The Incidence and Risk Factors of Cisplatin and Carboplatin Ototoxicity in Pediatric Oncology Patients at Tertiary Oncology Center

Abstract

Pediatric cancers are relatively rare diseases when considering all types of cancer. Platinum-based chemotherapeutic agents are potent agents against a variety of pediatric malignancies. An important adverse effect of platinum-based agents is the occurrence of hearing loss. This hearing loss can pose a challenge to detect especially if the child is in his early of life. It will also significantly affect the child development of social, pedagogical, and personal dimensions. It is integral to identify incidence of platinum-based ototoxicity and risk factors that increase the likelihood of developing hearing loss in cancer children. We performed a retrospective chart review of 123 pediatric patients who had completed cisplatin and carboplatin therapy for a variety of malignancies. Patients were diagnosed at Princess Nourah Oncology Centre between January 2011 and December 2016, were less than 14 years old at diagnosis. Audiograms were scored using the International Society of Pediatric Oncology (SIOP) Boston Scale (0–4), a validated grading system for cisplatin-related hearing loss. Ototoxicity was reported in 16 patients out of 123 with a rate of 13%. The incidence of ototoxicity was highest in CNS tumors such as medulloblastoma (37.5%) and optic glioma (25%). Males were at greater risk for developing hearing loss than females. Cumulative cisplatin dose and addition radiation therapy were also identified as risk factors for development of ototoxicity (P = 0.008). Nature and location of cancer, gender, cumulative dose, and addition of radiation therapy are important clinical biomarkers of cisplatin ototoxicity.

Introduction

Childhood cancers are rare diseases that represent 0.5% and 4.6% of all cancers [1]. The overall incidence rate of childhood cancer varies between 70 and 160 per million children across the world [2, 3]. Several drugs including platinum-based anticancer agents, aminoglycosides, and loop diuretics are associated with damage to the inner ear and/or vestibular system leading to ototoxicity. Platinum-based agents which include cisplatin and carboplatin are effective chemotherapy agents against several pediatric malignancies. One of its significant side effects is ototoxicity which ranges from 22 to 70% [4].

The severity of hearing loss appears to be worse at high frequencies (4–8 kHz) and is related to the cumulative dose of cisplatin and carboplatin [5]. Other factors including age, concurrent medications, administration schedule, renal function, and cranial irradiation play a less clearly defined role. The degree of hearing loss is highly variable. Some children experience loss of only high-frequency hearing while others experience hearing loss at frequencies less than 4 kHz and require subsequent intervention with an assistive device [6]. The associated hearing loss tends to be permanent, and although most studies have found that the degree of hearing loss remains stable over time, there is some evidence that it may be progressive, even after discontinuation of cisplatin therapy. High-frequency hearing loss renders certain consonants inaudible and may compromise speech recognition and comprehension [7].

Given that hearing is an integral component of speech development, young children receiving cisplatin may be at risk for cognitive and psychosocial delays, delayed language development, and failure to thrive intellectually and socially. Moreover, hearing loss may lead to deleterious consequences, such as lack of vocabulary and syntax acquisition. In fact, it has been shown in several studies that children with even mild bilateral or unilateral hearing loss have more difficulty with language acquisition and often score more poorly in vocabulary and spelling than children with normal hearing capacity [8].

The purpose of this study is to determine the incidence, severity, and risk factors of cisplatin and carboplatin induced ototoxicity in the pediatric oncology patients at Princess Nourah Oncology Center, King Abdul Aziz Medical City, Jeddah, Saudi Arabia.

Methods

The Institutional Review Board at King Abdullah International Medical Research Center (KAIMRC) approved this retrospective cohort study with a reference study number (SP 17/315/J).

