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Journal of Clinical Oncology, Vol 25, No 24 (August 20), 2007: pp. 3759-3765 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.08.9540 Ototoxicity in a Randomized Phase III Trial of Intra-Arterial Compared With Intravenous Cisplatin Chemoradiation in Patients With Locally Advanced Head and Neck Cancer
From the Department of Otorhinolaryngology and Department of Audiology, Academical Medical Centre; and the Department of Head and Neck Oncology and Surgery, Department of Radiation Therapy, and Department of Medical Oncology, the Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands Address reprint requests to Charlotte L. Zuur, MD, Department of Otorhinolaryngology, 1D-116, VUMC, De Boelelaan 1117, 1081 HV, Amsterdam, the Netherlands; email: cl.zuur{at}vumc.nl
Purpose Cisplatin concomitantly administered with radiotherapy is increasingly used in locally advanced head and neck squamous cell carcinoma. We aimed to compare the incidence of hearing loss between patients treated with intra-arterial high-dose cisplatin chemoradiation with sodium thiosulfate (CRT-IA) and intravenous high-dose cisplatin chemoradiation without sodium thiosulfate (CRT-IV). Patients and Methods We conducted a prospective analysis of hearing thresholds at low and (ultra-) high frequencies obtained before, during, and after treatment in 158 patients. Patients were randomly assigned for either CRT-IA (150 mg/m2, four courses) with sodium thiosulfate cisplatin neutralization or CRT-IV (100 mg/m2, three courses) without rescue. All patients received concomitant radiation therapy (RT; 70 Gy). Results CRT-IA resulted in approximately 10% less hearing loss at frequencies vital for speech perception, compared with CRT-IV (P < .001). In CRT-IA, fewer ears qualified for hearing aids (36% v 49%; P = .03). However, in both treatment arms, the incidence expressed in National Cancer Institute Common Terminology Criteria of Adverse Events (version 3) did not deviate (P > .14). Age, cumulative cisplatin dose, cumulative RT dose, and the considered frequency area determine the degree of hearing loss (P < .001). Cisplatin induced increasing hearing loss of 24% to 60% with increasing frequencies. RT induced hearing loss at speech frequencies of 9% to 12%. Conclusion Depending on the criteria used to assess hearing loss due to treatment, differences in ototoxicity between CRT-IA and CRT-IV were found in favor of CRT-IA. It is desirable to specify hearing loss criteria toward frequencies vital for speech perception, and to refine grading scales to reveal subtle and clinically relevant dissimilarities in ototoxicity between different treatment protocols.
Chemoradiotherapy has become increasingly important for treatment of head and neck squamous cell carcinoma.1,2 In the past, high-dose cisplatin chemotherapy schemes induced a 58% to 81% incidence of hearing loss at frequencies from 0.250 to 8 kHz.3,4 Others reported an incidence up to 46% of notable hearing loss.5 In addition, radiation-induced sensorineural hearing loss has been observed to an incidence of 49% immediately after treatment and to an incidence of 55% at 2 to 8 years after therapy of patients treated with cranial irradiation that exposed the inner ear.6-14 In studies of the combined-modality treatment of intravenously applied high-dose cisplatin and radiotherapy, a 53% incidence of sensorineural hearing loss more than 30 dB at 4 and 8 kHz and a 14% incidence of ototoxicity interfering with the chemotherapy regimen were described.15,16 Other studies did not comment on ototoxicity.17-19
To increase drug doses in the tumor with minimal systemic toxicity, a superselective administration of intra-arterial high-dose cisplatin chemoradiation with sodium thiosulfate (CRT-IA) was designed. In this treatment model, cisplatin was infused directly in the nutrient artery of the tumor with concurrent intravenously administered sodium thiosulfate (STS) for cisplatin neutralization. Favorable results have been reported.20-23 Nevertheless, in this treatment modality, incidence rates up to 60% of hearing loss The objective of this study was to compare the incidence of hearing loss in a phase III randomized trial comparing CRT-IA and intravenous high-dose cisplatin chemoradiation without sodium thiosulfate (CRT-IV).31
Patients and Treatment Characteristics From 1999 to 2004, 162 patients with locally advanced head and neck squamous cell carcinoma participated in a randomized phase III trial in our center. Patients were assigned to either targeted intra-arterial cisplatin infusions (150 mg/m2, cisplatin 1 mg/mL in saline, automatic pump 1 to 2 mL/sec, four courses on days 1, 8, 15, and 22) with simultaneous intravenously administered STS (9 g/m2/30 minutes, followed by 12 g/m2/2 hours) for cisplatin neutralization (CRT-IA), or to intravenously administered cisplatin infusions (100 mg/m2 in 500 mL saline during 30 minutes, three courses on days 1, 22, 43) without rescue (CRT-IV). All patients received concurrent radiation therapy (RT). One hundred fifty-eight patients were included in our study (78 CRT-IA and 80 CRT-IV). Four patients were excluded from analysis; three patients did not receive high-dose cisplatin CRT and in one patient audiometry was not performed.
