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Journal of Ear, Nose and Throat Disorders

Cite this article: Smith N, Schellack N, Ehlert K, Gous AGS (2017) Understanding Ototoxicity in Paediatric Oncology Patients at a Large Teaching Hospital in South Africa. J Ear Nose Throat Disord 2(3): 1029.

*Corresponding authorNatasha Smith, Department of Pharmacy, Sefako Makgatho Health Sciences University, BMS Building, N310, Molotlegi Street, Ga-Rankuwa, 0208, South Afric, Tel: 27082-465-4239; Email: sweet.

Submitted: 19 May 2017

Accepted: 29 August 2017

Published: 31 August 2017

ISSN: 2475-9473

Copyright© 2017 Smith et al.

OPEN ACCESS

Keywords•Ototoxicity•Paediatric•Oncology•Chemotherapeutic agents•Therapeutic drug monitoring

Abstract

Background: Chemotherapy with platinum compounds and aminoglycosides are extensively used in the treatment of paediatric cancers. With increasing survival rates, changes in hearing and cochlear function in paediatrics should be evaluated. Monitoring ototoxicity with distortion product otoacoustic emissions (DPOAEs) and pure-tone audiometry (PTA) is recommended in ototoxicity screening protocols. Literature pertaining to how these patients should be screened and followed up is limited.

Method: Baseline and serial measurement of DPOAEs (1 to 8 kHz) would be conducted. When necessary serial measurements of PTA with extended-high frequency (EHF) audiometry (9 to 20 kHz) were performed. Audiological data would be descriptively analyzed to determine the incidence and severity of ototoxicity.

Results: A total of 27 patients were enrolled over a period of eleven months. However, only 16 patients completed the study, aged three months to 16 years, who were treated with Cisplatin/Carboplatin/Vincristine/Vinblastine or Amikacin. The majority (69%) of patients received single chemotherapeutic agents. DPOAEs and PTA with EHF indicated changes in auditory function. Overall, the majority (81%) of participants passed the overall DPOAE, however significant changes in DPOAE’s were evident.

Conclusion: The most important finding of the study points to the fact that although paediatric patients treated with chemotherapeutic agents pass DPOAE assessments, significant changes occur in the amplitude of DPOAEs, and has implications with regard to academic achievement, speech, language and social development. These are important considerations, especially in paediatrics under five years of age and influence quality of life.

ABBREVIATIONSABR: Auditory Brainstem Response; AIDS: Acquired

Immunodeficiency Syndrome; ALL: Acute Lymphocytic Leukemia; CEO: Chief Executive Officer; DGMAH: Dr George Mukhari Academic Hospital; DPOAE: Distortion Product Otoaccoustic Emissions; EHF: Extended-High-Frequency; HIV: Human Immunodeficiency Virus; NDoH: National Department of Health; NICHD: National Institute of Child Health and Human Development; PTA: Pure-tone audiometry; SA: South Africa; SMU: SefakoMakgatho Health Sciences University; TB: Tuberculosis; TDM: Therapeutic Drug Monitoring.

INTRODUCTION

Chemotherapeutic agents

The treatment of a disease or cancer, using chemical agents or drugs that are selectively toxic to the causative agent of the disease, such as a virus, bacterium or other microorganism [1,3].

Ototoxicity

The tendency of certain substances to cause functional impairment and cellular damage to the tissues of the inner ear and especially to the end organs of the cochlear and vestibular divisions of the eight cranial nerve [3].

Research Article

Understanding Ototoxicity in Paediatric Oncology Patients at a Large Teaching Hospital in South AfricaNatasha Smith1*, Natalie Schellack1, Katerina Ehlert2 and Andries GS Gous1

1Department of Pharmacy, Sefako Makgatho Health Sciences University, South Africa2Department of Speech-Language, Pathology and Audiology, Sefako Makgatho Health Sciences University, South Africa

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Therapeutic drug monitoring (TDM)

The mathematical relationship between a drug dosing regimen and its resulting serum concentrations (pharmacokinetics).The relationship between drug concentrations at the site of action and the resultant pharmacologica lresponse (pharmacodynamics).The use of serum drug concentrations to optimise drug therapy in individual patients, in conjunctionwith their clinical status and response to therapy [4].

The vast majority of patients diagnosed with paediatric cancer are from low- and middle-income countries. The majority of paediatrics from these countries have very limited access to health care [5,6]. The incidence of paediatric cancer in South Africa (SA) represents around 1% of all cancers in the population [7,8]. Cancer registries are relatively limited [8]. Of the African population, only 2% is covered by cancer registries [9].

