Cisplatinum ototoxicity in children, long-term follow up

International Journal of Pediatric Otorhinolaryngology 74 (2010) 913–919

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Cisplatinum ototoxicity in children, long-term follow up Talal Al-Khatib a,*, Natasha Cohen a, Anne-Sophie Carret b, Sam Daniel a a b

Department of Otolaryngology-Head and Neck Surgery, McGill University, Montreal, Canada Department of Hematology/Oncology, Montreal’s Children Hospital, Montreal, Canada

A R T I C L E I N F O

A B S T R A C T

Article history: Received 28 February 2010 Received in revised form 6 May 2010 Accepted 9 May 2010 Available online 3 June 2010

Objective: To assess the long-term ototoxicity effect of platinum chemotherapy in a series of pediatric patients. Design: A prospective cohort study. Methods: Patients who received platinum chemotherapy were identified through review of the pharmacy records from 2000 to 2005. Audiograms pre- and post-treatment with cisplatin were noted. The patients were brought back long after treatment for a repeat audiogram and a questionnaire to assess the impact of ototoxicity on their quality of life. Results: Forty-nine patients received platinum chemotherapy. Patients’ exclusion: two had no prechemo audiograms, one had retinoblastoma with congenital hearing loss, three were lost to follow up, five deceased, and seven refused participation. The total number of patients included was 31 with longterm follow up total of 21 patients. The follow up period ranged from 1.5 to 6.6 years (median of 3.4 years). Fourty-two percent (13/31) of the patients suffered from otoxicity (3 mild, 3 moderate, 7 severeprofound). Thirty-three (7/21) of audiograms worsened on long-term follow up. Questionnaire revealed 70% subjective hearing loss with 40% requiring hearing aids. Conclusion: Ototoxicity after platinum chemotherapy can present or worsen years after completion of therapy. Therefore, we recommend long-term follow up. Crown Copyright ß 2010 Published by Elsevier Ireland Ltd. All rights reserved.

Keywords: Pediatric otolaryngology Platinum-compound chemotherapy Ototoxicity Long-term follow up

1. Introduction Platinum-compound ototoxicity is a well-recognized sideeffect in children undergoing platinum-compound chemotherapy [2–6]. Ototoxicity is often used as a surrogate marker for chemotherapeutic toxicity and dosing adjustments are sometimes warranted based on the severity of hearing loss [7]. In fact, cisplatinum has been shown to single-handedly cause moderate to severe hearing loss in nearly 55% of patients [8]. As such, appropriate detection and management of platinum chemotherapy induced ototoxicity is necessary. The long-term side effects of hearing loss in the developing child have various deleterious consequences, such as delayed language development and failure to thrive intellectually and socially [9]. Children learn vocabulary, syntax and the rules of language, as well as how to thrive socially through repeated verbal cues and interactions. In fact, it has been shown in several studies that children with even mild bilateral or unilateral hearing loss have more difficulty with language

* Corresponding author at: The Montreal Children’s Hospital, McGill University Health Centre, 2300 Tupper St., Montreal, QC H3H 1P3, Canada. Tel.: +1 514 412 4304/4303; fax: +1 514 412 4342. E-mail address: [email protected] (T. Al-Khatib).

acquisition and often score more poorly in vocabulary and spelling than children with normal hearing capacity [10–12]. Current monitoring practices for platinum related ototoxicity consist of audiological testing prior to treatment as a baseline, repeat testing during the course of chemotherapy and a final audiometry at the end of treatment. No further follow up or monitoring is performed on a long-term basis. It is unclear if hearing loss secondary to ototoxicity can have a delayed presentation. As such, patients who are not followed up may be suffering from undiagnosed hearing loss and its consequences. In fact, recent studies have suggested that hearing loss due to platinum chemotherapy is underreported [7]. Our study is aimed at assessing late sequellae of platinum chemotherapy on hearing in the pediatric population and subsequently evaluating the adequacy of current screening practices. 2. Methods and statistics We retrospectively reviewed all patients with a benign or malignant tumor at the Montreal Children’s Hospital who were diagnosed between 2000 and 2005. We conducted a review of pharmacy records to establish the number of patients who received cisplatin or carboplatin. Demographic variables which were analyzed included age at diagnosis, gender, type of

