ABSTRACT
Background: Children treated for retinoblastoma with carboplatin have an increased risk for ototoxicity. Impaired hearing may have major consequences for these children, because they often suffer from reduced vision. Previous studies have shown limited information on the incidence and severity of carboplatin-induced ototoxicity and the used audiologic methods. The frequency of audiological testing is often limited and the audiologic follow-up time is relatively short.
Objective: The aim of this study was to determine the long-term effects of carboplatin ototoxicity in children with retinoblastoma.
Materials and methods: In this retrospective non-randomized single center cohort study, we reviewed audiologic results of 25 patients. Experienced audiologists analyzed the pure-tone audiograms.
Results: All patients had normal hearing prior to therapy and had a mean age of 11 months at first carboplatin administration. The mean audiologic follow-up was 12.0 years with a median of 11.6 (IQR 4.8) years. Three patients were excluded: two passed away and one could not participate in the audiologic tests. One of the 22 included patients developed sustained low-grade bilateral high-frequency hearing loss between 2 and 7 years after the last carboplatin dose. In one patient it was not possible to make a reliable conclusion due to a conductive hearing loss component. Twenty patients had normal hearing.
Conclusions: We observed no clear effect between carboplatin administration in young children and clinical significant ototoxicity in the long term. One child showed low-grade bilateral high-frequency hearing loss.
Introduction
Retinoblastoma is the most frequent primary intraocular malignancy in children.Citation1–Citation4 Worldwide there is a constant incidence of one case per 16,000–18,000 births.Citation3–Citation7 Ninety-five percent of these patients are diagnosed before the age of five years.Citation3,Citation8 The chance of survival in developed countries is currently 98%Citation3,Citation4,Citation7 and 70–90% of the children retain normal vision in at least one eye.Citation9–Citation11 Approximately 40% of retinoblastoma cases are hereditary and 60% are non-hereditary.Citation8 Hereditary retinoblastoma presents itself mostly bilaterally and before the age of 1 year. Non-hereditary retinoblastoma presents unilaterally and slightly later. Biallelic inactivation or deletion of the tumour-suppressor retinoblastoma 1 (RB1) gene on chromosome 13q14.2 causes retinoblastoma.Citation12 Besides child survival, the current treatment strategy aims are preserving vision, salvage of the globe and reducing the risk of late effects associated with the disease and therapy. Therefore, radiotherapy has been replaced by a conservative approach of systemic chemotherapy combined with local ophthalmic therapy. Nowadays local intra-arterial or intra-vitreal chemotherapy is recommended.Citation13 The goal of chemotherapy can be chemoreduction, thermochemotherapy or chemoprevention. Chemoreduction facilitates local treatment (laser photocoagulation therapy, cryotherapy and plaque radiotherapy). Thermochemotherapy renders the tumor more sensitive for laser photocoagulation therapy.Citation14 Chemoprevention is used when pathologic risk factors for metastasis are present in the enucleated eye. Carboplatin, a second generation analogue of platinum compound, is the principal effective agent in retinoblastoma chemotherapy protocols.Citation15,Citation16 Ototoxicity is a known potential side-effect of platinum drugs and manifests as bilateral high-frequency sensorineural hearing loss with progression towards low-frequency loss upon increasing cumulative dose.Citation17–Citation21 This permanent hearing loss may have a negative effect on speech, language and social development in a young child.Citation1,Citation22 High-frequency speech sounds are critical for speech recognition and even mild loss of these frequencies may affect academic and social-emotional development.Citation23 The incidence and severity of carboplatin-induced ototoxicity varies across studies. presents an overview of articles published since 2000 about carboplatin-induced ototoxicity in children with retinoblastoma. These studies provide the limited information available about the used audiological testsCitation1,Citation24 and about the presence of known risk factors for developing ototoxicity. These risk factors are age at initial dose,Citation20 high total cumulative dose,Citation20,Citation24 prior cisplatin exposure,Citation1,Citation22,Citation24,Citation25 radiotherapy,Citation1,Citation26 other ototoxic agentsCitation24,Citation25 and renal failure.Citation25 The follow-up time is limited in most studies, thus long-term effects of carboplatin might be undetected. The aim of the current study was to reassess the hearing status of the patients who have been previously analyzed in Smits and colleagues 2006.Citation1 Smits and colleagues evaluated the hearing status of 25 young children with retinoblastoma who were treated with carboplatin. They found no hearing loss in the included patients. Because of the young age of their patient group, Smits and colleaguesCitation1 used different age-appropriate measurement methods: tympanometry, otoacoustic emission (OAE) measurements, auditory brainstem responses (ABR) and visual reinforcement audiometry (VRA) or play audiometry. This study will determine the risk of carboplatin-induced ototoxicity in these children with a much longer audiologic follow-up and more accurate audiological tests. The main outcomes will be the incidence, the severity and the moment at which carboplatin-induced ototoxicity occurs, in order to map the long-term side effects of carboplatin.
