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Table 1. 
Distribution of Both Study Groups After Treatment by Tumor Site
Distribution of Both Study Groups After Treatment by Tumor Site
Table 2. 
Cisplatin and Radiotherapy Total Doses per Patient and the Correspondent Percentage of the Ear Included in the Irradiation Field*
Cisplatin and Radiotherapy Total Doses per Patient and the Correspondent Percentage of the Ear Included in the Irradiation Field*
Table 3. 
Hearing Thresholds for the Right Ear in Both Study Groups
Hearing Thresholds for the Right Ear in Both Study Groups
Table 4. 
Hearing Thresholds for the Left Ear in Both Study Groups
Hearing Thresholds for the Left Ear in Both Study Groups
1.
Wang  SJWang  MBCalcaterra  TC Radiotherapy followed by neck dissection for small head and neck cancers with advanced cervical metastases. Ann Otol Rhinol Laryngol 1999;108128- 131
PubMed
2.
Cheng  PWYoung  YHLou  PJ Patulous Eustachian tube in long-term survivors of nasopharyngeal carcinoma. Ann Otol Rhinol Laryngol 1999;108201- 204
PubMed
3.
Smouha  EEKarmody  CS Non-osteitic complications of therapeutic irradiation to the temporal bone. Am J Otol 1995;1683- 87
PubMed
4.
Varghese  GSahota  JSHazarika  PHajashekar  B Hearing anomalies following radiation therapy for head and neck cancers. Indian J Exp Biol 1996;34878- 879
PubMed
5.
Moretti  JA Sensorineural hearing loss following radiotherapy to the nasopharynx. Laryngoscope 1976;86598- 602
PubMedArticle
6.
Oliveira  JAA Ototoxicidade.  In: Costa  SS, Cruz  OLM, Oliveira  JAA. Otorrinolaringologia. Porto Alegre, Brazil: Editora Artes Medicas; 1994
7.
Pedalini  MEBCruz  OLMBensadon  RL Aspectos audiológicos na radioterapia, na quimioterapia em tumores do ângulo ponto cerebelar.  In: Angelis  EC, Furia  CLB, Mourão  LF, Kowalski  LP, eds. Atuação da Fonoaudiologia no Câncer de Cabeça e Pescoço. São Paulo, Brazil: Editora Lovise; 2000
8.
Kenyon  ELLeidenheim  SEZwillenberg  S Speech discrimination in the sensorineural hearing loss patient: how is it affected by background noise? Mil Med 1998;163647- 650
PubMed
9.
Kubo  TSakashita  TKusuki  M  et al.  Sound lateralization and speech discrimination in patients with sensorineural hearing loss. Acta Otolaryngol Suppl 1998;53863- 69
PubMedArticle
10.
Amercican Speech-Language-Hearing Association (ASHA), Guidelines for the audiologic management of individuals receiving cochleotoxic drug therapy. ASHA 1994;36(suppl 12)11- 19
11.
Martensen  KAnthony  BT Crânio e ossos do crânio.  In: Bontrages  KL. Tratado de Técnica Radiológica e Base Anatômica. 4th ed. Rio de Janeiro, Brazil: Koogan; 1997
12.
Schweitzer  VG Ototoxicty of chemotherapeutic agents. Otolaryngol Clin North Am 1993;26759- 789
PubMed
13.
Ozturan  OJerger  JLew  H Monitoring of cisplatin ototoxicity by distortion-product otoacoustic emissions. Auris Nasus Larynx 1996;23147- 151
PubMedArticle
14.
Rybak  LP Ototoxicity and antineoplastic drugs. Curr Opin Otolaryngol Head Neck Surg 1999;7239- 243Article
15.
Dreschler  WAUrbanus  NAMVan der Hulst  RJ High frequency audiometry in prospective clinical research of ototoxicity due to platinum dericatives. Ann Otol Rhinol Laryngol 1988;97133- 137
PubMed
16.
Cavaletti  GBogliun  GCrespi  V  et al.  Neurotoxicity and ototoxicity of cisplatin plus paclitaxel in comparison to cisplatin plus cyclophosphamide in patients with epithelial ovarian cancer. J Clin Oncol 1997;15199- 206
PubMed
17.
Chen  WCLiao  CTWang  CC  et al.  Radiation-induced hearing impairment in patients treated for malignant parotid tumor. Ann Otol Rhinol Laryngol 1999;1081159- 1164
PubMed
18.
Lacava  JAFerreyra  RLeone  BALosada  CElem  YLVallejo  CT High dose of cisplatin as neoadjuvant organ-preserving chemotherapy for squamous cell carcinoma of the larynx. Cancer J Sci Am 1996;246
PubMed
19.
Hoistad  DLOndrey  FGMutlu  CSchachern  PAPaparella  MMAdams  GL Histopathology of human temporal bone after cis-platinum, radiation, or both. Otolaryngol Head Neck Surg 1998;118825- 832
PubMedArticle
Original Article
November 2004

Auditory Effects After Organ Preservation Protocol for Laryngeal/Hypopharyngeal Carcinomas

Arch Otolaryngol Head Neck Surg. 2004;130(11):1265-1268. doi:10.1001/archotol.130.11.1265
Abstract

Objective  To investigate the prevalence of hearing loss after concomitant radiochemotherapy in patients enrolled in a larynx preservation protocol.

