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Sensory neural hearing loss after concurrent cisplatin and radiation therapy for nasopharyngeal carcinoma
Radiotherapy and Oncology 72 (2004) 79–82 www.elsevier.com/locate/radonline
Short Communication
Sensory neural hearing loss after concurrent cisplatin and radiation therapy for nasopharyngeal carcinoma Young-Taek Oha,*, Chul-Ho Kimb, Jin-Hyuk Choic, Seung-Hee Kanga, Mison Chuna a
Department of Radiation Oncology, Ajou University School of Medicine, San 5, Woncheon-Dong, Paldal-Gu, Suwon 442-721, South Korea b Department of ENT, Ajou University School of Medicine, Suwon 442-721, South Korea c Department of Hemato-Oncology, Ajou University School of Medicine, Suwon 442-721, South Korea Received 30 October 2003; received in revised form 30 January 2004; accepted 6 February 2004 Available online 15 April 2004
Abstract Sensory neural hearing loss (SNHL) was evaluated in the patients who were treated with concurrent chemoradiation therapy for nasopharyngeal carcinoma. Ten from 48 ears showed persistent SNHL. Radiotherapy techniques, radiation dose to inner ear and posttreatment otitis media were significant predicting factors for SNHL. q 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Sensory neural hearing loss; Concurrent chemoradiation therapy; Nasopharyngeal carcinoma
1. Introduction Sensory neural hearing loss (SNHL) is not a rare complication after radiation therapy for nasopharyngeal carcinoma (NPC) because the inner ear is usually included in the radiation field. In recent years, concurrent cisplatin and radiation therapy (CCRT) is widely used in the treatment for NPC. In addition, it is expected that the combined cisplatin and radiation therapy for NPC results in more SNHL compared to radiation therapy alone because ototoxicity is well known complication of cisplatin. However, Kwong et al. [11] reported that pre-irradiation cisplatin did not increase the risk of SNHL compared to radiation therapy alone even though the dosage of cisplatin was low. In addition, there were few data about SNHL after CCRT for NPC in literature search. We planned this prospective study to evaluate the incidence and features of SNHL after CCRT for NPC.
2. Methods and materials 2.1. Patients and treatment From January 1998 through September 2001, 32 patients with locally advanced NPC who received CCRT at Ajou * Corresponding author. 0167-8140/$ - see front matter q 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2004.02.009
University Hospital were evaluated sensory neural hearing function by pure tone audiogram (PTA). All patients received one cycle of pre-irradiation chemotherapy with 5-FU (1000 mg/m2 for 4 days) and cisplatin (20 mg/m2 for 4 days) and then 2 or 3 cycles of cisplatin (20 mg/m2 for 4 days) every 3 weeks concurrently during radiation therapy. The daily radiation dose was 2 Gy with single fraction per day and treated for 5 or 6 days per week. The total dose to primary tumor was 70 Gy in 6 –7 weeks. Primary tumor was irradiated with 6 MV X-ray using conventional bilateral portals or multiple portals of conformal or intensity modulated radiation therapy (IMRT) techniques. Some patients were treated with conventional bilateral portals initially followed by boost dose of 10– 16 Gy with conformal or IMRT techniques. When using three-dimensional radiotherapy techniques such as conformal or IMRT, PTV included GTV and nasopharynx proper with 0.5 –1 cm margin. We did not limit the radiation dose to inner ear structure on radiation treatment planning. Sixteen ears were excluded due to following reasons: persistent local disease or local recurrence within 1 year after treatment, pre-existing significant SNHL as bone conduction threshold is more than 50 dB at any of the four frequencies (0.5, 1, 2 and 4 kHz) or incomplete auditory assessment. The auditory function of remaining 48 ears from 25 patients was analyzed as an independent case.