RT and the Inner Ear Radiation Dose
The inner ear radiation dose was determined by measuring the distance of the inner ear to the boundary of the radiation field. Thereafter, we converted these distances into Grays according to a computed tomography (CT) –simulated patient model with cochleas located at several distances from the field and the RT dose computed digitally. In patients treated in a conventional way (two lateral radiation portals and one anterior-posterior adjacent supraclavicular field with customized shielding) the planning x-rays were reviewed to measure the distance of the center of the bony external auditory canal to the boundary of the field. By repeating this measurement twice we found a median uncertainty of 3.2 mm. In later years, radiation portals were planned at the time of a CT scan. By revision of these images, we computed the distance from cochlea to the radiation field digitally. By repeating the procedure twice, we found a median variation of 1.0 mm. In most recent years, patients received intensity-modulated radiation therapy (IMRT; based on digital planning of radiation portals in CT scans). The cochlea radiation dose was calculated directly.
Audiometry In the audiograms up to 8 kHz, 69% to 96% of the AC thresholds were measured. At ultrahigh frequencies (8 to 16 kHz), and particularly as the treatment progressed, many thresholds could not be measured because the patient was not able to complete the audiometry session. At 8, 10, and 12.5 kHz, the number of ears measured in CRT-IA and CRT-IV patients were 67% and 71%, 54% and 64%, and 27% and 29%, respectively. Excluding these patients may lead to an underestimation of hearing thresholds and to exclusion of patients with potentially the highest hearing threshold (shift) during CRT. Therefore, we reconstructed missing thresholds by extrapolating with the same slope as was found on average in the audiograms of our patients who were actually measured at all (ultra-) high frequencies.
Common Terminology Criteria of Adverse Events
Statistics Two statistical analyses were performed, in which hearing loss was defined as a percentage change in decibels of pretreatment hearing level: a comparison of hearing loss between CRT-IA and CRT-IV, and an explanatory analysis to determine the separate effects of patients and treatment variables. Repeated-measurement analysis of covariance was performed using all PTAs per patient. A logarithmic transformation was applied to the audiometric (measurements + 10 dB) to improve normality and constancy of variation. No structure was imposed on the variances and correlations of the 10 measurements per time point; based on Akaike's information criterion, the (co)variances of the same PTA at the same ear were assumed to be constant over time (compound symmetry). PROC MIXED of SAS version 8.2 for Windows (SAS Institute, Cary, NC) was used. In the first analysis, the development over time of the PTAs was modeled by a second-order polynomial during treatment and a separate difference between pretreatment and post-treatment value. The slopes during treatment were assumed to vary between patients according to a multivariate normal distribution. The coefficients of the polynomial and the pretreatment versus post-treatment difference were allowed to vary between thresholds as well as arms. To simplify interpretation, we tested whether the quadratic components could be removed from the model. The analysis was adjusted for baseline measurement, the effect of which was allowed to vary over the PTAs. In the second analysis, relations between quantitative variables (cisplatin and RT dose, time, and age) and transformed PTA values were assumed to be linear. Other effects considered were ear at the side of infusion (no, yes, or intravenous), ipsilateral or contralateral to cisplatin infusin side in case of CRT-IA, and sex. The effect of cumulative cisplatin dose was allowed to vary with ear at the side of infusion, age, and sex. All effects were allowed to vary with type of PTA. The slopes against cumulative cisplatin dose were assumed to vary between patients in accordance with a multivariate normal distribution. In view of the large number of effects evaluated, P < .001 was considered statistically significant. Hierarchical backward elimination (P > .10) was applied to facilitate interpretation.