0165-5876/$ – see front matter . Crown Copyright ß 2010 Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijporl.2010.05.011

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Table 1 Patient data and audiometry/OAE results. Sex

Age at Dx

Dx/ tumor site

Cisplatin dose

Mb Mb M M M F Fb Fb M Mb F F M M F F M Fb Fb F Mb Mb Mb M F M Mb M Mb M M

10 5 1.2 9 3 6 17 12 1 15 7 13 2 14 15 12 9 8 7 6 7 3 5 1.2 3 11 9 17 1.3 2 0.4

HL Brain Brain NHL Abdo Brain OS Genital RB OS OG OS Abdo Brain OS Genital Brain Genital Brain Brain Brain Abdo Brain Abdo Brain NPC Genital OS Abdo RB RB

292 110 56

Carboplatinum dose

XRT dose (Gy)

XRT to head and neck

23 50

+ +

2669

45

+

15550 1177

36

+

1030

n/a

+

1695 2296

36

+

n/a

+

23

+

55

+

45 n/a

+ +

36

+

396 3093

575 185

412

344.8 182 53.5 140

7782 495

140 498.5 394 68

843 444 427 1326 261

Rt 4K pre/post (dB)

Lt 4K pre/post (dB)

Rt 8K pre/ post (dB)

Lt 8K pre/post (dB)

OAE

F/u period (years)a

0/60 30/40 30/30 10/10 10/10 0/0 0/0 20/100 30/30 0/0 10/10 0/10 10/10 0/0 10/10 0/0 0/0 10/70 10/20 10/20 0/40 20/90 0/0 20/20 10/10 20/20 10/80 0/0 10/100 50/20 50/30

10/60 20/40 30/30 0/0 10/10 0/0 0/0 20/90 30/30 0/0 10/10 0/10 0/0 0/0 0/10 0/10 0/0 10/70 10/30 20/10 0/40 20/70 10/10 20/20 10/0 10/10 10/80 10/10 10/80 n/a n/a

10/60 40/50 30/30 10/10 10/10 20/10 10/30 30/100 30/30 0/40 20/20 10/0 20/20 10/10 10/20 10/10 0/0 10/70 10/30 10/20 0/80 20/90 0/60 30/30 10/30 30/30 10/90 0/0 10/100 n/a n/a

10/60 40/40 30/30 10/10 10/10 20/10 10/60 30/90 30/20 0/40 20/20 10/10 20/20 10/10 0/10 0/10 0/0 10/70 10/40 20/20 0/50 20/70 10/60 30/30 10/20 10/10 10/90 10/10 10/80 n/a n/a

Absent Absent Absent Reduced Reduced Reduced Present Present Present Present Present Present

4.25c 5.3c 0.3, Died 4.2c 1.9c 4.7c 2.3c 2c, Died 1.8c 3.25c 6.6c 3c 3.5c 2.1c 0.24 0.3 n/a 3c 2.2c 2c n/a 4.2c 2.9c 1.9c 2.7c 1.9c 1.5 0.7, Died 4c, Died 0.8 5.1c

Dx: diagnosis, HL: Hodgkin’s lymphoma, NHL: non-Hodgkin’s lymphoma, NPC: nasopharyngeal carcinoma, RB: retinoblastoma, OS: osteosarcoma, OG: optic glioma and Abdo: abdominal. a Time of diagnosis is the start of follow up period. b Patients showing signs of ototoxicity. c Patients included in long-term F/U group.

