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ORIGINAL ARTICLE
Year : 2016  |  Volume : 3  |  Issue : 1  |  Page : 9-15

Early detection of changes to hearing status attributed to treatment regimen with ototoxicity in the state of Qatar


Otolaryngology Section, Audiovestibular Unit, Department of Surgery, Hamad Medical Corporation, Doha, Qatar

Date of Web Publication28-Sep-2016

Correspondence Address:
Zainab Al Musleh
Consultant Hearing and Balance Disorders, MBBS, Arab Board Otolaryngiology, Doha-Qatar, Hamads General Hospital, PO box 3050
Qatar
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2314-8667.191236

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  Abstract 

Background
Ototoxicity resulting from cisplatin chemotherapy constitutes a significant clinical problem and challenge. Therefore, an early and effective detection of hearing loss in pediatric oncology patients receiving ototoxic medication and early intervention are critical to help these patients in achieving these developmental milestones and improving their quality of life.
Materials and methods
This prospective, observational study was designed as an initial pilot study to collect and analyze data from January 2014 to January 2015 on a variety of parameters. All pediatric patients, aged less than 14 years, referred from the Pediatric Hematology/Oncology Clinic to the new Ototoxic Clinic were included in the study. Descriptive statistics were used to summarize the above data, and associations between two or more qualitative variables were assessed using the χ2-test or Fisher's exact test as appropriate.
Results
A total of 20 patients were included in the study. Diagnostic otoacoustic emission findings were found to be normal in 14 patients (80%); four patients (20%) had abnormal findings, and in two cases this test was not carried out. High-frequency audiometry test indicated that nine (52.9%) patients had normal findings, whereas five (29.4%) had abnormal results. High-frequency audiometry could not be carried out for six (30%) patients because of their ages. Hearing loss involving the speech frequencies affected only two patients (10%; 95% confidence interval 1.7–29.3); they were diagnosed to have β-thalassemia and retinoblastoma and are currently using xjade and cisplatin.
Conclusion
Early and effective identification of ototoxicity is vital in children receiving cancer treatments because of the impact acquired hearing loss has on social and educational outcomes in children. This study highlights the role of early detection of hearing loss in pediatric patient receiving ototoxic medication and of possible potential interventions to enhance their quality of life during and after treatment.

Keywords: hearing status, oncology, ototoxicity, pediatric population


How to cite this article:
Al Musleh Z, Al Suliteen M, Hadi K, El Abbadi M, Omar W, Ali A, Al Amin A, Alsufi M, Alnajar N, Ahmed N. Early detection of changes to hearing status attributed to treatment regimen with ototoxicity in the state of Qatar. Adv Arab Acad Audio-Vestibul J 2016;3:9-15

How to cite this URL:
Al Musleh Z, Al Suliteen M, Hadi K, El Abbadi M, Omar W, Ali A, Al Amin A, Alsufi M, Alnajar N, Ahmed N. Early detection of changes to hearing status attributed to treatment regimen with ototoxicity in the state of Qatar. Adv Arab Acad Audio-Vestibul J [serial online] 2016 [cited 2019 Jul 23];3:9-15. Available from: http://www.aaj.eg.net/text.asp?2016/3/1/9/191236


  Introduction Top


Any drug with the potential to cause toxic reactions to structures of the inner ear, including the cochlea, vestibule, semicircular canals, and otoliths, is considered ototoxic [1],[2]. Drug-induced damage affecting the auditory and vestibular systems can be called, respectively, cochleotoxicity and vestibulotoxicity. Although ototoxicity can result from occupational and/or environmental exposure to ototoxins, the majority of cases result from drug therapy [3]. The benefits of ototoxic drugs must be weighed against their potential for permanent damage to the inner ear.

Permanent hearing loss or balance disorders caused by ototoxic drugs can have serious vocational, educational, and social consequences. These effects may be minimized, or even prevented, if the ototoxic process is detected early during treatment. An effective monitoring program should detect ototoxic damage before the patient becomes aware of the ototoxic symptoms. Such an early detection allows healthcare providers to consider treatment alternatives such as modifying drug dosage or changing to a less toxic drug to slow or halt the progression of inner ear damage. Unfortunately, monitoring for ototoxicity is not a common practice and measurement procedures tend to be inconsistent, largely because guidelines specifying patient selection, monitoring methods, and criteria for interpreting results do not exist [4],[5].

