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Short title (Running head)	Audiometry before Cisplatin in Head and Neck Cancer	
Section title 	Clinical Study	
Issue ID	000	
Citation line	Oncology	
DOI: 10.1159/000	468522	
Article title	The Role of Audiometry prior to High-Dose Cisplatin in Patients with Head and Neck Cancer	
Subtitle		

Author(s)
Example: 	Initials
S.-J.	Given name
Seo-Jin	Surname/Collaboration
Park	
357826	M.	Miguel	Caballeroa	
417436	P.	Paula	Mackersa	
417437	O.	Oscar	Reigb	
417438	E.	Elvira	Buxob	
417439	P.	Pilar	Navarretea	
417440	J.L.	Jose L.	Blancha	
357821	J.J.	Juan J.	Graub	

Institute(s)	Departments of aOtorhinolaryngology and bMedical Oncology, University of Barcelona, IDIBAPS, Hospital Clinic of Barcelona, Barcelona, Spain	

Additional information		

Received	Received: January 31, 2017	
Accepted	Accepted after revision: March 2, 2017	
Revised		
Published Online	Published online: ■■■	

Name for correspondence	Dr. Miguel Caballero	
Full address	Department of Otorhinolaryngology, Hospital Clinic of Barcelona	
	Villarroel Street 170	
	ES–08036 Barcelona (Spain)	
(Tel., E-Mail)	E-Mail mcaba@clinic.cat	

Keywords	Audiometry
Cisplatin
Carboplatin
Head and neck cancer
Hearing loss	

Abbreviations		

Abstract	
Objectives: To analyze the role of audiometry in considering change to a less ototoxic treatment in head and neck cancer (HNC) patients. Methods: Consecutive patients prescribed high-dose cisplatin (100 mg/m2) between January 2013 and February 2015 were enrolled. Audiometry was performed at baseline and before cisplatin. Change to a less ototoxic agent or reduced cisplatin dose was considered with audiometric decreases >25 dB. Results: A total of 103 patients were included; the median age of the patients was 59 years (range 18−75). Cisplatin was intended curative (58%), adjuvant (32%), or palliative (10%). Forty-two participants (41%) did not commence high-dose cisplatin because of baseline audiometric alterations. Of 61 patients treated with high-dose cisplatin, 40 (66%) showed marked ototoxicity at the end of treatment. The mean hearing loss between initial and final audiometries showed a hearing loss at 4 and 8 kHz in both ears (p = 0.002). Thirteen patients switched to carboplatin and 15 to a lower dose of cisplatin. The outcome was not significantly altered when cisplatin was replaced with carboplatin or cetuximab. Conclusions: Audiometric alterations are common in HNC with high-dose cisplatin, and switching to a less ototoxic regimen does not adversely affect outcome. Audiometric examination could help to prevent hearing loss in this population.	