malignancy and dose of cisplatin. Consideration was also given to other factors such as additional chemotherapeutic agents and use of radiation therapy to the head and neck. Pre- and post-chemotherapy audiograms were performed using frequencies between 250 and 8000 Hz and were then compared using a paired t-test (Table 2). We used bone conduction thresholds to compare hearing loss. Otoacoustic emission (OAE) testing was used when possible as an alternative for monitoring hearing impairment (Table 1). We did not test parameters which would allow us to differentiate central from peripheral hearing loss. Ototoxicity was defined using the ASHA criteria for hearing loss which is defined in three categories: (A) 20 dB or greater hearing loss in pure tone threshold in at least one frequency, (B) 10 dB or greater decrease at two adjacent test frequencies, and (C) loss of responses at three consecutive frequencies where responses were previously obtained [13]. The degree of hearing loss was defined according to ASHA criteria (Fig. 1). We used multiple linear regression analysis to evaluate correlation between development of ototoxicity and age, treatment with radiation therapy to the head and neck, tumor size, or tumor location. We considered pvalues <0.05 as significant. In addition, we recruited the above cohort of patients and conducted a prospective study. As such, we were able to repeat an audiogram as well as administer a questionnaire which assessed for hearing impairment markers only in those patients identified by audiogram as having suffered otoxicity. The questionnaire addressed factors such as usage of a hearing aid; subjective speech alteration and school performance to subjectively assess the impact of hearing loss on the patients’ quality of life (Fig. 2).

Exclusion criteria included patients who were older than 18 years of age at the onset of treatment, and who did not have a pretreatment audiogram (n = 2), and patients with known hearing loss prior to chemotherapy (n = 1). 3. Results One hundred eighty-two patients were diagnosed with benign or malignant tumors at the Montreal Children’s Hospital between

Fig. 1. ASHA classification for degree of hearing loss [1].

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915

Fig. 2. Questionnaire.

the years of 2000 and 2005. Of those, 49 patients received platinum-compound chemotherapy as part of their treatment protocol. Two patients did not have pre-treatment audiograms and one patient who was diagnosed with retinoblastoma also had congenital hearing loss. Three patients were lost to follow up, 5 patients were deceased, and 7 refused participation. The final number of participants included in the study was 31, and 21 patients were followed up long-term. Eighteen patients (58%) were administered cisplatinum, 10 received carboplatinum (32%) and 3 patients (10%) received both platinum agents. The minimum ototoxic dose was found to be 302.06 mg/m2 (Table 4). The average age at diagnosis was 8 years (range: 5 months to 17 years). In terms of gender, males were more represented than females with 64% vs. 36%, respectively. The distribution of tumor types is illustrated in Fig. 3. In the cohort of 31 patients, the immediate post-chemotherapy audiograms showed 58% (18/31) of patients retaining their normal hearing, while 42% (13/31) of patients having developed bilateral hearing loss. Of those, 3 patients had mild hearing loss, another 3 had moderate hearing loss, and 7 developed severe-to-profound hearing loss. Moreover, 12 patients had radiation therapy to the head and neck, but this was not found to significantly impact hearing loss (Table 5). There was no correlation between the tumor site and incidence of hearing loss (Table 6). Twenty-one patients were followed up long-term, for a period ranging between 1.5 and 6.6 years (median = 3.4 years). Of the patients followed up long-term, 67% (14/21) of patients had unchanged audiograms, whereas the remaining 33% (7/21) had

Fig. 3. Distribution of tumor types.

worsening high frequency (4000–8000 Hz) hearing loss bilaterally, with decreases reaching up to 50 dB. Table 1 lists all 31 patients with results of the audiograms pre- and post-treatment and Table 2 lists post-treatment and long-term audiograms in 21 patients. As mentioned previously, we administered a questionnaire to the patients which were followed up long-term. Thirteen patients or their guardians returned the questionnaire. Results showed that as many as 69% of patients (n = 9) had subjective hearing loss, 40% of patients required a hearing aid (n = 5). 15.4% of the cohort had subjective speech alteration and decreased school performance noticed by patients or their family members (n = 2).

