Abstract
Cisplatin is a chemotherapeutic agent effective against head and neck carcinoma but unfortunately it is cochleotoxic. This study has been designed to investigate the efficacy of OAE in identifying early effects of cisplatin on the cochlea and the importance of protocol for audiological monitoring of cisplatin induced ototoxicity. This is a prospective observational study conducted from October 2012 to September 2014 on 70 patients, receiving Cisplatin for various malignant conditions. Audiological criteria for ototoxicity was considered as a difference of 10 d B or more in pure tone thresholds of two or more adjacent frequencies in conventional audiometry and in DPOAE-Signal noise ratio less than 6 dB or DPOAE amplitude less than 20 dBSPL (irrespective of SNR > 6 dB). According to PTA, 60.7% patients showed ototoxicity after completion of chemotherapy. In DPOAE, according to SNR and amplitude criteria more than 60% patients showed ototoxicity after first cycle of cisplatin at high frequencies (4–8 kHz). DPOAEs is a sensitive tool for early detection of ototoxicity and protocol is necessary for monitoring ototoxicity in patients receiving cisplatin to improve the quality of life.
Keywords: Cisplatin, Ototoxicity, Otoacoustic emission, OAE
Introduction
Ototoxicity is defined by Gray and Hawthorn [1], as the damage to cochlear and/or vestibular part of the inner ear by drugs.
Cisplatin is a chemotherapeutic agent effective against many solid tumours, including head and neck carcinoma. There are lots of chemotherapeutic agents nowadays which have less side effects but cisplatin is still more effective than most of these agents, and is also less expensive, so it is still being used widely in countries like India [2]. Ototoxicity is one of the main factors which limits the use of cisplatin.
Otoacoustic emissions (OAEs) are acoustic signals emitted from cochlea which is generated by active mechanical contraction of outer hair cells, spontaneously or in response to sound.
As the survival rates are increasing nowadays, attention is focused on ototoxicity by cisplatin aiming at its prevention and /or early detection. In order to achieve that, a protocol should be established that can be of high predictive value [3].
This study has been designed to investigate the efficacy of OAE in identifying early effects of cisplatin on the cochlea and the imporatance of protocol for audiological monitoring of cisplatin induced ototoxicity.
Methods
The study was conducted from October 2012 to September 2014 on 70 patients receiving Cisplatin for any malignant conditions without any active or recent ear diseases. All cases in this study were subjected to complete history taking and clinical examination followed by audiological examination with PTA, Immittance audiometry and DPOAE.
Baseline audiological evaluation was done prior to drug administration using Pure tone audiometry, Immittance audiometry including Tympanometry and acoustic reflex thresholds and DPOAE. Using PTA, air and bone conduction thresholds are calculated for both the ears from 250 Hz to 8 kHz in octaves for AC and 250 Hz to 4 kHz for BC).
Distortion product otoacoustic emissions (DPOAE’s)—is recorded with a microphone that is placed in the sealed external auditory canal. The sealed probe also includes tube for sound delivery to the ear canal. The microphone records all sounds in the ear canal which includes in DPOAEs, sound evoking the OAEs, and other patient—generated sounds. DPOAEs are formed in the cochlea in response to two simultaneous pure tone stimuli (primary tones). This tonal response is not present in the eliciting stimuli, and is therefore referred to as distortion. The primary tones (f1 and f2) are separated in frequency within one third octave (typically f2 = f1 × 1.2) and the distortion product is then typically at a frequency of 2 f1 − f2. Because the 2f1-f2 DPOAEs have been shown to originate from the region of the cochlea that maximally responds to the primary tones, DPOAEs are typically presented in a magnitude /frequency plot, in which frequency is determined by f2 (at low levels) or the geometric mean of f1 and f2, and magnitude is determined for the DPOAEs at the 2f1 − f2 frequency bin. This is called DP-gram [4].
In this study DPOAE’s were collected using custom software (Audera Grason Stadler PC software version 2.6.5.2116) run on a computer. The software utilized a card deluxe digital signal processing board to generate stimuli and record responses. The two DPOAE stimulus frequencies (f1 and f2, where f1 < f2) were separately digitized, delivered to sealed ear canal through separate ports in the probe assembly.