Body
Introduction
The cytotoxic agent cisplatin is currently standard treatment for head and neck carcinomas, often in combination with radiotherapy and/or other chemotherapeutic agents [1, 2]. High-dose cisplatin (100 mg/m2) is indicated as a definitive curative treatment in most patients with locally advanced squamous cell carcinoma of the oropharynx, and is also indicated as induction therapy for larynx preservation or inoperable tumors [3, 4]. High-dose cisplatin concurrent with radiotherapy in an adjuvant setting is another treatment option that is frequently used in clinical practice. In the EORTC22931 study, addition of cisplatin 100 mg/m2 to adjuvant radiotherapy significantly improved 5-year progression-free survival (hazard ratio [HR] 0.75; 95% CI 0.56−0.99; p = 0.004) and overall survival (OS; HR 0.70; 95% CI 0.52−0.95; p = 0.02) in high-risk patients with stage III/IV head and neck cancer (HNC) [5]. The median time to death in patients who received cisplatin radiotherapy was 72 months. In addition, cisplatin is indicated as a palliative treatment in patients with advanced squamous cell carcinoma of the head and neck (SCCHN) in combination with 5-fluorouracil and the monoclonal antibody cetuximab, with a median OS of 10.1 months [6].
Cisplatin is one of the most ototoxic drugs currently used in clinical practice, with a mean reported ototoxicity incidence of 33% [7]. Moreover, platinum-induced hearing loss tends to be permanent [8], which can have a considerable impact on communication ability and quality of life [9]. In a clinical study evaluating the effects of cisplatin dose and schedule on ototoxicity in 97 patients with lung cancer, most patients showed a decrease in hearing thresholds at higher frequencies (4, 8, and 12.5 kHz) after treatment with doses of approximately 60 mg/m2 compared with before treatment. The pure tone averages at 1, 2, and 4 kHz, the frequency region relevant for the perception of speech in noise, showed a mean hearing loss of 19 dB after cisplatin administration at doses above 90 mg/m2 [10].
The options for reducing ototoxicity include reducing the cisplatin dose or switching to a less ototoxic agent. Lowering cisplatin dose intensity can reduce the efﬁcacy of the drug, and although no clinical trial has yet shown that changing cisplatin to carboplatin is effective in the adjuvant setting, many oncologists chose to make this change for patients experiencing hearing loss. In our experience, replacing cisplatin with carboplatin in patients with advanced squamous HNC does not appear to be accompanied by an appreciable decrease in the effectiveness of the combination treatment regimen. Alternatively, patients with locally advanced squamous cell carcinoma of the oropharynx or larynx can be treated using a combination of radiotherapy with cetuximab, which is generally less toxic than cisplatin and is nonototoxic [11].
Baseline audiogram evaluation should always be performed before the administration of any ototoxic drug and should include measurement of pure tone thresholds at the conventional frequencies of speech audiometry. At our institute, the Hospital Clinic of Barcelona, Spain, it is common practice to perform audiometry in cancer patients prior to administration of high-dose cisplatin because preexisting hearing impairment is more common than clinical symptomatic hearing loss (many patients are adapted to their progressive hearing loss and do not relate it in the anamnesis). Audiometric data for cisplatin-associated ototoxicity in adults with HNC are limited [12–14], and the risk-benefit ratio of switching agents to reduce ototoxicity is unknown. Moreover, no clinical study in adults has investigated whether audiometry before and during cisplatin treatment can aid clinical decision making and help oncologists determine whether one chemotherapy agent is more appropriate than the other.
This study examined the use of audiology to aid clinical decision making. The effects of cisplatin on hearing were examined, and the effects on survival of switching to a less ototoxic agent in the event of ototoxicity were evaluated. Here, we report the results of the initial audiometries in these patients, and the alteration of cisplatin schedule according to audiometric alterations observed on subsequent audiometries performed before every course of ototoxic chemotherapy.
Materials and Methods
Study Design and Patients
This prospective study was conducted at Hospital Clinic of Barcelona, Spain, between January 2013 and February 2015. Consecutive patients with locally advanced SCCHN confirmed by biopsy or cytology that indicated treatment with cisplatin at a dose of 100 mg/m2 were included in the study. Additionally, only patients with an Eastern Cooperative Oncology Group performance status of 2 or less, no neurological deficits, and the intellectual ability to understand how to participate in audiometry testing were included. Other eligibility criteria included an age of at least 18 years, adequate hematological parameters (absolute neutrophil count of 2.0 × 109/L and platelet count of 100 × 109/L), and adequate hepatic and renal function.
Patients with other complications or characteristics that contraindicated the administration of cisplatin, such as renal failure, severe liver disease, severe polyneuritis or age >75 years were excluded. Patients were also excluded if they had symptomatic brain metastases, carcinomatous leptomeningitis, or a well-documented ototoxicity of Grade 2 or more based on the National Cancer Institute Common Toxicity Criteria (NCI-CTC) caused by drugs other than cisplatin [15].
