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Sensorineural Hearing Loss After Radiotherapy and Chemoradiotherapy: A Single, Blinded, Randomized Study

Wong Kein Low, Song Tar Toh, Joseph Wee, Stephanie M.C. Fook-Chong, De Yun Wang

From the Departments of Otolaryngology and Clinical Research, Singapore General Hospital; Department of Radiation Oncology, National Cancer Centre; and Department of Otolaryngology, National University of Singapore, Singapore

Address reprint requests to Wong Kein Low, FRCS, Department of Otolaryngology, Block 6 Level 6, Singapore General Hospital, Singapore 169608, Singapore; e-mail: low.wong.kein{at}sgh.com.sg

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
PURPOSE: The synergistic ototoxicity of radiation and cisplatin (CDDP) has not been adequately studied. This study investigated whether the use of concurrent and postradiotherapy CDDP in patients with nasopharyngeal carcinoma (NPC) resulted in a difference in postradiotherapy sensorineural hearing when compared with the use of radiotherapy alone.

PATIENTS AND METHODS: Newly diagnosed patients were randomly assigned to the radiotherapy or chemoradiotherapy groups. Bone conduction hearing thresholds were performed before treatment and at 1 week, 6 months, 1 year, and 2 years after completion of radiotherapy. Statistical analysis was performed using the Mann-Whitney U test.

RESULTS: Hearing thresholds averaged over 0.5, 1, and 2 kHz were found to be poorer in the chemoradiotherapy group (58 patients) compared with the radiotherapy group (57 patients) at 1 year (P = .001) and 2 years (P = .03) after radiotherapy. Hearing thresholds at 4 kHz were significantly worse for patients in the chemoradiotherapy arm at all of the postradiotherapy time points studied and were more severely affected than the thresholds at lower speech frequencies. In the radiotherapy group, deterioration of median hearing thresholds, which occurred in the immediate post-treatment period, improved within the first year but deteriorated again at 2 years. In the chemoradiotherapy group, median hearing threshold deterioration, which started immediately after radiotherapy, stabilized by 1 year.

CONCLUSION: Patients with NPC who received radiotherapy and concurrent/adjuvant chemotherapy using CDDP experienced greater sensorineural hearing loss compared with patients treated with radiotherapy alone, especially to high-frequency sounds in the speech range. Normal inner ear tissue tolerance, which was once defined only for radiotherapy patients alone, should be redefined in chemoradiotherapy patients.

	INTRODUCTION

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Combined chemoradiotherapy is increasingly being used to treat advanced head and neck cancers. The ear is often included in the radiation fields, and radiation-induced sensorineural hearing loss can result.^1,2 Cisplatin (CDDP), which is widely used as an effective antineoplastic drug for these cancers, is also known to cause ototoxicity. Therefore, it is expected that the use of combined chemoradiotherapy results in greater sensorineural hearing loss than using radiotherapy alone, which was shown to be the case in several reports.^3-7 However, a number of other reports showed that sensorineural hearing after combined therapy was not significantly worse than after radiotherapy alone.^8-11 Many of these previous reports were based on studies that were either retrospective or involved a limited number of patients, and data emanating from randomized trials were lacking. The true differences in extent, onset, and clinical course of sensorineural hearing loss between patients treated with combined chemoradiotherapy and patients treated with radiotherapy alone remain unknown. The aim of this study was to investigate the difference in postradiotherapy sensorineural hearing between patients with nasopharyngeal carcinoma (NPC) who were treated with chemoradiotherapy using CDDP versus radiotherapy alone.

	PATIENTS AND METHODS

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Patients
A phase III prospective randomized trial was conducted to examine the benefit of adding chemotherapy during and after a standard course of radiotherapy for patients with locally advanced NPC.¹² All patients who had International Union Against Cancer/American Joint Committee on Cancer (1997) T3-4NxM0 or TxN2-3M0 previously untreated NPC of the WHO type II or III histology and who were medically fit to undergo chemoradiotherapy were eligible for entry onto the trial. The diagnosis of NPC was histologically confirmed on biopsy. The exclusion criteria were previous treatment for NPC, presence of distant metastases at diagnosis, and other concomitant malignant disease. Written informed consent was obtained from all patients before random assignment. The protocol was approved by the hospital’s ethics committee. Patients were randomly assigned to receive either radiotherapy or chemoradiotherapy.

