        • Lunsford L.D.
        • Linskey M.E.
        • et al.
        Gamma knife radiosurgery for acoustic tumors: multivariate analysis of four year results.
        ,
        • Rowe J.G.
        • Radatz M.W.
        • Walton L.
        • et al.
        Clinical experience with gamma knife stereotactic radiosurgery in the management of vestibular schwannomas secondary to type 2 neurofibromatosis.
        ).
      • (5)
        Cerebral spinal fluid shunt has been suggested to increase the risk of HL after RT in children and perhaps adults (
        • Merchant T.E.
        • Gould C.J.
        • Xiong X.
        • et al.
        Early neuro-otologic effects of three-dimensional irradiation in children with primary brain tumors.
        ).

      6. Mathematical/Biological Models

      The values of TD5/5 = 60 Gy, TD50/5 = 70 for SNHL suggested by Emami (
      • Hirsch A.
      • Noren G.
      Audiological findings after stereotactic radiosurgery in acoustic neurinomas.
      ) are not supported in the literature and should not be utilized in treatment planning. Nevertheless, the information on dose–response modeling for post-RT SNHL remains limited.
      Pan (
      • Pan C.C.
      • Eisbruch A.
      • Lee J.S.
      • et al.
      Prospective study of inner ear radiation dose and hearing loss in head-and-neck cancer patients.
      ) constructed a linear model demonstrating the differences between pre-RT and post-RT BCTs (corresponding to frequencies varying from 0.25 to 8 kHz) for the ipsilateral and contralateral ears and their association with relative dose scale, age, test frequency, and baseline (i.e., pre-RT) BCT and presented these differences in the form of nomograms. Because of its complexity, the details of the model cannot be presented here (
      • Pan C.C.
      • Eisbruch A.
      • Lee J.S.
      • et al.
      Prospective study of inner ear radiation dose and hearing loss in head-and-neck cancer patients.
      ). In brief, hearing loss was found to depend on frequency tested, age, baseline hearing, and dose to inner ear.
      Honore (
      • Honore H.B.
      • Bentzen S.M.
      • Moller K.
      • et al.
      Sensori-neural hearing loss after radiotherapy for nasopharyngeal carcinoma: Individualized risk estimation.
      ) presented a logistic model of the probability of post-RT hearing loss ≥15 dB at 4 kHz, including only dose, which indicated that D50 = 48 Gy (95% confidence interval not reported) and γ50 = 0.70 (range, 0.22–1.18). Adjusting for patient age and pretreatment hearing level revealed a steeper dose-response curve with γ50 = 3.4 (95% confidence interval, 0.3–6.5).
      Their multivariate logistic regression model is presented.
      P=exp(b0+ibixi)/[1+exp(b0+ibixi)]
      (1)


