Cisplatin-induced ototoxicity in 401 consecutive Geneva cancer patients

doi:10.21203/rs.3.rs-1747607/v1

Download PDF

Article

Cisplatin-induced ototoxicity in 401 consecutive Geneva cancer patients

https://doi.org/10.21203/rs.3.rs-1747607/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Objective

Robust epidemiological and audiological data are needed to prepare for future clinical trials aiming at preventing cisplatin-induced ototoxicity in this suffering cancer population. We precisely assessed the incidence, severity and potential risk factors of symptomatic cisplatin-induced ototoxicity in a large cohort of adults.

Methods

Retrospective cohort study at a tertiary care university hospital. Study group included 401 consecutive patients over 18 years old treated with cisplatin-based chemotherapy, without concomitant inner ear radiotherapy nor other ototoxic medication. Every participant underwent baseline pre-treatment audiometry and were asked for otological symptoms (tinnitus, hearing loss). If symptomatic, comparative audiometry was performed. Ototoxicity was defined by a threshold shift ≥ 15 dB HL in at least one of the tested frequencies.

Results

A total of n = 401 cancer patients (59% males) with a mean age of 56 years (range 18–80 years). N = 81 patients (20%) developed symptomatic ototoxicity, affecting predominantly the high frequencies from 4 to 8 kHz. Among the patients with cisplatin-induced hearing loss, n = 49 (60%) experienced simultaneous tinnitus, occurring in over half of them after the first cycle of chemotherapy. None of the analyzed potential risk factors age, gender, smoking, hypertension, diabetes, vasculopathy, dyslipidemia, chemotherapeutic regimen and cumulative cisplatin dose was statistically correlated with the occurrence or severity of cisplatin-induced hearing loss.

Conclusion

One out of five adult cancer patients treated with cisplatin chemotherapy developed a symptomatic and predominant high-frequency hearing loss, with simultaneous occurrence of tinnitus in over half of them. Standardized audiological monitoring before and during cisplatin chemotherapy allows to quantitatively assess early and objective signs of ototoxicity and offers to optimize anticancer therapy while minimizing morbidity in a multidisciplinary setting.

According to the World Health Organization (WHO), cancer is the leading cause of death worldwide with 10 million human lives lost in 2020¹. Nevertheless, ever improving anticancer therapies and a generally longer life-expectancy lead to a higher number of cancer survivors^2,3. Therefore, chemotherapy-induced acute adverse effects such as nausea, anorexia, diarrhea, loss of hair, as well as long-term sequelae such as neurotoxicity, nephrotoxicity and hearing loss⁴, among others, are becoming more prevalent and important.

The inner ear is sensitive to a variety of insults and among them iatrogenic insults such as surgery⁵, ionizing radiations⁶ and certain drugs⁷. When side-effects of drugs impair hearing (cochlear damage) and/or balance (vestibular damage), the phenomenon is referred to as ototoxicity. Several drugs, as summarized in Table 1, are ototoxic and among them, cisplatin stands out in terms of potency and prevalence. Vestibulotoxicity is poorly investigated and the correlation between symptoms and examination should be interpreted with caution^{8, 9}. Additionally, measurements of vestibular impairment are expensive and time-consuming, and therefore not routinely performed in our clinic in the absence of symptoms. For these reasons, this article will focus only on cochleotoxicity.

Cisplatin (Cis-diamminedichloroplatinum(II), [Pt(NH₃)₂Cl₂]) is an active platinum-based complex authorized for human use since 1978³⁶. Today, cisplatin is one of the most efficient anticancer agents used against solid tumors³⁷ in adults and children and has been included into the WHO’s list of “essential medicines”³⁸. Synergistic effects with different molecules have been described³⁷ together with a radio-sensitization effect, thus potentializing radiotherapy³⁹. In a wide range of clinical settings such as cervical, head and neck, lung, bladder and testicular cancer, cisplatin-containing regimen are given with curative intent. Thousands of chemical analogues of cisplatin with different toxicity and efficacy profiles have been produced, but only 13 reached clinical trials. Among them, only carboplatin and oxaliplatin has brought about a certain advantage over cisplatin in terms of adverse event profile, particularly regarding ototoxicity^{36, 37}, and are also considered by the WHO as essential medicines³⁸.

Because of the intrinsic and unspecific cytotoxic mechanisms (DNA alkylation, DNA repair and replication inhibition), cisplatin is widely associated with toxic adverse effects, such as nausea, nephrotoxicity, neurotoxicity, cardiotoxicity, hepatotoxicity, gastrotoxicity, myelosuppression, allergic reactions and a prevalent ototoxicity³⁷. To date, some adverse event such as nephrotoxicity can be partly palliated⁴⁰, but no preventive drug or measure have been validated against ototoxicity.