Table 2 Long-term follow up. Age at diagnosis

9b 1 1.2 11 6 7b 17b 3 5b 8b 13 15b 2 9 3b 10b 6 0.4 0.4 7b 5 a b

F/U audioa

0.9 1.2 1.7 1.7 1.4 1.3 2.3 1.1 1.9 1.7 2.3 2.3 2 2.6 2.1 3.1 2.1 3.7 4.2 1.6 5

Post-treatment audio

Long-term F/U audio

OAE

Rt 4K

Rt 8K

Lt 4K

Lt 8K

Rt 4K

Rt 8K

Lt 4K

Lt 8K

80 30 20 20 20 20 0 10 0 70 10 0 10 10 90 60 0 20 30 40 10

90 30 30 30 20 30 30 30 60 70 0 40 20 10 90 60 10 20

80 30 20 10 10 30 0 0 10 70 10 0 0 0 70 60 0 20

90 20 30 10 20 40 60 20 60 70 10 40 20 10 70 60 10 20

50 20

40 10

40 20

80 20 0 20 60 30 0 10 10 60 10 0 10 0 100 70 0 10 20 30 10

90 20 0 20 60 50 30 30 70 50 10 40 0 20 90 80 0 10 20 40 20

100 20 10 10 60 40 0 10 10 60 10 0 10 10 70 70 0 20 20 40 10

100 20 10 20 60 50 60 20 70 60 10 50 10 10 80 70 0 20 20 50 20

Time period between post-treatment and long-term follow up audiogram. Identified as having developed ototoxicity post-chemo.

Present

Present

Reduced Reduced Present Absent Present

Absent Reduced

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Table 3 Comparison of pre- and post-chemotherapy audiogram results with 95% confidence interval as per analysis using a paired t-test. Outcome LPostCh250 LPostCh500 LPostCh1K LPostCh2K LPostCh4K LPostCh8K RPostCh250 RPostCh500 RPostCh1K RPostCh2K RPostCh4K RPostCh8K LFUCh250 LFUCh500 LFUCh1K LFUCh2K LFUCh4K LFUCh8K RFUCh250 RFUCh500 RFUCh1K RFUCh2K RFUCh4K RFUCh8K

Estimate 0.016248081 0.018459937 0.013396243 0.031230655 0.036146725 0.011851240 0.010925652 0.008439027 0.018405308 0.022907280 0.050112613 0.047957193 0.036519630 0.041414317 0.037880265 0.051028705 0.024887185 0.002999284 0.007189122 0.025793185 0.001300943 0.076543875 0.046977873 0.004418792

Lower CL 0.007646805 0.014056112 0.029298210 0.036952096 0.047857489 0.084106009 0.013342410 0.020064306 0.027797807 0.050171262 0.049748602 0.055370399 0.018108447 0.044505526 0.081021311 0.131153239 0.145488112 0.172503013 0.059144518 0.036736949 0.089455127 0.122790870 0.177720461 0.222441471

Upper CL 0.040142967 0.050975986 0.056090696 0.099413406 0.120150939 0.107808489 0.035193715 0.036942360 0.064608423 0.095985823 0.149973827 0.151284784 0.091147707 0.127334160 0.156781840 0.233210650 0.195262482 0.166504446 0.073522762 0.088323318 0.086853240 0.275878621 0.271676208 0.213603887

4. Discussion Platinum chemotherapy has become an important part of modern cancer treatment for various solid childhood malignancies, such as retinoblastoma [14], CNS tumors [6], osteosarcoma [2], etc. Even though this class of medication has improved survival rates in patients with these ailments, this life-preserving treatment is associated with a significant and well-recognized morbidity, that being hearing loss. Ototoxicity is a side-effect of platinum administration and the importance of adequate diagnosis and management of hearing loss cannot be underscored as it has a great impact on a child’s social and intellectual development [9,15]. There is little literature addressing the long-term effects of platinum compound related hearing loss, leading to insufficient data available for determining duration of follow up. Bertolini et al. [8] studied the evolution of platinum compound induced hearing loss in 122 survivors of childhood cancers with a median follow up of 7 years. In their study, high-dose carboplatin did not significantly contribute to ototoxicity, even when combining carboplatin and cisplatin. They found that although only 5% of their patients had signs of ototoxicity prior to the end of treatment, this increased to 11% in the early post-treatment period, and up to 44% of the cohort showed hearing loss at 2 years follow up. Our results were similar, with 42% of our patients having developed hearing loss, most of these patients manifesting severeto-profound hearing loss. In contrast, 67% of our patients showed unchanged audiograms, whereas the rest (33%) had an element of worsening hearing loss. However, it is clear that our patients had significant long-term auditory sequelae, as 69% of patients reported subjective hearing loss and 40% of our patients required amplification with hearing aids. We compared pre- and postchemotherapy ototoxicity using a paired t-test, the results are detailed in Table 3. Several mechanisms have been proposed in the mechanism for development of hearing loss secondary to platinum-compound chemotherapy ototoxicity. Multiple animal studies have found differences in the morphology of the cochlea, in particular in the organ of Corti, the spiral ganglion and the lateral wall (stria vascularis and spiral ligament) [16]. Cells in the spiral ganglion undergo myelin sheath detachment [17], whereas the stria

