Distortion product otoacoustic emissions: An objective technique for the screening of hearing loss in children treated with platin derivatives.
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Ingeborg Dhooge, Catharina Dhooge*, Sven Geukens, Bieke De Clerck, Eddy De Vel and Bart M. Vinck
Univ.-HNO-Klinik Heidelberg, GermanyENT Department, Department of Pediatric Hematology and Oncology *
Ghent University Hospital, Ghent Belgium
Published in
Int J Audiol. 2006 Jun;45(6):337-43. |
1. INTRODUCTION
The platinum-containing chemotherapeutic agents play a key role in the treatment of selected pediatric solid tumors. The administration of cisplatin is complicated by long-term sequelae such as high frequency (HF) sensorineural hearing loss (SNHL). Carboplatin, an analogue of cisplatin, has also proven antitumor activity but is less nephrotoxic and less ototoxic than cisplatin (Stern and Bunin 2002).
Monitoring ototoxicity during therapy is usually performed by means of repeated pure tone audiometry. Various degrees (grade 0-4) of hearing loss can be scoredusing the Brock grading system (Brock et al 1991). However, this technique has three major drawbacks:
1) Ototoxic effects often show their first impact in the frequency regions above 8000 Hz.
2) In young children pure tone audiometry is often problematic.
3) The Brock scale assumes normal hearing at baseline which may not always be the case.
This retrospective study was designed to examine the efficacy of DPOAEs as an objective alternative to HF pure tone audiometry in the detection of ototoxic SNHL due to treatment with standard doses of platin derivatives in a pediatric and young adult population.
2. Materials and Methods
Thirty-four children and young adults treated for cancer at the Pediatric Division of Hematology and Oncology at the Ghent University Hospital were included.
Sixteen patients were formerly treated with standard doses of cisplatin (six patients) or carboplatin (eight patients) or both (two patients). Indications for chemotherapy were neuroblastoma (NB, three patients), hepatoblastoma (one patient), teratocarcinoma (one patient), rhabdomyosarcoma (RMS, three patients), PNET-CNS (4 patients), osteosarcoma (one patient) and nephroblastoma (three patients).
Besides cisplatin and or carboplatin, chemotherapy schedules consisted of high dose of methotrexate, ifosfamide, cyclofosfamide, vincristine, etoposide, adriamycin, bleomycin, actinomycin and epirubicin depending on the type of cancer.
Eighteen patients, who did not receive platin derivatives, served as controls. Both groups received similar antibiotic treatment schedules and the same schedules for febrile neutropenia.
Nephrotoxicity was measured by means of glomerular filtration rate of creatinine (GFR crea) using the Schwartz formula. Patient characteristics are listed in Table 1.
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Platin treated group |
Controls |
Number
Mean age at diagnosis
Mean age at audiologic protocol
Mean follow-up post therapy
Sex
Creatinine levels (Schwartz formula)
Complaints (vertigo, tinnitus)
Otoscopy
Mean cumulative dose of cisplatin
Mean cumulative dose of carboplatin |
16
5.08 yrs
9.6 yrs (2.3 Ð 26 yrs)
3.3 yrs
9M/ 7F
94mL/ min /1.73 m2 *
none
normal
580 mg/m2(400-720)
2226 mg/m2 |
18
4 yrs
15.6 yrs (3.75 Ð 29.8 yrs)
11.4 yrs
9M/ 9F
87mL/ min /1.73 m2*
none
retraction of the TM** in 1
-
- |
* p: ns (ANOVA)
**TM : tympanic membrane
Normal otoscopy and immittance parameters were considered to be mandatory for inclusion into the test protocol.
Standard air and bone conduction pure tone threshold audiometry was carried out in a sound treated booth using an Interacoustics AC40 clinical audiometer (calibration: ISO389, 1975). The modified Hughson-Westlake technique was applied. High-frequency air conduction audiometry was tested with the same audiometer using Koss HV/Pro digital high frequency headphones. Pulsed pure tones were presented at 8000, 10000, 12500 and 16000 Hz.
Instrumental conditioned reflexes (ICR) were used in children under the age of 3 years. Six frequencies (250, 1000, 4000, 10000, 12500 and 16000 Hz) were tested in this group to approximate the degree of hearing loss.
DPOAEs were recorded using the Otodynamics Analyzer (ILO-96 Research version) with a frequency ratio of 1.22 and two stimulus levels of 75-70 and 65-55 dB SPL, obtaining the 2f1-f2 DP-GRAM. The DPOAE ranged from f2 frequencies comprised between 1001 and 6165 Hz, using an eight point per octave resolution. The criterion for a valid DPOAE response was a 2f1-f2 level of 3 dB above noise floor.
3. RESULTS
Fig 1 shows the mean thresholds for all groups (control and the three treatment subgroups). The mean amplitude of the DP-grams as a function of f2 frequency is shown in Fig 2 . There was a significant difference between the cisplatin group and every other group, for the mean audiometric thresholds, as well as for the response levels for all f2 frequencies of 3088 Hz and above.
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Further analysis of the audiometric data of the cisplatin group was carried out using the classification of Brock et al (1991). The risk for developing ototoxicity, i.e. grade of HF hearing loss, increases with the cumulative dose of cisplatin (significant Spearman-rank correlation of .74, p < 0.05). The importance of the cumulative dose explains the absence of substantial HF hearing loss in the carboplatin/cisplatin subgroup where the cumulative cisplatin dose did not exceed 560 mg/m2.
The grade of toxicity and cumulative cisplatin dose received are shown in Table 3. A significant correlation of .83 (Spearman-rank correlation, p < 0.05) was found between 2f1-f2 response level and cumulative cisplatin dose. Patients who had received a low or median dose (< 600 mg/m2) had significantly better DP-grams (p < 0.0001) as compared to patients who had received 600 mg/m2 or more.