Patient and Treatment Characteristics Patient and treatment characteristics are summarized in Table 1. Eleven CRT-IA patients received one to three infusions. Seven CRT-IV patients received zero to two infusions. In 70 CRT-IA patients and in 67 CRT-IV patients we were able to review sufficient RT data to calculate the amount of Gray received in the inner ear. The median RT dose of the inner ear was higher in CRT-IV, due to skewness in distribution of RT doses within the CT scan–guided patients (CRT-IV, 19.2 Gy; CRT-IA, 10.8 Gy).
Overall Hearing Loss
Both treatment schemes induced increasing hearing loss with increasing frequency. Table 2 lists (sensorineural) hearing loss after the individual cisplatin infusions. Pretreatment hearing capability at all PTAs was similar between the two patient groups (P = .053 to .97, univariate analysis), as expected after the randomization procedure. Mean total threshold shifts at PTA BC 1, 2, and 4 kHz were 5.3 and 8.9 dB for CRT-IA and CRT-IV, respectively, whereas mean total threshold shifts at PTA 8, 10, and 12.5 kHz were 20.4 and 19.6 dB for CRT-IA and CRT-IV, respectively.
Comparison of Hearing Loss During and After Treatment Between the Two Treatment Arms In both CRT schemes, hearing thresholds deteriorated during treatment at low frequencies (0.4%/day), high frequencies (0.7%/day), and ultrahigh frequencies (1%/day; all P < .0005). No evidence was found for a difference between the two arms during treatment (P  .34). After treatment, differences between the two arms were found to be approximately 10% in favor of CRT-IA for low and high frequencies (P < .001;Table 3). No difference was found at ultrahigh frequencies.
The comparison of hearing loss during therapy took place at 4 weeks and therefore included in CRT-IA four doses of 150 mg/m2 cisplatin, and included in CRT-IV two doses of 100 mg/m2 cisplatin. It seems likely that after that period, hearing loss increased more in the CRT-IV arm, given that an additional cisplatin dose was administered at 7 weeks.
Eligibility for Hearing Aids
CTCAE
When we left out ultrahigh frequencies (> 8 kHz), a redistribution of ototoxicity grades was observed (Table 4). Eighteen CRT-IA patients (24%) and 15 CRT-IV patients (21%) had threshold shifts less than 15 dB in both ears and no subjective changes in hearing due to treatment. Again, in both treatment schemes the incidence of hearing loss was equal (P .36).
ABG
Explanatory Analysis Averaged over all frequencies and patients, the degree of hearing loss was not influenced by the treatment arm (whether intra-arterial cisplatin injection with STS was administered; P = .11) Nevertheless, the effect of cumulative cisplatin dose was found to be higher in CRT-IV (63%) than in CRT-IA (24%).