Fig. 4. Hearing loss in Rt Ear (4K) related to cisplatin dose.

vascularis at the basal turn of the cochlea undergoes deleterious structural changes including edema, bulging, rupture and depletion of cytoplasmic organelles [18]. Apoptosis has also been shown to play a role in spiral ligament degeneration [19,20]. Cisplatin also prevents the formation of antioxidants which allows for reactive oxygen species (ROS) to induce apoptosis of cochlear cells [21,22]. There are several risk factors identified in the literature that render certain children more vulnerable to the platinum ototoxicity others. Total chemotherapeutic dose has been shown to have a direct correlation with ototoxicity and hearing loss. Although there is no established ototoxic dose, many studies have found cumulative doses between 300 and 400 mg/m2 to be associated with a greater risk for ototoxicity [2,7,8,23–26]. Our results are concordant with these findings with a minimum ototoxic dose of 302.06 mg/m2 (Figs. 4 and 5; Table 4). Young age has also been identified as a risk factor, with children under 5 years of age being the most vulnerable [23]. As well, radiation to the skull base has been shown to be associated with greater susceptibility to ototoxicity and high-frequency sensorineural hearing loss. A study in adults undergoing cisplatinum chemotherapy with concurrent

Fig. 5. Hearing loss in Lt ear (4K) related to cisplatin dose.

T. Al-Khatib et al. / International Journal of Pediatric Otorhinolaryngology 74 (2010) 913–919 Table 4 Summary of F-values for the effects of cisplatin on hearing in each frequency (with 95% CI). Outcome

Estimate

LPostCh250 LPostCh500 LPostCh1K LPostCh2K LPostCh4K LPostCh8K RPostCh250 RPostCh500 RPostCh1K RPostCh2K RPostCh4K RPostCh8K LFUCh250 LFUCh500 LFUCh1K LFUCh2K LFUCh4K LFUCh8K RFUCh250 RFUCh500 RFUCh1K RFUCh2K RFUCh4K RFUCh8K

9.777777778 11.22222222 13.55555556 15.11111111 17.22222222 17.77777778 5.555555556 6.611111111 6.500000000 8.555555556 17.44444444 7.777777778 1.666666667 4.166666667 10.00000000 12.50000000 9.166666667 5.000000000 7.500000000 6.666666667 5.416666667 10.83333333 7.500000000 5.000000000

Lower CL 22.56773873 24.71432206 27.32888906 32.02565812 37.80628950 40.26915138 11.21668555 13.98381978 17.40295431 24.49814380 41.16299626 34.24490226 9.905483451 16.66613329 26.75932292 38.22569716 38.86229210 40.45299986 18.82029926 19.64838238 20.95768209 37.91100925 41.04482207 32.42811227

Upper CL

Outcome LPostCh250 LPostCh500 LPostCh1K LPostCh2K LPostCh4K LPostCh8K RPostCh250 RPostCh500 RPostCh1K RPostCh2K RPostCh4K RPostCh8K LFUCh250 LFUCh500 LFUCh1K LFUCh2K LFUCh4K LFUCh8K RFUCh250 RFUCh500 RFUCh1K RFUCh2K RFUCh4K RFUCh8K