Because symptoms of ototoxicity are poorly correlated with drug dosage, peak serum level, and other toxicities, the only way to detect ototoxicity is by assessing auditory and vestibular function directly. Initial ototoxic drug exposure typically affects cochlear region coding at high frequencies. Continued exposure results in a spread of damage to progressively lower frequencies. A variety of drugs, such as certain powerful antibiotics and some antineoplastic drugs generally used against (potentially) life-threatening diseases, can cause auditory and/or vestibular dysfunction. Auditory damage can include permanent hearing loss and tinnitus secondary to sensorineural degradation. In general, the site of lesion is almost exclusively cochlear, and balance dysfunction may derive from comparable degeneration. A given drug may not have equal affinity for the two systems; hence there is a need to consider both. Currently, ototoxicity monitoring is most clearly established for peripheral auditory function, but there remain significant gaps in knowledge that preclude the formulation of a standard of practice in this area per se. Yet, the existence of substantial information on ototoxicity monitoring allows (a) evaluating the overall efficacy of current clinical methods for ototoxicity monitoring; (b) justifying inclusion of this area in the audiologist's scope of practice; and (c) developing useful ototoxicity monitoring programs for clinical and research applications. The dual purpose of this document is thus to provide a position statement on the clinical audiologist's role in ototoxicity monitoring and guidelines for the implementation of an ototoxicity monitoring program.

Audiologic monitoring for ototoxicity is primarily carried out for two purposes: (a) early detection of changes to hearing status presumably attributed to a drug/treatment regime so that changes in the drug regimen may be considered, and (b) audiologic intervention when handicapping hearing impairment has occurred. These clinical goals are differentiated in the following.

The term ‘ototoxicity monitoring’ is generally taken to express the principle of early identification, and yet the concept also embraces the principle of early intervention. For example, when changes are detected early, the physician can be alerted so that the alternative treatment protocols, possibly with less ototoxic medications, may be considered. Furthermore, when clinically significant changes occur, especially hearing deterioration that has migrated into the speech frequencies, the purpose of a monitoring program becomes to assist the patient and/or patient's family to maintain effective communication, especially as hearing loss progresses. Unfortunately, this degree of hearing impairment may be unavoidable even with proactive ototoxicity monitoring, as priority is the effective treatment of the disease via the given drug therapy.

These two major objectives of an ototoxicity-monitoring program often may create substantially different roles for the audiologist than does conventional practice [6], as it makes clear that it would be advantageous for audiologists to be well aware of the same sort of considerations of the environment in which the patient is being sought and/or examined, as the logistical issues are not trivial. For example, oncology nurses are essential contact persons for the successful implementation of ototoxicity-monitoring protocols for cancer chemotherapy patients, just as recognizing key nursing personal in well-baby and newborn intensive care nurseries is essential for successful implementation of newborn hearing screening programs. At the same time, the audiologist's native skills and talents are/should be paramount in the establishment and management of the program, including in-service education and certainly the interpretation of results.

Once ototoxicity-monitoring protocols are established, the audiologist can accomplish the second objective of such scrutiny – that is, the management of a case of hearing loss that is not treatable medically. Such assistance to the patient/patient's family may include counseling, communication strategies, and prescribing amplification and/or assistive listening device(s).

Only the audiologist is endowed by their professional training with the ability to achieve both objectives of ototoxicity monitoring. The audiologist thus should take the lead in developing ototoxicity-monitoring programs, driven by the dual goals, again, of preventing or minimizing hearing loss and helping the patient to maintain the most effective hearing communication possible. These clearly are important ‘quality of life’ issues and quality of life is now recognized as global imperatives, whatever the medical management. Consequently, that the patient may suffer a serious and possibly life-threatening illness does not diminish the importance of these issues.

Audiologic monitoring for ototoxicity has been a very active area of research. Still, it is worth concluding this section with a brief note. Namely, ongoing work at a number of clinical and research centers are generating results that provide or are expected to permit comparisons among monitoring and analysis techniques for a variety of patient populations. Furthermore, new drugs are being developed, which appear to have excellent therapeutic efficacy without ototoxic side effects [7]. Still, other drugs and dietary supplements are being evaluated specifically to prevent ototoxicity when delivered either before or in combination with ototoxic drugs [8],[9],[10],[11],[12]. The results of research on otoprotectants might lead to the assumption that the need for ototoxicity monitoring will disappear with effective ototoxicity prevention. It seems more likely, however, that monitoring will be essential to ensure effectiveness of such counter measures.