The current standard treatment for paediatric malignancies are the platinum compounds, cisplatin and carboplatin [10-12]. Although these drugs have been proven to have higher survival rates [13-15], they do present with numerous side-effects, in this case ototoxicity, that negatively impact the quality of life [13,16,17]. Health care professionals in SA should therefore be trained and be knowledgeable on information regarding certain treatment regimens that cause ototoxicity [17-20].

Treatment regimens that cause hearing loss as an adverse effect is a known risk factor [18,22], and patients receiving chemotherapy for cancer are at a higher risk for ototoxicity and require specific attention and monitoring [20,3]. Paediatric patients are at a critical stage of growth in which hearing loss can impact speech, language development and literacy negatively [24-26]. Hearing loss in the high-frequencies also has an impact on educational achievement, social-emotional development, and quality of life [24,25].

Ototoxicity is described as damage to the basal region of the cochlea (where the higher frequency sounds are coded) and damage can further progress to the apex of the cochlea (where the lower frequency sounds are coded). The outer hair cells are affected first followed by the inner hair cells as the damage progresses throughout the whole cochlea [27,28].

SAas a developing country is burdened with a high incidence of Human Immunodeficiency Virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS), tuberculosis (TB), malaria

[29] and malnutrition [30]. The majority of the disease burden in SA is communicable diseases, with non-communicable diseases, such as cancer, often being noted to be less of a priority [29]. A recent study showed that HIV-positive children in SA were at high risk of developing cancer with overall incidence rateof 82/100000 person-years [31]. The pathogenesis of HIV-related malignancy is related to several factors. HIV deteriorates the immune system, thus diminishing the body’s innate tumour surveillance ability, much in the way that immunosuppressive agents put transplant patients at risk of malignancy [32].

Among the many alterations and/or complications that HIV can cause, directly or indirectly, alterations in the auditory system are often neglected. Hearing loss of several types (conductive, sensorineural, and mixed) in individuals affected by this virus

can be associated with opportunistic infections, ototoxic drugs, and the direct action of the virus upon the auditory system. In HIV-infected individuals a significant cause of mortality and morbidity is cancer, and according to statistics up to 40% will develop a malignancy during their lifetime [33]. Certain types of cancer affect HIV-positive people and are those established as AIDS-defining: Kaposi’s sarcoma, non-Hodgkin’s lymphoma, and invasive cervical cancer [33]. The audiological and otologic complaints most commonly reported in children infected by HIV, with or without hearing loss, are otalgia, otorrhea, vertigo, and buzzing in the ears [34].

Trends

International research collectively shows the survival rate of paediatric oncology is increasing [25,35-37]. Further to this, ototoxicity following chemotherapy with platinum compounds are common worldwide [8,17,38] and can often progress long after the completion of treatment [38]. The severity of ototoxicity might be more severe in younger pediatric patients who have been exposed for a longer time to the ototoxic agent [39. In SA there is no dedicated research performed on paediatrics treated in the oncology unit focussing on ototoxicity. In SA a need for ototoxicity monitoring has been identified hence highlighting the need for this study [20].

National core standards

In 2011, the National Department of Health (NDoH) of SA established the domain of patient safety, clinical governance and clinical care, which provided guidelines on how to ensure quality nursing and clinical care and ethical practice, how to reduce unforeseen harm to health care users or patients in identified cases of greater clinical risk, how to prevent or manage problems or adverse events and support any affected patients or staff [40].

According to the NDoH, core standards for patient safety is a main responsibility of the health care provider, but also includespromoting health, reducing further patient complications and ensuring that adverse events are identified and managed through an effective, integrated patient management plan [40]. A closer look at identified medications that cause ototoxicity and are used regularly in the paediatric oncology unit is needed. Various authors identified that the health care worker in SA should become an active member of the health care team in the management of ototoxicity [18-21].

It is therefore the responsibility of the health care provider to ensure that pharmacotherapy-induced ototoxicity, identified as part of patient safety incidents, is instantly identified and managed to minimize patient harm and loss of hearing, and to ensure that early hearing loss is routinely investigated and managed to prevent repetition and to learn from those identified [40]. There is a need for disciplines to work together to serve the need for ototoxic monitoring among the community, with the potential to improve the quality of life for oncology patients.