Table 1. Current overview on carboplatin-induced ototoxicity in retinoblastoma patients.
Materials and methods
Twenty-five patients diagnosed with retinoblastoma (6 non-hereditary, 19 hereditary) and treated with systemic carboplatin earlier assessed in the retrospective, non-randomized, single center cohort study of Smits and colleagues in 20061 were reassessed. The original study included patients between January 1992 and January 2002 in the Department of Paediatric Oncology at VU University Medical Center. One patient could not participate in the audiologic tests due to mental retardation, two patients passed away; one due to development of trilateral retinoblastoma and one due to development of CNS metastasis. The remaining 22 patients had recent audiologic evaluations and are included in the current study. All parents and all children aged over 12 years have signed informed-consent forms.
The patients had received chemotherapeutic treatment with Carboplatin between March 1992 and February 2002 in the Department of Paediatric Oncology at VU University Medical Center. Smits and colleagues described the chemotherapeutic treatment of the patients in detail (see their Table II).Citation1 The chemotherapeutic treatment consisted of four options: regimen A thermochemotherapy; regimen B chemoprevention; regimen C chemoreduction; regimen D: long-term chemotherapeutic treatment.
The chemotherapeutic treatment of the children was described by Smits and colleagues in 2006 (see their Table II).Citation1 The carboplatin was administered intravenously during 1 hour. Patients received hyperhydration at least 4 hours before carboplatin and 24 hours after carboplatin. All patients’ medical records were screened for adequate hyperhydration during the carboplatin course and for the administration of other potentially ototoxic drugs. Audiological tests were conducted at the Department of Otolaryngology/Audiology of VU University Medical Center. The audiologic test protocol consisted of one test before the first carboplatin dose, before every following carboplatin dose, a test following completion of the chemotherapy and thereafter annually or every 5 years following treatment. The latter was dependent on whether or not the patient had aberrant audiological test results before or during treatment with carboplatin. For the current study the most recent audiologic data were reviewed. All patients were old enough to be examined with standard pure-tone audiometry with a Decos audiometer (Decos Audiology, the Netherlands) equipped with TDH-39 headphones for measurement of frequencies up to 8 kilohertz (kHz). High-frequency audiometry (up to 16 kHz) with Sennheiser HDA 200 headphones was performed additionally to detect subtle signs of ototoxicity. Speech audiometry was performed with the standard Dutch CVC (consonant-vowel-consonant) test. The outcomes of the different test results were assessed for signs of ototoxicity by experienced audiologists. Hearing impairment was defined as a loss of more than 20 dB at any frequency. The severity of hearing loss was graded using the Brock criteriaCitation18 and using the new SIOP (International Society of Paediatric Oncology) Boston scale,Citation23 see . In particular, bilateral changes in high-frequency thresholds together with normal tympanograms were considered as signs of carboplatin-induced ototoxicity as disclosed in previous literature.Citation19,Citation20
Table 2. Overview according to the systems used.
Results
The 22 patients (10 males and 12 females) had a mean age at diagnosis of 9.2 (range = 0.3–33) months with a median of 4.0 (IQR 12.3), the patients received the first carboplatin dose at a mean age of 11.9 (range = 0.5–43) months with a median of 7.6 (IQR 13.7) and the total mean cumulative carboplatin dose was 2240 (range = 900–5600) mg/mCitation2. shows a summary of the data. Adequate hyperhydration (3000 ml/mCitation2/day, maximum 5000 ml/day) was conducted prior to and 24 hours after carboplatin administration. None of the patients were born before a gestational age of 37 weeks. Patient 2 and patient 21 received dose adjustments due to temporary tubular renal impairment. Three of the included patients received potentially ototoxic drugs concomitant with or in between chemotherapy courses. Patient 10 is the only patient who received aminoglycosides. This patient received intravenous aminoglycosides (12 days) and glycopeptides (1 day). Patient 15 and patient 16 received intravenous glycopeptides (respectively 7 and 10 days). No harmful diuretics were used. Patient 4 was treated for osteosarcoma and received a total cumulative dose of 480 mg/mCitation2 cisplatin 11 years after carboplatin treatment.
Table 3. Patient characteristics of the included and excluded children.