Finally, a Pearson correlation analysis of these data showed a highly significant correlation of .82 (p < 0.01) between audiometric data and DPOAE amplitude.
Table 2: classification of cisplatin-induced bilateral high-frequency hearing loss according to Brock et al. (1991), the grade of toxicity and the cumulative cisplatin dose received.
Bilateral hearing loss
|
Grade |
Designation |
Number of children |
Cumulative dose of cisplatin mg/m2 |
< 40 dB at all frequencies |
0 |
None |
1 |
400 |
³ 40 dB at 8000 Hz only |
1 |
Mild |
1 |
550 |
³ 40 dB at 4000 Hz and above |
2 |
Moderate |
2 |
650 |
³ 40 dB at 2000 Hz and above |
3 |
Marked |
2 |
710 |
³ 40 dB at 1000 Hz and above |
4 |
Severe |
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4. DISCUSSION
Monitoring for ototoxicity is essential in the management of cancer patients treated with possible ototoxic agents. Early detection is important for adjusting treatment. If further damage is unavoidable, early rehabilitative measures can be taken.
An association between the cumulative cisplatin dose and incidence of hearing impairment was confirmed in our group of patients. HF audiometry is more sensitive to ototoxic damage compared to conventional pure tone audiometry. For the carboplatin group no significant pure tone hearing losses were found, nor for the patients treated with a combination of cisplatin and carboplatin.
The moderate cumulative doses given for carboplatin in our patient group, the intersubject variability in susceptibility to ototoxicity and the fact that the dose of carboplatin per course was low, may explain the absence of ototoxicity in these patients. (Freilich et al 1996; Parsons et al 1998; Watanabe et al 2002).
Several authors argument the use of DPOEAs in assessing cochlear function after cisplatin chemotherapy (Zorowka et al 1993; Littman et al 1998; Ress et al 1999; Stavroulaki et al 2001). Our observations confirm the results in these studies, in that DPOAEs correlate extremely well with the audiometric data. It is however important to stress that, though their response levels seem higher than the controls, the OAE responses obtained from the carboplatin patients and carboplatin-cisplatin patients are within normal ranges and do not differ significantly from each other.
A significant reduction was only observed in the cisplatin group. Monitoring ototoxicity with the use of DPOAEs is particularly useful in the follow-up of young children and infants because it is a non-invasive method, fairly rapid to administer and easy to use. Otoacoustic emissions are not influenced by subjective interpretations, making this technique highly reproducible and more precise than audiometry.
REFERENCES
Brock P.R., Bellman S.C., Yeomans E.C.; Pinkerton C.R. & Pritchard J. 1991. Cisplatin ototoxicity in children: a practical grading system. Med Pediatr Oncol, 19, 295 Ð 300.
Freilich R.J., Kraus D.H., Budnick A.S., Bayer L.A. & Finlay J.L. 1996. Hearing loss in children with brain tumors treated with cisplatin and carboplatin-based high-dose chemotherapy with autologous bone marrow rescue. Med Pediatr Oncol, 26, 95 Ð 100.
Littman T.A., Magruder A. & Strother D.R. 1998. Monitoring and predicting ototoxic damage using distortion-product otoacoustic emissions: pediatric case study. J Am Acad Audiol,. 9, 257Ð262.
Parsons S.K., Neault M.W., Lehmann L.E., Brennan L.L., Eickhoff C.E., et al. 1998. Severe ototoxicity following carboplatin-containing conditioning regimen for autologous marrow transplantation for neuroblastoma. Bone Marrow Transplant, 22, 669 Ð 674.
Ress B.D., Sridhar K.S., Balkany T.J., Waxman G.M., Stagner B.B. & Lonsbury-Martin B.L. 1999. Effects of cis-platinum chemotherapy on otoacoustic emissions: The development of an objective screening protocol. Third placeÑResident Clinical Science Award 1998. Otolaryngol Head Neck Surg, 21, 693Ð701.
Stavroulaki P., Apostolopoulos N., Segas J., Tsakanikos M. & Adamopoulos G. 2001. Evoked otoacoustic emissions--an approach for monitoring cisplatin induced ototoxicity in children. Int J Pediatr Otorhinolaryngol, 59, 47 Ð 57.
Stern J.W. & Bunin N. 2002. Prospective study of carboplatin-based chemotherapy for pediatric germ cell tumors. Med Pediatr Oncol, 39, 163 Ð 167.
Watanabe K.C., Jinnouchi K., Hess A., Michel O., Baba S. & Yagi T. 2002. Carboplatin induces less apoptosis in the cochlea of guinea pigs than cisplatin. Chemotherapy, 48, 82 Ð 87.
Zorowka P.G., Schmitt H.J. & Gutjahr P. 1993. Evoked otoacoustic emissions and pure tone threshold audiometry in patients receiving cisplatinum therapy. Int J Pediatr Otorhinolaryngol, 25, 73 Ð 80.
About the Author
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Dr. Bart Vinck, is the Director of the ENT Dept., University of Ghent and was born in Aalst Belgium in 1963. He received his MS and PhD degrees in logopedical and Audiological Sciences, from the University of Ghent. His scientific activity is dedicated to objective audiometry (otoacoustic emissions and auditory evoked potentials) Parallel to this, he is also deeply involved in audiology education and the training of students and professionals. He is the author of more than 22 international articles in peer-reviewed journals.
Address:
ENT Department,
Ghent University Hospital, Ghent Belgium
E-Mail: bart.vinck@ugent.be
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