The probe also contained a microphone to record DPOAE responses. The signal recorded by microphone was amplified 20 dB by the ER-10B + preamplifier, digitized in 64-ms time windows, and stored in two interleaved buffers, which were averaged in the time domain.
The DPOAE level at 2f1 − f2 was estimated from a Fast Fourier transform of the grand average of two response buffers ([A + B]/2). Measurement—based stopping rules were used such that any test frequency, sampling stopped when the noise floor was < − 20 dBSPL.
Both DPOAE’s and stimulus levels were measured at the plane of microphone near the entrance to the ear canal. DPOAEs, response elicited using two tones, and intensity adjusted to 65/55 dBSPL. The frequencies tested ranged from 0.5 to 8 kHz.
DPOAE responses were considered valid and present if they met all of the following criteria:
DPOAE amplitude was greater than − 20 dBSPL, a conservative estimate of the system distortion.
DPOAE amplitude should be of at least 6 dB or greater than the measured noise floor.
The results of baseline evaluation are used as a reference criterion for comparison with post-therapy follow up evaluation.
Chemotherapy protocol used was a single agent Cisplatin [Cisplatin; Cipla, India] (40 mg/m2 weekly once for 4–6 weeks) along with radiation (Intensity modulated radiation therapy).
Follow up evaluations was repeated using PTA and DPOAES after scheduled chemotherapeutic dose regimen within 24 h of Cisplatin administration.Post treatment follow up monitoring is done after 1 month and 3 months to study a possible change in the amplitude of the response.
Audiological criteria for Ototoxicity was considered as a difference of 10 d B or more in pure tone thresholds of two or more adjacent frequencies in conventional audiometry [5] and DPOAE-Signal noise ratio less than 6 dB or DPOAE amplitude less than – 20 dBSPL (irrespective of SNR ratio).
Statistical Analysis
Mean, standard deviation and paired t test were used for statistical evaluation. Significance was accepted at the p ≤ 0.01. The results from the left and right ears were treated as independent data. Statistical software used is SPSS version 20 v.
Results
The study was conducted on 70 patients including 52 (74%) males and 18 (26%) females. The age of patients varied from 31 to 72 year. Twenty seven (38.6%) patients belonged to age group of 31–45 year, 30 (42.9%) patients belonged to 46–60 year, and 13 (18.6%) belonged to more than 60 year.
In this study males and females were separately compared with respect to right and left ears to study any significant difference among them.
In right ear of 52 male patients, average of pure tone thresholds was increasing at all frequencies during course of cisplatin,but it was statistically significant after completion of cisplatin course in 1 and 2 kHz; and from first cycle in 4, 6 and 8 kHz. In right ear of 18 female patients, average of pure tone thresholds was increasing at all frequencies during course of cisplatin, but it was statistically significant after completion of cycle in 1 kHz; after second cycle in 2 and 4 kHz and from first cycle in 6 and 8 kHz.
In left ear of 52 male patients, average of pure tone thresholds was increasing at all frequencies during course of cisplatin, but it was statistically significant after completion of cisplatin course in 1 and 2 kHz; and from second cycle in 4, 6 and from first cycle in 8 kHz. In left ear of 18 female patients, average of pure tone thresholds was increasing at all frequencies during course of cisplatin, but it was statistically significant after second cycle in 4 kHz and from first cycle in 6 and 8 kHz.
According to ASHA criteria, deterioration of pure tone thresholds of 10 dB or more at two or more adjacent frequencies is an ototoxic damage. In our study, 20.7%, 45%, 60.7% of ears showed ototoxicity after first cycle, second cycle and after completion of cycle respectively. After 1 month follow up, this increased to 66.4% and further after 3 months there was no change from results of 1 month follow up (Table 1).
Table 1.
Number of ears showing Ototoxicity based on ASHA criteria in PTA
| Course of cisplatin | No. of ears showing ototoxicity |
|---|---|
| After 1st cycle | 29 (20.7%) |
| 2nd cycle | 63 (45%) |
| After completion | 85 (60.7%) |
| 1 month | 93 (66.4%) |
| 3 month | 93 (66.4%) |
ASHA American speech hearing association, PTA pure tone audiogram
DPOAE-SNR Ratio Results
In right ear of 52 male patients, average of SNR ratio (DPOAE) was reduced at all frequencies during course of cisplatin, and statistically significant at all frequencies. In right ear of 18 female patients, average of SNR ratio (DPOAE) was reduced at all frequencies during course of cisplatin, and was statistically significant at all frequencies.