Design  Prospective study.

Setting  Consecutive patients treated in a tertiary cancer center hospital between 2001 and 2002.

Patients  Eligible subjects included patients prospectively enrolled in an organ preservation protocol based on concomitant radiotherapy and chemotherapy (cisplatin and paclitaxel).

Main Outcome Measures  Descriptive analysis of the results of audiologic evaluations, including pure-tone audiometry and immitance audiometry, which were performed prior to and 8 months after treatment. Change in hearing sensitivity was computed relative to baseline measures. Criteria to indicate hearing decrease after the treatment were defined as either a 20-dB decrease at any single test frequency or a 10-dB decrease at any 2 adjacent test frequencies.

Results  A total of 11 patients were analyzed. Four patients (36%) had hearing loss after the treatment.

Conclusion  Our results suggest that the prevalence of hearing loss after radiochemotherapy in larynx preservation protocols is high (36%); however, it was usually mild and asymptomatic.

Radiotherapy is a very common treatment approach for head and neck cancer and is either used exclusively or combined with surgery or chemotherapy. The temporal bone is frequently included in the irradiation field.1,2 The potential adverse effects of this procedure may include ear canal necrosis, temporal bone osteoradionecrosis, and otitis media, generally in association with conductive hearing loss (HL) of different degrees, earache, and tinnitus.3 Furthermore, it may also lead to stiffness of the ossicular chain and the tympanic membrane layers.4 Other studies have shown the occurrence of sensorineural HL after radiotherapy, so besides the middle and external ear lesions, the inner ear may be affected as well.5 It is well documented that the latency for the development of a sensorineural HL is approximately 12 months or more, differing from the conductive HL that usually appears earlier during the treatment course. Surprisingly, some studies have not considered HL as an adverse effect after advanced radiotherapy.1

Chemotherapy has been used most frequently in the treatment of head and neck cancer, mainly in association with radiotherapy. One of the more commonly used drugs is cisplatin. Despite its therapeutic action, there are some known adverse effects, among which ototoxic effects are the most significant. Cisplatin primarily affects outer hair cells and stria vascularis in the cochlear basal turn, resulting in a high-frequency bilateral sensorineural HL.6 According to Pedalini et al,7 hearing disorders may vary according to many factors such as mode of administration, site of tumor, renal function, age, associated drugs, individual susceptibility, previous radiation, previous HL, and cumulative dose.

Ototoxic symptoms may be tinnitus and/or HL, but the main complaint is difficulty in understanding speech in noisy environments, which is likely to occur in high-frequency HL. Nevertheless, some patients present with HL and do not have any speech perception complaints.8,9

There are many ongoing protocols that include radiotherapy in association with chemotherapy, and it is plausible that this combination may not only improve its therapeutic effects but also increase its toxicity. The identification of the auditory effects after combined radiochemotherapy may be helpful to guide preventive actions. The objective of this prospective study was to investigate the prevalence of HL after concomitant radiochemotherapy in patients enrolled in a larynx preservation protocol.

METHODS

We conducted a prospective phase 2 study of weekly paclitaxel (30 mg/m2) and cisplatin (20 mg/m2) concurrent with radiotherapy up to a dose of 7040 cGy in 180 cGy/d fractions in patients with advanced resectable laryngeal and hypopharyngeal squamous cell carcinoma. Since 2000, patients from that protocol have been invited to participate in the present study. To be included, patients should also have no medical history of ototoxic treatment or HL. Patients were instructed about the study procedures, and participants signed a postinformed consent form. This study was conducted with approval of the institutional ethics committee.

Eleven male patients volunteered to participate in this study, with ages ranging from 39 to 64 years (average, 48 years). All of them underwent air conduction pure-tone audiometry (Orbiter 922; Madsen Electronics, Minnetonka, Minn) at the conventional frequencies from 250 Hz to 4000 Hz, with octave intervals and with half octave intervals between 4000 Hz and 8000 Hz, inside an acoustically treated booth. In addition, an immitance audiometry (Zodiac 901; Madsen Electronics), including tympanometry, and a contralateral acoustic reflex test were carried out. Tests were performed at least 5 months after treatment (mean ± SD time after treatment, 6.9 ± 1.8 months [range, 5-10 months]). Whenever a threshold under the normal limits (25-dB HL) in frequencies from 500 to 4000 Hz was detected, a bone conduction audiometry was done to identify the type of HL.