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Table 1 Characteristics and predicting factors for SNHL Ears with SNHL N ¼ 22 Age (median) Sex Male Female Pre-RT SOM/V-tube insertion RT dose to inner ear* (mean ^ SD) Cisplatin dose (mg/m2) (mean ^ SD) Total Concurrent RT technique* Conventional Mixed Three-dimensional Post-RT SOM* Intermittent Persistent Initial bone conduction threshold (dB) Low frequency High frequency
20–64 (52) 19 (86.4%) 3 (13.6%) 8 (16.7%)/5 (62.5%) 6854 ^ 244 cGy 228 ^ 58 139 ^ 40
Ears without SNHL N ¼ 26 20–74 (43) 19 (73.1%) 7 (26.9%) 6 (12.5%)/3 (50.0%) 6501 ^ 790 cGy 229 ^ 60 138 ^ 49
All ears N ¼ 48 20–74 (46) 38 (79.2%) 10 (20.8%) 14 (29.2%)/8 (57.1%) 6663 ^ 623 cGy 229 ^ 58 139 ^ 44
15 (68.2%) 7 (31.8%) 0 (0%)
7 (26.9%) 11 (42.3%) 8 (30.8%)
22 (45.8%) 18 (37.5%) 8 (16.7%)
5 (22.7%) 12 (54.6%)
5 (19.2%) 4 (15.4%)
10 (20.8%) 16 (33.3%)
14 ^ 8 28 ^ 17
17 ^ 11 31 ^ 18
16 ^ 10 29 ^ 17
* Means statistically significant ðP , 0:05Þ:
The follow-up duration was 24 – 57 months and 40 months in median. In addition, the date of last PTA was within one-year interval from the time of last follow-up. 2.2. Auditory assessment ENT physician prospectively assessed auditory function by PTA at pre-treatment and at 3 –6 months and 1 year after treatment. Then PTA was performed when there were auditory symptoms or no PTA within last one year. PTA included bone conduction threshold at 0.5, 1, 2 and 4 kHz. The mean of bone conduction threshold at 0.5, 1 and 2 kHz was analyzed for SNHL at low frequencies and 4 kHz at a high frequency. An increase in bone conduction threshold of at least 15 dB from baseline was considered as significant and represented SNHL. The persistent SNHL was defined that SNHL was continued more than 1 year and on last follow-up. The transient SNHL was defined that SNHL was recovered during follow-up period. The indeterminate SNHL was defined that SNHL was continued less than 1 year and on last follow-up. Serous otitis media (SOM) was diagnosed by otologist when there were clinical findings suggesting SOM and more than 10 dB air – bone gap [11]. The protocol and definition of terminology was as Kwong’s report for comparison of data. 2.3. Statistical methods The Fisher’s exact test were used for analysis of the data shown in Table 2 with the significance level P , 0:05:
3. Results The age of patients were 20– 74 years and 46 years in median. Thirty-eight ears were from 20 male patients and 10 ears were from 5 female patients. The radiation dose to inner ear was 66.6 ^ 6.2 Gy, and 69.6 ^ 11.8, 64.4 ^ 7.1, 63.4 ^ 9.1 Gy with conventional, mixed, conformal technique, respectively. Fourteen patients showed SOM at the time of diagnosis and the characteristics of the ears are in Table 1. During the follow-up, 8 ears (16.7%) showed SNHL on low frequencies and 21 ears (43.8%) on high frequency. There were 2 persistent, 3 transient and 3 indeterminate SNHL on low frequencies and 9, 9 and 3 on high frequency, respectively. At 3 – 6 months after completion of treatment, total 13 ears (27.1%) showed SNHL and 61.5% ðN ¼ 8Þ among them were persistent. All the 3 ears, showed SNHL on low and high frequencies at 3 –6 months after treatment, were transient. At 1 year after treatment, 14 ears (29.2%) showed SNHL and 71.4% ðN ¼ 10Þ among them were persistent. At last follow-up of 2 – 5 years, 14 ears (29.2%) showed SNHL and 71.4% ðN ¼ 10Þ among them were persistent and rest 4 ears were indeterminate (Table 2). Four ears of indeterminate SNHL, which means SNHL at last follow-up only, suffered from persistent SOM after the treatment. Ears without SNHL received lower dose of radiation (65.0 ^ 7.9 vs. 68.5 ^ 2.4 Gy) with mainly three-dimensional technique (73.1% vs. 31.8%) and showed less persistent post-treatment SOM (15.4% vs. 54.6%) compared with ears with SNHL. These factors were statistically significant (Table 1). Female and younger patients showed less SNHL even though it was not statistically significant.