In left ear of 52 male patients, average of SNR ratio (DPOAE) was reduced at all frequencies during course of cisplatin, and statistically significant at all frequencies. In left ear of 18 male patients, average of SNR ratio (DPOAE) was reduced at all frequencies during course of cisplatin, and statistically significant at all frequencies (Tables 2, 3).
Table 2.
Number of ears showing ototoxicity based on criteria, DPOAE-Signal noise ratio less than 6 dB
| Frequency (kHz) | After 1st cycle | After 2nd cycle | After completion | After 1 month | After 3 month |
|---|---|---|---|---|---|
| 0.5 | 0 | 3 (2.1%) | 5 (3.6%) | 5 (3.6%) | 5 (3.6%) |
| 1 | 4 (2.9%) | 12 (8.6%) | 24 (17.1%) | 28 (20%) | 28 (20%) |
| 2 | 4 (2.9%) | 21 (15%) | 36 (25.7%) | 37 (26.4%) | 38 (27.1%) |
| 4 | 35 (25%) | 74 (52.9%) | 103 (73.6%) | 103 (73.6%) | 103 (73.6%) |
| 6 | 75 (53.6%) | 81 (57.9%) | 118 (84.3%) | 120 (85.7%) | 120 (85.7%) |
| 8 | 81 (57.9%) | 110 (78.6%) | 131 (93.6%) | 132 (94.2%) | 132 (94.2%) |
DPOAE distortion product otoacoustic emission
Table 3.
Number of ears showing Ototoxicity based on the criteria, DPOAE amplitude less than -20dBSPL (irrespective of signal noise ratio)
| Frequency(kHz) | After 1st cycle | After 2nd cycle | After completion | After 1 month | After 3 month |
|---|---|---|---|---|---|
| 0.5 | 0 | 3 (2.1%) | 5 (3.5%) | 5 (3.5%) | 5 (3.5%) |
| 1 | 0 | 7 (5%) | 13 (9.2%) | 13 (9.3%) | 13 (9.3%) |
| 2 | 1 (0.7%) | 13 (9.3%) | 26 (18.6%) | 26 (18.6%) | 28 (20%) |
| 4 | 32 (22.9%) | 65 (46.4%) | 95 (67.9%) | 95 (67.9%) | 96 (68.6%) |
| 6 | 62 (44.3%) | 90 (64.38%) | 106 (75.7%) | 111 (79.3%) | 111 (79.3%) |
| 8 | 82 (58.6%) | 103 (73.6%) | 125 (89.1%) | 125 (89.1%) | 125 (89.1%) |
DPOAE distortion product otoacoustic emission
In this study, more than 50% of ears of patients show ototoxicity at 6 and 8 kHz from first cycle of cisplatin and from second cycle at 4 kHz. Lower frequencies are affected in less than 27% of patients.
Dpoae Amplitude (dBSPL) Results
In right ear of 52 male patients, average of amplitude (DPOAE dBSPL) was reduced at all frequencies during course of cisplatin, and statistically significant at 1and 2 kHz. In higher frequencies as number of cases reduced p value was not significant.
In right ear of 18 female patients, average of amplitude (DPOAE-dBSPL) was reduced at all frequencies during course of cisplatin, and statistically significant (p 0.001) at all frequencies. In the left ear of 52 male patients, average of amplitude (DPOAE-dBSPL) was reduced at all frequencies during course of cisplatin, and statistically significant at 0.5, 1 and 2 kHz. At higher frequencies p value was not significant as number of cases was reduced. In left ear of 18 female patients, average of amplitude (DPOAE-dBSPL) was reduced at all frequencies during course of cisplatin and statistically significant at all frequencies except 8 kHz because number of cases was reduced.
This study shows ototoxicity in more than 45% of patients at 4 kHz from second cycle of cisplatin and from first cycle at 6 and 8 kHz.
