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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.
Radiation therapy (RT) may damage the cochlea and/or acoustic nerve, leading to sensorineural hearing loss (SNHL) (1–4), 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).
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 (5,6) and/or pure tone average [PTA] of frequencies between 0.5–3.0 kHz) (7–9); (b) the control/standard used for comparison (e.g., pre-RT BCT of same ear (10) or post-RT BCT of the contralateral ear (5), or age-specific standard (4)); and (c) the change in BCT (ΔBCT) that is defined as clinically significant (e.g., 20 dB(5, 6), 15 dB(7, 8), 10 dB(5)). The degree of hearing loss after RT for head-and-neck cancer is worse at higher frequencies, as presented in Figures 1a–c (5–8, 10–12). Although early changes in hearing can be reversible, persistent hearing loss (HL) continues to increase with time (11). Selected studies on SNHL after head-and-neck radiation therapy are shown in Table 1.
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) (13). 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.
Acute SNHL has been reported after SRS (14), but not after fractionated RT. Hearing impairment has been reported within 3 to 24 months after single-fraction SRS (13, 15), with a median time to onset of 4 months (15, 16). Although it can occur as early as 3 months after completing fractionated RT, the median latency is 1.5–2.0 years (10, 11).
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) (17) to 0.56 mL (range, 0.15–0.91 mL) (5).
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 (6, 10, 18).
Pan (5) 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 (10) 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 (6) 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 (12) 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 (8) 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.
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 (16, 19). 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 (20). 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 (13). Intracanalicular tumor volume (<100 mm3 vs.≥100 mm3) and intracanalicular integrated dose (dose × volume) are also thought to influence hearing loss (21).
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 (22). 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 (13). Other studies noted increased hearing preservation with marginal tumor doses of 10–16 (vs. 25) Gy (23), and 12–14 (vs. 16–20) Gy (24, 25).
The values of TD5/5 = 60 Gy, TD50/5 = 70 for SNHL suggested by Emami (34) 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 (5) 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 (5). In brief, hearing loss was found to depend on frequency tested, age, baseline hearing, and dose to inner ear.
Honore (10) 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.
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 (10) 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 (6) 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 (12) 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 (10), Chen (6), and Pan (5) are shown in Figures 1a and 1b. The data of Van der Putten (12), 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 (5) 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 (6). However, the complication rate seen by Honore (10) (in patients treated without chemotherapy) is of the same order as that of Chen (6).
Flickinger (19) 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.
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.
Conflict of interest: None.