The study was approved by the local ethics committee, and all patients provided written informed consent.
Outcomes
The primary endpoint of the study was to evaluate the role of audiometry in considering change to a less ototoxic treatment in HNC patients. Although assessment of antitumor activity was not the primary objective, patients with measurable disease were evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [16]. All toxicities were graded according to NCI-CTC version 2.0.14 [15].
Audiometric Assessment
A technical nurse performed air conduction pure-tone audiometry in all patients to independently evaluate whether they had symptoms of hearing loss, tinnitus, or other hearing difficulties. The same audiometry apparatus (GSI 61 Clinical Audiometer; Grason-Stadler, Eden Prairie, MN, USA) was used for all patients. Measurements were performed at baseline (1 week before treatment), before every administration of cisplatin, and 1 week after the end of the treatment. Both ears were examined at 6 different frequencies (0.25, 0.5, 1, 2, 4, and 8 kHz) in all times. The results were recorded on a chart and archived directly in a tailored healthcare database (SAP) as an electronic medical record, which could be consulted by physicians at any time.
NCI-CTC version 2.0.14 grades for ototoxicity were used [15]. Grade 2 ototoxicity was defined as an average hearing loss at two contiguous test frequencies of >25 dB in at least one ear. Only hearing loss of Grade 2 or greater led to consideration of changing the initial treatment, replacing cisplatin with a different drug after one or more cycles, or using a different cisplatin dose.
All audiometric studies were jointly interpreted by a specialist of otolaryngology and a medical oncologist. Therapeutic decisions, based on audiometry performed before the first cisplatin treatment, were made collectively by both specialists. In cases of hearing loss, exploration of hearing status including the determination of bone conduction thresholds, was performed by the otolaryngologist to ensure that no acute transmission or other cause of hearing loss had occurred.
Treatment Planning
A treatment decision algorithm devised at our Institute was used for all participants (Fig. 1). Following our protocol, patients with locally advanced squamous cell carcinoma and normal audition were treated with cisplatin plus radiotherapy. But, those with an initial audiometry with a hearing loss (level <25 dB in any of the conversational frequencies) were treated with cetuximab 250 mg/m2 weekly for 8 weeks instead of cisplatin as per the schedule outlined by Bonner et al. [11]. All other patients received cisplatin 100 mg/m2 every 3 weeks for up to 3 cycles plus radiotherapy at doses of up to 70 Gy in 1.8-Gy fractions. In patients for whom adjuvant radiotherapy with cisplatin was indicated, if the initial audiometry results changed on audiometries before the second or third cycle or an appreciable reduction in hearing loss was observed before the second or third cycle, cisplatin was switched to carboplatin at a dose of AUC (area under the curve) 5. 
Patients for whom palliative cisplatin with or without cetuximab was indicated, but who showed an initial hearing loss, were treated with carboplatin AUC5 instead of cisplatin, until progression of the disease or the development of intolerance to the drug regimen. All other patients received cisplatin 100 mg/m2 plus fluorouracil 1,000 mg/m2 every 3 weeks, with or without cetuximab 250 mg/m2 for up to 6 cycles according to the schedule outlined by Vermorken et al. [6]. 
Statistical Analysis
The applied treatment schedule, other described factors, and relevant interactions were included as ﬁxed effects. A paired-sample t test was performed to identify significant differences between the two repeated audiometry measurements in the same individual. The Kaplan-Meier method was used to analyze time to progression (TTP) and OS according to the initial drug used in combination with radiotherapy in patients treated with curative intent. All p values were two-sided, with p < 0.05 considered statistically signiﬁcant. Statistical analyses were conducted using SPSS version 21.0 for Windows (SPSS Inc., Chicago, IL, USA). 
Results
Patient Characteristics
A total of 193 air conduction pure-tone audiometries were performed on 103 patients with SCCHN prior to chemotherapy with 100 mg/m2 intravenous cisplatin. The characteristics of the study cohort are shown in Table 1. Patient age ranged from 18 to 75 years, with 26% women and 74% men. The most common primary tumor locations were the oropharynx (n = 41), larynx (n = 21), and mouth (n = 15), and the majority of patients (68%) had stage III or IVa tumors (Table 1). Treatment was intended curative in 60 (58%) patients, adjuvant in 33 (32%), and palliative in 10 (10%). 
In all, 26 of the 103 enrolled patients (25%) had previously received induction chemotherapy with 3 cycles of docetaxel, cisplatin, and fluorouracil (TPF), with an intravenous cisplatin dose of 75 mg/m2 [17]. In these patients, audiometry was performed before the first administration of high-dose cisplatin.
Audiometric Alterations and Treatments Administered