Y.-T. Oh et al. / Radiotherapy and Oncology 72 (2004) 79–82
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Table 2 Sensorineural hearing loss status after concurrent cisplatin and radiation therapy SNHL ðN ¼ 48Þ
Persistent Transient Indeterminate Total (%)
At 3– 6 months F/U
At 1 year F/U
At last F/U (2–5 years)
Low freq.
High freq.
Both freq.
Total (%)
Low freq.
High freq.
Both freq.
Total (%)
Low freq.
High freq.
Both freq.
Total (%)
0 0 – 0 (0.0)
8 2 – 10 (20.8)
0 3 – 3 (6.3)
8 (16.7) 5 (10.4) – 13 (27.1)
1 0 – 1 (2.1)
8 4 – 12 (25.0)
1 0 – 1 (2.1)
10 (20.8) 4 (8.4) – 14 (29.2)
1 – 1 2 (4.2)
8 – 1 9 (18.8)
1 – 2 3 (6.3)
10 (20.8) – 4 (8.3) 14 (29.2)
Low freq., low frequencies only; high freq., high frequency only; both freq., both frequencies.
4. Discussion The feature of SNHL after irradiation on inner ear was well documented in literatures. The main characteristics of radiation induced SNHL is as following. (1) It is radiation dose dependent [20]. (2) It usually develops within 6 –12 months after radiation therapy [4]. (3) Higher frequencies were more commonly affected than lower frequencies [2,13, 20]. There is a radiation induced pathophysiologic changes of the auditory system starting from the Eustachian tube to the brain stem [1,3,13,17] and the mechanism of SNHL is not clear. However, there is clear correlation between missing hair cells on the organ of Corti and radiation dose [2]. In addition, outer hair cells of higher frequency area are more commonly affected [1,17] and it is closely correlated with clinical findings. Similar pathologic damages are found in cisplatininduced ototoxicity and its clinical findings are similar with radiation induced SNHL. Clinical features of SNHL after CCRT were also similar with SNHL after radiation therapy alone. In our study, patients without SNHL received less radiation dose, persistent SNHL developed within 1 year after treatment, and high frequency was more commonly affected than low frequencies. In addition, post-radiation SOM was the most significant predicting factor for persistent SNHL and female and younger patients were more resistant to SNHL even though it was not statistically significant. These results were comparable to Kwong’s study, in which age, sex and post-radiation SOM were the significant prognostic factors for persistent SNHL after radiation therapy for NPC. Because both radiation and cisplatin have ototoxicity, combined cisplatin and radiation could increase the incidence of SNHL and several authors have reported severe hearing impairment or deafness after irradiation combined with cisplatin [8,21]. However, the incidence showed the differences according to the combination sequence. Pre-irradiation cisplatin did not increase the risk of SNHL compared with radiation therapy alone in the patients with NPC. It was also true in the cases of pediatric brain tumors [10]. However, prior cranial irradiation increased cisplatin ototoxicity in children and young adult patients [8,9,14,21]. With cisplatin alone, there is a
negligible risk of hearing loss at doses of 90– 360 mg/m2 and this risk increases to 60 –80% when combined with prior irradiation. It is also dependent on cisplatin dose [19]. The incidence of SNHL after CCRT in present study was similar with other data of radiotherapy alone. The incidence of SNHL after radiotherapy for NPC was 0 –54% [15] and Kwong et al. reported that 24.2% persistent SNHL at median follow-up 30 months with conventional radiotherapy technique. Our study used similar protocol and same terminology with Kwong’s report and 20.8% of persistent SNHL was found at median follow-up of 40 months. After excluding the patients who used conformal technique, persistent SNHL incidence was 25.0% in the patients irradiated with conventional technique. Ototoxicity