Aims and objectives

The study aimed to determine the incidence and severity ofototoxicity following the use of chemotherapeutic agents and calculate the pharmacokinetics and pharmacodynamics of

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amikacin and/or vancomycinin the paediatric oncology unit at a large tertiary academic hospital.

MATERIALS AND METHODS

Study design

A quantitative cohort study was performed prospectively.

Study site

The study was conducted at a large teaching hospital in SA. Dr George MukhariAcademic Hospital (DGMAH) is a rural public sector academic hospital (teaching facility) with 1,500 active beds and utilizes a paper-based patient management system.The study was conducted over a period of 11 months, from 1 October 2015 to 30 September 2016.

The baseline visit took place mostly in the oncology ward and, in some instances, in the surrounding paediatric wards before a patient received any ototoxic medication. Follow-up visits were also performed in the oncology unit. PTA with EHF took place at the Audiology Department. This facility is based at the SefakoMakgatho Health Sciences University (SMU), which is situated close to the DGMAH but required patients to be wheel-chaired out of the hospital.

Study population and sampling

All paediatric participants up to the age of 18 years, who provided informed consent and initiated on chemotherapeutic agents, were included in the study. A total of 27 patients, who met the inclusion criteria, were screened for eligibility. Purposive sampling was done to include all paediatrics that met the following inclusion criteria: All paediatric participants up to the age of 18 years, whose legal guardian provided informed consent and initiated on chemotherapeutic agents with no previous history of any ototoxic medication, were included in the study. Paediatrics seven years and older also provided assent and willingly agreed to partake in the research study.

Study procedure and duration

Paediatric patients who were newly admitted and initiated on chemotherapeutic agents were recruited. Ethical consent and assent (where applicable) was obtained. Subsequent to this, screening was done.

i.) Otoscopy/DPOAE: The audiologist performed a baseline otoscopy and DPOAE assessment. In the instance where a patient’s baseline DPOAE referred, tympanometry was performed to rule out middle ear pathology. A 24-hour follow-up assessment was performed; where after weekly follow-up assessments were performed.

ii.) ABR/Tympanometry: In the instance where a patient’s DPOAE referred, weekly assessments and other measurements were done, such as tympanometry and/or Auditory Brainstem Response (ABR). In the instance where a patient was stable and out of danger for infection the patient was referred to the Audiology Department for PTA with EHF.

iii) Audiology: The Otoport Advance® was used for all screening applications as well as advanced diagnostic testing. Regular calibration ensured reliable data and was performed

during October 2015 to September 2016. This instrument is an all-purpose DPOAE instrument with customisable protocols including optimised paediatric modes. An option exists for simple “pass” and “refers’ results, however, this study made use of the option for detailed data display and diagnostic testing. A constant display of signal-to-noise ratio ensures reliability of the data. The protocol used for diagnostic purposes consisted of a 13-frequency clinical DPOAE. This protocol is frequency-specific and starts at 1000Hz and ends at 8000Hz. The research used a binary scale (refer/pass). In order to qualify as a pass outcome, the signal-to-noise ratio was > 6db. For a DPOAE to be considered a pass, nine or more of the 13 frequencies should pass, whereas a fail is considered when less than nine of the 13 frequencies pass. The results obtained are more effective and reliable when a participant is asleep or is in a content state and is in a quite environment.

iv.) Ototoxicity monitoring: Ototoxicity monitoring before, during, and after treatment is an important component in the early detection and management of hearing loss in young cancer patients [42,43].

The standards for monitoring ototoxicity are baseline and serial measurement of pure-tone hearing thresholds within the conventional frequency range of 0.25 to 8 kHz. EHF audiometry (10 to 20 kHz) and DPOAEs are audiologic tests that are more sensitive to initial ototoxic damage. EHF audiometry and DPOAEs may detect changes in cochlear or auditory function before ototoxicity affects hearing at frequencies important for speech recognition. Platinum ototoxicity initially affects the sensory cells within the basal region of the cochlea, where high-frequency sounds are processed and changes in hearing are usually first detected in the highest audible frequencies [44]. For the purpose of this study, decreases in DPOAE greater than 8 dB SPL were considered a significant clinical change to report ototoxicity.

Data analysis

All data were captured on Microsoft Excel™ spread sheets and were checked for accuracy and completeness by a second person. Corrections were made prior to data analysis. Data were statistically analysed in consultation with a statistician via a Statistical Analysis System® using SAS® Release 9.3. Demographic and clinical data were expressed as frequency percentages, with confidence intervals, where feasible, and as means, medians, inter-quartile ranges, minimum and maximum values, where appropriate.