We first performed baseline audiometry and included these findings in decision making when assigning patients to the appropriate cisplatin-containing treatment. Subsequent audiometry measurements were used in planning changes to the treatment to help avoid further ototoxicity. Forty-two of the 103 participants (41%) had hearing loss at baseline, including 9 of the 26 patients who had previously received TPF. These patients did not initiate high-dose cisplatin. Thirty-six of these 42 patients (86%) had been assigned to nonpalliative treatment. Two of the 42 patients refused to undergo adjuvant radiotherapy. For the remaining 40 patients, the oncologist chose to initiate treatment with carboplatin in 23 cases, cisplatin at reduced doses (60 mg/m2) in 2 patients and cetuximab with radiotherapy in 15 patients.
High-dose cisplatin treatment was initiated in the 61 patients who did not have ototoxicity at baseline. Because of subsequent audiometry alterations, 13 of these patients were switched to carboplatin and 15 were changed to a lower dose of cisplatin during the course of treatment. Overall, 11 of the 17 patients who had previously received TPF and who started high-dose cisplatin showed alterations in audiometry during or after treatment. In total, 33 patients completed the high-dose cisplatin course.
At the end of treatment, 40 of the 61 patients (66%) who were administered high-dose cisplatin showed significant ototoxicity (see results below). Overall, in 82 of the initial 103 patients (80%), either cisplatin treatment was not initiated or severe cisplatin-related ototoxicity developed.
Audiometric Alterations with High-Dose Cisplatin
To determine the effects of high-dose cisplatin on hearing, we compared audiometry results before and after treatment. In the 61 patients who started high-dose cisplatin, the most severe hearing loss was observed at frequencies of 4 and 8 kHz. The mean hearing loss measured at various frequencies at the first and last audiometry performed in the right and left ear of each patient is shown in Figure 2. At completion of treatment, the mean hearing loss from baseline was significant in both ears at 4 and 8 kHz. In the right ear, the mean hearing loss was 9.524 dB at 4 kHz (95% CI, 24.036–3.583; p < 0.011) and 18.571 dB at 8 kHz (95% CI, 32.047–8.408; p = 0.002). In the left ear, the mean hearing loss was 17.381 dB at 4 kHz (95% CI, 25.638–9.124; p < 0.001) and 27.143 dB at 8 kHz (95% CI, 34.671–19.609; p < 0.001).
TTP and OS
To determine whether switching cisplatin to cetuximab or carboplatin altered patient outcome, we compared PFS and OS in the 60 consecutive patients treated with curative intent. With a median follow-up of 18 months, neither TTP nor OS differed significantly between patients receiving radiotherapy in combination with cisplatin (n = 38) and those receiving radiotherapy in combination with cetuximab or carboplatin (n = 22; Fig. 3). We also noted that complete response was not significantly worse in patients treated with drugs other than cisplatin and that additional salvage surgery in these patients resulted in similar OS.
Discussion
In our study, the first to use audiometry as a decision aid to guide treatment, audiometry performed before every course of high-dose cisplatin revealed that 80% of patients either had audiometric alterations prior to chemotherapy or developed significant hearing loss after consecutive courses of cisplatin. It was particularly notable that a high number of patients with preexisting hearing loss were among those for whom high-dose cisplatin treatment was indicated. We used the audiometry findings to inform the treatment plan for the patients, and found that switching from cisplatin to less ototoxic options, such as carboplatin or cetuximab, did not adversely affect patient outcome.
Most studies on cisplatin ototoxicity have been conducted in children or adolescents, have not involved patients with HNC, and have generally used doses of cisplatin less than 100 mg/m2 [18, 19]. Our findings of hearing loss occurring mainly at high frequencies (4 and 8 kHz) are in line with those of other studies in adults with HNC examining the combined ototoxic effects of radiotherapy and cisplatin [12, 14], and with one study in adults with non-small cell lung cancer treated with high-dose cisplatin [10].
In a phase III randomized study comparing intraarterial with intravenous administration of cisplatin with concurrent radiotherapy (70 Gy in 35 daily fractions of 2 Gy) in 158 patients with locally advanced SSCHN, 58 of 73 patients (79%) treated with intravenous cisplatin 100 mg/m2 developed NCI Common Terminology Criteria for Adverse Events version 3.0 Grade ≥1 ototoxicity using audiometry up to 8 kHz [14]. Age and cumulative doses of cisplatin and radiotherapy influenced the degree of hearing loss. Similarly, a study which used retrospective data from patients with SSCHN treated with high-dose cisplatin and radiotherapy to develop a statistical model to predict treatment-induced hearing loss after cisplatin infusions reported American Speech-Language-Hearing Association-defined hearing loss in 140 of 156 (90.7%) of patients.
It is important to note that reports of 3 studies that have been important in informing the clinical practice of head and neck oncologists focused only on Grade ≥3 adverse events, and therefore did not report rates of ototoxicity [3, 5, 6]. However, given the effect of hearing loss on patient quality of life [9] and the fact that hearing loss tends to be permanent [8], we think it is important to search for suitable options for the prevention of ototoxicity.