from cisplatin is bilateral and dose dependent [18,19,22]. In present study, however, there was no bilateral SNHL induced by CCRT and no difference in cisplatin dose between the patients with or without SNHL (Table 1). It means there was no additive effect on SNHL because the dose level of cisplatin for CCRT was too low to induce ototoxicity by itself. Therefore, it is not rational to change cisplatin to other agent such as carboplatin to reduce the incidence of SNHL in the chemo-radiation therapy for NPC. In addition, we could conclude that cisplatin has no or minimal effect on SNHL over radiation therapy alone in the patients with NPC even though our study has limitations that there was no radiotherapy control group and relatively small number of cases. The only way to reduce the incidence of SNHL is to minimize the radiation dose to inner ear [5,6,8,16]. Radiation dose to inner ear is the most important factor for hearing damage [5,16] and treatment with IMRT can achieve a lower rate of hearing loss, from 64 to 13% [6]. During the later study period, we used three-dimensional techniques from start and could reduce the radiation dose to inner ear from 69.6 ^ 11.8 to 63.4 ^ 9.1 Gy. It resulted in the reduction of the incidence of SNHL from 68.2% (15/22) to 0% (0/8). Post-radiation SOM was also significant predicting factor for SNHL. Some toxic materials from chronic inflammation can affect on auditory nerve system [7]. However, the mechanism is not clear. In addition, there was no effective management for post-radiation SOM [12].
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In conclusion, the incidence and features of SNHL after CCRT for NPC was similar with historical data from radiotherapy alone. In addition, three-dimensional radiation therapy techniques such as conformal or IMRT can reduce the radiation dose to inner ear and reduce the incidence of SNHL after CCRT for NPC.
References [1] Bohne BA, Marks JE, Glasgow GP. Delayed effects of ionizing radiation on the ear. Laryngoscope 1985;95(7 Pt 1):818–28. [2] Grau C, Moller K, Overgaard M, Overgaard J, Elbrond O. Sensorineural hearing loss in patients treated with irradiation for nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 1991;21(3):723–8. [3] Grau C, Moller K, Overgaard M, Overgaard J, Elbrond O. Auditory brain stem responses in patients after radiation therapy for nasopharyngeal carcinoma. Cancer 1992;70(10):2396–401. [4] Grau C, Overgaard J. Postirradiation sensorineural hearing loss: a common but ignored late radiation complication. Int J Radiat Oncol Biol Phys 1996;36(2):515 –7. [5] Honore HB, Bentzen SM, Moller K, Grau C. Sensori-neural hearing loss after radiotherapy for nasopharyngeal carcinoma: individualized risk estimation. Radiother Oncol 2002;65(1):9 –16. [6] Huang E, Teh BS, Strother DR, et al. Intensity-modulated radiation therapy for pediatric medulloblastoma: early report on the reduction of ototoxicity. Int J Radiat Oncol Biol Phys 2002;52(3):599–605. [7] Jung TTLR, Nam BH, Park SK, Kim PD, John EO. Effects of nitric oxide on morphology of isolated cochlear outer hair cells: possible involvement in sensorineural hearing loss. Otol Neurotol 2003;24(4): 682–5. [8] Kirkbride P, Plowman PN. Platinum chemotherapy, radiotherapy and the inner ear: implications for ‘standard’ radiation portals. Br J Radiol 1989;62(737):457– 62. [9] Kortmann RD, Kuhl J, Timmermann B, et al. Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: results of the German