Ethical considerations

DGMAH is affiliated to SMU and approval to conduct the study was obtained from the Research Ethics Committee (SMUREC/H/137/2015: PG) before commencement of the study. Permission to conduct the study was requested and obtained from the Chief Executive Officer (CEO) of DGMAH and the Head of the Paediatrics Department. The parents of the participants were provided with a study information leaflet and the information was also verbally transferred. Written informed consent, which was translated into the local language, was obtained. In the instance where a participant was seven years or older, the assent form was utilized to obtain assent from the potential research participant him/herself.

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The term “vulnerable population” refers to the disadvantaged sub-segment of the community requiring utmost care, specific ancillary considerations and augmented protections in research [45]. The vulnerable population refers to, but is not limited to children and minors [45] as per inclusion criteria for this research study. The research team ensured that all potential benefits and risks were reasonably balanced and risks were minimized. Interventions or procedures that hold out the prospect of direct diagnostic, therapeutic or preventive benefit for the individual subject were justified by the expectation that they were at least as advantageous to the individual subject, in the light of foreseeable risks and benefits, as any available alternative [46]. Confidentiality and anonymity of patient information were maintained throughout the study. Participants were allocated study numbers to ensure confidentiality and anonymity.

RESULTSPatient enrolment

Initially 27 patients who met the inclusion criteria were enrolled. More than half (n=16, 59%) of the patients were evaluable. The remaining number of patients (n=11, 41%) were in evaluable for various reasons: one patient received the first dose of chemotherapy before baseline audiometry could be performed, two patients were transferred to other hospitals, one patients’ parents refused hospital treatment, one patient was unable to be tested after baseline and six patients had no confirmed cancer diagnosis. These patients were therefore excluded from the research and data were evaluated for the remaining 16 patients. Of the evaluable patients, three (19%) also completed EHF audiometry.

Patient demographics

The total number of evaluable patients (n=16) enrolled were between 3 months and 16 years of age at their baseline hearing evaluation and classified according to the National Institute of Child Health and Human Development (NICHD) [47] (Table 1). The majority of patients were male (56%) and the entire population were black (100%). The most common diagnosis was: acute lymphocytic leukaemia (n=4) followed by Hodgkin’s lymphoma (n=3). The remainder of patients were treated for rhabdomyosarcoma (n=2), osteosarcoma (n=2), nephroblastoma (n=2), acute myeloid leukaemia (n=1), plasmoblastic lymphoma (n=1) and fibrosarcoma (n=1). The majority of patients were treated with vincristine (69%), the remainder of patients was treated with vinblastine (13%), cisplatin (6%), carboplatin (6%) and just less than a half (44%) received amikacin. Two patients had radiation after chemotherapy. One patient was HIV-positive. The mean length of stay was 98.88 (±91.82) days with an average of 9.25 (±7.39) visits for hearing assessments.

The evaluable group was divided into different treatment groups: Exposure to a single agent and exposure to combination therapy. Combination therapy included exposure to a combination of two agents: cisplatin and amikacin; vincristine and amikacin; and exposure to a combination of three agents: carboplatin, vincristine and amikacin.

Chemotherapeutic agents and audiological assessments

The patients received chemotherapeutic agents as part of

the treatment regimens as set out by hospital oncology policy documents. Only the selected agents will be described as part of the inclusion criteria. The majority of the patients (n=11, 69%) received a single agent (Table 2). Of these patients, six (55%) patients received vincristine, three (27%) received vinblastine and two (18%) received amikacin. The average dose for vincristine per cycle was 1.25mg (±0.59 mg) and the cumulative dose 3.29mg (±3.04mg), for vinblastine 5.37mg (±0.90mg) per cycle and a cumulative dose of 14.47mg (±4.73mg) as for amikacin a daily dose of 20.5mg/kg.

Significant changes in DPOAE for one ear was observed in two patients (18%), one received vincristine, and the other vinblastine. Significant changes in DPOAEs for both ears were observed in five patients (45%), of these patients two received vincristine, one received vinblastine and two received amikacin. Significant changes in DPOAEs for either ear were observed in four patients (36%), and the majority received vincristine. Refer to Table 2.

Study patient 8 was a 3-month old baby with nephroblastoma and severe thrombocytopaenia, PTA could not be performed due to age and instead an ABR was performed that showed no site of lesion. Study patient 9 had normal hearing up to 2000 Hz with a mild slope from 4000-8000 Hz in the right ear, the left ear was normal. A contributing factor might be hesitant participation which can affect behavioral results. The remainder of the patients either passed the overall DPOAE or had other contributing factors that led to the patients not being referred for PTA.

