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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 24  |  Issue : 1  |  Page : 33-37

Treatment of cisplatin-induced ototoxicity by intra-tympanic corticosteroid injection


1 Department of Otorhinolaryngology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
2 Department of Otorhinolaryngology, Audiology Unit, Faculty of Medicine, Zagazig University, Zagazig, Egypt

Date of Web Publication24-May-2018

Correspondence Address:
Prof. Wail Fayez Nasr
Department of Otorhinolaryngology, Faculty of Medicine, Zagazig University, Zagazig
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/indianjotol.INDIANJOTOL_115_17

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  Abstract 


Background: Cisplatin is a common chemotherapeutic drug often causes ototoxicity attributed to the formation of reactive oxygen and nitrogen species damaging critical inner ear structures. Steroids have been shown to reduce the formation of reactive oxygen species, and thus, may reduce ototoxicity. In this study, intratympanic corticosteroid injection is proved to help the recovery of cisplatin ototoxicity. Objectives: The objective of this study was to assess the efficacy of intratympanic corticosteroid injection in the treatment of cisplatin ototoxicity. Patients and Methods: This study was applied on 20 patients that have sensorineural hearing loss caused by cisplatin, which was used as a chemotherapeutic agent for the treatment of their malignancies. All cases were subjected to intratympanic corticosteroid injection. All patients were exposed to pure-tone audiometry before and after the procedure. Results: Significant increases in the average pure-tone thresholds (PTTs) at 8000 Hz were found in both the study and control groups after the cumulative dose: 43.15 ± 15.557 dBHL and 55.7 ± 13.2589 dBHL, a value of P = 0.0004 and <0.001, respectively. Significant increases in the average PTTs at 6000 Hz were found in both the study and control groups after the cumulative dose: 39.7 ± 11.885 dBHL and 52.6 ± 7.456 dBHL, a value of P = <0.001 and <0.001, respectively. Conclusion: Intratympanic corticosteroid injection appears to have the only minimal therapeutic effect to cisplatin-induced hearing loss, especially for 6000 and 8000 HZ.

Keywords: Chemotherapy, cisplatin, corticosteroid, intratympanic injection, ototoxicity


How to cite this article:
Nasr WF, Abdelhady M, Abd Elbary ME, Nada E. Treatment of cisplatin-induced ototoxicity by intra-tympanic corticosteroid injection. Indian J Otol 2018;24:33-7

How to cite this URL:
Nasr WF, Abdelhady M, Abd Elbary ME, Nada E. Treatment of cisplatin-induced ototoxicity by intra-tympanic corticosteroid injection. Indian J Otol [serial online] 2018 [cited 2019 Sep 21];24:33-7. Available from: http://www.indianjotol.org/text.asp?2018/24/1/33/233121




  Introduction Top


Cisplatin is a common chemotherapeutic agent used to treat many different types of cancer including, medulloblastoma, neuroblastoma, osteosarcoma, testicular, ovarian, cervical, bladder, lung, and head-and-neck cancers.[1] Cisplatin has several side effects attributed to its nonspecific cytotoxic action. The most common dose limiting side effect is ototoxicity. Cisplatin-induced ototoxicity generally manifests as tinnitus and sensorineural hearing loss (SNHL)[2] which persists in the high frequencies, but extends into lower frequencies that are important for speech perception.[3] It has long been recognized that cisplatin results in the loss of cochlear outer hair cells (OHC), persisting in the base of the cochlea.[4],[5] More recent evidence suggests that in addition to the OHCs, the stria vascularis, and the spiral ganglion cells are also injured and that the latter injury occurs in a time course paralleling the loss of OHCs suggesting that cisplatin targets them directly.[6]