Discussion
Anticancer drugs containing platinum are the basis for chemotherapy for a wide range of malignant tumours. Cisplatin, which is the first generation platinum drug is widely used and is very effective against many cancers. Cisplatin is used as a radiosensitizer as a standard protocol during concurrent radiotherapy [2]. Cisplatin (CDDP-cis diamine dichloroplatinum) was synthesized in 1845 by Peyrone and thereafter it was named as Peyrone’s chloride [6]. In 1978 cisplatin was approved as a chemotherapeutic agent by Food and Drug Administration (FDA) [7]. However, it is also considered to be the most ototoxic compound in clinical use [8]. It has been suggested that cause of the apical to base difference in outer hair cell sensitivity to ototoxic substances is because of the apical to basal differences in levels of intracellular antioxidants in the cochlea [9]. An ototoxic insult may affect the hearing, vestibular function or both, depending upon the type of chemical and its dose [10].
Though the risk for developing hearing loss from ototoxic drugs depends on the dose, duration, frequency, and route of administration, there is marked individual variability in these relationships [11] It has also been observed that concomitant exposure to other toxins such as noise, chemicals, other ototoxic medications as well as genetic factors and physiological factors can lead to increased rates of ototoxicity [12, 13]. This damage is in the form of functional impairment due to cellular degeneration of tissues of the inner ear and especially of the end organs and neurons of the cochlear and vestibular divisions of the eighth cranial nerve [14].
For incipient detection, change criteria developed by the American Speech Language Hearing Association (ASHA) and described in “Guidelines for the Audiologic Management of Individuals Receiving Cochleotoxic Drug Therapy” (ASHA 1994) are the most widely used (AAA 2009).
Otoacoustic emission (OAE) testing has been proposed as an objective indicator of ototoxic damage because OAE generation depends on the physiological status of the outer hair cells [15]. There are 4 types of Otoacoustic Emissions: Spontaneous otoacoustic emission, transient evoked otoacoustic emissions, distortion product otoacoustic emissions, stimulus frequency otoacoustic emissions [16]. The evoked otoacoustic emission is provided by a mechanism of electro motility observed in cochlear outer hair cells Distortion products are an objective method of hearing assessment that provides a rapid way to evaluate the functional status of the cochlea, so they are ideal for monitoring drug ototoxicity.
We studied the role of OAE in evaluating early detection of cisplatin induced ototoxicity in 70 patients. In this study PTA and DPOAE were used for detection of cisplatin induced ototoxicity.
After first and second cycle of chemotherapy there was no significant change in PTA hearing thresholds. After full course of chemotherapy there showed significant audiometric elevation of hearing thresholds at 4, 6 and 8 kHz in 42.9, 52.9 and 62.7% of patients respectively. After 1 month and 3 months of follow up there was no significant change in results. This result shows ototoxicity mainly in high frequency ranges which are consistent with the observations of Stavroulaki et al., who concluded that there was elevation of hearing thresholds at 4–8 kHz in children receiving cisplatin [3].
Durant et al. reported that frequencies above speech range were most severely affected in patients receiving cisplatin therapy [17]. It is also consistent with Hallmark et al. who found that among affected patients hearing loss was above speech range with no effect on the word discrimination score [18]. This was consistent with our results where high frequencies were more affected (4–8 kHz) from first cycle of cisplatin and lower frequencies (1and 2 kHz) were affected after completion of cisplatin course. After 1 month follow up there was increase in number of ears showing ototoxicity from 60.7% to 66.4%. While after 3 months there was no change in results compared with 1 month follow up.
While comparing with DPOAE amplitude, ototoxicity was seen after first course at 6 and 8 kHz in 44.3 and 58.6% of ears respectively, after second course at 4, 6 and 8 kHz in 46.4, 64.6 and 73.6% ears respectively and after completion of chemotherapy at 4, 6 and 8 kHz in 48.6, 68.6, 76.4 and 88.6% ears respectively. While considering the average of amplitude value among ears of patients with amplitude more than − 20dBSPL, there was decrease in amplitudes during course of cisplatin and it was statistically significant in all frequencies in both right and left ear.
According to SNR criteria of less than 6 dB for ototoxicity, 53.6% and 57.9% of ears showed ototoxicity at 4,6 and 8 kHz respectively after first cycle, 52.9%, 57.9% and 78.6% at 4,6 and 8 kHz after second cycle and 73.6%,84.3% and 93.6% showed ototoxicity at 4, 6 and 8 kHz after completion of course. In lower frequencies (0.5 2 kHz) less than 30% of ears were affected. While taking average SNR ratio, it was statistically significant (p < 0.001) in all frequencies from first cycle of cisplatin.