Review of an internal database at the Princess Nourah Oncology Center identified 141 pediatric patients who had received platinum-based chemotherapy for neuroblastoma, medulloblastoma, optic glioma, or hepatoblastoma between January 2011 and December 2016. Princess Nourah Oncology Center of KAMC is a well-recognized referral oncology center with high flow patients including pediatric. Patients were excluded if age at diagnosis was greater than 14 years, if baseline hearing evaluation was abnormal, if audiograms were not performed or missing data, or if a child is known to have hearing loss disorders.

Patients’ demographics, type of malignancy, cisplatin dosage, radiotherapy dosage, and audiological record were extracted and added to SPSS. To detect a difference of 0.25 (50% in risk factor group of 25%) with 0.005 significance of 80%, 123 patients were recruited. The confidentiality of the patients’ medical records was preserved and only accessed by the research team. The data were collected from medical records using predesigned data collection sheet which includes quantitative and qualitative variables. Data collected included as follows: gender, type, dose, and duration of chemotherapy therapy (cisplatin and carboplatin), type of cancer (optic glioma, medulloblastoma, neuroblastoma, and hepatoblastoma), radiotherapy treatment, and audiology assessment including air-conduction threshold, bone-conduction threshold, tympanogram type, and the International Society of Pediatric Oncology (SIOP) Classification Scale. The International Society of Pediatric Oncology (SIOP) Boston classification scale of ototoxicity was adopted from Brock scale modification. It is a 5-point scale, adopting components of Brock, CTCAE, Chang, and Muenster grading scales and taking into account the functional outcome of a patient at the end of treatment.

Statistical Analysis

The data analysis for this study was generated using IBM SPSS version 23. For the continues variables, the mean (standard deviation) and median (interquartile range) were reported for normal distributed data and skewed data, respectively. For the categorical variables, frequency and percentages were used. Two-tailed Student’s t-test was used to compare means, chi-square test was performed for comparisons of categorical variable, and linear regression was used to analyze continuous variables. P value of < 0.05 was considered statistically significant.

Results

In total, 123 pediatric oncology patients met the inclusion and exclusion criteria. Sixty patients (48.8%) were males, and 63 patients (51.2%) were females. The age in months of study population had a median of65 ± 51 months. Different types of cancers include neuroblastoma in 30 patients (24.4%), followed by medulloblastoma in 29 patients (23.6%), and osteosarcoma in 24 patients (19.5%). Ototoxicity was reported in 16 patients out of 123 with an incidence rate of 13%. Six (37.6%) cases had severe hearing loss. Table 1 summarizes the audiological investigations of those 16 patients including air conduction, bone conduction, tympanometry, and the SIOP grades. Ototoxicity was mostly seen in medulloblastoma with 6 patients and a rate of 37.5% and the rest of cases are summarized in Table 2. Optic glioma was the only type of cancer which had a statistically significant association with ototoxicity (P = 0.01). Gender, age, the type and duration of chemotherapy, and the exposure to radiotherapy were also compared to the presence or absence of ototoxicity as shown in Table 3. Males had hearing loss more than females (16.7% vs. 9.5%, P = 0.24). There was significant association between addition of radiation therapy to chemotherapeutic agents and the risk of ototoxicity (P = 0.008). Table 4 summarizes the association between the other risk factors and the ototoxicity. A total of 86 patients who were treated using cisplatin only were compared according to the dosage and the presence of ototoxicity. The cases with ototoxicity were treated by a higher cumulative dose of cisplatin in comparison to non-ototoxicity cases; however, it was statistically not significant (180 ± 98 mg/m² vs. 144 ± 80 mg/m², P = 0.44).

Table 1.

Audiological assessment for patients with ototoxicity

Audiological variable	N (%)
AC
Normal	10 (62.5%)
Abnormal	6 (37.5%)
BC
Normal	10 (62.5%)
Abnormal	6 (37.5%)
n
A	4 (25%)
B	3 (18.8%)
C	4 (25%)
As	3 (18.8%)
Ad	-
Unknown	2 (12.5%)
SIOP grade
0	5 (31.3%)
1	1 (6.3%)
2	4 (25%)
3	2 (12.5%)
4	-
Unknown	4 (25%)

AC, air conduction; BC, bone conduction; SIOP, International Society of Pediatric Oncology

Table 2.