In the current clinical practice, treatment of cancer with cisplatin is either interrupted when ototoxicity develops (by switching to another less potent antineoplastic agent such as carboplatin) or the resulting hearing impairment is tolerated as an acceptable side effect of cancer treatment. At the molecular level, cisplatin induces the generation of reactive oxygen species (ROS),[7] such as superoxide anion.[8] With an increased ROS, glutathione, and antioxidant enzymes are depleted.[9] As the antioxidant enzymes are depleted, superoxide, hydrogen peroxide, and toxic lipids lead to calcium influx within cochlear cells and triggering apoptosis.[7] Dozens of experimental studies have attempted to find an ideal otoprotectant by the administration of antioxidants against ROS at an early stage in the ototoxic pathways.[10] Unfortunately, many of these agents have been found to inhibit the tumoricidal effects of cisplatin and/or have toxicities or unknown effects in humans.[1] Glucocorticoids (prednisone, dexamethasone, and methylprednisolone) have a significant role for the treatment of SNHL. In fact, systemic glucocorticoids are currently in use for the treatment of hearing loss in a variety of cochlear disorders such as autoimmune inner ear, endolymphatic hydrops and Meniere's disease, and tinnitus and cases of sudden or idiopathic rapidly progressing hearing loss when the etiology is unclear.[11] Corticosteroids have been shown to limit the formation of ROS in the inner ear.[12],[13] Animal studies have shown corticosteroids to have a protective benefit against aminoglycoside ototoxicity, which is believed to have similar pathogenesis to cisplatin ototoxicity.[14],[15]

The presence of corticosteroid receptors within the critical mouse inner ear structures provides further evidence that steroids can exert an effect on the inner ear.[16] Unfortunately, corticosteroids also down-regulate apoptosis genes in tumor cells.[17] Therefore, their systemic application to protect and treat cisplatin-induced ototoxicity may result in decreased efficacy of cisplatin's tumoricidal properties. Intratympanic administration of drugs is a contemporary method of locally treating inner ear disorders, allowing diffusion across the round window into the inner ear where it can exert its effects. Specifically, steroids placed into the middle ear have been shown to diffuse across the round window into the inner ear and bathe the inner ear structures.[16],[18],[19]

This method allows the concentration of steroid to much higher levels within the inner ear compared to oral or parenteral routes.[18],[19],[20] Furthermore, local administration prevents systemic absorption avoiding the common systemic side effects of steroids, including hyperglycemia, peptic ulcers, hypertension, and osteoporosis [11],[18] and more problematic, reduced the efficacy of chemotherapeutic agents.[19] Intratympanic administration of steroids has been used to safely treat other inner ear disorders such as sudden SNHL and Méniere's disease for several years.[11],[21]

Intratympanic dexamethasone (ITD) was clinically tested for its otoprotective effect in patients suffering from a neoplastic diseases for which the treatment protocol included cisplatin and ITD is slightly protective against cisplatin-induced hearing loss.[22]

In this study, the intratympanic steroids had been tested for treating cisplatin ototoxicity. In this study, we use ITD injection to determine if cisplatin ototoxicity can be treated by the intratympanic administration of corticosteroids.


  Patients and Methods Top


This study was conducted from May 2015 to August 2016 on 20 patients suffering from a neoplastic disease for which the primary curative treatment protocol included cisplatin and complicated by ototoxicity with a diagnosis of bilateral SNHL in Otolaryngology-Head-and-Neck Surgery Department, Zagazig University Hospitals.

Clinically significant CIHL was defined according to the guidelines of the American Speech-Language-Hearing Association as hearing loss of 20 dBHL or more in a single-frequency or hearing loss of at least 10 dBHL in two or more adjacent frequencies.[23] Ototoxicity is not a reported side effect in any of these chemotherapeutic agents. In this study, we had selected the patients that were diagnosed with bilateral SNHL as early as possible after persisting the cisplatin treatment (within 1-week). This was accomplished through screening the neoplastic patients treated with cisplatin by performing pure-tone audiometry (PTA) 1-week after the onset of cisplatin treatment.

Exclusion criteria

  • Age <18 years
  • The pathological findings on otoscopy that did not allow safe IT drug delivery such as acute or chronic otitis media
  • Retrocochlear disorder evidenced on magnetic resonance imaging (MRI)
  • The previous surgery in the affected ear
  • Known causes of hearing impairment including Meniere's disease, autoimmune HL, trauma, radiation-induced HL, noise-induced HL, or any other identifiable etiologies for SNHL
  • Patients treated by cisplatin and having bilateral SNHL but coming after >2 weeks of the onset of the treatment.