Treatment
All patients received standard-course radiotherapy to a dose of 70 Gy in 35 fractions, 2 Gy per fraction, using a modified Ho’s technique.^13,14 Using 6-MV linear accelerators, the primary tumor of each patient was treated with two lateral opposed facial fields to 20 Gy, followed by a three-field technique (anterior facial and lateral opposed facial fields) to a total dose of 70 Gy. The neck was treated to a dose of 60 Gy, and lymph nodes were boosted with electrons for another 10 Gy. All fields were treated once daily, 5 times a week. Patients who had high cervical lymph nodes or inferior extension of the tumor toward the oropharynx were treated with a shrinking field technique, using long opposing faciocervical fields for the first 40 Gy and followed by the three-field plan for the rest of the treatment.

For patients who were allocated to the chemoradiotherapy group, three cycles of concurrent CDDP were administered on weeks 1, 4, and 7 of radiotherapy. Subsequently, a further three cycles of adjuvant chemotherapy comprising a combination of CDDP and fluorouracil were administered between weeks 11 and 19. The dose schedules for chemotherapy are listed in Table 1.

Random Assignment
Random assignment on the trial was conducted through the central randomization office of the National Medical Research Council of Singapore, Clinical Trials and Epidemiology Research Unit, Singapore, by means of a telephone call. Patients were entered onto the trial using randomized blocks of four and six patients (stratified by nodal stage) based on a 1:1 treatment allocation. The treatment assignment was generated using a computer program.

Inclusion Criteria for the Present Report on Hearing Outcomes
The data presented in the present report were based on subsets of patients from the two arms of the trial, which accrued patients from different centers. All patients who originated from one of the centers, the Singapore General Hospital, underwent additional audiologic assessments, and the results form the basis of this report.

Audiologic Assessment
Pure-tone audiograms were performed by trained audiologic technicians who did not have prior knowledge of a patient’s treatment group. Pretreatment and postradiotherapy audiograms at 1 week, 6 months, 1 year, and 2 years were obtained. The audiograms included assessment of bone conduction thresholds at 0.5, 1, 2, and 4 kHz. As in previous reports by other authors,^9,10,15 high and lower frequencies in the speech range were represented by the threshold at 4 kHz and the average of 0.5-, 1-, and 2-kHz thresholds, respectively. For each patient, the left and right hearing levels were analyzed separately.

Statistical Methods
The data were analyzed using SPSS version 11.5 (SPSS Inc, Chicago, IL). The Mann-Whitney U test was performed to compare the hearing levels between the radiotherapy and chemoradiotherapy groups at various postradiotherapy time points.

	RESULTS

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Fifty-seven patients were randomly assigned to the radiotherapy group, and 58 patients were randomly assigned to the chemoradiotherapy group. The age, sex, and race distributions for each group are listed in Table 2. For the radiotherapy group, hearing thresholds for 106, 62, 46, and 30 ears could be studied at 1 week, 6 months, 1 year, and 2 years after treatment, respectively. For the chemoradiotherapy group, hearing levels for 100, 82, 48, and 42 ears could be studied at 1 week, 6 months, 1 year, and 2 years after treatment, respectively. These declining enrollments were the result of patients who declined further audiologic assessments, patients who were lost to follow-up, or patients who died from advanced disease. The median CDDP dose received by the patients was 160 mg (range, 112 to 213 mg).

View larger version (15K): [in this window] [in a new window]   Fig 1. Box plots to compare pretreatment (PreTX) median sensorineural hearing thresholds in the lower frequencies of the speech range (SR; averaged over 0.5, 1, and 2 kHz), with the corresponding values at different postradiotherapy time points for patients in the radiotherapy (RT) and chemoradiotherapy (Chemo-RT) groups. (*) Extreme values more than three box-lengths from the 25th or 75th percentile; () outliers or values more than 1.5 box-lengths from the 25th or 75th percentile.