In current clinical practice, it is reasonable to consider changing cisplatin to carboplatin among patients receiving palliative treatment for locally advanced SSCHN. In addition to ototoxicity, high-dose cisplatin is often associated with severe nausea and vomiting, renal dysfunction, and neurotoxicity [5, 20]; therefore, some clinical trials have examined the change of cisplatin to carboplatin in combination with radiotherapy to avoid serious toxicities, with positive results [15]. A retrospective study in 25 patients with locally advanced SSCHN deemed ineligible for cisplatin therapy, showed carboplatin plus radiotherapy to be well tolerated, with no Grade 3/4 neurotoxicity, nephrotoxicity, nausea, or vomiting reported [20]. In addition, the combination was associated with a median progression-free survival of 42.7 months, with median OS not yet reached after a median of 30.9 months of follow-up, leading the authors to conclude that carboplatin plus radiotherapy is a feasible option in patients ineligible for high-dose cisplatin. These results provide additional evidence to our observations that, for patients treated with curative intent, the change of cisplatin to cetuximab or carboplatin, which are less ototoxic, did not markedly alter patient outcome or OS.
Several clinical studies of treatments to prevent ototoxicity induced by cisplatin have been performed, such as the intravenous administration of intratympanic dexamethasone, L-N-acetylcysteine [21, 22], or amifostine [23]. However, most of those studies were performed in children and a Cochrane systematic review concluded that the evidence was insufficient to allow for recommendation of such preventative treatments [24]. Similarly, our group has previously studied the effect on ototoxicity of maintaining serum calcium concentrations via calcium gluconate infusion in HNC patients treated with high-dose cisplatin, but we did not observe any protection against ototoxicity using this treatment [25]. Therefore in our opinion, while novel preventative treatments should continue to be sought, in the meanwhile, switching to less ototoxic treatment regimens, such as carboplatin or cetuximab, is a useful option. Careful ototoxicity monitoring can allow the physician to consider altering the treatment regimen before permanent ototoxic damage occurs, and it can allow the audiologist to work with the patient and their family to maintain communication in cases in which hearing loss cannot be prevented or reversed. Maintaining optimal communication abilities in these patients can greatly help maintain or improve their quality of life.
A limitation of our study is that we did not record smoking history, a known risk factor for hearing loss in older people [26–28]. It is plausible that such habits could explain why 66% of the patients in our study with normal audiometry previous to treatment developed hearing deficits during the course of cisplatin treatment. Also, we did not compare hearing loss in patients who remained on high-dose cisplatin with those who switched regimens; therefore, further research is necessary to validate our treatment algorithm.
The high rate of previous audiometric alterations we observed suggests that audiometry should be mandated for all patients before every course of high-dose cisplatin to determine the risk of the development or exacerbation of auditory deficits by cisplatin. For patients treated with curative intent, a switch to cetuximab or carboplatin in the event of ototoxicity before or during cisplatin treatment appears to be a reasonable option. Close collaboration between oncologists and audiologists in treatment planning might therefore avoid irreversible hearing loss in HNC patients treated with high doses of cisplatin and improve their quality of life.
Acknowledgements
We thank Vicky Ferrandez, Marta Llubera, and Susana Martinez for their help in data collection and organization of the patients’ schedules. Assistance with editing of the manuscript was provided by Andrea Bothwell on behalf of Springer Healthcare Communications. This medical writing assistance was funded by Merck.
Disclosure Statement
All authors declare no conflict of interest.
References
1	Chan AT, Gregoire V, Lefebvre JL, Licitra L, Hui EP, Leung SF, Felip E; EHNS-ESMO-ESTRO Guidelines Working Group: Nasopharyngeal cancer: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012;23(suppl 7):vii83–vii85.
2	Gregoire V, Lefebvre JL, Licitra L, Felip E; EHNS-ESMO-ESTRO Guidelines Working Group: Squamous cell carcinoma of the head and neck: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010;21(suppl 5):v184–v186.
3	Forastiere AA, Zhang Q, Weber RS, Maor MH, Goepfert H, Pajak TF, Morrison W, Glisson B, Trotti A, Ridge JA, Thorstad W, Wagner H, Ensley JF, Cooper JS: Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol 2013;31:845–852.
4	Vermorken JB, Remenar E, van Herpen C, Gorlia T, Mesia R, Degardin M, Stewart JS, Jelic S, Betka J, Preiss JH, van den Weyngaert D, Awada A, Cupissol D, Kienzer HR, Rey A, Desaunois I, Bernier J, Lefebvre JL: Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 2007;357:1695–1704.
5	Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefebvre JL, Greiner RH, Giralt J, Maingon P, Rolland F, Bolla M, Cognetti F, Bourhis J, Kirkpatrick A, van Glabbeke M: Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004;350:1945–1952.