Audiologic follow-up
The mean period of audiologic follow-up after the last carboplatin dose was 12.0 (range = 5.4–21.3) years with a median of 11.6 (IQR 4.8) years. None of the patients had pre-existing hearing loss. At the last audiologic evaluation neither one of the children, nor their parents reported subjective hearing loss. All 22 patients were tested using standard pure-tone audiometry (250–8000 Hz) and high-frequency audiometry (10–16 kHz). Six patients were assessed up to 12 kHz, three patients up to 14 kHz and 13 patients up to 16 kHz. For 20 of these 22 patients it could be concluded that there are no signs of carboplatin-induced ototoxicity, because the hearing thresholds were normal for all tested frequencies. For patient 9 it was not possible to draw a reliable conclusion, due to a conductive hearing loss component. For patient 10 a bilateral high-frequency sensorineural hearing loss, with thresholds ranging from 25 dB HL at 8 kHz to 35 dB HL at 16 kHz in the left ear and 35 dB HL at 5 kHz to 40 dB HL at 16 kHz in the right ear was found. The last normal audiologic result was monitored with play audiometry up to 10 kHz 2.2 years after the last carboplatin dose. Therefore the ototoxicity emerged in between 2.2 and 7.1 years after treatment and is judged as carboplatin-induced ototoxicity. According to the BrockCitation18 grading scale it corresponds to Brock grade 0 ototoxicity, because the hearing loss did not reach bilateral thresholds of at least 40 dB at 8 kHz. Despite the Brock grading of 0 the audiograms of this patient clearly showed mild loss in the high frequencies. According to the SIOP Boston scaleCitation23 these audiometric results are graded as grade 1. Speech audiometry was normal for all patients, except for patient 10.
Patient 4 was censored at the time of cisplatin administration to isolate the effects of carboplatin. Prior to cisplatin administration, 10.8 years after the last dose of carboplatin, no hearing loss was detected measured with pure tone audiometry up to 12 kHz.
Discussion
In the present study, a long follow-up of the patients studied by Smits and colleaguesCitation1 we did not observe a clear effect of carboplatin administration in young children and clinical significant ototoxicity in the long term. Although the sample size is too small to define specific relationships, this absence of significant ototoxicity is consistent with previous studies regarding carboplatin-induced ototoxicity.Citation24–Citation27 The long mean audiologic follow-up period of 12.0 years since the last dose of carboplatin is one of the main strengths of our study. Up to now, effects of carboplatin in children with retinoblastoma have been studied for a maximum mean audiologic follow-up period of 6.1 years since start of treatment, instead of starting follow-up from the last dose of carboplatin;Citation20 most studies had a shorter follow-up time.Citation14,Citation24–Citation27 Thanks to this long follow-up period all subjects were old enough to be examined with high-frequency pure-tone audiometry, the most reliable method for defining sensorineural hearing loss. We analyzed up to 16 kHz, as this high frequency demonstrates the earliest sign of carboplatin-induced ototoxicity.Citation17–Citation21 Recent publications which studied the sensitivity of used audiologic methods to detect carboplatin-induced ototoxicity, concluded that OAE and ABR may not be valid as a single method to measure carboplatin-induced ototoxicity, because they are insensitive for hearing loss above 4 kHz.Citation23,Citation28,Citation29 Prior studies have largely relied on OAE and ABR which limits their value.Citation24,Citation26,Citation27 In this study patient 9 had a mixed hearing loss. Patient 10 developed a mild bilateral high-frequency sensorineural hearing loss, we consider this hearing loss to be carboplatin-induced although a different cause cannot be ruled out. Patient 10 had a normal audiogram 2.2 years after the last carboplatin dose, measured by play audiometry up to 10 kHz. During the following audiologic tests after 7.1 and after 11.0 years the patients hearing was assessed with high-frequency pure-tone audiometry up to 16 kHz. At both tests, ototoxicity was graded grade 0 to 1 according to the BrockCitation18 and the SIOP Boston scaleCitation23 respectively. Jehanne and co-workers in 200925 and Qaddoumi and co-authors in 201220 have both described ototoxicity to emerge respectively within 2.4–7.7 years and 3–6 years following carboplatin administration. Qaddoumi and co-authorsCitation20 also reported early-onset ototoxicity within 1–7 months following carboplatin initiation. These outcomes of both early and delayed-onset of hearing loss are possibly related to either the used audiologic methods in young children, which are insensitive for detecting early carboplatin-induced ototoxicity in high frequencies, or due to a possibility that carboplatin can induce both