View larger version (19K): [in this window] [in a new window]   Fig 2. Box plots to compare pretreatment (preTX) median sensorineural hearing thresholds at 4 kHz, with the corresponding values at different postradiotherapy time points for patients in the radiotherapy (RT) and chemoradiotherapy (Chemo-RT) groups.

Chemoradiotherapy group. In this group, the median hearing threshold deterioration, which started in the immediate postradiotherapy period, seemed to stabilize by 1 year (Figs 1 and 2).

	DISCUSSION

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Radiation-induced sensorineural hearing loss has long been recognized as an important adverse effect. Early-onset sensorineural hearing loss occurs during or shortly after radiation.¹ Late-onset sensorineural hearing loss typically occurs several months or years after radiation.^2,8 The extent of hearing loss is related to the radiation dose used. Most human studies have reported the effects over a narrow dose range (50 to 70 Gy) for a limited number of patients; the rate of permanent hearing loss ranged from 24.2% to 36% in patients receiving doses approaching 60 Gy.⁵ High-frequency hearing is generally more severely affected by radiation.² CDDP-induced ototoxicity is also well known; is characterized by bilateral, irreversible, and progressive high tone loss; and is directly related to dose and inversely related to age.¹⁶ Although combined chemoradiotherapy using CDDP has increasingly been used to treat advanced head and neck cancers, the synergistic ototoxic effect of radiation and CDDP has not been adequately studied.

The present study is the first randomized controlled trial that compares the effects of radiotherapy and CDDP chemoradiotherapy on sensorineural hearing. In NPC, relatively high doses of radiation are used in standard treatment regimens, and the ear structures are included in the radiation fields. In our previous study on NPC patients, we found the average minimum, maximum, and mean point doses (± standard deviation) delivered to the inner ear to be 36.2 ± 11.9, 56.9 ± 7.1, and 46.7 ± 11.2, respectively.¹⁷ Because the same radiotherapy technique has been used in both the previous and present studies, these radiation doses are also applicable to the patients in both arms of the present study. However, poor survival in individuals with advanced NPC is a limitation, and the relatively narrow range of radiation dose to the inner ear limits the ability to study the effects of dose on hearing in NPC patients.

Patients in the chemoradiotherapy group experienced greater sensorineural hearing damage than patients in the radiotherapy group. In animal and pathology studies, outer hair cells of the cochlea suffered pronounced damage after radiotherapy, and similar changes were observed in CDDP ototoxicity.⁸ The observation in our study that higher frequency hearing was generally more affected than lower frequency hearing is consistent with findings from other clinical studies.^2,9 Higher frequency sounds were more severely affected possibly because the outer cells at the basal turn were arranged in three regular rows compared with four rows at the apex.¹⁰ High-frequency hearing loss can have a significant impact on quality of life because it affects speech discrimination.⁸

In the radiotherapy group, early post-treatment deterioration of median hearing thresholds improved within 1 year but worsened again at 2 years. Reversal of acute sensorineural hearing loss after radiation was also reported by Ho et al¹⁵ in approximately 40% of the ears in NPC patients treated with radiotherapy. That hearing loss fluctuated during the first year in this group was the overall result of multifactorial processes that affected sensorineural hearing, including resolution of radiation-induced acute inflammatory changes. The addition of CDDP during and after radiotherapy resulted in less fluctuation.

The finding that combined CDDP-radiotherapy resulted in worse sensorineural hearing compared with radiotherapy alone was consistent with the results of a previous report by Schell et al.³ In that study, it was found that children and young adults treated with CDDP suffered an additional 20- to 30-dB sensorineural hearing loss if they received prior cranial radiotherapy. Skinner et al⁴ also reported more severe CDDP ototoxicity in patients who had previously received radiotherapy encompassing the ear. Although Merchant et al⁵ observed enhanced ototoxicity in children with brain tumors treated with preradiotherapy ototoxic chemotherapy, a prospective study on 32 patients with NPC who were treated with chemoradiotherapy (where CDDP was administered before and during radiotherapy) found the incidence of sensorineural hearing loss to be similar to the incidence of patients treated with radiotherapy alone.⁹ Two other studies on patients with NPC treated with chemoradiotherapy (where CDDP was administered before radiotherapy) also showed that CDDP did not have an additional adverse effect on sensorineural hearing.^8,10