6	Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D, Kienzer HR, Cupissol D, Peyrade F, Benasso M, Vynnychenko I, De Raucourt D, Bokemeyer C, Schueler A, Amellal N, Hitt R: Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008;359:1116–1127.
7	Malhotra H: Cisplatin ototoxicity. Indian J Cancer 2009;46:262–263.
8	Nitz A, Kontopantelis E, Bielack S, Koscielniak E, Klingebiel T, Langer T, Paulides M: Prospective evaluation of cisplatin- and carboplatin-mediated ototoxicity in paediatric and adult soft tissue and osteosarcoma patients. Oncol Lett 2013;5:311–315.
9	Paken J, Govender CD, Pillay M, Sewram V: Cisplatin-associated ototoxicity: a review for the health professional. J Toxicol 2016;2016:1809394.
10	Rademaker-Lakhai JM, Crul M, Zuur L, Baas P, Beijnen JH, Simis YJ, van Zandwijk N, Schellens JH: Relationship between cisplatin administration and the development of ototoxicity. J Clin Oncol 2006;24:918–924.
11	Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, Raben D, Baselga J, Spencer SA, Zhu J, Youssoufian H, Rowinsky EK, Ang KK: Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 2010;11:21–28.
12	Chen WC, Jackson A, Budnick AS, Pfister DG, Kraus DH, Hunt MA, Stambuk H, Levegrun S, Wolden SL: Sensorineural hearing loss in combined modality treatment of nasopharyngeal carcinoma. Cancer 2006;106:820–829.
13	Theunissen EA, Zuur CL, Jozwiak K, Lopez-Yurda M, Hauptmann M, Rasch CR, van der Baan S, de Boer JP, Dreschler WA, Balm AJ: Prediction of hearing loss due to cisplatin chemoradiotherapy. JAMA Otolaryngol Head Neck Surg 2015;141:810–815.
14	Zuur CL, Simis YJ, Lansdaal PE, Hart AA, Schornagel JH, Dreschler WA, Rasch CR, Balm AJ: Ototoxicity in a randomized phase III trial of intra-arterial compared with intravenous cisplatin chemoradiation in patients with locally advanced head and neck cancer. J Clin Oncol 2007;25:3759–3765.
15	National Cancer Institute: Guidelines for Reporting of Adverse Drug Reactions. Bethesda, National Cancer Institute, Division of Cancer Treatment, 1988.
16	Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228–247.
17	Posner MR, Hershock DM, Blajman CR, Mickiewicz E, Winquist E, Gorbounova V, Tjulandin S, Shin DM, Cullen K, Ervin TJ, Murphy BA, Raez LE, Cohen RB, Spaulding M, Tishler RB, Roth B, Viroglio Rdel C, Venkatesan V, Romanov I, Agarwala S, Harter KW, Dugan M, Cmelak A, Markoe AM, Read PW, Steinbrenner L, Colevas AD, Norris CM Jr, Haddad RI: Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 2007;357:1705–1715.
18	Landier W, Knight K, Wong FL, Lee J, Thomas O, Kim H, Kreissman SG, Schmidt ML, Chen L, London WB, Gurney JG, Bhatia S: Ototoxicity in children with high-risk neuroblastoma: prevalence, risk factors, and concordance of grading scales – a report from the Children’s Oncology Group. J Clin Oncol 2014;32:527–534.
19	Zsiros J, Brugieres L, Brock P, Roebuck D, Maibach R, Zimmermann A, Childs M, Pariente D, Laithier V, Otte JB, Branchereau S, Aronson D, Rangaswami A, Ronghe M, Casanova M, Sullivan M, Morland B, Czauderna P, Perilongo G: Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): a prospective, single-arm, feasibility study. Lancet Oncol 2013;14:834–842.
20	Hamauchi S, Yokota T, Onozawa Y, Ogawa H, Onoe T, Kamijo T, Iida Y, Nishimura T, Onitsuka T, Yasui H: Safety and efficacy of concurrent carboplatin plus radiotherapy for locally advanced head and neck cancer patients ineligible for treatment with cisplatin. Jpn J Clin Oncol 2015;45:1116–1121.
21	Marshak T, Steiner M, Kaminer M, Levy L, Shupak A: Prevention of cisplatin-induced hearing loss by intratympanic dexamethasone: a randomized controlled study. Otolaryngol Head Neck Surg 2014;150:983–990.
22	Riga MG, Chelis L, Kakolyris S, Papadopoulos S, Stathakidou S, Chamalidou E, Xenidis N, Amarantidis K, Dimopoulos P, Danielides V: Transtympanic injections of N-acetylcysteine for the prevention of cisplatin-induced ototoxicity: a feasible method with promising efficacy. Am J Clin Oncol 2013;36:1–6.
23	Fouladi M, Chintagumpala M, Ashley D, Kellie S, Gururangan S, Hassall T, Gronewold L, Stewart CF, Wallace D, Broniscer A, Hale GA, Kasow KA, Merchant TE, Morris B, Krasin M, Kun LE, Boyett JM, Gajjar A: Amifostine protects against cisplatin-induced ototoxicity in children with average-risk medulloblastoma. J Clin Oncol 2008;26:3749–3755.
24	van As JW, van den Berg H, van Dalen EC: Medical interventions for the prevention of platinum-induced hearing loss in children with cancer. Cochrane Database Syst Rev 2012;5:CD009219.
25	Grau JJ, Estape J, Cuchi MA, Firvida JL, Blanch JL, Ascaso C: Calcium supplementation and ototoxicity in patients receiving cisplatin. Br J Clin Pharmacol 1996;42:233–235.
26	Chang J, Ryou N, Jun HJ, Hwang SY, Song JJ, Chae SW: Effect of cigarette smoking and passive smoking on hearing impairment: data from a population-based study. PLoS One 2016;11:e0146608.
27	Itoh A, Nakashima T, Arao H, Wakai K, Tamakoshi A, Kawamura T, Ohno Y: Smoking and drinking habits as risk factors for hearing loss in the elderly: epidemiological study of subjects undergoing routine health checks in Aichi, Japan. Public Health 2001;115:192–196.
28	Kim JS: Prevalence and factors associated with hearing loss and hearing aid use in Korean elders. Iran J Public Health 2015;44:308–317.
Appendix after References (Editorial Comments)