Table 5 Summary of F-values for the effects of radiation therapy on hearing in each frequency (with 95% CI). Outcome LPostCh250 LPostCh500 LPostCh1K LPostCh2K LPostCh4K LPostCh8K RPostCh250 RPostCh500 RPostCh1K RPostCh2K RPostCh4K RPostCh8K LFUCh250 LFUCh500 LFUCh1K LFUCh2K LFUCh4K LFUCh8K RFUCh250 RFUCh500 RFUCh1K RFUCh2K RFUCh4K RFUCh8K

Estimate 9.777777778 9.666666667 12.00000000 12.00000000 15.66666667 26.11111111 2.222222222 6.611111111 6.500000000 8.555555556 19.00000000 18.66666667 1.666666667 6.666666667 10.00000000 7.500000000 19.16666667 27.50000000 5.000000000 11.66666667 7.916666667 13.33333333 22.50000000 27.50000000

Lower CL 22.56773873 23.35305613 26.00588805 29.31498560 36.45170460 47.17784794 8.259373193 13.98381978 17.40295431 24.49814380 42.52353960 44.23450729 9.905483451 18.85804219 26.75932292 33.76592822 47.49066615 59.92723277 16.70156041 23.61564472 23.15348600 40.09582588 54.10476832 62.07562456

Table 6 Summary of F-values for the effect of brain tumor on hearing loss in all frequencies (with 95% CI).

3.012183174 2.269877614 0.217777950 1.803435896 3.361845055 4.713595829 0.105574440 0.761597563 4.402954313 7.387032688 6.274107366 18.689346704 6.572150118 8.332799955 6.759322923 13.225697164 20.528958769 30.452999862 3.820299260 6.315049049 10.124348756 16.244342580 26.044822068 42.428112268

radiation therapy for nasopharyngeal carcinoma found that patients who received doses of radiation of the order of 48 Gy or more were significantly more at risk of developing sensorineural hearing loss at all frequencies [27,28]. Our study did not find any significant correlation between age or use of radiation therapy and the incidence of hearing loss (Table 5). We also did not find any correlation between tumor site (head and neck vs. other) and hearing loss (Table 6). We attribute this finding to the small sample size, which lacks the power to show significant correlations between these factors. Moreover, there were only 12 patients who underwent radiation therapy, and even fewer were irradiated in the head and neck region, which further limits our analysis, and explains our failure to show statistical significance (Fig. 6).

Upper CL 3.012183174 4.019722793 2.005888052 5.314985597 5.118371269 5.044374282 3.814928748 0.761597563 4.402954313 7.387032688 4.523539603 6.901173952 6.572150118 5.524708857 6.759322923 18.765928216 9.157332821 4.927232769 6.701560414 0.282311391 7.320152671 13.429159215 9.104768317 7.075624561

917

Estimate 9.777777778 11.22222222 13.55555556 15.11111111 17.22222222 17.77777778 5.555555556 6.611111111 6.500000000 8.555555556 17.44444444 7.777777778 1.666666667 4.166666667 10.00000000 12.50000000 9.166666667 5.000000000 7.500000000 6.666666667 5.416666667 10.83333333 7.500000000 5.000000000

Lower CL 22.56773873 24.71432206 27.32888906 32.02565812 37.80628950 40.26915138 11.21668555 13.98381978 17.40295431 24.49814380 41.16299626 34.24490226 9.905483451 16.66613329 26.75932292 38.22569716 38.86229210 40.45299986 18.82029926 19.64838238 20.95768209 37.91100925 41.04482207 32.42811227

Upper CL 3.012183174 2.269877614 0.217777950 1.803435896 3.361845055 4.713595829 0.105574440 0.761597563 4.402954313 7.387032688 6.274107366 18.689346704 6.572150118 8.332799955 6.759322923 13.225697164 20.528958769 30.452999862 3.820299260 6.315049049 10.124348756 16.244342580 26.044822068 42.428112268