Change in hearing sensitivity was computed relative to baseline measures. The American Speech-Language-Hearing Association (ASHA) criteria was used to indicate hearing decrease after the treatment: a 20-dB decrease at any single test frequency or a 10-dB decrease at any 2 adjacent test frequencies.10

Change in hearing sensitivity was analyzed in both air conduction and bone conduction thresholds. Changes only in air conduction are classified as a conductive HL, whereas changes in both air and bone conduction are classified as a sensorineural HL. Besides the hearing thresholds, tympanometry and acoustic reflexes are also additional tools for the identification of the type of HL. Tympanometry reveals the changes in the acoustic immitance properties of the middle ear responding to pressure changes, showing a middle ear system disorder. At the same time, a minimum conductive problem is sufficient to prevent the contralateral acoustic reflex from being registered in the efferent ear.

Patients were divided into 2 groups. Group 1 was composed of those who did not show any change in hearing status after treatment, and group 2 was composed of those who showed a change in hearing according to the ASHA criteria.

For each subject, the portal film was analyzed to determine the inclusion of the auditory system in the irradiation field.11 After defining the position of the ear canal, a 2.5-cm-diameter circle surrounding it was traced out to include the region of the middle and internal ear, making it possible to infer the percentage of the ear that was reached by the radiotherapy as well as the dose.

The presence of HL was analyzed and compared with the tumor site and average cisplatin and radiotherapy doses. To compare the results pretreatment and posttreatment, statistical analysis was performed using a nonparametric paired test, the Wilcoxon signed rank test, with a significance level of P<.05.

RESULTS

In this study, 4 patients (36%) showed a sensorineural HL after the chemotherapy. Two patients presented with bilateral sensorineural HL and 2 with unilateral HL. Nevertheless, none of them complained about HL. We have studied the site of the tumor to check for any correlation, but no difference in the distribution of the patients with and without HL were found (Table 1).

All patients received an average cisplatin dose of 120 mg/m2, and a mean radiotherapy dose of 4660 cGy in the ear region, varying from 345 to 5110 cGy. Hearing loss was not associated with the total radiotherapy dose or with the dose given in the ear region (Table 2).

Immitance audiometry revealed altered tympanograms in 2 patients (18%) from group 1 who did not present with HL and who had already started the treatment with the same type C tympanogram.

Acoustic reflexes were absent in only 1 patient from group 2 who had also started the treatment with absence of the reflexes.

The absence of middle ear dysfunctions confirm the sensorineural characteristic of the HL found in group 2.

Table 3 and Table 4 give the hearing threshold means for the right and left ear, respectively, before and after the treatment for both groups. Although patients in group 2 met the criteria, no difference before and after treatment was statistically significant in any frequency. Threshold means appeared to be higher in both ears in group 2, even before the treatment. Statistically significant differences were observed in the frequencies of 1000 and 2000 Hz in group 1 when comparing thresholds before and after treatment. These differences reflect an improvement in thresholds in the normal range and do not have clinical relevance.

COMMENT

We have observed 4 of 11 patients whose hearing decreased after the organ preservation protocol in head and neck cancer. Nevertheless, the incidence of HL was not related to the tumor site.

Cisplatin and radiation can contribute to otologic sequelae, including sensorineural HL, vascular changes, serous effusion, or fibrosis. The ototoxic effect of cisplatin has been studied by many authors.1215 On the other hand, paclitaxel, which is used with cisplatin to increase its potential effect, has not been reported, to our knowledge, to be ototoxic.16

Radiotherapy is harmful to the ear when the auditory system is in the irradiation field. According to Chen et al,17 the tolerance dose in the ear region is 6000 cGy. In our protocol, patients received an average dose of 4660 cGy in the ear region.

Organ preservation protocols have become a common practice in head and neck cancer treatment. However, cisplatin and radiation and their use in combination can lead to HL. The effects of the combined use of these therapeutic modalities are relevant for the patients’ quality of life. Lacava et al,18 had already described a 43% HL in an organ preservation protocol for larynx cancer. In our study, we found a 36% HL.

Hoistad et al19 did not find differences in the temporal bone histopathologic characteristics of patients who had been treated with radiotherapy alone, cisplatin alone, and a combination of the two. We believe that the HL identified in this protocol sample may be due to the combined use of cisplatin and radiotherapy, actually maximizing its ototoxic effects, considering that paclitaxel might not be ototoxic and that radiotherapy and cisplatin was administered under the tolerance dose.

We have to consider that mean thresholds appeared to be higher in both ears in group 2, even before treatment. This may be owing to the patients being more susceptible to HL or having weaker health or more aggressive cancer, which might have influenced the results. Our results suggest that the prevalence of HL after radiochemotherapy in larynx preservation protocols is high (36%); however, it was mild and asymptomatic.