Treatment with ototoxic medications can cause hearing loss with potential social, emotional, and vocational consequences. The early detection of ototoxic-induced hearing loss is therefore essential to patients and their healthcare providers, including those patients who are unable to provide reliable behavioral responses. Ototoxicity monitoring provides opportunities to consider alternative treatment regimens to minimize or prevent hearing loss progression. Audiological management of such patients can be an integral part of a therapeutic treatment plan, improving quality of life during and after treatment. Having in mind the hearing alterations caused to those patients who use ototoxic agents, it becomes paramount to monitor their hearing, thus allowing for an early diagnosis and identification of the lesion progression. This study aimed to increase the audiologist's awareness of ototoxicity and the importance of comprehensive audiological monitoring. This research has the potential to improve patient hearing care and consequently improve their quality of life.


  Objectives Top


Primary objectives

  1. Early detection of hearing loss in patients receiving ototoxic medication.
  2. More specifically, early detection of hearing loss in patients aged 0–14 years and diagnosed to have hematology or solid tumor receiving ototoxic drugs.


Secondary objectives

  1. To provide us with a statistical data about how common is the hearing loss after ototoxic medication in Qatar (prevalence).
  2. Pattern of ototoxicity in Qatar.
  3. Early intervention of hearing loss as it will improve quality of life and save a lot of money in case of patients with profound hearing loss, starting from the fitting of hearing aid, programming, audio verbal therapy, and ending to cochlear implant surgery as well as vestibular rehabilitation dilemma.



  Materials and methods Top


Study design and sample size

This prospective, observational study was designed as an initial pilot study to collect and analyze data from January 2014 to January 2015 on a variety of parameters.

Patients included in this study were those referred from the Pediatric Hematology/Oncology Department to newly ototoxic clinic specialized in treating such patients.

All pediatric patients aged younger than 14 years, those referred from Pediatric Hematology/Oncology Department to newly ototoxic clinic from January 2014 to January 2015, and those who fulfilled the inclusion and exclusion criteria listed below and gave a informed consent to participate were included in the study.

This research study was approved by the research and ethics committees of institution (11158/11).

Eligibility criteria

Eligibility criteria included (a) age younger than 14 years; (b) presentation with otoxicity features; and (c) referred from Pediatric Hematology/Oncology to newly specialized ototoxic clinic.

Data collection tools and methods

A database was developed to capture and store all data contained in the data capture form (DCFs). The following data were collected using the DCF:

  1. Demographics, patient medical history, and clinical examination findings (ENT).
  2. Audiological test, which included otoscopy, tympanometry, acoustic reflex, high-frequency audiometry, diagnostic otoacoustic emission (OAE), auditory brainstem response, speech test, and vidionystagmography.
  3. Subjective tests, which included conventional audiogram, high-frequency audiogram, and the determination of speech discrimination score.
  4. Objective tests, which included acoustic impedance tests, acoustic emittance tests, frequency-specific auditory brainstem-evoked response, diagnostic OAE testing, and electronystagmography when applicable.
  5. Direct communications were conducted with the nurse assigned to follow-up these patient results to allow correction of the dose or changing the regimen.


Timeline for monitoring tests

  1. First visit: before administration of the ototoxic medication.
  2. Second visit: between 24 and 72 h after administration.
  3. Then monitoring was carried out once a week during the treatment course immediately before the initiation of each new treatment cycle.


At the completion of treatment

  1. Follow-up assessment took place at 2, 4, 12 weeks, and 6 months.
  2. In case of any hearing loss detected during monitoring, the patient was asked to attend follow-ups on a daily basis.


Introduced over the years, many hearing loss grading scales were used for the diagnosis of hearing loss secondary to ototoxic medication.

Grading scale of hearing loss

  1. Children Oncology Group (COG), ACNS0332 for high-risk medulloblastoma.
  2. Children Cancer Group (CCG), A9961 for average-risk medulloblastoma.
  3. COG, ARET0321 for extraocular retinoblastoma.
  4. COG, AGCT0132 for germ cell tumors.


In case of a disparity between ears, the grading should reflect the better ear.

Ototoxic medications administered to the patients were (a) carboplatin, (b) cisplatin, (c) amikacin, and xjade.

Mechanisms for data collection

Research coordinators and research assistants were identified and the procedures for data collection, entry, storage with password-protected access, and data validation were established. Original DCF hard copies were maintained securely with a patient unique identifying number. Once all data had been entered into the database, to be used for statistical analysis, it was audited by investigators and the research coordinators. Data verification, validation, and evaluation of accuracy were carried out at regular intervals. Quality of data (review of completeness, accuracy, security, and confidentiality of data) was maintained by lead investigators and assigned research coordinators. All missing fields were verified as truly not available.