The conflicting results from most of these reports could be related to whether chemotherapy was administered before or after radiotherapy. Walker et al¹⁶ observed enhanced ototoxicity when CDDP was administered simultaneously with radiation or after radiation and suggested that postirradiation hyperemia could be the cause of increased sensitivity of the cochlear to CDDP damage. Synergistic ototoxic effects could also result if radiation provided a predisposition to damage¹⁸ or caused changes in permeability of the inner ear and/or CNS barriers leading to an enhanced effect of CDDP in inner ear tissues.⁷ In our present study, CDDP was administered during (concurrent chemotherapy) and after (adjuvant chemotherapy) radiotherapy, which was consistent with the belief that enhanced ototoxicity would occur. With preradiotherapy administration of CDDP, the synergistic effects of CDDP and radiation might be reduced.¹¹

Beyond the follow-up period of this study, the post-treatment sensorineural hearing in both groups is expected to further decline over time with the onset of delayed radiation-induced hearing loss.^5,15,19 It remains to be seen how the post-treatment sensorineural hearing outcomes between the two groups will differ in the longer term because the rate and degree of deterioration may not necessarily be the same. Nevertheless, it would not be unreasonable to expect, over the longer term, for the sensorineural hearing of patients in the chemoradiotherapy group to remain significantly poorer than sensorineural hearing of patients in the radiotherapy group, possibly to an even greater extent.

This study addresses an important issue that has received little attention in the published literature. As combined chemoradiation increases in use in advanced head and neck cancers, normal tissue tolerance once defined for radiation alone should be redefined when used together with chemotherapy. According to Emami et al,²⁰ the tolerance dose with a probability of 5% complication within 5 years from treatment and the tolerance dose with a probability of 50% complication within 5 years from treatment of the inner ear are 60 and 70 Gy, respectively. Doses less than 30 Gy are said to have little effect on hearing.^5,21 In light of the results of the present study, these doses may not apply in patients who have received radiotherapy combined with concurrent/adjuvant chemotherapy.

This study demonstrated that patients with NPC who had received combined radiotherapy and concurrent/adjuvant chemotherapy using CDDP experienced greater sensorineural hearing loss compared with patients treated with radiotherapy alone, especially with respect to high-frequency sounds in the speech range. Normal inner ear tissue tolerance, which was once defined only for radiation alone, should be redefined for radiotherapy used together with chemotherapy.

	Authors’ Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Wong Kein Low, De Yun Wang, Joseph Wee Provision of study materials or patients: Wong Kein Low, Joseph Wee Collection and assembly of data: Wong Kein Low, Song Tar Toh, Joseph Wee Data analysis and interpretation: Wong Kein Low, Stephanie M.C. Fook-Chong, De Yun Wang Manuscript writing: Wong Kein Low, Joseph Wee, De Yun Wang, Stephanie M.C. Fook-Chong Final approval of manuscript: Wong Kein Low, Joseph Wee, De Yun Wang, Stephanie M.C. Fook-Chong

 

	ACKNOWLEDGMENTS

 
We thank colleagues from the Department of Therapeutic Radiology, National Cancer Centre, and Department of Otolaryngology, Singapore General Hospital, who referred the patients.