Legend(s)
Fig. 1.	Treatment algorithm showing planned treatment according to audiometry results. Audiometry-detected hearing loss was defined as initial hearing loss at two contiguous test frequencies of >25 dB in any test frequencies. NCI-CTC Grade 2 hearing loss was defined as hearing loss at two contiguous test frequencies of >25 dB in at least one ear. AUC, area under the curve; SCCHN, squamous cell carcinoma of the head and neck.
Fig. 2.	Mean audiometric results at initial audiometry (continous line) and after cisplatin treatment (dashed line)  among 61 patients who were started on high-dose cisplatin treatment. * p < 0.05 vs. initial audiometry.
Fig. 3.	Kaplan-Meier plots showing median time to progression (mTTP) and overall survival (OS) among patients undergoing curative therapy according to the initial drug combined with radiotherapy.
Table(s)

Footnote(s)

Table 1. Baseline patient characteristics and demographics (n = 103)

Age, years		
Median	59	
Range	18−75	
Sex, n (%)		
Male	76 (74)	
Female	27 (26)	
Primary tumor location, n (%)		
Oropharynx	41 (40)	
Larynx	21 (20)	
Hypopharynx	10 (10)	
Nasopharynx	10 (10)	
Mouth	15 (15)	
Other	06 (5)	
Stage, n (%)		
III	30 (29)	
IVa	40 (39)	
IVb	21 (20)	
IVc	12 (12)	
Previous cisplatin-containing therapy, n (%)	26 (25)	

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