Cisplatin-induced ototoxicity typically induces bilateral, symmetrical, irreversible sensorineural hearing loss, affecting primarily high frequencies, commonly in combination with tinnitus⁶, which can occur transiently or permanently and even without hearing loss. Cumulative dose, number of cycles, method of administration (bolus, continuous) and impaired renal function influence the incidence and severity of cisplatin ototoxicity^{41, 42}. In addition, noise exposure, concomitant chemicals and other ototoxic drugs can potentiate the hearing loss⁴¹. Interestingly, genetic susceptibility may be an important factor⁴³. In the oncological context, it is important to note that cranial radiotherapy–another free-radical inducing therapy–is per se an important risk factor, with a sensorineural hearing loss incidence up to 33%⁴⁴. At the cellular level, the most reported cisplatin-related ototoxic mechanism involves reactive oxygen species (ROS) upregulation, leading to cochlear inflammation, stria vascularis degeneration and apoptosis of outer hair cells, inner hair cells and spiral ganglion neurons⁴⁵.

Hearing loss can develop years after cisplatin therapy completion⁴⁶. Platinum has been found in plasma even 20 years after treatment with cisplatin⁴⁷ and is indefinitely retained in cochleae of humans and mice^{48, 49}, as the inner ear has a very small capacity to eliminate platinum. These findings suggest that cisplatin accumulation, rather than hypersensitivity, can drive the progressive hearing loss observed in a high percentage of patients⁴⁸. The incidence of cisplatin-induced ototoxicity reported from clinical studies ranges from 26 to 100% and a selection of the most relevant articles in this context is listed in Table 2. The important variation of incidence and severity across different studies is mainly a consequence of differences in methodologies, outcome measurements (especially hearing loss criteria), patient characteristics and grading scales used^50–55. Indeed, different grading systems have been proposed (e.g. CTCAE, Brock, ASHA and Davis and Silverman, detailed in Table 2 legend), with limitations regarding to their objectivity, lack of sensitivity, complexity of use and certain choices of auditory frequencies and thresholds⁵⁶. Furthermore, the baseline, pre-treatment audiometry is often missing, limiting adequate interpretation of later exams during or after chemotherapy; this limitation is especially relevant in elderly cancer patients often suffering from concomitant age-related hearing loss⁵⁷. Despite the methodological differences, a significantly higher incidence and severity of ototoxic hearing loss has been observed in young children⁵⁶.

At the dawn of a new age of otology, where promising treatment strategies aiming at otoprotection and regeneration are being tested in preclinical trials and await translation into clinical trials, there is an increasing need for high quality epidemiological, clinical and audiological data in the context of cisplatin ototoxicity. The present study therefore aims at establishing solid epidemiological, clinical and audiological bases for our own institution and others with the same interests, in order to prepare for future clinical trials aiming at preventing cisplatin-induced ototoxicity and offer to this suffering patient population adequate and timely translation of innovative treatment modalities to minimize morbidity. This study assesses the incidence, severity and potential risk factors of cisplatin-induced ototoxicity in a large cohort of symptomatic adults with a variety of cancer types who were treated with cisplatin.

Design

We established a single-center (tertiary care) retrospective study in a cohort of consecutive cisplatin-treated patients, after obtaining authorization from the Ethics Committee of Geneva (protocol n°2018–02065). All the analyses were performed anonymously in accordance with the Declaration of Helsinki. No consent was obtained due to the retrospective anonymous analysis, in agreement with the Ethics Committee.

Participants

Patients above 18 years of age, with baseline audiometric examination and treated with at least one dose of cisplatin-based chemotherapy between January 2015 and January 2019 at the Geneva University Hospitals (HUG) were included. Excluded were patients with bilateral pre-existing cophosis, bilateral ear pathology not compatible with accurate hearing measurement, disease of the central auditory pathways, concomitant ototoxic drug therapy (such as aminoglycosides, deferoxamine, carboplatin, cyclophosphamide), concomitant inner ear radiotherapy and chronic renal insufficiency.

The medical files of all patients were obtained from the Oncology Department and analyzed for disease and treatment specific data, pre-existing and concomitant risk factors including age, gender, smoking, hypertension, diabetes, vasculopathy, dyslipidemia and cumulative cisplatin dose. Cisplatin was either administrated alone or in combination with etoposide phosphate, gemcitabine, bleomycin, pemetrexed, docetaxel, cetuximab, fluorouracil, vinorelbine, ifosfamide, paclitaxel, cytarabine, mitomycin, rituximab, bevacizumab, cetuximab, methotrexate, vinblastine, doxorubicin, dacarbazine and interferon alpha (Table 3). Cisplatin chemotherapy was flanked in every case with intravenous administration of dexamethasone for anti-emetic purposes.