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prospective randomized trial HIT ’91. Int J Radiat Oncol Biol Phys 2000;46(2):269– 79. Kretschmar CS, Warren MP, Lavally BL, Dyer S, Tarbell NJ. Ototoxicity of preradiation cisplatin for children with central nervous system tumors. J Clin Oncol 1990;8(7):1191 –8. Kwong DL, Wei WI, Sham JS, 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 1996;36(2):281–9. Lau SK, Wei WI, Sham J, Hui Y, Choy D. Effect of irradiation on middle ear effusion due to nasopharyngeal carcinoma. Clin Otolaryngol 1992;17(3):246– 50. Lau SK, Wei WI, Sham JS, Choy DT, Hui Y. Early changes of auditory brain stem evoked response after radiotherapy for nasopharyngeal carcinoma—a prospective study. J Laryngol Otol 1992; 106(10):887–92. Miettinen S, Laurikainen E, Johansson R, Minn H, Laurell G, Salmi TT. Radiotherapy enhanced ototoxicity of cisplatin in children. Acta Otolaryngol Suppl 1997;529:90–4. Moretti JA. Sensori-heural hearing loss following radiotherapy to the nasopharynx. Laryngoscope 1976;86(4):598 –602. Raaijmakers E, Engelen AM. Is sensorineural hearing loss a possible side effect of nasopharyngeal and parotid irradiation? A systematic review of the literature. Radiother Oncol 2002;65(1):1 –7. Sataloff RT, Rosen DC. Effects of cranial irradiation on hearing acuity: a review of the literature. Am J Otol 1994;15(6):772–80. Schaefer SD, Post JD, Close LG, Wright CG. Ototoxicity of low- and moderate-dose cisplatin. Cancer 1985;56(8):1934–9. Schell MJ, McHaney VA, Green AA, et al. Hearing loss in children and young adults receiving cisplatin with or without prior cranial irradiation. J Clin Oncol 1989;7(6):754–60. Schot LJ, Hilgers FJ, Keus RB, Schouwenburg PF, Dreschler WA. Late effects of radiotherapy on hearing. Eur Arch Otorhinolaryngol 1992;249(6):305 –8. Walker DA, Pillow J, Waters KD, Keir E. Enhanced cis-platinum ototoxicity in children with brain tumors who have received simultaneous or prior cranial irradiation. Med Pediatr Oncol 1989; 17(1):48–52. Weatherly RA, Owens JJ, Catlin FI, Mahoney DH. cis-Platinum ototoxicity in children. Laryngoscope 1991;101(9):917– 24.
Short Communication
Sensory neural hearing loss after concurrent cisplatin and radiation therapy for nasopharyngeal carcinoma Young-Taek Oha,*, Chul-Ho Kimb, Jin-Hyuk Choic, Seung-Hee Kanga, Mison Chuna a
Department of Radiation Oncology, Ajou University School of Medicine, San 5, Woncheon-Dong, Paldal-Gu, Suwon 442-721, South Korea b Department of ENT, Ajou University School of Medicine, Suwon 442-721, South Korea c Department of Hemato-Oncology, Ajou University School of Medicine, Suwon 442-721, South Korea Received 30 October 2003; received in revised form 30 January 2004; accepted 6 February 2004 Available online 15 April 2004
Abstract Sensory neural hearing loss (SNHL) was evaluated in the patients who were treated with concurrent chemoradiation therapy for nasopharyngeal carcinoma. Ten from 48 ears showed persistent SNHL. Radiotherapy techniques, radiation dose to inner ear and posttreatment otitis media were significant predicting factors for SNHL. q 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Sensory neural hearing loss; Concurrent chemoradiation therapy; Nasopharyngeal carcinoma
1. Introduction Sensory neural hearing loss (SNHL) is not a rare complication after radiation therapy for nasopharyngeal carcinoma (NPC) because the inner ear is usually included in the radiation field. In recent years, concurrent cisplatin and radiation therapy (CCRT) is widely used in the treatment for NPC. In addition, it is expected that the combined cisplatin and radiation therapy for NPC results in more SNHL compared to radiation therapy alone because ototoxicity is well known complication of cisplatin. However, Kwong et al. [11] reported that pre-irradiation cisplatin did not increase the risk of SNHL compared to radiation therapy alone even though the dosage of cisplatin was low. In addition, there were few data about SNHL after CCRT for NPC in literature search. We planned this prospective study to evaluate the incidence and features of SNHL after CCRT for NPC.