early and delayed-onset of hearing loss. Patient 10 developed a mild bilateral high-frequency sensorineural hearing loss but received intravenous aminoglycosides during treatment. The aminoglycoside levels in this patient were frequently monitored and stayed within therapeutic range. Aminoglycosides can cause either unilateral or bilateral sensorineural high-frequency hearing loss.Citation21,Citation30,Citation31 No specific literature on drug interactions of simultaneous carboplatin and gentamicin administration has been published before. Therefore the hearing loss measured in patient 10, which is considered to be carboplatin-induced, could also be gentamicin-induced or could be a result of an interaction between gentamicin and carboplatin. Patient 15 and patient 16 have received glycopeptides, of which a low incidence of ototoxicity is reported in recently published studies.Citation32 However, the audiologic results of these two patients showed normal hearing. Our literature review concerning the latest studies on carboplatin-induced ototoxicity shows that there are discrepancies between previously published studies on the incidence of carboplatin-induced ototoxicity, see . This might be explained by the low incidence of this side effect, the dissimilarities in cumulative doses of carboplatin caused by differences in local guidelines, the insufficient knowledge of significant confounders or to the difference in age at the time of initial carboplatin administration. Qaddoumi and colleagues found young age (< 6 months) at start of treatment to be an independent, significant predictor of ototoxicity.Citation20 In our study, 10 patients were younger than 6 months at start of carboplatin treatment and none of them developed ototoxicity. The discrepancies may be further explained by the heterogeneity in the definition of ototoxicity, the timing of audiologic monitoring after the last carboplatin dose as well as the audiologic methods used to assess hearing loss. According to new insights in pharmacogenomics, this might also be explained by genetic predictors of platinum-induced ototoxicity.Citation23,Citation33,Citation34 Following the observation of inter-individual variability for developing hearing loss due to platinum toxicity, genetic risk factors for cisplatin-induced ototoxicity have been recently studied and published. The TPMT,Citation23,Citation33,Citation34 COMT,Citation23,Citation33,Citation34 and ABCC333 variants were found to predict cisplatin-induced hearing loss with a combined sensitivity of 50.3%Citation33 and a specificity of 92.7%.Citation33 We expect that similar genetic risk factors exist for carboplatin ototoxicity.
In conclusion, this study did not observe clinical significant ototoxicity in the long term in carboplatin-treated children with retinoblastoma. Although the incidence of carboplatin-induced ototoxicity is low, the problem of hearing loss is particularly important for these children who are at risk for having a visual handicap and are prelingual or in the early stages of language development. We advise age appropriate hearing assessmentCitation1 and as soon as the patients are old enough we advise to incorporate high-frequency pure-tone audiometry (up to 16 kHz) in screening protocols for early detection of hearing loss. We also recommend long-term monitoring, given the potential development of delayed-onset hearing loss.
Declaration of interest
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
References
- Smits C, Swen SJ, Theo Goverts S, et al. Assessment of hearing in very young children receiving carboplatin for retinoblastoma. Eur J Cancer 2006;42:492–500.
- Dimaras H, Kimani K, Dimba EAO, et al. Retinoblastoma. Lancet 2012;379:1436–1446.
- Kivela T. The epidemiological challenge of the most frequent eye cancer: retinoblastoma, an issue of birth and death. Br J Ophthalmol 2009;93:1129–1131.
- Houston SK, Murray TG, Wolfe SQ, et al. Current update on retinoblastoma. Int Ophthalmol Clin 2011;51:77–91.
- Moll AC, Kuik DJ, Bouter LM, et al. Incidence and survival of retinoblastoma in The Netherlands: a register based study 1862–1995. Br J Ophthalmol 1997;81:559–562.
- Seregard S, Lundell G, Svedberg H, et al. Incidence of retinoblastoma from 1958 to 1998 in Northern Europe: advantages of birth cohort analysis. Ophthalmology 2004;111:1228–1232.
- MacCarthy A, Draper GJ, Steliarova-Foucher E, et al. Retinoblastoma incidence and survival in European children (1978–1997). Report from the Automated Childhood Cancer Information System Project. Eur J Cancer 2006;42:2092–2102.
- MacCarthy A, Birch JM, Draper GJ, et al. Retinoblastoma in Great Britain 1963–2002. Br J Ophthalmol 2009;93:33–37.
- Rodriguez-Galindo C, Krailo M, Frazier L, et al. Children’s Oncology Group’s 2013 blueprint for research: rare tumors. Pediatr Blood Cancer 2013;60:1016–1021.
- Lin P, O’Brien JM. Frontiers in the management of retinoblastoma. Am J Ophthalmol 2009;148:192–198.