	NOTES

 
Supported by the National Medical Research Council of Singapore. Audiograms were funded by the Department of Otolaryngology, Singapore General Hospital.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
1. Talmi YP, Finkelstein Y, Zohar Y, et al: Postirradiation hearing loss. Audiology 28:121-126, 1989[Medline]

2. Raajmakers E, Engelen AM: Is sensorineural hearing loss a possible side effect of nasopharyngeal and parotid irradiation? A systematic review of the literature. Radiother Oncol 65:1-7, 2002[CrossRef][Medline]

3. Schell M, McHaney VA, Green AA, et al: Hearing loss in children and young adults receiving cisplatin with and without prior cranial irradiation. J Clin Oncol 7:754-760, 1989[Abstract]

4. Skinner R, Pearson ADJ, Amineddine HA, et al: Ototoxicity of cisplatinum in children and adolescent. Br J Cancer 61:927-931, 1990[Medline]

5. Merchant TE, Gould CJ, Xiong X, et al: Early neuro-otologic effects of three-dimensional irradiation in children with primary brain tumors. Int J Radiat Oncol Biol Phys 58:1194-1207, 2004[Medline]

6. Weatherly RA, Owens JJ, Catlin FI, et al: Cis-platinum ototoxicity in children. Laryngoscope 101:917-924, 1991[Medline]

7. Miettinen S, Laurikainen E, Johansson R, et al: Radiotherapy enhanced ototoxicity of cisplatin in children. Acta Otolaryngol (Stockholm) Suppl 529:90-94, 1997

8. Kwong DLW, Wei WI, Sham JST, et al: Sensorineural hearing loss in patients treated for nasopharyngeal carcinoma: A prospective study of the effect of radiation and cisplatin treatment. Int J Radiat Oncol Biol Phys 36:281-289, 1996[Medline]

9. Oh YT, Kim CH, Choi JH, et al: Sensory neural hearing loss after concurrent cisplatin and radiation therapy for nasopharyngeal carcinoma. Radiother Oncol 72:79-82, 2004[Medline]

10. Wang LF, Kuo WR, Ho KY, et al: Hearing loss in patients with nasopharyngeal carcinoma after chemotherapy and radiation. Kaohsiung J Med Sci 19:163-169, 2003[Medline]

11. Kretschmar CS, Warren MP, Lavally BL, et al: Ototoxicity of preradiation cisplatin for children with central nervous system tumors. J Clin Oncol 8:1191-1198, 1990[Abstract]

12. Wee J, Tan EH, Tai BC, et al: Randomized trial of radiotherapy versus concurrent chemo-radiotherapy followed by adjuvant chemotherapy in patients with American Joint Committee on Cancer/International Union Against Cancer stage III and IV nasopharyngeal cancer of the endemic variety. J Clin Oncol 23:6730-6738, 2005[Abstract/Free Full Text]

13. Ho JH: An epidemiologic and clinical study of nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 4:182-198, 1978[Medline]

14. Wee JTS, KhooTan HS, Chua EJ: Radiotherapy, in Chong VH, Tsao SY (eds): Nasopharyngeal Cancer. Singapore, Armour Publishing, 1997, pp 90-102

15. Ho WK, Wei WI, Kwong DLW, et al: Long-term sensorineural hearing deficit following radiotherapy in patients suffering from nasopharyngeal carcinoma: A prospective study. Head Neck 21:547-553, 1999[Medline]

16. Walker DA, Pillow J, Waters KD, et al: Enhanced cis-platinum ototoxicity in children with brain tumours who have received simultaneous or prior cranial irradiation. Med Pediatr Oncol 17:48-52, 1989[CrossRef][Medline]

17. Low WK, Burgess R, Fong KW, et al: Effect of radiotherapy on retro-cochlear auditory pathways. Laryngoscope 115:1823-1826, 2005[Medline]

18. Mencher GT, Novotny G, Mencher L, et al: Ototoxicity and irradiation: Additional etiologies of hearing loss in adults. J Am Acad Audiol 6:351-357, 1995[Medline]

19. Sweetow RW, Will TI: Progression of hearing loss following the completion of chemotherapy and radiation therapy: Case report. J Am Acad Audiol 4:360-363, 1993[Medline]

20. Emami B, Lyman J, Brown A, et al: Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 21:109-122, 1991[Medline]

21. Linskey ME, Johnstone PAS: Radiation tolerance of normal temporal bone structures: Implications for gamma knife stereotactic radiosurgery. Int J Radiat Oncol Biol Phys 57:196-200, 2003[Medline]

Submitted November 17, 2005; accepted February 7, 2006.

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