Hearing assessment

An examination by an otorhinolaryngologist followed by a tonal audiometry with a frequency range from 125 to 8000 Hz (Equinox 2.0, Interacoustics, in a soundproof booth) by a trained audiometrist were performed in every case prior to the onset of the chemotherapy. Speech audiometry was not routinely performed. During the chemotherapy, the oncologists routinely asked patients about any otological symptoms, especially the occurrence of hearing loss and tinnitus. If one of these two otological symptoms was reported by the patient, a new consultation with tonal audiometry was performed. The baseline and follow-up audiometric curves were compared by the otorhinolaryngologist. A threshold shift of ≥ 15 dB HL in any of the tested frequencies was defined as hearing loss, keeping in mind an experimental error of ± 5 dB HL across audiograms⁷⁷. As a consequence, a 10 dB HL threshold shift in any isolated tested frequencies would still be considered non-significant and was not defined as ototoxicity in this study. We did not use previously used ototoxic hearing loss criteria such as CTCAE, Brock, ASHA and Davis and Silverman’s, because of their obvious limitations, such as subjectivity and lack of baseline measures (detailed in Table 2 legend)⁵⁸.

Statistical analysis

The incidence of hearing loss and tinnitus were expressed as percentage. The severity of hearing loss (i.e. degree of hearing threshold shift) was expressed in mean. The statistical correlation between qualitative variables (gender, smoking, diabetes, hypertension, vascular, dyslipidemia) and ototoxicity incidence was assessed with a χ² test. For the correlation analysis between ototoxicity incidence and quantitative variables (age and mean cumulative cisplatin dose), and between severity of hearing loss and gender, we employed a Student’s t-test. Additionally, the correlation between hearing loss, age and mean cumulative cisplatin dose was assessed by linear regression. All employed statistical tests included two-sided analysis and the significance level was set as α = 0.05.

A total of n = 401 patients with a mean age of 56 years (ranging from 18 to 80 years) were included in the study. Table 3 summarizes the pertinent patient-related data, including the number of patients with risk factors. Cisplatin-chemotherapy was administered for 30 different types of cancers in the patient collective.

Significant hearing loss was found in n = 81 out of n = 401 patients (20%). Of the n = 81 patients with symptomatic hearing loss, n = 49 (60%) reported the occurrence of simultaneous tinnitus and n = 48 patients (60%) had preexisting hearing loss detected at baseline audiometry. When the information was available (n = 37), hearing loss was reported to occur after the first cycle of chemotherapy in 54% of the cases and in 29% after the second cycle.

In patients exhibiting significant hearing loss (≥ 15 dB in any frequency), the average threshold shift over the entire frequency spectrum was 9.5 dB (SD = 6.5), with greater involvement of the 4, 6 and 8 kHz frequencies (see Fig. 1 and Fig. 2). No statistical difference was found between hearing loss incidence and severity between the right and left ears (overlapping of 95% confidence interval).

Risk factors

On average, the patients received a mean cumulative cisplatin dose of 418 mg/m² (SD = 223). Patients who developed hearing loss had on average a 51 (95% CI [-5, 107], n = 355, p = 0.07) mg/m² higher mean cumulative cisplatin dose compared to patients without. However, the difference, although expected and clearly visible, was not statistically significant. The average hearing threshold shift was not correlated with the cumulative dose of cisplatin (r² = 0.02, n = 355, p = 0.17).

Furthermore, we observed a difference of 0.8 (95% CI [-2.1, 3.7], p = 0.6) years in the average age, between patients with hearing loss and those without. There was no statistical association between age and average of hearing threshold shift (r² = 0, p = 0.5). There was a difference of 0.3 (95% CI [-2.5, 3.2], p = 0.8) dB HL in the average threshold shift in males compared to females without reaching statistical significance. None of the other investigated potential risk factors including diabetes, hypertension, dyslipidemia and vasculopathy were correlated with the occurrence of ototoxic hearing loss (Table 4). There was no significant difference of ototoxicity incidence in the different most prevalent chemotherapeutic regimen compared to cisplatin only regimen (all p-values > 0.3).

In our large collective of n = 401 consecutive adult patients treated with a mean cisplatin dose of 418 mg/m² (SD = 223) flanked by intravenous application of dexamethasone (mostly 12 mg), a total of 20% developed a symptomatic and significant hearing loss with a threshold shift ≥ 15 dB HL in at least one of the tested frequencies between the pretreatment baseline and the follow-up audiometry during or after the chemotherapy. As expected, the high frequencies from 4 to 8 kHz were mainly affected (shown in Fig. 1) with an average threshold shift of 18 dB HL (SD = 12). Other large studies including baseline audiometry and no other concomitant ototoxic insults reported incidence of ototoxicity up to 49%⁶¹ and 55%⁶⁶, but their use of questionable (see Table 2 legend) hearing loss criteria makes comparative analysis difficult. In our experience, symptomatic hearing loss is far from extreme incidence reported in some studies which should not be communicated to the patients during their informative pretreatment consultation.