It is important to note that study patients 18, 20 and 26 had significant changes in either one or both ears at certain frequencies but still passed the overall DPOAE. Patients 19, 21, 22 and 23 had head and neck cancers that were situated close to the ear, which likely affected the DPOAE results in the specific affected ear. These patients were still enrolled and followed-up and results were obtained for the ears which were not affected by the site of the tumors. Patient 24 had measureable results in the left ear, and while assessing the patient further for reliable baseline, the patient demised.

The remaining five (n=31, 25%) received combination therapy (Table 3). The majority of these patients (n=3, 60%) received combination 1, vincristine and amikacin, one (20%) patient received combination 2, cisplatin and amikacin and one (20%) patient received combination 3, carboplatin, vincristine and amikacin. The cumulative dose for cisplatin was 434mg in combination with 760mg amikacin. The average cumulative dose of vincristine was 5.8mg (±3.62) in combination with amikacin 318.3mg (±120.7). The cumulative dosages of combination 3 were carboplatin 960mg, vincristine 15.7mg.

The average number of visits for DPOAE hearing assessments in this group was 16.6 (±9.45) over a period of 11 months and conventional frequencies with EHF were performed on two (40%) patients in this group. For study patient 13 no reliable results could be obtained due to severe otitis confirmed by tympanometry shortly after the patient was transferred to another hospital and thus loss to follow-up. The remaining four eligible patients had significant changes in DPOAEs in both ears.

Study patient 1 had normal hearing bilaterally for both

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Table 1: Patient demographics.

Parameter All patients (n=27)

Evaluable patients (n=16)

Exposure to a single agent

Exposure to a combination of two agents

Exposure to a combination of three agents three medicines

Age (no & %):Mean (± SD)Median (IQR)According to NICHD:Foetal Stage Infancy stage (birth to 12 months)Toddler stage (13 months to 2 years) Early childhood (2 to 5 years)Middle childhood (6 to 11 years)Early adolescence (12 to 18 years)Late adolescence (19 to 21 years)

7.29 (±4.44)8.00

04 (14.81%)1 (3.70%)4 (14.81%)13 (48.15%)5 (18.52%)0

7.66 (±4.37)8.00

02 (12.50%)03 (18.75%)8 (50.00%)3 (18.75%)0

GenderMaleFemale

17 (62.96%)10 (37.04%)

9 (56.25%)7 (43.75%)

Ethnic group:Black 27 (100%) 16 (100%)HIV Status:PositiveNegative

2 (7.41%)25 (92.59%)

1 (6.25%)15 (93.75%)

MedicineAs a single agentVincristineVinblastineAmikacinCombinationsCisplatin & amikacin Vincristine & amikacinCarboplatin, vincristine & amikacin

7 (43.75%)2 (12.50%)2 (12.50%) 1 (6.25%)

3 (18.75%)1 (6.25%)

Diagnosis:NoneRhabdomyosarcoma (RM)Acute Myeloblastic Leukemia (AML)Osteosarcoma (OS)Juvenile Dermatomyositis*Nephroblastoma (NB)Haemophilia*Acute Lymphocytic Leukemia (ALL)Hodgkins Lymphoma (HL)Plasmoblastic Lymphoma (PL)Fibrosarcoma (FS)

2 (7.41%)4 (14.81%)2 (7.41%)4(14.81%)1 (3.70%)2 (7.41%)3 (11.11%)4 (14.81%)3 (11.11%)1 (3.70%)1 (3.70%)

2 (12.50%)1 (6.25%)2 (12.50%)

2 (12.50%)

4 (25.00%)3 (18.75%)1 (6.25%)1 (6.25%)

Length of stay:Mean (± SD) 98.88

(±91.82)Number of visits:Mean (± SD)Median (IQR)

9.25 (±7.39)6.50

RM: Rhabdomyosarcoma; AML: Acute Myeloblastic Leukemia; OS: Osteosarcoma; NB: Nephroblastoma; ALL: Acute Lymphocytic Leukemia; HL: Hodgkins Lymphoma; PL: PlasmoblasticLymphom; FS: Fibrosarcoma*Patients had more than one diagnosis/comorbid conditions

conventional and EHF. Study patient 3 had normal conventional frequencies up until 2000 Hz where after the audiogram dips severely from 2000 to 8000 Hz. This patient also showed severe to profound hearing loss in the EHF bilaterally. Study patient 7 was too young to be evaluated with PTA. Study patient 15 was not ambulant and in isolation for most of the hospital stay and was therefore not referred for PTA.