Type of cancer and its ototoxicity

Type of cancer	Number of ototoxicity cases n = 14	P value*
Medulloblastoma	n = 6 (37.5%)	0.34
Optic glioma	n = 4 (25%)	0.01
Hepatoblastoma	n = 2 (12.5%)	0.6
Osteosarcoma	n = 1 (6.25%)	0.52
Others	n = 1 (6.25%)	0.52

^*Chi-square test or Mann–Whitney U test was used

Table 3.

Comparison between ototoxicity and non-ototoxicity groups

Variable	Overall n = 123	Ototoxicity patients n = 16	Non-ototoxicity patients n = 107	P value*
Gender				0.24
Male	60	10 (16.7%)	50 (83.3%)
Female	63	6 (9.5%)	57 (90.5%)
Age in months				0.68
Median (IQR)	65 (41)	55 (84)	65 (51)
Type of chemotherapy				0.76
Cisplatin	86	10 (11.6%)	76 (88.4%)
Carboplatin	32	5 (15.6%)	27 (84.4%)
Cisplatin and carboplatin	5	1 (20%)	4 (80%)
Duration of chemotherapy in months				0.24
Median (IQR)	5 [4]	6.5 [3]	5 [4]
Radiotherapy				0.008
Yes	29	8 (27.6%)	21 (72.4%)
No	94	8 (8.5%)	86 (91.5%)

^*Chi-square test or Mann–Whitney U test was used

Table 4.

Binary logistic regression comparing risk factors for the presence of ototoxicity

Variables	P value
Gender	.338
Age in months	.759
The use of radiotherapy	.021
Chemotherapy type	.643
Optic glioma	.006
Medulloblastoma	.212
Neuroblastoma	.999
Hepatoblastoma	.177

Discussion

We evaluated ototoxicity in 123 pediatric oncology patients who had received platinum-based chemotherapy drugs (cisplatin or carboplatin) as part of their cancer therapy. We observed an overall incidence of hearing loss of 13%. Cumulative cisplatin dose and male gender were found to be independent risk factors for developing ototoxicity. Addition of radiation therapy to chemotherapeutic agents was strongly associated with risk of ototoxicity.

The association of cisplatin therapy with ototoxicity in pediatric oncology patients still poses a limitation in its efficacy [9]. Hearing loss significantly affects the quality of life of the surviving children impacting their social, cognitive, personal, and pedagogical development, particularly in younger age. It also affects the development of linguistic abilities and speech intelligibility [10].

Overall incidence of ototoxicity of 13% was observed in this study. Most of ototoxicity cases 31.2% had SIOP grade 0 ototoxicity, which denotes ≤ 20 dB hearing loss at all frequencies, followed by grade 2 which denotes a > 20 dB sensorineural hearing loss at 4000 Hz and above. Only 2 patients (12.5%) had moderately severe sensorineural hearing loss at grade 3. No patients were found with severe sensorineural hearing loss at grade 4 [11]. In contrast, a multicenter study by Stöhr et al. evaluated 74 patients who had received cisplatin for the treatment of osteosarcoma. The study found that 51% patients were affected with > 20 dB of hearing loss at 4000–8000 Hz. Only one patient had hearing loss at 2000 Hz, and none at 1 kHz [12].

The incidence of ototoxicity was highest in CNS tumors such as medulloblastoma (37.5%) and optic glioma (25%). These results are similar to a study published by Weiss et al. in which they reported the highest hearing loss in CNS tumor survivors [13].

11.6% patients developed ototoxicity who were treated with cisplatin only. Comparing these results to other studies, Dean et al. reported 57% prevalence of ototoxicity in the cisplatin-treated patients [14].