Audiological testing with PTA, speech reception threshold (SRT), and speech discrimination (SD) score was carried out in all patients. MRI with gadolinium was carried out (to exclude cerebellopontine angle tumors) with a laboratory evaluation that included the assessment of complete blood count, electrolyte, erythrocyte sedimentation rate, thyroid function testing, fasting blood sugar, and lipid profile. An informed consent was signed by every patient included in this study and Zagazig university IRB approval was obtained. Before each cisplatin treatment session, ITD was injected to one ear, which serves as the study ear while the other ear of the same patient did not receive an injection served as the control ear. The dexamethasone used in this study is available in the form of dexamethasone sodium phosphate (Epidrone ® 4 mg/1 ml [Dexamethasone sodium phosphate] 2 ml, EPICO) vials.

Technique

EMLA cream (AstraZeneca, Wilmington DE, USA) was applied for topical anesthesia. EMLA cream was placed in the outer ear canal and the tympanic membrane and left for 30–45 min, after which it was removed. Next, the patient's head was placed at 45° toward the untreated ear. Under the microscope, a 40 mg/ml methylprednisolone solution was warmed to body temperature in a water bath. About 0.3–0.5 ml of the solution was injected into the middle ear by a 27G spinal needle slightly angled to allow proper visualization of the puncture site which penetrated the tympanic membrane at the posterior–inferior quadrant, avoiding puncturing in the same place twice during the treatment. The injection was administered slowly so that the solution pooled around the round window niche, completely filling the middle ear cavity. The dose variations due to patient specific factors, although in most cases, at least 0.3 ml was injected.

After intratympanic application of the steroid, the patient was instructed to avoid swallowing, speaking, or moving in the supine position with the head tilted 45° to the untreated side for 30 min to provide a maximal absorption of the medication through the round window and to prevent drug leakage through the  Eustachian tube More Details. Patients were asked to avoid water in the treated ear for at least 2 weeks. The procedure is repeated 1-week after each cisplatin session after doing PTA to detect if SNHL had occurred after the session or not, IT injection was done only if SNHL had been developed after the sessions.

Follow-up PTA was performed 1-week after the last IT injection session had been finished and also after the cumulative dosage of cisplatin reached at least 400 mg, a level at which a maximal ototoxic effect is anticipated.


  Results Top


This study included 20 patients; of which 13 males and 7 females their ages ranged from 40 to 65 years (mean 57.9 ± 6.797). ITD is injected into the right and left ears in 12 and 8 patients, respectively. Except for the slight pain during injection and short, mild vertigo secondary to the uneven caloric stimulation, no side effects were recorded. The average cumulative dose of cisplatin was 546.3 ± 111.58 mg, the average number of cisplatin treatment sessions was 5.5 ± 1, and the average number of IT injections was 13.1 ± 3.78.

Before the start of the IT injection, there were no significant differences between the control and the study ears as regards hearing thresholds [Table 1].
Table 1: Pure tone audiometry results before the start of cisplatin treatment in control and test ears

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Within the groups, after the cumulative dose of cisplatin is reached the PTA at 500, 1000, 2000, and 3000 Hz; did not reveal any statistically significant differences while, the PTA for 4000–8000 Hz showed a significant increases in both the study and control groups [Table 2] and [Table 3].
Table 2: Pure tone thresholds in the control ear before and after the treatment

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Table 3: Test ear before and after the treatment

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Significant increases in the average pure-tone thresholds (PTTs) at 8000 Hz were found in both the study and control groups after the cumulative dose: 43.15 ± 15.557 dBHL and 55.7 ± 13.2589 dBHL, a value of P = 0.0004 and 0.00, respectively. Significant increases in the average PTTs at 6000 Hz were found in both the study and control groups after the cumulative dose: 39.7 ± 11.885 dBHL and 52.6 ± 7.456 dBHL, a value of P = 0.000 and 0.00, respectively [Table 2] and [Table 3].