2. Methods and materials 2.1. Patients and treatment From January 1998 through September 2001, 32 patients with locally advanced NPC who received CCRT at Ajou * Corresponding author. 0167-8140/$ - see front matter q 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2004.02.009
University Hospital were evaluated sensory neural hearing function by pure tone audiogram (PTA). All patients received one cycle of pre-irradiation chemotherapy with 5-FU (1000 mg/m2 for 4 days) and cisplatin (20 mg/m2 for 4 days) and then 2 or 3 cycles of cisplatin (20 mg/m2 for 4 days) every 3 weeks concurrently during radiation therapy. The daily radiation dose was 2 Gy with single fraction per day and treated for 5 or 6 days per week. The total dose to primary tumor was 70 Gy in 6 –7 weeks. Primary tumor was irradiated with 6 MV X-ray using conventional bilateral portals or multiple portals of conformal or intensity modulated radiation therapy (IMRT) techniques. Some patients were treated with conventional bilateral portals initially followed by boost dose of 10– 16 Gy with conformal or IMRT techniques. When using three-dimensional radiotherapy techniques such as conformal or IMRT, PTV included GTV and nasopharynx proper with 0.5 –1 cm margin. We did not limit the radiation dose to inner ear structure on radiation treatment planning. Sixteen ears were excluded due to following reasons: persistent local disease or local recurrence within 1 year after treatment, pre-existing significant SNHL as bone conduction threshold is more than 50 dB at any of the four frequencies (0.5, 1, 2 and 4 kHz) or incomplete auditory assessment. The auditory function of remaining 48 ears from 25 patients was analyzed as an independent case.
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Table 1 Characteristics and predicting factors for SNHL Ears with SNHL N ¼ 22 Age (median) Sex Male Female Pre-RT SOM/V-tube insertion RT dose to inner ear* (mean ^ SD) Cisplatin dose (mg/m2) (mean ^ SD) Total Concurrent RT technique* Conventional Mixed Three-dimensional Post-RT SOM* Intermittent Persistent Initial bone conduction threshold (dB) Low frequency High frequency
20–64 (52) 19 (86.4%) 3 (13.6%) 8 (16.7%)/5 (62.5%) 6854 ^ 244 cGy 228 ^ 58 139 ^ 40
Ears without SNHL N ¼ 26 20–74 (43) 19 (73.1%) 7 (26.9%) 6 (12.5%)/3 (50.0%) 6501 ^ 790 cGy 229 ^ 60 138 ^ 49
All ears N ¼ 48 20–74 (46) 38 (79.2%) 10 (20.8%) 14 (29.2%)/8 (57.1%) 6663 ^ 623 cGy 229 ^ 58 139 ^ 44
15 (68.2%) 7 (31.8%) 0 (0%)
7 (26.9%) 11 (42.3%) 8 (30.8%)
22 (45.8%) 18 (37.5%) 8 (16.7%)
5 (22.7%) 12 (54.6%)
5 (19.2%) 4 (15.4%)
10 (20.8%) 16 (33.3%)
14 ^ 8 28 ^ 17
17 ^ 11 31 ^ 18
16 ^ 10 29 ^ 17
* Means statistically significant ðP , 0:05Þ:
The follow-up duration was 24 – 57 months and 40 months in median. In addition, the date of last PTA was within one-year interval from the time of last follow-up. 2.2. Auditory assessment ENT physician prospectively assessed auditory function by PTA at pre-treatment and at 3 –6 months and 1 year after treatment. Then PTA was performed when there were auditory symptoms or no PTA within last one year. PTA included bone conduction threshold at 0.5, 1, 2 and 4 kHz. The mean of bone conduction threshold at 0.5, 1 and 2 kHz was analyzed for