|Ahead of print publication
Comparison of radiation and chemoradiation-induced sensorineural hearing loss in head and neck cancer patients
Seied Rabi Mahdavi1, Abolhasan Rezaeyan2, Alireza Nikoofar3, Mohsen Bakhshandeh4, Saeid Farahani5, Susan Cheraghi6
1 Radiation Biology Research Center; Department of Medical Physics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
2 Department of Medical Physics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
3 Department of Radiation Oncology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
4 Department of Radiation Technology, Allied Medicine Faculty, Shahid Beheshti University of Medical Sciences, Tehran, Iran
5 Department of Audiology, School of Rehabilitation, Tehran University of Medical Sciences, Tehran, Iran
6 Radiation Biology Research Center; Department of Radiation Sciences, Allied Medicine Faculty, Iran University of Medical Sciences, Tehran, Iran
|Date of Submission||15-Aug-2016|
|Date of Acceptance||07-Aug-2018|
|Date of Web Publication||31-Jan-2020|
Department of Radiation Sciences, Allied Medicine Faculty, Iran University of Medical Sciences, Shahid Hemmat Highway, P. O. Box 1449614535, Tehran
Source of Support: None, Conflict of Interest: None
Aim: The purpose of this study was to assess and compare the incidence and severity of sensorineural hearing loss (SNHL) in head-and-neck patients undergoing radiotherapy (RT) and concurrent cisplatin-based chemoradiotherapy (CRT).
Materials and Methods: Pure tone audiometry (PTA) was performed at 0.25–12 kHz on 35 RT and 25 CRT patients after 12-month followed up. The hearing loss was evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) criteria.
Results: SNHL increased to 84% in patients who had received CRT, compared with 26% increasing in patients who had treated with RT. There was an increased risk of SNHL at all frequencies for ears received a cochlear mean dose >50 Gy in RT group, compared to those receiving cochlear mean dose >30 Gy in CRT group. SNHL was more severe at higher frequencies in both patient groups.
Conclusion: Characteristic of radiation-induced SNHL is different from CRT-induced SNHL, especially in threshold radiation dose and PTA frequency.
Keywords: Concurrent chemotherapy, head, neck, pure tone audiometry, radiotherapy, sensorineural hearing loss
|How to cite this URL:|
Mahdavi SR, Rezaeyan A, Nikoofar A, Bakhshandeh M, Farahani S, Cheraghi S. Comparison of radiation and chemoradiation-induced sensorineural hearing loss in head and neck cancer patients. J Can Res Ther [Epub ahead of print] [cited 2020 Feb 24]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=277466
| > Introduction|| |
Many head-and-neck tumors are treated with radiotherapy (RT) alone, but those are more advanced may require concurrent chemoradiation therapy (CRT). Chemotherapy improved survival in patients that treated for nonmetastatic head-and-neck squamous cell carcinoma (HNSCC), even concurrent CRT is more benefit., CRT is superior to RT alone in the better survival of patient and reduce recurrence of tumors. Several different cisplatin schedule is use in CRT. Administration 100 mg/m2 dose of cisplatin once every 3 weeks concurrently with RT is a commonly recommended treatment regimen during CRT for HNSCC, but 40 mg/m2/week in cervical cancer is effective and has lower toxicity.
One of the serious adverse effects in head-and-neck RT or CRT is sensorineural hearing loss (SNHL).,,, Synergetic effect of radiation and cisplatin has been well-documented,, but to the best of our knowledge, there is no prospective study to compare RT- and CRT-induced SNHL. In this study, we aimed to assess and compare incidence and severity of SNHL in head-and-neck cancer patients undergoing RT and CRT. Furthermore, we obtained relationships of SNHL with cochlear dose, hearing frequency range of pure tone audiometry (PTA), time after treatment, and patient-related factors.
| > Materials and Methods|| |
We conducted this study on 60 head-and-neck cancer patients (35 RT and 25 CRT) with different stages including T1-T4, N0-N3, and M0 which diagnosed and treated between September 2014 and December 2015. Informed consent was obtained from all individual participants included in the study. Patient treatment procedure was approved by the Ethics Committee of Iran University of Medical Sciences in accordance with the ethical standards of the responsible committee on human experimentation and in compliance with the 1975 Helsinki Declaration. Patients who were excluded from the study were (1) primary or secondary tumors of any part of the auditory system; (2) metastatic tumors; (3) previous head-and neck RT; (4) palliative RT; and (5) discontinued RT before the treatment completion.