      Where x1 = dose in Gy, x2 = pretreatment hearing threshold in dB, x3 = observation time in years, b0 = -24.9, b1 = 0.30 Gy−1 (0.03–0.56), b2 = -0.44 dB−1 (-0.86–0.01), and b3 = 0.46 year−1 (0.02–0.90) with a p value of <0.05. Honore (
      • Honore H.B.
      • Bentzen S.M.
      • Moller K.
      • et al.
      Sensori-neural hearing loss after radiotherapy for nasopharyngeal carcinoma: Individualized risk estimation.
      ) also modeled a post-RT increase in BCT at 4 kHz with multiple linear regressions. Dose, age, and pretherapeutic hearing level were significant (p < 0.05), with the coefficients (95% confidence intervals): 0.31 (±0.15) dB/Gy, 0.53 (±0.21) dB/year, and -0.28 (±0.22) dB/dB, respectively. The constant shift in hearing level in this model, -21.6 (±11.2) dB, was relatively large.
      Chen (
      • Chen W.C.
      • Jackson A.
      • Budnick A.S.
      • et al.
      Sensorineural hearing loss in combined modality treatment of nasopharyngeal carcinoma.
      ) constructed linear models for post-RT changes in BCTs at frequencies between 0.5 and 4 kHz and found that dose was significant at all frequencies. In a multivariate linear model, RT dose, number of cycles of cisplatin, and time to post-RT hearing test were significant at 4 kHz. At 2 and 3 kHz, RT dose and time to posttreatment hearing test were significant. At 1 kHz, only RT dose was significant. In addition, hearing loss in the opposite ear was seen to be highly significant, which may provide additional evidence of the toxicity of concurrent plus adjuvant cisplatin.
      Van der Putten (
      • van der Putten L.
      • de Bree R.
      • Plukker J.T.
      • et al.
      Permanent unilateral hearing loss after radiotherapy for parotid gland tumors.
      ) fitted an NTCP model to the incidence of asymmetrical SNHL (with a minimum of three frequencies from 0.25–12 kHz) as a function of mean dose to the ipsilateral inner ear and obtained D50 = 53.2 Gy with γ50 of 2.74 and D10 = 42 Gy.
      The incidence of hearing loss at 4 and 2 kHz as reported by Honore (
      • Honore H.B.
      • Bentzen S.M.
      • Moller K.
      • et al.
      Sensori-neural hearing loss after radiotherapy for nasopharyngeal carcinoma: Individualized risk estimation.
      ), Chen (
      • Chen W.C.
      • Jackson A.
      • Budnick A.S.
      • et al.
      Sensorineural hearing loss in combined modality treatment of nasopharyngeal carcinoma.
      ), and Pan (
      • Pan C.C.
      • Eisbruch A.
      • Lee J.S.
      • et al.
      Prospective study of inner ear radiation dose and hearing loss in head-and-neck cancer patients.
      ) are shown in Figures 1a and 1b. The data of Van der Putten (
      • van der Putten L.
      • de Bree R.
      • Plukker J.T.
      • et al.
      Permanent unilateral hearing loss after radiotherapy for parotid gland tumors.
      ), on hearing loss at combined frequencies, are shown for comparison in Figure 1c. The sources for these data and caveats concerning the comparisons implied by these plots are given in the figure legend. It is clear that the response seen by Pan (
      • Pan C.C.
      • Eisbruch A.
      • Lee J.S.
      • et al.
      Prospective study of inner ear radiation dose and hearing loss in head-and-neck cancer patients.
      ) is considerably smaller than that seen by the other studies. This could be due to a number of factors, the most obvious being the relative endpoint and relative dose scale used by Pan, and the influence of chemotherapy in Chen (
      • Chen W.C.
      • Jackson A.
      • Budnick A.S.
      • et al.
      Sensorineural hearing loss in combined modality treatment of nasopharyngeal carcinoma.
      ). However, the complication rate seen by Honore (
      • Honore H.B.
      • Bentzen S.M.
      • Moller K.
      • et al.
      Sensori-neural hearing loss after radiotherapy for nasopharyngeal carcinoma: Individualized risk estimation.
      ) (in patients treated without chemotherapy) is of the same order as that of Chen (
      • Chen W.C.
      • Jackson A.
      • Budnick A.S.
      • et al.
      Sensorineural hearing loss in combined modality treatment of nasopharyngeal carcinoma.
      ).
      Flickinger (
      • Flickinger J.C.
      • Kondziolka D.
      • Lunsford L.D.
      Dose and diameter relationships for facial, trigeminal, and acoustic neuropathies following acoustic neuroma radiosurgery.
      ) modeled the effects of minimum tumor dose Dmin and transverse tumor diameter (Td) with multivariate logistic regression analysis (equation 1) for the risk of acoustic neuropathy (defined as any variation in either PTA or SDS resulting in decline in GRHG for patients with at least Class IV hearing) in patients treated with SRS for VS in two datasets. The coefficients b1 (1/Gy) for Dmin were 0.166, 0.158 (with respective p = 0.00745, 0.1084; SEcoeff, 0.091, 0.097). The coefficients b2 (1/cm) for Td were 0.752, 0.818 (with respective p = 0.0079, 0.039; SEcoeff, 0.276, 0.276). The constants b0 were -4.57, -4.48 (with respective p = 0.0044, 0.0076; SEcoeff, 1.56, 1.64).
      In addition to the limited information on modeling SNHL, there remain several limitations in both prospective and retrospective studies in the current literature, such as a relatively small number of patients, variation in the standard for HL, frequencies evaluated, and other approximations (e.g., the use of a proxy phantom in retrospective studies), thereby making the choice of any specific model for routine clinical utilization difficult.

      7. Special Situations

      • (1)
        Data on cisplatin-RT suggest that radiation doses to the cochlea should be strictly limited when delivered with cisplatin.
      • (2)
        Data presented may not be applicable to fractionation schedules beyond the ranges studied.
      • (3)
        Data presented in this review apply to adult patients only; for data on pediatric patients, see Hua et al.(
        • Hua C.
        • Bass J.K.
        • Khan R.
        • et al.
        Hearing loss after radiotherapy for pediatric brain tumors: Effect of cochlear dose.
        ).
      • (4)
        Data for hearing response after SRS or FSRT for sporadic tumors may not be representative of the patients with VS secondary to NF2.

      8. Recommended Dose–Volume Limits (Where Possible While Retaining the Desired Target Coverage)

      • (1)
        For conventionally fractionated RT, to minimize the risk for SNHL, the mean dose to the cochlea should be limited to ≤45 Gy (
        • Pan C.C.
        • Eisbruch A.
        • Lee J.S.
        • et al.
        Prospective study of inner ear radiation dose and hearing loss in head-and-neck cancer patients.
        ,
        • Chen W.C.
        • Jackson A.
        • Budnick A.S.
        • et al.
        Sensorineural hearing loss in combined modality treatment of nasopharyngeal carcinoma.
        ) (or more conservatively ≤35 Gy) (
        • Honore H.B.
        • Bentzen S.M.
        • Moller K.
        • et al.
        Sensori-neural hearing loss after radiotherapy for nasopharyngeal carcinoma: Individualized risk estimation.
        ). Because a threshold for SNHL cannot be determined from the present data, to prevent SNHL the dose to the cochlea should be kept as low as possible.
      • (2)
        For SRS for VS, the prescription dose should be limited to 12–14 Gy for hearing preservation(
        • Combs S.E.
        • Volk S.
        • Schulz-Ertner D.
        • et al.
        Management of acoustic neuromas with fractionated stereotactic radiotherapy (FSRT): Long-term results in 106 patients treated in a single institution.
        ,