Recently, it was found that the benefit in survival of chemotherapy added to the locoregional treatment1,2 is accompanied by an increase of 37% to 43% of acute adverse effects (CTCAE grade 3) for cisplatin added to RT.17,18 The current study reports on a prospective analysis of ototoxicity within a randomized phase III trial comparing CRT-IA versus CRT-IV. The first clinical evaluation of this trial showed no significant difference between CRT-IA and CRT-IV in locoregional control (62% and 68%, respectively) or overall survival (61% and 63%, respectively) at 2 years of follow-up.31 Whether differences in ototoxicity between CRT-IA and CRT-IV were revealed depended on the criteria used to assess the incidence and/or degree of hearing loss due to treatment. When we expressed hearing loss in a percentage change of baseline hearing (in decibels), differences in hearing loss after treatment between CRT-IA and CRT-IV were approximately 10% in favor of CRT-IA at frequencies vital for speech perception (P < .001). No difference of hearing loss after therapy was found at ultrahigh frequencies. In correspondence, CRT-IA resulted in fewer ears that qualified for HAs after therapy (36%) compared with CRT-IV (49%). These results are in agreement with the report on DNA-adduct formation from our group, which observed less DNA damage in healthy tissue in CRT-IA patients compared with CRT-IV patients,33 assuming that a higher cisplatin dose leads to increased adduct formation. Given that we did not measure serum cisplatin concentrations in our patients, the potential effect of the mode of cisplatin application on its serum level cannot be identified. However, from our previous study, it became evident that hearing loss correlated better with cisplatin dose than with serum level.34 In our explanatory analysis, the effect of an equal dose of cisplatin was found to be larger in the CRT-IV arm than in the CRT-IA arm. A protective effect of CRT-IA may be explained by a first-pass extraction of the tumor area in intra-arterial infusion of cisplatin,35 and/or the infusion of STS. In previous studies, the otoprotective capacity of thiols was tested in animal models.36-38 The chemoprotectant and chemotherapy treatment were separated in time and space to avoid a potential reduction of the tumoricidal effect of cisplatin: in a rat model, vertebral arteries were perfused with cisplatin whereas STS was applied intravenously. Depending on the timing of thiol administration, full otoprotection was observed.37 In the guinea pig model, intracochlear application of STS was found to protect the organ of corti when cisplatin was infused intravenously.38 In the future, it may be desirable to examine additional possibilities for two-route administration schemes for chemotherapy and otoprotective drugs in humans. We could not find a major confounding effect of RT imbalance in our conclusion of cisplatin-induced ototoxicity, given that the different RT doses in CRT-IV subgroups (13.4 Gy in IMRT/conventional therapy together v 19.5 Gy in CT-guided therapy; P < .002, Mann Whitney U test) were related to equal hearing losses at PTA BC 1, 2, and 4 kHz (10.0 v 9.2 dB; P = .840). Moreover, between treatment schemes, a similar discrepancy in hearing deterioration was found in patients with CT-guided therapy with RT imbalance (9.2 dB in CRT-IV therapy and 3.3 dB in CRT-IA therapy; discrepancy, 5.9 dB) versus IMRT/conventional therapy without RT imbalance (10.0 dB in CRT-IV therapy and 3.3 dB in CRT-IA therapy; discrepancy, 6.7 dB).
The incidence of hearing loss expressed in CTCAE criteria32 was equal in both treatment arms. When we applied these criteria to frequencies up to 8 kHz (not to 16 kHz), a decrease in the total incidence of 91% to 76% in CRT-IA and 88% to 79% in CRT-IV was found, and a redistribution of patients toward lower CTCAE grades was observed. This was expected, given that the mean ultrahigh frequency hearing loss (at PTA 8, 10, and 12.5 kHz) was larger than the mean high frequency hearing loss (at PTA 1, 2, and 4 kHz). Evidently, CTCAE grades 2 and 3 are too coarsely defined and do not allow for subtle differences in hearing loss between both treatment arms. Nevertheless, the incidence of CTCAE grade 2 to 3 ototoxicity up to 8 kHz (50% and 59% in CRT-IA and CRT-IV, respectively) is in accordance with previous studies of high-dose cisplatin CRT, which report up to 60% of To evaluate the effect of treatment on hearing function in future studies, we suggest that hearing loss per ear be reported at frequencies of ultrahigh sounds (PTA AC 8, 10, and 12.5 Hz) for the early detection of ototoxicity; at PTA AC 1, 2, and 4 kHz for hearing loss at frequencies vital for speech perception in noise; and at PTA 0.5, 1, and 2 kHz for analysis of conductive hearing impairment. Furthermore, hearing loss criteria should be defined as threshold shifts relative to the pretreatment audiogram, and may be graded as 0 to 10, 15 to 25, 30 to 50, and more than 50 dB. A pretreatment and post-treatment audiogram is indispensable. In addition, the impact of hearing loss on daily life performance may be reflected as whether a patient will qualify for an HA after treatment (PTA AC 1, 2, and 4 kHz > 35 dB HL). To improve future study methodology, we suggest that researchers focus on IMRT to obtain the most accurate assessment of the inner ear and retrocochlear RT dose.40-44
The author(s) indicated no potential conflicts of interest.