This study shows ototoxicity in high frequency range (4–8 kHz) where more than 50% of ears showed ototoxicity compared to the observations of Plinkert et al. where there was a reduction in overall response level of OAEs in patients treated with cisplatin [19]. These results show that the measurement of OAE makes it possible to detect cisplatin induced ototoxic effects, prior to any change in conventional audiometry.
Orts et al. showed that Cisplatin produced little effect on audiometric thresholds and an evident effect on the amplitude of distortion products which was consistent with this study [20]. In our study average PTA thresholds showed significant ototoxicity in more than 60% of patients after completion of course of cisplatin and it was statistically significant at higher frequencies (4–8 kHz). Based on DPOAE SNR ratio and amplitude criteria, ototoxicity is seen from first cycle in more than 60% of patients and it was statistically significant at all frequencies(0.5–8 kHz).
According to Biro k et al., in patients receiving Cisplatin dose of 300 mg/m2 or lesser than300mg/m2, no amplitude changes were detected. In patients receiving Cisplatin dose of 400 mg/m2 or more than 400 mg/m2 significant hearing impairment was detected at lower frequencies that are important for speech perception. At 400 mg/m2, significant amplitude change was detected at 3 kHz; at 500–600 mg/m2, significant amplitude change was detected at 1.5, 2 and 3 and at 700 mg/m2 significant amplitude change was detected at 3 kHz [21].
In this study significant amplitude changes were seen at all frequencies with cisplatin dose of 240–480 mg/ m2 but ototoxicity was proven according to DPOAE amplitude criteria in more than 60% of patients at high frequencies (4–8 kHz).
If hearing changes are identified, physicians may alter dosages or discontinue treatment with current medications, switch to less toxic medications, or continue treatment and prepare the patient and family to cope with hearing loss. If no hearing changes are noted, physicians may aggressively treat the disease. Early identification and monitoring of ototoxic hearing loss provides opportunities for counselling regarding communication strategies, the synergistic effects of noise exposure with ototoxic medication and implementation of auditory rehabilitation.
In designing treatment protocols, the health care professionals should consider the roles of hearing and balance in maintaining quality of life following therapy. Permanent hearing loss caused by ototoxic drugs can have serious vocational, educational, and social consequences. An effective monitoring program should detect ototoxic damage before the patient becomes aware of ototoxic symptoms.
Conclusion
Cisplatin produces bilateral, symmetrical sensorineural hearing loss affecting mostly high frequency range. The early detection of ototoxic induced hearing loss is therefore essential to patients undergoing chemotherapy with cisplatin. DPOAEs are a sensitive and time efficient tool for early detection of ototoxicity, which do not require behavioural response. Ototoxic monitoring provides opportunities to consider alternative treatment regimen to minimize or prevent hearing loss and its progression. If no hearing changes are noted, physicians may aggressively treat the disease with the same medication. Audiological management of such patients can be an integral part of therapeutic plan, improving the quality of life during and after treatment.
Cisplatin produces ototoxicity and DPOAE detects ototoxicity is a known fact. This paper proposes that DPOAE detects early ototoxicity and requires no behavioural response as compared to PTA. This paper also proposes to integrate audiological monitoring protocol for patients receiving Cisplatin. New born screening with OAE has been effective tool in diagnosing Deafness and managing thereafter, similarly monitoring ototoxicity by DPOAE protocol will help in improving quality of life of malignancy patients.
Summary
Cisplatin produces bilateral, symmetrical sensorineural hearing loss affecting mostly high frequency range
PTA detects ototoxicity only after completion of chemotherapy
DPOAEs are a sensitive and time efficient tool for early detection of ototoxicity, which do not require behavioural response.
Ototoxic monitoring protocol provides opportunities to consider alternative treatment regimen to minimize or prevent hearing loss and its progression or counsel the patient for continuation of chemotherapy.
Funding
This research received no specific grant from any funding agency, commercial or not-for-profit sectors.
Compliance with Ethical Standards
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical Statement
Ethics committee approval has been obtained from Institutional ethics committee for the study.
Informed Consent
Informed consent was obtained from all individual participants included in the study.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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