Yancey et al. in their study reported that gender and cumulative dose of cisplatin are the most significant risk factors for cisplatin ototoxicity [15]. In our study, male gender was observed to be more at risk of developing ototoxicity at a rate of 16.7% as compared to 9.5% in females, which is in similarity with other studies [16]. The median age of pediatric patients who developed ototoxicity was 55 months in our study, which is similar to the study by Li et al., in which they reported that children under 5 years of age are at a greater risk of developing cisplatin-induced ototoxicity, implying that there is an inverse relation between severity of ototoxicity and age [17]. Similarly, Soliman et al. found statistically significant relationship (P = 0.01) between age and ototoxicity [18]. Kushner et al. also reported same findings [19]. However, Liberman et al. and Castelán-Martínez et al. observed no statistically significant relationship between gender and cisplatin [20, 21]. Castelán-Martínez et al., Gunn et al., Brock et al., and Simon et al. found no evidence for any statistically significant relationship between age and cisplatin therapy in their studies [21–24]. The higher median cumulative dose of cisplatin was associated with increased incidence of ototoxicity in this study, which has been similarly reported by many studies to be the inducive factor for hearing loss [25–28]. The prolonged duration of administration of cisplatin with a median of 6.5 months had increased risk for development of ototoxicity. Same results were reported in an earlier study on the effects of prolonged cisplatin infusion [29].

In this study, 15.6% patients had developed carboplatin-associated ototoxicity. The results are in accordance with the studies by Clemens et al. and Qaddoumi et al., in which they reported ototoxicity in 17% and 20% of carboplatin-treated patients respectively [30, 31]. However, in contrast to these findings, Stöhr et al. reported low ototoxicity after carboplatin treatment and no patients (0%) had hearing loss > 20 dB [32]. Bertolini et al. and Dean et al. also reported that carboplatin alone was not significant ototoxic chemotherapeutic agent [14, 33].

In our study, 20% of cases who treated with a combination of cisplatin and carboplatin developed ototoxicity. Bertolini et al. reported 43% prevalence of ototoxicity for patients treated with carboplatin and cisplatin combined while Dean et al. reported a prevalence of 70% for the combined group [14, 33].

Radiotherapy is used to treat head and neck cancers and is efficacious, but it poses a risk for the development of sensorineural hearing loss [34]. Twenty-nine out of the 123 patients also underwent radiotherapy in this study. Eight (27.6%) of the patients developed radiation-induced ototoxicity. Bhandare et al. in their retrospective study found that 41.8% of the patients who received radiotherapy had developed ototoxicity [35]. Sensorineural hearing loss was reported in 15.1% of the patients. The risk for ototoxicity significantly increases when radiotherapy is given in conjunction with cisplatin-based chemotherapy. Cheraghi et al. reported that sensorineural hearing loss was observed in 51% patients who underwent radiotherapy; however, in patients who had received at least five concurrent cisplatin cycles, the sensorineural hearing loss was 77% [36]. Similarly, in another study, sensorineural hearing loss increased to 84% in patients who had concurrent radiotherapy and cisplatin, in contrast to 26% in patients just receiving radiotherapy [37]. The hearing loss caused by these platinum-based antineoplastic agents is irreversible and worsens years after the cessation of treatment [38, 39].

Conclusion

The use of platinum-compounds cisplatin and carboplatin for childhood malignancies is associated with increased incidence of ototoxicity. This hearing loss is irreversible and affects the quality of life in their social, pedagogical, and personal development. The incidence of ototoxicity observed in this study was 13%, with CNS tumors such as medulloblastoma (37.5%) and optic glioma (25%) being the commonest. A combined regimen of carboplatin and cisplatin in this study was observed to have higher rate of ototoxicity than single regimen of either carboplatin or cisplatin. There is increased risk of hearing loss if platinum-based chemotherapy was given in conjunction with radiotherapy. Screening and long-term follow-up are crucial to deal with such cases. A limitation of this study is its retrospective nature. Audiologic data was incomplete for some patients, both at baseline and post-cisplatin time points.

Declarations

Conflict of Interest

The authors declare no competing interests.