All patients were treated using 3D-Conformal Radiation Therapy, Treatment Planning System (TPS), and CorePlan (version 188.8.131.52, Seoul C & J Co., South Korea), based on the patient computed tomography (CT) scans. For small structures such as cochlea, the accuracy of dose–volume data is strongly dependent on the CT slice thickness, cochlea contouring, and monitoring resolution. Hence, CT scans were obtained using a multislice CT scanner with a slice thickness of 2 mm and dose calculations were made using a dose voxel size of 2 mm × 2 mm × 2 mm. To ensure the accuracy of the doses delivered, validation of TPS was initially made using TLDs-embedded Alderson Rando phantom.
The gross tumor volume (GTV) and/or tumor bed, clinical target volume (CTV), and planning target volume (PTV) were outlined by radiation oncologist. The bilateral cochleae were contoured on each slice of the CT scans. The radiation therapy procedure was done using a total dose 50–66 Gy (RT patients) and 63–70 Gy (CRT patients) by the dose prescribed to the planning target volume 1.8–2 Gy/fraction in 5 consecutive days per week.
Auditory assessment was described in detail in our previous work. In brief, audiologic assessment was obtained from 0.25 kHz up to 12 kHz as low (0.25–1 kHz), medium (2–6 kHz), and high (8–12 kHz) frequencies. All patients had 1-year follow-up course after completion of RT. Auditory thresholds were measured prior RT as a baseline and at middle RT, immediately, 3-, 6-, and 12- months after RT. Each individual ear was evaluated independently for radiation doses and hearing status. Ototoxicity was measured using intrasubjective audiogram comparisons using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03: June 14, 2010. Accordingly, the clinically significant hearing change was at least 15 dB averaged at two contiguous test frequencies as Grade 1., 2, and 3 of SNHL are threshold shift of >25 dB averaged at two contiguous frequencies and threshold shift of >25 dB averaged at three contiguous test frequencies, respectively.
Twenty-five CRT patients (42% of all patients) were planned on the 40 mg/m2/week of cisplatin chemotherapy intravenously. These patients received at least five cycles of cisplatin concurrent radiation therapy. Chemotherapy was started in the first week of radiation therapy and repeated every week by the end ofRT.
| > Results|| |
Occurrence of sensorineural hearing loss
SNHL was observed in 84% of the CRT versus 26% in RT patients. Patient demography, tumors localization, and SNHL characteristics were shown in more detail in [Table 1].
|Table 1: Patient demography, tumor sub localization and sensorineural hearing loss characteristics|
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Pure tone audiometry frequency
[Figure 1] shows discrepancy of hearing threshold before and after treatment. In RT group, discrepancies were statically significant for 6 frequencies (1, 3, 4, 6, 8, and 10 kHz) while CRT patients had significant SNHL at all frequencies except 12 kHz (t-test two-paired, P ≤ 0.05). The most severe SNHL occurred at 8 kHz and 10 kHz in RT and CRT groups, respectively.
|Figure 1: Mean hearing thresholds before and after treatment in RT (a) and CRT (b) groups. In RT (a) group discrepancies were significant for 6 frequencies (1, 3, 4, 6, 8 and 10 kHz) whilst CRT (b) patients had significant SNHL at all frequencies except 12 kHz. *Statistical significance, P < 0.05. RT: Radiotherapy, CRT: Chemoradiotherapy|
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Incidence frequency of SNHL based on PTA frequency is shown in [Figure 2]. In RT group, increasing of SNHL incidence is considerable at high frequencies. In CRT group, the incidence of SNHL increased as frequency of PTA increased except for 12 kHz. The slope of SNHL incidence is steeper at 6–8 kHz and maximum incidence was occurred at 10 kHz in both groups.
|Figure 2: Frequency of SNHL incidence at pure tone frequencies in RT and CRT groups. SNHL: Sensorineural hearing loss|
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Rate of CRT-induced SNHL to RT-induced SNHL for each frequency is plotted in [Figure 3]; we found medium frequencies of PTA are more susceptible to ototoxicity in CRT than RT. The highest and lowest rate occurs at 3 kHz and at 12 kHz, respectively.