Conception and design: Charlotte L. Zuur, Augustinus A. Hart, Coen R. Rasch, Alfons J. Balm Administrative support: Charlotte L. Zuur Provision of study materials or patients: Charlotte L. Zuur, Pauline E. Lansdaal Collection and assembly of data: Charlotte L. Zuur Data analysis and interpretation: Charlotte L. Zuur, Yvonne J. Simis, Augustinus A. Hart, Jan H. Schornagel, Wouter A. Dreschler, Coen R. Rasch, Alfons J. Balm Manuscript writing: Charlotte L. Zuur, Augustinus A. Hart, Wouter A. Dreschler, Alfons J. Balm Final approval of manuscript: Charlotte L. Zuur, Yvonne J. Simis, Pauline E. Lansdaal, Augustinus A. Hart, Jan H. Schornagel, Wouter A. Dreschler, Coen R. Rasch, Alfons J. Balm
Presented in part at the International Workshop on Intra-Arterial Chemotherapy for Head and Neck Cancer, August 20-22, 2006, Springfield, IL. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Presented at the 48th Annual Meeting of ASTRO, Philadelphia, PA, November 5-9, 2006 (abstr) 32. National Cancer Institute: Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 3.0. http://ctep.cancer.gov/reporting/ctc.html 33. Hoebers FJ, Pluim D, Verheij M, et al: Prediction of treatment outcome by cisplatin-DNA adduct formation in patients with stage III/IV head and neck squamous cell carcinoma, treated by concurrent cisplatin-radiation (RADPLAT). Int J Cancer 119:750-756, 2006[CrossRef][Medline] 34. Rademaker-Lakhai JM, Crul M, Zuur L, et al: Relationship between cisplatin administration and the development of ototoxicity. J Clin Oncol 24:918-924, 2006 35. Sileni VC, Fosser V, Maggian P, et al: Pharmacokinetics and tumor concentration of intraarterial and intravenous cisplatin in patients with head and neck squamous cell cancer. Cancer Chemother Pharmacol 30:221-225, 1992[CrossRef][Medline] 36. Dickey DT, Muldoon LL, Kraemer DF, et al: Protection against cisplatin-induced ototoxicity by N-acetylcysteine in a rat model. Hear Res 193:25-30, 2004[CrossRef][Medline] 37. Dickey DT, Wu YJ, Muldoon LL, et al: Protection against cisplatin-induced toxicities by N-acetylcysteine and sodium thiosulfate as assessed at the molecular, cellular, and in vivo levels. J Pharmacol Exp Ther 314:1052-1058, 2005 38. Wang J, Faulconbridge RVL, Fetoni A, et al: Local application of sodium thiosulfate prevents cisplatin-induced hearing loss in the guinea pig. Neuropharmacology 45:380-393, 2003[CrossRef][Medline] 39. Dropcho EJ, Rosenfeld SS, Morawetz RB, et al: Preradiation intracarotid cisplatin treatment of newly diagnosed anaplastic gliomas. J Clin Oncol 10:452-458, 1992 40. Bohne BA, Marks JE, Glasgow GP, et al: Delayed effects of ionising radiation on the ear. Laryngoscope 95:818-828, 1985[Medline] 41. Greene JS, Giddings NA, Jacobson JT: Effect of irradiation on guinea pig ABR thresholds. 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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
, 
, 
), after therapy (CRT-IA: 
; CRT-IV, 
2 test). In 2007, 55% of all ears that qualified for HAs (of the 25% of patients that were still alive and in our follow up), actually received (or planned to receive) a hearing aid, given that they suffered dysfunctional hearing capability after treatment. 