For the study population seven (44%) patients received amikacin (Table 4) empirically. These patients received an

average dose in mg/kg of 20.57mg (±0.53 mg). Of these patients a full kinetic and dynamic profile could be done for four (57%) of the patients. Kinetic and dynamic profiles could not be done on the remaining patients due to in evaluable peak and trough levels. Study patient 7 had severe thrombocytopaenia at the time, which made it difficult to draw extra blood samples for TDM. The average true peak value for this population was 24.40ug/ml (±23.95) and the average true trough was 4.56ug/ml (±5.72). Other kinetic parameters were as follows: the average half-life of amikacin in this study population was 5.60h (±6.48) and the

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Dia

gnos

is

Pati

ent

RVD

Exp

osed

Gend

er

Age

BSA

(m2 )

Vincristine (mg/m2)

Vinblastine (mg/ m2) Amikacin

Tota

l num

ber

of

visi

ts fo

r he

arin

g as

sess

men

t

Oto

toxi

city

con

ven-

tion

al fr

eque

ncie

s

Sign

ifica

nt c

hang

es in

O

AEs

Oto

toxi

city

EH

F

Per

cycl

e

Cum

ulat

ive

at la

st d

ose

Per

cycl

e

Cum

ulat

ive

at la

st d

ose

Dos

e (m

g/kg

)

Dos

e (m

g)

NB 8 No F 3/12 0.27 0.2 0.6 3 None Right NoOS 9 No M 7 0.75 20.5 400 7 Yes Both YesHL 18 No M 8 0.82 4.9 19.8 9 None Both NoAML 19 No M 9 0.86 20.5 450 9 None Both* NoHL 20 No M 6 0.80 4.8 10.8 9 None Left NoRM 21 No F 11 1.17 1.75 8.16 6 None Both* NoPL 22 Yes M 13 1.00 1.4 1.4 6 None Neither* NoHL 23 No M 13 1.07 6.4 12.8 6 None Neither* NoALL 24 No M 4 0.63 0.95 1.9 3 None Neither* NoALL 26 No M 9 0.98 1.5 6 6 None Both NoFS 27 No F 9 1.13 1.7 1.7 2 None Neither No

N=11

N=3 females (27.27%);N=18 males (72.72%)

8.11 (±3.78)

0.86 (±0.26)

1.25(±0.59)

3.29 (±3.04)

5.37 (±0.90)

14.47(±4.73) 20.5 425

(±35.36)6 (±2.49)

Abbreviations: M: Male; F: Female; NB: Nephroblastoma; OS: Osteosarcoma; HL: Hodgkins Lymphoma; AML: Acute Myeloblastic Leukemia; RM: Rhabdomyosarcoma; PL: Plasmoblastic Lymphoma; ALL: Acute Lymphocytic Leukemia; FS: Fibrosarcoma

Table 2: Chemotherapy and Audiological assessments for patients treated with a single agent.

Dia

gnos

is

Pati

ent

HIV

Exp

osed

Gend

er

Age

BSA

(m2 )

Combination 1 Combination 2 Combination 3

Tota

l num

ber

of v

isit

s fo

r he

arin

g as

sess

men

t

Oto

toxi

city

con

vent

iona

l fr

eque

ncie

s

Sign

ifica

nt c

hang

es in

O

AEs

Oto

toxi

city

EH

F

Cisplatin (mg/m2) Amikacin Vincristine

(mg/m2) AmikacinCarbopla-tin (mg/m2)

Vincristine (mg/m2)

Ami-kacin

Per

cycl

e

Cum

ulat

ive

at

last

dos

e

Dos

e (m

g/kg

)

Dos

e (m

g)

Per

cycl

e

Cum

ulat

ive

at

last

dos

e

Dos

e (m

g/kg

)

Dos

e (m

g)

Per

cycl

e

Cum

ulat

ive

at

last

dos

e

Per

cycl

e

Cum

ulat

ive

at

last

dos

e

Dos

e (m

g/kg

)

Dos

e (m

g)