Hence, the PTTs in both control and the study ears after cumulative cisplatin treatment had shown significant differences, especially in 6 and 8 kHz, representing that even hearing loss had occurred, but in a significantly lower amounts in the ITD treated ear, especially in the much higher frequencies which are most vulnerable to cisplatin ototoxicity table [Table 4].
Table 4: Pure tone thresholds in both control and test ears after the cumulative treatment

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Non-significant differences were detected when comparing speech reception thresholds and speech discrimination scores between the control ear and the test ear either before or after treatment, but on comparing speech reception thresholds within each group separately there was significant difference before and after the treatment while the speech discrimination had shown non significant difference when comparing the control ear with the test ear before treatment [Table 5].
Table 5: Speech reception threshold and speech discrimination scores before and after treatment

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  Discussion Top


The main finding of this study is that ITD delivered shortly after detection of CIHL following each cisplatin session provided only a minimal therapeutic effect to CIHL. Although significant threshold increase was observed in both the study and control groups for PTA 4000–8000 Hz, the PTTs in both control and the study ears after the cumulative cisplatin treatment had shown significant differences, especially in 6 and 8 kHz, representing that even hearing loss had occurred, but in a significantly lower amounts in the ITD treated ear, especially in the much higher frequencies which are most vulnerable to cisplatin ototoxicity pointing to the mild therapeutic effect of ITD for CIHL.

The finding that early ototoxic effects caused hearing loss at 6000 and 8000 Hz corroborates with the previous reports.[24] The increase in high frequencies PTTs from 4000 to 8000 Hz in both control and the study groups confirming the previous observations pointing to the organ of corti OHC as the primary target for cisplatin ototoxicity.[3],[25] The specific mechanisms involved in the attenuation of CIHL by corticosteroid are not known yet. However, recent studies suggest the relevance of various cellular processes that might explain this effect. The high presence of mineralocorticoid and glucocorticoid receptors was observed in the outer and inner hair cells, spiral ganglion neurons, and spiral ligament.[16],[26],[27] The mineralocorticoid receptors reveal higher affinity to steroidal hormones, which points to the significant role of steroids in maintaining fluid regime and homeostasis of the inner ear.[16],[28] The blood-labyrinthine barrier is composed of capillary endothelial cells with tight junctions that inhibit absorption of chemicals from the systemic circulation into the inner ear. The rising level of ROS operates the vascular endothelial cells to secreting of different cytokines that damage the tight junctions, cause violation of the inner ear fluid homeostasis, damaging the endocochlear potential, and hence lead to apoptosis of cell lines in the organ of corti.[29] Glucocorticosteroids were reported to bring a new creation of the tight junctions between endothelial cells, thus restoring endothelial function in the stria vascularis.[30]

We could not find any previous study that examined IT corticosteroid in the treatment of CIHL in humans. However, there was only one study that test the otoprotective effect of IT corticosteroid on CIHL in human, patients enrolled in the study underwent unilateral ITD administration before every cisplatin treatment session, with the contralateral ear used as a control. Serial follow-up audiometry and distortion product optoacoustic emissions testing were performed to check the functional state of both study and control ears. The statistically significant results showed that the ITD is slightly protective against cisplatin-induced hearing loss at 6000 Hz and decreases the OHC dysfunction in the frequency range of 4000–8000 Hz. The conclusion of the study is that ITD has minimal effect toward reducing cisplatin ototoxicity.[22]

Yet, the beneficial role of IT corticosteroid in the treatment of CIHL has been documented in a few small mammals' studies. Calli et al., 2012 in his study on the recovery of hearing in cisplatin-induced ototoxicity in the guinea pig with ITD had concluded that ITD might have a significant therapeutic effect after cisplatin ototoxicity with different dose and application regimens.[31] Our results correlate with that of Marshak et al., 2014, where the ITD given shortly before each cisplatin session was slightly protective against cisplatin-induced hearing loss at 6000 and 8000 Hz [22] whereas, in this study IT corticosteroid, given shortly after each cisplatin session in patients developed CIHL had provided only minimal therapeutic effect at 6000 and 8000 Hz.

Further studies using different concentrations of corticosteroid and a perfect timing of administration are necessary to investigate its role in the treatment of hearing loss after the cisplatin therapy.


  Conclusion Top


IT dexamethasone delivered shortly after the detection of CIHL following each cisplatin session appears to have only a minimal therapeutic effect to CIHL, especially for 6000 and 8000 HZ. The sample size was small so further randomized and controlled studies with larger sample sizes are needed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]


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