Statistical analyses

Categorical and continuous values were expressed as frequency (%) and mean ± SD or median and range, as appropriate. Descriptive statistics were used to summarize demographic, clinical sign and symptoms, audiological measurements and findings of the patients. Associations between two or more qualitative variables were assessed using the χ2-test or Fisher exact test as appropriate. The results were presented along with 95% confidence interval. Pictorial presentations of the key results were made using appropriate statistical graphs. A two-sided P value less than 0.05 was considered statistically significant. All statistical analyses were carried out using statistical packages SPSS, 22.0 (SPSS Inc., Chicago, Illinois, USA) and Epi Info 2000 (Centers for Disease Control and Prevention, Atlanta, Georgia, USA).


  Results Top


The results of this study are presented mainly in two sections. First, the details of pretreatment assessments obtained from patients’ files are presented, followed by the audiometric data collected from the post-treatment assessments. Among 77 cases admitted at HMC with different malignancies and hematological disorders, a total of 20 patients (seven cases with a history of different oncology disorders, 12 cases with history of thalassemia major, and one case of sickle cell disease) from January 2014 to January 2015 were included in this study with suspected ototoxic hearing loss. Of the 20 patients reported, 10 were boys (50%) and 10 were girls (50%), giving a male to female ratio of 1: 1, and one patient (5%) was a Qatari national. Their mean age was 3.9 ± 3.7 years (median 2 years; range 3 months–13 years).

Careful history was obtained from the patient using medications carboplatin, cisplatin, amikacin and xjade during their treatment course and follow-up. Fifteen (75%) of the cases were found to have a history of ototoxic medication exposure previously. On the other hand, none of the cases had previously complained of sudden sensory neural hearing loss or history of noise exposure. Only two (10%) patients had reported history of renal and liver diseases. Among the 20 patients included in the study, 17 patients (85%) had completely normal otoscopy findings, whereas the remaining three patients (15%) were found to have abnormalities such as bilateral retracted tympanic membrane, congested right ear canal, and right dull tympanic membrane. Tympanometry results showed that 15 (75%) patients had normal type A while five patients (25%) had abnormal results either for type B or type C ([Figure 1]).
Figure 1 Evaluation before, during and after treatment.

Click here to view


Despite the fact that normal pure tone audiometry was documented for 11 patients (78.6%), abnormal results were obtained for three patients only (24.4%), as they had decreased hearing on right ear at 8 kHz only, bilateral mild conductive hearing, and hearing loss on the right ear at 6 and 8 kHz. In addition, six patients (30%) did not undergo this test because of their age, as we could not obtain the result from them; they were tested by using auditory brainstem response, which is normal for four tested frequencies. Of these 20 patients, diagnostic OAE findings were found to be normal in 14 (80%) patients; four patients (20%) had abnormal findings and in two cases this test was not carried out. High-frequency audiometry indicated that nine (52.9%) patients had normal findings, whereas five (29.4%) had abnormal results. High-frequency audiometry could not be performed in six (30%) patients because of their ages. Among these 20 patients, there was no evidence of imbalance, accordingly no Video computerize NystaGmogram (VCNG) records for them.

Hearing loss involving the speech frequencies affected only two patients (10%; 95% confidence interval 1.7–29.3); at the same time, these patients reported to have hyperacusis; on top of this, only one patient (5%) complained of tinnitus. Hearing loss was documented in two patients, as they were diagnosed to have β-thalassemia and retinoblastoma, and they were put under a dose of xjade and cisplatin. All the patients with documented hearing loss had no pre-existing sensory neural hearing loss, history of previous noise exposure, or renal and/or liver diseases. Only one patient in this study underwent a medical intervention by adjusting the chemotherapy dose with a tapered oral steroid treatment.

The percentage of the normal OAE findings was higher among patients who had normal pure tone audiometry findings compared with abnormal pure tone audiometry findings (8/11, 72.7% vs. 0/2, 0%; P = 0.256). Similarly, the percentage of the normal OAE findings was significantly higher among patients who had normal high-frequency audiometry findings compared with abnormal high-frequency audiometry findings (7/8, 87.5% vs. 2/4, 50%; P = 0.473). There was no significant association between sex and documented hearing loss (male 2/10, 10% vs. female 0/10, 0%; P = 0.474). Although it was not statistically significant, the percentage of normal otoscopy (1/2, 50% vs. 6/6, 50%; P = 0.250) and diagnostic OAEs findings (1/2, 50% vs. 6/6, 50%; P = 0.250) were found to be less in patients who had documented hearing loss compared with patients who did not have documented hearing loss.