RM 1 No F 6 0.64 320 960 1.9 15.7 20 320 27 Yes Both YesOS 3 No M 16 1.2 144 434 19 760 24 Yes Both YesNB 7 No F 9/12 0.4 0.3 2.4 20.5 185 14 None Both NoALL 13 No F 3.5 0.62 0.9 5.4 20 350 3 None NRR NoALL 15 No F 8 0.79 1.2 9.6 21.5 420 15 None Both No

N=5

n=4 females (80%); n=1 male (20%)

6.85 (±5.79)

0.73 (±0.30)

0.8 (±0.46)

5.8 (±3.62)

20.67 (±0.76)

318.3 (±120.7)

16.6 (±9.45)

Abbreviations: [M: Male; F: Female; NB:Nephroblastoma; OS: Osteosarcoma; RM: Rhabdomyosarcoma; ALL: Acute Lymphocytic Leukemia; NRR: No Reliable Results]

Table 3:Chemotherapy and Audiological assessments for patients treated with combinations of therapy.

average volume of distribution was 0.39l/kg (±0.39). Significant changes in OAEs were observed in both ears for the entire study population that received amikacin as part of combination therapy.

DISCUSSIONThis study evaluated the possible ototoxic effects of

chemotherapeutic agents used in paediatrics treated at an oncology unit. From the initial eligible patients, more than half (59%) were evaluated. More than 50% (56%) were male and all of the participants were African. Seemingly males have a higher susceptibility to develop cancer [48]. The patients were

on average seven years old at diagnosis and were classified as middle childhood (6 to 11 years) according to the NICHD [47]. The average age of paediatrics at diagnosis differs for the various types of childhood cancer. For instance, embryonal tumors (such as neuroblastoma, retinoblastoma and nephroblastoma) and acute lymphoblastic leukaemia (ALL)are most prevalent in paediatrics under five years of age, whereas bone tumours are very rare in younger children, increasing in incidence with age and peaking in adolescence [49].

Patients were dosed according to hospital ward oncology protocol which is based on The National Guidelines of Paediatric

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Stud

y

Gend

er

Age

Wei

ght (

kg)

Dos

e (m

g)

Dos

e (m

g/kg

)

Peak

(ug/

ml)

Trou

gh (u

g/m

l)

True

Pea

k (u

g/m

l)

True

Tro

ugh

(ug/

ml)

K v

alue

T1/2

Vd (l

)

Vd (l

/kg)

Sign

ifica

nt c

hang

-es

in O

AE

Inte

rven

tion

Yes

/N

o

1 F 5 16 320 20 2.3 1.3 - - - - - - Both- No

3 M 16 40 760 19 50 12.4 53 12 0.062 11.22 18.35 0.459 Both Yes

7 F 0.9 9 185 20.5 - - - - - - - - Both No

9 M 7 19.5 400 20.5 9.9 2.5 - - - - - - Both Yes

13 F 3.5 17.2 350 20 33.3 10.4 36 10 0.055 12.55 13.27 0.771 Both Yes

15 F 8 19.5 420 21.5 29.9 10.2 32 9.9 0.051 13.59 18.45 0.946 Both Yes

19 M 9 22 450 20.5 22.3 0.01 49.8 0.01 0.375 1.85 11.73 0.533 Both Yes

Reference Range 20-40 <10 4-8 0.4-0.6

N=7

N=4 females (57.14%); N=3 males (42.86%)

Mean (±SD)

19.91 (±8.28)

20.57 (±0.53)

412.14 (±176.35)

24.40 (±23.95)

4.56 (±5.72)

0.03 (±0.03)

5.60 (±6.48)

8.83 (±8.61)

0.39 (±0.39)

Abbreviations: M: Male; F: Female

Table 4: Amikacin Therapeutic drug monitoring.

Oncology and Haematology (2016) [50]. Four (25%) of the patients were diagnosed with ALL and this is the most prevalent type of cancer in paediatrics across the world [49,51,52]. The treatment regimen is in line with the National Guidelines of Paediatric Oncology and Hematology (2016) [50]. To this effect, the majority of the patients (n=11, 69%) were treated with a single agent (e.g. vincristine or an antibiotic, e.g. amikacin).On the contrary combination chemotherapy is the mainstay of treatment for most childhood cancer, either alone or in combination with surgery and radiotherapy [7]. The remainder (31%) of the study population received combination therapy (e.g. cisplatin and amikacin, or vincristine and amikacin), the majority (80%) received vincristine as part of the combination therapy.