To acquire language and linguistic skills, children must be able to differentiate and perceive all frequencies of sounds. The highfrequency speech phonemes contain the least acoustic power, yet contribute significantly to speech intelligibility [29]. High-frequency hearing impairment reduces audibility and recognition of the following speech sounds: s, f, th, sh, h, k, and t. These contain a primary acoustic energy of about 2000 Hz. High-frequency hearing is important for the perception of fricative phonemes, which constitute approximately 50% of the consonant sounds in the English language. Moreover, the phoneme /s/ is the third to fourth most frequently occurring consonant [9]. The sounds s, t and z are also considered to be linguistic markers, as they indicate tense, plurals, possession and sex. Reduction in audibility of these sounds can cause errors in the development of noun-verb morphology. Without high frequency speech information of about 4000 Hz, children may not hear plural forms of words or they may hear them inconsistently, especially when listening to the voices of women or other children [10]. Also, since damage to the basal turn of the cochlea has been shown to decrease encoding of lower frequency information, audibility of low-frequency speech cues is decreased despite seeming unaffected on an audiogram. This affects their ability to understand normal speech [30] which is further impaired in noisy environments [9]. Furthermore, young children with normal hearing have greater difficulty understanding speech in noisy and reverberant environments than adults, which is primarily due to developmental factors and inexperience with language [9,31], which along with the greater morbidity associated with even mild hearing loss in children (discussed below), makes adequate detection of hearing loss in children of essence. There is limited research investigating language development, psychosocial development and academic achievement in children with high frequency hearing loss with platinum-based chemotherapy. Bess et al. [32] evaluated the educational performance and social-emotional functioning of 1218 children with minimal sensorineural hearing loss. In this study it was found that 37% of the children with minimal hearing loss failed at least one grade in school compared with a normative rate of 3%. They also experienced greater dysfunction in social-emotional domains including behavior, energy, stress, self-esteem, and social support than did their normally hearing peers. In fact, children with

918

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Fig. 6. Correlation between radiation to head and neck regions and hearing loss (left and right sided).

hearing loss are often found poorer over function and competency in a classroom than their normal hearing peers, reflecting the social and emotional maladjustment which occurs more frequently when hearing loss is present [33]. These children have difficulty integrating into their peer social groups [12], and even mild hearing loss is associated with poorer functional health status [32]. However, early detection of hearing loss and appropriate management can avoid poor scholastic performance and language acquisition impairment [15]. There is emerging evidence that there may benefit in use of certain protective agents to prevent hearing loss, which would be particularly significant in the group of patients we studied, that being young children subjected to potential ototoxicity. Future research should be directed towards establishing a role for such compounds. Research has shown that there may be a role for thiols, adenosine A1 receptors, pifthrin inhibitors, oral ebselen and allopurinol, sodium butyrate, and salicylates [16]. Unfortunately, prophylactic measures for avoiding or decreasing the likelihood of developing hearing loss in patients undergoing platinum-compound chemotherapy has yet to be determined, and is definitely an area of focus which would bring immense benefit to such patients. 5. Conclusion Ototoxicity following platinum-compound chemotherapy is a well known toxicity. However, according to our study, current monitoring and detection is inadequate, as children were found to have new onset and/or progression of sensorineural hearing loss up to years after the completion of therapy, which would have been undetected unless long-term follow up is established. We recommend long-term follow up in the order of years to be considered in patients who have undergone therapy with platinum chemotherapy. We also recommend further research be directed towards establishing a regimen for follow up as our study was not geared towards studying these outcomes. References [1] J.G. Clark, Uses and abuses of hearing loss classification, ASHA 23 (1981) 493–500. [2] M.J. Lewis, S.G. DuBois, B. Fligor, X. Li, A. Goorin, H.E. Grier, Ototoxicity in children treated for osteosarcoma, Pediatr. Blood Cancer 52 (2009) 387–391. [3] M.J. Schell, V.A. McHaney, A.A. Green, Hearing loss in children and young adults receiving cisplatin with or without prior cranial irradiation, J. Clin. Oncol. 7 (1989) 754–760.

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