|Figure 3:The ratio of chemoradiotherapy to radiotherapy-induced sensorineural hearing loss at pure tone frequencies|
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Cochlear radiation dose
[Figure 4] shows the incidence probability of SNHL as function of cochlear mean dose at all PTA frequencies. A comparison between two graph shows that maximum probability of SNHL in RT group occurs at 50–56 Gy for all frequencies. In CRT group, incidence probability of SNHL is the same for all frequencies up to 30 Gy then will be maximum at 45–50 Gy and 60–64 Gy for 0.25–2 kHz and higher PTA frequencies, respectively. Also in CRT group, incidence of SNHL in 0.25–1 kHz decreases after define dose.
|Figure 4: Probability of sensorineural hearing loss incidence as function of cochlear mean dose for PTA frequencies in radiotherapy (a) and chemoradiotherapy (b) groups. PTA: Pure tone frequency|
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As [Figure 4] shows, SNHL occurs in different threshold cochlear dose. In RT group, threshold variations change from 13 to 45 Gy (13 Gy for frequencies ≥3 kHz and 38–45 Gy for frequencies ≤2 kHz). On the other hand, in CRT patients, threshold shifted to the lowest dose and there are not definitive levels of threshold dose in this group.
SNHL incidence based on follow-up time appears to be variable in both groups [Figure 5]. Additional follow-up to 12 months showed mild progression of SNHL in RT and further progression in CRT group. The frequency of SNHL incidence increased by time and Grade 3 had the highest incidence after 12-month follow-up.
|Figure 5: Frequency of sensorineural hearing loss incidence according to the time of audiometry assessment in radiotherapy and chemoradiotherapy groups|
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Other factors related to sensorineural hearing loss
Univariate and multivariate logistic regression analysis performed to identify the predicting factors of SNHL. The cochlear mean dose, gender, age, and cochlear volume are tested (95% confidence interval). In RT group, only mean cochlear dose was significant for determining SNHL (P< 0.005).
Box plot of age and cochlear mean dose for patients with and without hearing loss damage in two groups is shown in [Figure 6].
|Figure 6: Boxplots provide the minimum, first quartile, median, third quartile, and maximum of age and cochlear mean dose for patients with and without hearing loss damage in radiotherapy (a) and chemoradiotherapy (b) groups|
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None of above factors is not important determinants for SNHL incidence in CRT group.
Our finding shows in RT group hearing damages begin at high frequencies (≥8 kHz) versus in CRT group damages may be start at any frequency even at audible range.
Patients PTAs show three patients of RT group (8.6%) that had Grade 1 of SNHL at high frequency were recovered 3 or 6 months after RT. In CRT patients, never grade of SNHL recovery was shown at 12-month follow-up course. Furthermore, we saw 3% of SNHL damages in RT group with compare to 86% in CRT group were bilaterally.
| > Discussion|| |
There are several studies that demonstrated the cochlea is more radiosensitive than auditory nerves., Hearing impairment is determined with cochlear radiation dose.,, In addition, radiation can induce outer and inner hair cell damages., There is a study which shows stria vascularies and cochlear hair cells are the two critical sites to high-dose-RT damage. Radiation-induced vascular and connective tissue damages have been suggested to result in cochlear anoxia which can manifest as SNHL.
The main mechanism of hearing impairment by cisplatin can be due to damages to outer hair cells,,, but ototoxicity can vary by individual sensitivity based on human genetics., Recent findings show that cisplatin ototoxicity involve the production of reactive oxygen species in inner ear tissues by activating an enzyme unique leads to the cascade resulting in oxidation of lipids and hair cell loss. In outer hair cells, the higher frequency areas are more affected by CRT.,
There are a considerable body of works on radiation- and cisplatin-induced SNHL,,,, also head-and-neck RT can potentially damage auditory structures. In this study, we aimed to investigate the differences between RT- and CRT-induced ototoxicity. Since high-frequency hearing loss can lead to impairment in speech perception,, PTA was performed from low (0.5 kHz) to high (12 kHz) frequencies on both ears in the present study.