The average number of visits for DPOAE hearing assessments in this group was six (±2.49) over a period of 11 months. More than 60% (69%) of the patients experienced significant changes in DPOAE, where one or more of the 13 frequencies were affected. A decrease in the amplitude of a DPOAE greater than 8 dB SPL was considered a significant clinical change to report ototoxicity [44]. A decrease in DPOAEs at frequencies of 4000-6000 Hz will affect speech discrimination and therefore will have detrimental effects on the language development of the affected paediatric patient [53].

Conventional pure tone audiometry is a behavioural test and requires a response from the patient [44]. In this study, as with other paediatric studies, the patients were either too young to be tested and in other instances too ill [44] and unable to leave the hospital ward to go to the Audiology Department for testing, hence the small number of patients (19%) that could be referred for PTA.

Just less than half of the patients (44%) received amikacin in combination with anti-neoplastic agents. Paediatric patients

receiving anti-neoplastic agents often require antibiotic therapy (e.g. amikacin) for complications and thus expose the patient to an additional ototoxic agent [54]. A full kinetic and dynamic profile could be done for the majority (57%) of the patients treated with amikacin. The average true peak value for this population was 24.40ug/ml and the average true trough was 4.56ug/ml. Literature pertaining to aminoglycoside kinetics and dynamics in the paediatric oncology population is limited, and hence a study conducted in 1996 showed an average peak concentration of 31.3ug/ml on day 2 of measurement. The average trough was lower than the results found in this research, where it was a trough of 1.1ug/ml. Kinetic parameters were also in/out of range for the study population: the average half-life of amikacin in this study population was 5.60 (±6.48), the average volume of distribution (in liters) was 8.83(±8.61).

CONCLUSION AND RECOMMENDATIONSPaediatric patients receiving chemotherapy are at risk of

developing ototoxicity as an adverse effect of the medication. Simultaneous use with other ototoxic medications, such as amikacin further affects the cochlear function of the patient. The pharmacist, audiologist and doctor as part of the health care team treating and caring for these patients, should be aware of these effects and manage them as far as possible to improve the therapeutic outcome for the patient.

Results obtained highlighted the fact that significant changes in the amplitudes of DPOAEs were seen in the majority of patients treated with chemotherapeutic agents.

Assessing DPOAEs will always be sensitive to noise. The use of equipment that is more tolerable to noise, such as the machine used for screening in this research study, is recommended. For the same purpose of reliable results it is recommended that hearing assessments are performed in a noise-controlled area however

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assessments were challenging at times as patients treated in the oncology unit were often in isolation rooms and could not be moved to a less noisy environment. The treatment that patients underwent also had an influence on DPOAE measurements as patients were connected to an intravenous infusion set. These sets and other monitors influenced DPOAE measurements as noise levels increased. Subsequently, re-testing had to be done on more than one occasion and results were often delayed.

Although the research was conducted at a tertiary academic referral hospital, the sample size for this study was small. Patients admitted to the hospital were often severely immunocompromised and very ill at the time of arrival to the hospital. The severity of disease when admitted to the hospital played a role on baseline measurements when patients had to be moved to go for PTA with EHF testing at the Audiology Department.

Another major influence was excluding patients from the study as they either failed a baseline audiometry or received chemotherapy before a baseline could be performed. Patients who were transferred from surrounding hospitals were, in some instances, treated before they were initially seen by the oncology multidisciplinary team (doctor, pharmacist and audiologist). The loss to follow-up was also problematic as patients were transferred to other hospitals closer to their homes or parents of patients refused hospital treatment.

For future studies it is recommended that research be conducted on both an experimental and control group. For this study, the patients served as their own control from a baseline and follow-up assessment. For the purpose of this study only selected chemotherapeutic agents were investigated. It would be suggested to include all chemotherapeutic agents, even those less likely to cause ototoxicity, as this will also increase the number of patients that would be included and enrolled into the research. Therefore, the sample size of future research should be large enough to allow for deviations in data. Previous longitudinal studies have reported a lower level of communication, socialization and motor function of paediatric cancer patients compared to their peers which is linked to the illness and treatment as well as hearing function [55]. It would be advisable to follow this population for longer periods of time, which will enable more results and possible patterns of hearing deviations and cochlear damage identified at an earlier stage.

ACKNOWLEDGEMENTSAudiologists at Doctor George Mukhari Hospital for assistance

with screening and further testing when required.

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Smith N, Schellack N, Ehlert K, Gous AGS (2017) Understanding Ototoxicity in Paediatric Oncology Patients at a Large Teaching Hospital in South Africa. J Ear Nose Throat Disord 2(3): 1029.

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