SNHL at low frequencies and 4 kHz at a high frequency. An increase in bone conduction threshold of at least 15 dB from baseline was considered as significant and represented SNHL. The persistent SNHL was defined that SNHL was continued more than 1 year and on last follow-up. The transient SNHL was defined that SNHL was recovered during follow-up period. The indeterminate SNHL was defined that SNHL was continued less than 1 year and on last follow-up. Serous otitis media (SOM) was diagnosed by otologist when there were clinical findings suggesting SOM and more than 10 dB air – bone gap [11]. The protocol and definition of terminology was as Kwong’s report for comparison of data. 2.3. Statistical methods The Fisher’s exact test were used for analysis of the data shown in Table 2 with the significance level P , 0:05:
3. Results The age of patients were 20– 74 years and 46 years in median. Thirty-eight ears were from 20 male patients and 10 ears were from 5 female patients. The radiation dose to inner ear was 66.6 ^ 6.2 Gy, and 69.6 ^ 11.8, 64.4 ^ 7.1, 63.4 ^ 9.1 Gy with conventional, mixed, conformal technique, respectively. Fourteen patients showed SOM at the time of diagnosis and the characteristics of the ears are in Table 1. During the follow-up, 8 ears (16.7%) showed SNHL on low frequencies and 21 ears (43.8%) on high frequency. There were 2 persistent, 3 transient and 3 indeterminate SNHL on low frequencies and 9, 9 and 3 on high frequency, respectively. At 3 – 6 months after completion of treatment, total 13 ears (27.1%) showed SNHL and 61.5% ðN ¼ 8Þ among them were persistent. All the 3 ears, showed SNHL on low and high frequencies at 3 –6 months after treatment, were transient. At 1 year after treatment, 14 ears (29.2%) showed SNHL and 71.4% ðN ¼ 10Þ among them were persistent. At last follow-up of 2 – 5 years, 14 ears (29.2%) showed SNHL and 71.4% ðN ¼ 10Þ among them were persistent and rest 4 ears were indeterminate (Table 2). Four ears of indeterminate SNHL, which means SNHL at last follow-up only, suffered from persistent SOM after the treatment. Ears without SNHL received lower dose of radiation (65.0 ^ 7.9 vs. 68.5 ^ 2.4 Gy) with mainly three-dimensional technique (73.1% vs. 31.8%) and showed less persistent post-treatment SOM (15.4% vs. 54.6%) compared with ears with SNHL. These factors were statistically significant (Table 1). Female and younger patients showed less SNHL even though it was not statistically significant.
Y.-T. Oh et al. / Radiotherapy and Oncology 72 (2004) 79–82
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Table 2 Sensorineural hearing loss status after concurrent cisplatin and radiation therapy SNHL ðN ¼ 48Þ
Persistent Transient Indeterminate Total (%)
At 3– 6 months F/U
At 1 year F/U
At last F/U (2–5 years)
Low freq.
High freq.
Both freq.
Total (%)
Low freq.
High freq.
Both freq.
Total (%)
Low freq.
High freq.
Both freq.
Total (%)
0 0 – 0 (0.0)
8 2 – 10 (20.8)
0 3 – 3 (6.3)
8 (16.7) 5 (10.4) – 13 (27.1)
1 0 – 1 (2.1)
8 4 – 12 (25.0)
1 0 – 1 (2.1)
10 (20.8) 4 (8.4) – 14 (29.2)
1 – 1 2 (4.2)
8 – 1 9 (18.8)
1 – 2 3 (6.3)
10 (20.8) – 4 (8.3) 14 (29.2)
Low freq., low frequencies only; high freq., high frequency only; both freq., both frequencies.