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Article Information

Correspondence: Luiz Paulo Kowalski, MD, PhD, Head and Neck Surgery and Otorhinolaryngology Department, Hospital do Câncer A.C. Camargo, Rua Professor Antônio Prudente, 211, 01509-900 São Paulo, Brazil (lp_kowalski@uol.com.br).

Submitted for Publication: May 23, 2003; final revision received July 5, 2004; accepted July 28, 2004.

Acknowledgment: We thank Inês Nobuko Nishimoto, MS, for the statistical analysis of our data.

References
1.
Wang  SJWang  MBCalcaterra  TC Radiotherapy followed by neck dissection for small head and neck cancers with advanced cervical metastases. Ann Otol Rhinol Laryngol 1999;108128- 131
PubMed
2.
Cheng  PWYoung  YHLou  PJ Patulous Eustachian tube in long-term survivors of nasopharyngeal carcinoma. Ann Otol Rhinol Laryngol 1999;108201- 204
PubMed
3.
Smouha  EEKarmody  CS Non-osteitic complications of therapeutic irradiation to the temporal bone. Am J Otol 1995;1683- 87
PubMed
4.
Varghese  GSahota  JSHazarika  PHajashekar  B Hearing anomalies following radiation therapy for head and neck cancers. Indian J Exp Biol 1996;34878- 879
PubMed
5.
Moretti  JA Sensorineural hearing loss following radiotherapy to the nasopharynx. Laryngoscope 1976;86598- 602
PubMedArticle
6.
Oliveira  JAA Ototoxicidade.  In: Costa  SS, Cruz  OLM, Oliveira  JAA. Otorrinolaringologia. Porto Alegre, Brazil: Editora Artes Medicas; 1994
7.
Pedalini  MEBCruz  OLMBensadon  RL Aspectos audiológicos na radioterapia, na quimioterapia em tumores do ângulo ponto cerebelar.  In: Angelis  EC, Furia  CLB, Mourão  LF, Kowalski  LP, eds. Atuação da Fonoaudiologia no Câncer de Cabeça e Pescoço. São Paulo, Brazil: Editora Lovise; 2000
8.
Kenyon  ELLeidenheim  SEZwillenberg  S Speech discrimination in the sensorineural hearing loss patient: how is it affected by background noise? Mil Med 1998;163647- 650
PubMed
9.
Kubo  TSakashita  TKusuki  M  et al.  Sound lateralization and speech discrimination in patients with sensorineural hearing loss. Acta Otolaryngol Suppl 1998;53863- 69
PubMedArticle
10.
Amercican Speech-Language-Hearing Association (ASHA), Guidelines for the audiologic management of individuals receiving cochleotoxic drug therapy. ASHA 1994;36(suppl 12)11- 19
11.
Martensen  KAnthony  BT Crânio e ossos do crânio.  In: Bontrages  KL. Tratado de Técnica Radiológica e Base Anatômica. 4th ed. Rio de Janeiro, Brazil: Koogan; 1997
12.
Schweitzer  VG Ototoxicty of chemotherapeutic agents. Otolaryngol Clin North Am 1993;26759- 789
PubMed
13.
Ozturan  OJerger  JLew  H Monitoring of cisplatin ototoxicity by distortion-product otoacoustic emissions. Auris Nasus Larynx 1996;23147- 151
PubMedArticle
14.
Rybak  LP Ototoxicity and antineoplastic drugs. Curr Opin Otolaryngol Head Neck Surg 1999;7239- 243Article
15.
Dreschler  WAUrbanus  NAMVan der Hulst  RJ High frequency audiometry in prospective clinical research of ototoxicity due to platinum dericatives. Ann Otol Rhinol Laryngol 1988;97133- 137
PubMed
16.
Cavaletti  GBogliun  GCrespi  V  et al.  Neurotoxicity and ototoxicity of cisplatin plus paclitaxel in comparison to cisplatin plus cyclophosphamide in patients with epithelial ovarian cancer. J Clin Oncol 1997;15199- 206
PubMed
17.
Chen  WCLiao  CTWang  CC  et al.  Radiation-induced hearing impairment in patients treated for malignant parotid tumor. Ann Otol Rhinol Laryngol 1999;1081159- 1164
PubMed
18.
Lacava  JAFerreyra  RLeone  BALosada  CElem  YLVallejo  CT High dose of cisplatin as neoadjuvant organ-preserving chemotherapy for squamous cell carcinoma of the larynx. Cancer J Sci Am 1996;246
PubMed
19.
Hoistad  DLOndrey  FGMutlu  CSchachern  PAPaparella  MMAdams  GL Histopathology of human temporal bone after cis-platinum, radiation, or both. Otolaryngol Head Neck Surg 1998;118825- 832
PubMedArticle
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