- Abramson DH. Retinoblastoma in the 20th century: past success and future challenges – the Weisenfeld lecture. Invest Ophthalmol Vis Sci 2005;46:2683–2691.
- Sachdeva UM, O’Brien JM. Understanding pRb: toward the necessary development of targeted treatments for retinoblastoma. J Clin Invest 2012;122:425–434.
- Fallaha N, Dubois J, Carret AS, et al. Real-time ophthalmoscopic findings of intraophthalmic artery chemotherapy in retinoblastoma. Arch Ophthalmol 2012;130:1075–1077.
- Friedman DL, Himelstein B, Shields CL, et al. Chemoreduction and local ophthalmic therapy for intraocular retinoblastoma. J Clin Oncol 2000;18:12–17.
- Rodriguez-Galindo C, Wilson MW, Haik BG, et al. Treatment of intraocular retinoblastoma with vincristine and carboplatin. J Clin Oncol 2003;21:2019–2025.
- Kim JW, Abramson DH, Dunkel IJ. Current management strategies for intraocular retinoblastoma. Drugs 2007;67:2173–2185.
- Brock P, Pritchard J, Bellman S, et al. Ototoxicity of high-dose cis-platinum in children. Med Pediatr Oncol 1988;16:368–369.
- Brock PR, Bellman SC, Yeomans EC, et al. Cisplatin ototoxicity in children: a practical grading system. Med Pediatr Oncol 1991;19:295–300.
- Yancey A, Harris MS, Egbelakin A, et al. Risk factors for cisplatin-associated ototoxicity in pediatric oncology patients. Pediatr Blood Cancer 2012;59:144–148.
- Qaddoumi I, Bass JK, Wu J, et al. Carboplatin-associated ototoxicity in children with retinoblastoma. J Clin Oncol 2012;30:1034–1041.
- Fausti SA, Larson VD, Noffsinger D, et al. High-frequency audiometric monitoring strategies for early detection of ototoxicity. Ear Hear 1994;15:232–239.
- Knight KRG, Kraemer DF, Neuwelt EA. Ototoxicity in children receiving platinum chemotherapy: underestimating a commonly occurring toxicity that may influence academic and social development. J Clin Oncol 2005;23:8588–8596.
- Brock PR, Knight KR, Freyer DR, et al. Platinum-induced ototoxicity in children: a consensus review on mechanisms, predisposition, and protection, including a new International Society of Pediatric Oncology Boston ototoxicity scale. J Clin Oncol 2012;30:2408–2417.
- Bhagat SP, Bass JK, White ST, et al. Monitoring carboplatin ototoxicity with distortion-product otoacoustic emissions in children with retinoblastoma. Int J Pediatr Otorhinolaryngol 2010;74:1156–1163.
- Jehanne M, Lumbroso-Le Rouic L, Savignoni A, et al. Analysis of ototoxicity in young children receiving carboplatin in the context of conservative management of unilateral or bilateral retinoblastoma. Pediatr Blood Cancer 2009;52:637–643.
- Pecora Liberman PH, Schultz C, Schmidt Goffi-Gomez MV, et al. Evaluation of ototoxicity in children treated for retinoblastoma: preliminary results of a systematic audiological evaluation. Clin Transl Oncol 2011;13:348–352.
- Lambert MP, Shields C, Meadows AT. A retrospective review of hearing in children with retinoblastoma treated with carboplatin-based chemotherapy. Pediatr Blood Cancer 2008;50:223–226.
- Lobarinas E, Salvi R, Ding D. Insensitivity of the audiogram to carboplatin induced inner hair cell loss in chinchillas. Hear Res 2013;302:113–120.
- El-Badry MM, McFadden SL. Evaluation of inner hair cell and nerve fiber loss as sufficient pathologies underlying auditory neuropathy. Hear Res 2009;255:84–90.
- Lerner SA, Matz GJ. Aminoglycoside ototoxicity. Am J Otolaryngol 1980;1:169–179.
- Dobie RA, Black FO, Pezsnecker SC, et al. Hearing loss in patients with vestibulotoxic reactions to gentamicin therapy. Arch Otolaryngol Head Neck Surg 2006;132:253–257.
- Levine DP. Vancomycin: a history. Clin Infect Dis 2006;42(Suppl. 1):S5–12.
- Pussegoda K, Ross CJ, Visscher H, et al. Replication of TPMT and ABCC3 genetic variants highly associated with cisplatin-induced hearing loss in children. Clin Pharmacol Ther 2013;94:243–251.
- Mukherjea D, Rybak LP. Pharmacogenomics of cisplatin-induced ototoxicity. Pharmacogenomics 2011;12:1039–1050.