4. Discussion The feature of SNHL after irradiation on inner ear was well documented in literatures. The main characteristics of radiation induced SNHL is as following. (1) It is radiation dose dependent [20]. (2) It usually develops within 6 –12 months after radiation therapy [4]. (3) Higher frequencies were more commonly affected than lower frequencies [2,13, 20]. There is a radiation induced pathophysiologic changes of the auditory system starting from the Eustachian tube to the brain stem [1,3,13,17] and the mechanism of SNHL is not clear. However, there is clear correlation between missing hair cells on the organ of Corti and radiation dose [2]. In addition, outer hair cells of higher frequency area are more commonly affected [1,17] and it is closely correlated with clinical findings. Similar pathologic damages are found in cisplatininduced ototoxicity and its clinical findings are similar with radiation induced SNHL. Clinical features of SNHL after CCRT were also similar with SNHL after radiation therapy alone. In our study, patients without SNHL received less radiation dose, persistent SNHL developed within 1 year after treatment, and high frequency was more commonly affected than low frequencies. In addition, post-radiation SOM was the most significant predicting factor for persistent SNHL and female and younger patients were more resistant to SNHL even though it was not statistically significant. These results were comparable to Kwong’s study, in which age, sex and post-radiation SOM were the significant prognostic factors for persistent SNHL after radiation therapy for NPC. Because both radiation and cisplatin have ototoxicity, combined cisplatin and radiation could increase the incidence of SNHL and several authors have reported severe hearing impairment or deafness after irradiation combined with cisplatin [8,21]. However, the incidence showed the differences according to the combination sequence. Pre-irradiation cisplatin did not increase the risk of SNHL compared with radiation therapy alone in the patients with NPC. It was also true in the cases of pediatric brain tumors [10]. However, prior cranial irradiation increased cisplatin ototoxicity in children and young adult patients [8,9,14,21]. With cisplatin alone, there is a
negligible risk of hearing loss at doses of 90– 360 mg/m2 and this risk increases to 60 –80% when combined with prior irradiation. It is also dependent on cisplatin dose [19]. The incidence of SNHL after CCRT in present study was similar with other data of radiotherapy alone. The incidence of SNHL after radiotherapy for NPC was 0 –54% [15] and Kwong et al. reported that 24.2% persistent SNHL at median follow-up 30 months with conventional radiotherapy technique. Our study used similar protocol and same terminology with Kwong’s report and 20.8% of persistent SNHL was found at median follow-up of 40 months. After excluding the patients who used conformal technique, persistent SNHL incidence was 25.0% in the patients irradiated with conventional technique. Ototoxicity from cisplatin is bilateral and dose dependent [18,19,22]. In present study, however, there was no bilateral SNHL induced by CCRT and no difference in cisplatin dose between the patients with or without SNHL (Table 1). It means there was no additive effect on SNHL because the dose level of cisplatin for CCRT was too low to induce ototoxicity by itself. Therefore, it is not rational to change cisplatin to other agent such as carboplatin to reduce the incidence of SNHL in the chemo-radiation therapy for NPC. In addition, we could conclude that cisplatin has no or minimal effect on SNHL over radiation therapy alone in the patients with NPC even though our study has limitations that there was no radiotherapy control group and relatively small number of cases. The only way to reduce the incidence of SNHL is to minimize the radiation dose to inner ear [5,6,8,16]. Radiation dose to inner ear is the most important factor for hearing damage [5,16] and treatment with IMRT can achieve a lower rate of hearing loss, from 64 to 13% [6]. During the later study period, we used three-dimensional techniques from start and could reduce the radiation dose to inner ear from 69.6 ^ 11.8 to 63.4 ^ 9.1 Gy. It resulted in the reduction of the incidence of SNHL from 68.2% (15/22) to 0% (0/8). Post-radiation SOM was also significant predicting factor for SNHL. Some toxic materials from chronic inflammation can affect on auditory nerve system [7]. However, the mechanism is not clear. In addition, there was no effective management for post-radiation SOM [12].
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Y.-T. Oh et al. / Radiotherapy and Oncology 72 (2004) 79–82
In conclusion, the incidence and features of SNHL after CCRT for NPC was similar with historical data from radiotherapy alone. In addition, three-dimensional radiation therapy techniques such as conformal or IMRT can reduce the radiation dose to inner ear and reduce the incidence of SNHL after CCRT for NPC.
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