  Discussion Top


There is no doubt that hearing monitoring in patients exposed to ototoxic medication, by means of highly sensitive and specific procedures, is vital for the early identification of hearing alterations. This statement is even more pertinent for the pediatric population undergoing treatment with potentially ototoxic medication, since hearing may seriously compromise their speech acquisition and development and, consequently, bring about difficulties in their psychosocial and learning development.

Thus, auditory assessment is essential for patients exposed to high doses of chemotherapeutic agents, for ototoxicity identification and rehabilitation purposes. Hearing tests and assessments should be carried out before and after the onset of ototoxic medication use, so that the patient may be appropriately followed up for better management and enhancing the quality of care. We should also stress the significance of always communicating and asking both the patient and his/her family about the recent use of ototoxic drugs, family or personal history of hearing impairment, and pay close attention to the use of another concurrent ototoxic drug. Such information is very useful to effectively examine and assess possible and potential risk factors for hearing loss.

There is a need to add details about clinical findings and compare it with other relevant studies available in the literature (ENT and audiology news). The clinical manifestations of the lesion may be variable; cochlear or vestibular damages can occur separately or in combination, producing tinnitus, dizziness, or hearing impairment. The symptoms can develop suddenly or gradually; they can be permanent, transient or progressive, predominantly bilateral or unilateral [13]. In the current study, only cochlear damage was reported and there was no evidence of vestibular damage; symptoms developed gradually, bilateraly, and it was permanent damage in affected patients.

How good is high-frequency testing? When researchers compared testing high frequencies versus testing conventional frequencies, one study revealed that 52% of the hearing loss cases were first detected in the high-frequency range only. That study revealed that more than half of the people with drug-induced hearing loss have hearing loss that was not detected by using the conventional means. If only high-frequency hearing testing had been done, 67% of all the ears demonstrating initial hearing loss due to ototoxicity would have been found [14]. In the current research, all cases of hearing loss were first detected in the high-frequency range only. In another research, evoked OAEs and extended high-frequency audiometry were more sensitive to initial ototoxic changes than was standard pure tone audiometry 12, 13, and these results will be reported in a future article [15].

Limitations

The fact that baseline measurements are often difficult to obtain for pediatric patients, particularly for very ill patients, and, in addition, that obtaining true auditory thresholds (response to lowest intensity level) can be challenging in pediatric patients were the limitations of this study. Instead, only minimal response levels are often obtainable, which makes calculating a true decrease in hearing sensitivity difficult and potentially inaccurate. Fewer subjects were recruited in the present study because of the following: patients not responding to calls; patients not attending follow-up appointments despite rescheduling several times; some non-Qatari patients leaving the country; and others refusing to participate in the study.


  Conclusion Top


Early and effective identification of ototoxicity is vital in children receiving cancer treatments because of the impact that acquired hearing loss has on social and educational outcomes in children. Close monitoring of hearing in children presents challenges that are unique to this pediatric population. Monitoring should be carried out, as it provides early evidence of dose limits for hearing loss, thus allowing for preventing or mitigating ototoxicity severity. This study highlights the role of early detection of hearing loss in pediatric patients receiving ototoxic medication and provides the initial data on the occurrence of hearing loss and possible potential interventions to enhance their quality of life during and after treatment. We hope that this study will increase audiologists’ awareness of the impact of ototoxicity and the importance of comprehensive audiological monitoring with the potential of improving quality of life for oncology patients. More precise and accurate estimation of prevalence of hearing loss in pediatric patient receiving ototoxic medication and determinants needs further prospective studies with a larger sample size.

Acknowledgements

This research became a reality with love, kind support and guidance from wonderful people surrounding us. I want to offer this attempt to Allah Almighty for the insight he bestowed upon me, the power, strength and his guidance to finish this research. Dr Abdulla Al-Nasser, Senior Consultant, Head of Pediatric Hematology – Oncology, was always there to help and cheer us up all the time. Thanks Dr Al-Nasser, for your support and constant patience. Thanks also to Dr Prem Chandra, Medical Research Center, Hamad Medical Corporation, for his continued support in statistical analysis and writing. Finally, I would like to express my thanks to the amazing audiology staff whom covering us with their help, love, and support.

Financial support and sponsorship

This study was supported by the Hamad Medical Corporation (ref. no. 11158/11).

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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Blakley BW, Cohen JI, Doolittle ND, Muldoon LL, Campbell KC, Dickey DT, Neuwelt EA. Strategies for prevention of toxicity caused by platinum-based chemotherapy: review and summary of the annual meeting of the Blood–Brain Barrier Disruption Program, Gleneden Beach, Oregon, March 10, 2001. Laryngoscope 2002; 112:1997–2001.  Back to cited text no. 12
    
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