        Williams J. Fractionated radiotherapy for acoustic neuromas. Congress of Neurological Surgeons: 50th Annual Meeting 2000. San Antonio, TX: 155.

        ,
        • Flickinger J.C.
        • Kondziolka D.
        • Niranjan A.
        • et al.
        Acoustic neuroma radiosurgery with marginal tumor doses of 12 to 13 Gy.
        ).
      • (3)
        A suggested hypofractionation schedule for VS, to provide likely tumor control and preserve hearing, is a total prescription dose of 21–30 Gy in 3–7 Gy per fraction over 3–10 days, though data on this schedule are limited.

      9. Future Toxicity Studies

      • (1)
        Larger single and multi-institutional prospective trials utilizing pre- and posttreatment hearing tests are required to establish absolute hearing loss as a function of frequency and the absolute radiation dose received by each cochlea, and verify the reported observations regarding SNHL after RT for head-and-neck cancers.
      • (2)
        The response of SNHL to chemoradiation needs to be determined in prospective trials as a function of both cisplatin and radiation doses as well as chemo-regimen (neoadjuvant, concurrent, or adjuvant).
      • (3)
        In the treatment of VS, the effects of fractionation (SRS vs. FSRT with standard fractionation and hypofractionation), the location and length of the acoustic nerve relative to the tumor, and doses received by it, require systematic prospective investigation.

      10. Toxicity Scoring

      Existing scoring systems (e.g., Radiation Therapy Oncology Group, Late Effects on Normal Tissues / Subjective, Objective, Management and Analytic, National Cancer Institute Common Terminology Criteria for Adverse Events) have limitations. We make the following recommendations for coding toxicity.

       SNHL after fractionated RT for head-and-neck cancers

      • (1)
        Hearing loss should be determined through pre- and post-RT audiometric evaluations of the same ear. In retrospective studies, if pre-RT audiometric evaluations for the ipsilateral ears are not available, the contralateral ear may be preferable to an age-specific standard, but both should be viewed as substandard relative to pre-RT ipsilateral data.
      • (2)
        To avoid transient post-RT hearing fluctuations, hearing should be tested starting 6 months post-RT and at least biannually thereafter.
      • (3)
        SDS and four-frequency (0.5, 1.0, 2.0, and 3.0 kHz) bone conduction pure tone average should be used, as endorsed by the American Academy of Otolaryngology-Head and Neck Surgery Committee on Hearing and Equilibrium (
        • Committee on Hearing and Equilibrium
        Committee on Hearing and Equilibrium guidelines for the evaluation of hearing preservation in acoustic neuroma (vestibular schwannoma). American Academy of Otolaryngology-Head and Neck Surgery Foundation, Inc.
        ).
      • (4)
        For high-frequency HL, 6 kHz bone conduction thresholds should be measured, because a) the basal turn of the cochlea (i.e., highest frequencies) are the first to be affected, b) 6 kHz is highest frequency bone conduction threshold measured with standard bone conducting transducers, and c) bone conduction thresholds minimize the influence of concomitant middle and external ear pathology.
      • (5)
        Additionally, a measurement at 4 kHz may facilitate comparison with the present datasets.
      • (6)
        “Clinically significant hearing loss” should be considered as an increase in the threshold of 10 dB in post-RT BCT, or a decline of 10% in an SDS evaluation, as assessed by an expert.
      • (7)
        Clinically significant HL observed in two consecutive PTA evaluations is considered as persistent.

       Toxicity scoring after RT for VS

      • (1)
        Preservation of pretreatment hearing level: (a) preservation pre-RT GRHG I-IV hearing or (b) in pre-RT GRHG V patients, with no speech discrimination but testable PTA, a preservation of PTA scores.
      • (2)
        SH (corresponding to GRHG I-II); commonly defined as PTA ≤ 0 and SDS ≥50%.
      • (3)
        MH is any hearing with detectable audiometric response.
      • (4)
        Either an improvement or loss in hearing expressed as a change in GRHG.

      References

        • Jereczek-Fossa B.A.
        • Zarowski A.
        • Milani F.
        • et al.
        Radiotherapy-induced ear toxicity.
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        • Harrington K.J.
        • Nutting C.M.
        Otological toxicity after postoperative radiotherapy for parotid tumours.
        Clin Oncol (R Coll Radiol). 2007; 19: 77-82
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