We observed SNHL in 84% CRT versus 26% RT patients. The results of our study are in good agreement with similar studies.,,,, Our findings showed more PTA frequencies are involved in CRT with comparison to RT patients (0.25–10 kHz versus 1.3–10 kHz). Furthermore, we observed that maximum incidence of SNHL occurred at 10 kHz in both groups, but maximum rate of CRT-induced SNHL to RT-induced SNHL occurred at 2, 3, and 4 kHz. Since 2–4 kHz frequencies are audible range, CRT patients are more compliant to hearing than RT patients. On the other hand, since high-frequency SNHL was considerable in RT and they are not in audible range, patients may don't perceive easily theses early ototoxicity until to tend recovery or to be progressive. Our results confirm early high frequency changes in hearing can be reversible in RT patients, and persistent hearing loss increased with time. Results of our study which showed RT-related SNHL tends to begin at high frequencies are in good agreement with other reports.,,, However, Bohne et al. reported the basal turn in cochlea, which encodes high frequencies, is more sensitive to the radiation than the apical region, Then, hearing loss continues toward the cochlear apex where lower frequency sounds are affected, that this statement confirmed our results. However, these our findings, may change the previous observations that RT-related effects are late effect such as Kwong, Wang, and Fuss studies.,,
Also in this study, we confirmed the previous observation that there is a statistically significant difference in the severity of low and medium frequency SNHL after combined CRT treatment. Result from our data is coincident with other studies that reported hearing loss due to CRT is permanent and bilateral.,
Our findings show that cochlear threshold dose of RT-induced SNHL was varied in the range of 13-45 Gy according to PTA frequency. Similar studies reported cochlear threshold dose 35-48 Gy for hearing loss.,, The other studies a mean dose constraint of 48 Gy to the cochlea is recommended to minimize SNHL after RT., Grau et al. and Chen et al. suggested cochlea tolerance doses of 50 and 60 Gy, respectively. Their result supports our findings that maximum probability of SNHL occurs in 50–56 Gy in RT group. With regard to our findings, a dose limit of 50 Gy need to prevent radiation ototoxicity and keeping it well under control during treatment.
Also similar with our study cochlear mean dose of >50 Gy had shown a trend to increase the risk of high frequency SNHL in intensity-modulated radiation therapy (IMRT). In the other study in patients treated with IMRT, the mean dose to the cochlea was 17.8 Gy (1.0–66.6 Gy) and hearing loss was 1.8–4.4 dB at 0.5–12.5 kHz. Hitchcock et al. found that patients receiving 100 mg/m2/ 3 weeks or 40 mg/m2/week of cisplatin chemotherapy had about 21.5 dB and 9.5 dB hearing loss, respectively, at 8000 Hz with radiation doses of 10 Gy, which rose to 38.4 dB and 18.9 dB for doses of 40 Gy.
According to this result, cisplatin and RT doses ≥30 Gy had an additive or synergic effect on SNHL. Therefore, we suggest to reducing ototoxicity effects of cisplatin, a 30 Gy radiation dose to cochlea is more conservatively, this concurred with the findings from Bhandare et al. study. Although Ying et al. reported 10 Gy as the threshold cochlear dose for hearing loss with combined CRT. Nagy et al. reported even after low-dose cisplatin administration hearing loss will be occurred. Decrease of SNHL incidence in CRT group at 0.25–1 kHz after a define dose need to be more study.
There are several variables that can affect on the risk of developing SNHL including mean of the cochlear dose,,,,, high dose cisplatin, and time after RT.,, Some authors found that older patients,, and males are more likely to develop SNHL after RT. In the present study, logistic regression showed the cochlea radiation dose is significant factor that affecting the risk of SNHL in RT patients. None of above factors is important determinants for SNHL incidence in CRT group.
| > Conclusion|| |
In the present study, we found characteristic of radiation-induced SNHL seems to be different from CRT-induced SNHL especially in threshold radiation dose, severity and frequency of SNHL and at the time of the incident. There are different criteria that should be examined in the future studies. They may include differences between RT/cisplatin-alone SNHL and cisplatin-alone/CRT SNHL. Recognition of side effects of hearing loss such as otitis, otalgia and tinnitus may be different in each modality but may be useful in differentiates of SNHL type. Also we suggest for precise mechanism of hearing loss change of vessels and central auditory pathways following radiation and platinum agents alone as well as CRT be more assessment.
We hope further investigate; enable the radiation oncologists to manipulated RTplanning process to reduce the development of SNHL.
This work was supported by the research chancellor of Iran University of Medical Sciences (grant no. 92-03-30-240-71). The authors would like to express their sincere appreciation to radiotherapy and audiometry departments at Pars general hospital and Hafte-Tir university hospital for their collaboration and facilities.
Financial support and sponsorship
This work was supported by the research chancellor of Iran University of Medical Sciences under grant no. 92-03-30-240-71.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]