Following our analysis, hearing loss primarily occurred after the first cisplatin cycle and to a lesser extent after the second, suggesting a cisplatin exponential ototoxicity with a fast saturation of the effect following the first dose. Hearing loss was sensorineural, affected both ears symmetrically and predominantly the high frequencies beyond 4 kHz, as demonstrated in Fig. 2. None of the patients developed a complete hearing loss (cophosis) in the cohort.

The reported hearing loss incidence was stronger in patients receiving higher cumulative doses of cisplatin, however without reaching statistical significance in our cohort (p = 0.07). A statistically significant correlation between hearing loss and the cumulative cisplatin dose has been shown in several articles on the subject and has been commonly accepted in daily practice^{62, 67, 71}. We can hypothesize that by adapting the cisplatin dose or changing the molecule (e.g. carboplatin instead of cisplatin) at first occurrence of hearing loss, one’s may actually diminish the incidence and severity of ototoxic hearing loss. At least, in our tertiary hospital, the multidisciplinary approach foresees to discuss the treatment regimen at first sight of ototoxic hearing loss for every patient.

The different cisplatin-based regimen did not influence the occurrence of ototoxicity, suggesting that cisplatin is the main accountant for the toxicity, which is not due to particular combinations with other drugs. Each treatment was accompanied by the adjuvant administration of dexamethasone, which has also anti-inflammatory effect besides their anti-emetic properties, but no ototoxicity.

None of the recorded medical factors significantly influenced the incidence and severity of ototoxic hearing loss. Vascular comorbidities did not seem to precipitate cochlear damage, as it could have been expected. Albeit there is a tendency of increased hearing loss incidence in men, it did not reach statistical significance. The literature about risk factors predisposing for ototoxic hearing loss remains non-conclusive today.

Another interesting finding was the high tinnitus prevalence (60%) reported in patients with hearing loss following cisplatin treatment. During a cisplatin-based chemotherapy, tinnitus is a relevant indicator of hidden hearing loss⁷⁸ and ototoxic susceptibility, which should be followed by a full audiometric evaluation. If mild and oligosymptomatic, the treatment should be thoroughly discussed between patient, otolaryngologist and oncologist. Either the therapy is continued with equivalent or lower dose, or modified including a lower ototoxic compound (carboplatin), if the overall oncological context allows a modification of the treatment regimen. If a severe symptomatic hearing loss is reported, this discussion needs to be held similarly, but strongly highlighting the eventual modification or even cessation of the chemotherapy, if the molecular biology and overall medical context allows.

If symptomatic hearing loss persists beyond the oncological phase, hearing rehabilitation needs to be discussed with the patient. In Switzerland, hearing aids are proposed to the patient, if the total hearing loss is calculated ≥ 20% using the classification of Council on Physical Therapy, American Medical Association [CPT-AMA]⁷⁹. Should hearing aids be insufficient, cochlear implants can be proposed, particularly in the case of partial deafness, with preserved hearing in the low frequencies and complete deafness in the higher frequencies > 2 kHz⁸⁰. In our cohort, none of the patients developed severe or profound hearing loss and no indication for cochlear implantation was discussed.

Ototoxic inner ear damage may occur simultaneously or sequentially in other progressive hearing loss etiologies such as presbycusis or genetic preconditions⁸¹. In our cohort, 60% (n = 48) of the patients with ototoxic hearing loss had preexisting hearing loss to some degree. This highlights the need for a thorough audiological baseline examination in every patient before the onset of cisplatin or any other ototoxic chemotherapy, a practice that is still not ubiquitously adopted today⁸².

Although the baseline audiological examination is performed in our institution, the present analysis is likely to underestimate the true incidence and severity of cisplatin-induced hearing loss. Partly because of its retrospective nature, but also because until 2019, auditory follow-up examinations were conducted only in patients reporting tinnitus or hearing loss spontaneously or after being specifically asked by their oncologist. For this reason, patients without auto-reported hearing-related symptoms - which is often not a priority in case of significant other cancer-related morbidity - may not have been included in the analysis and their hearing loss undetected. This hypothesis is corroborated by other studies with a prospective enrollment of cancer patients, following strict audiological work-up protocols including baseline examination and fixed follow-up evaluation. Those studies reported a much higher ototoxicity incidence, reaching up to 64%, depending on the hearing loss criteria used^{58, 73–75}. Furthermore, centers performing additional large high-frequency audiometry (up to 20 kHz) reported a higher incidence of cisplatin ototoxicity than centers with the standard audiometric measurements (up to 8 kHz), as used in the present study^{67, 69}. On the other hand, the patients may benefit of being informed on the risk of potential symptoms, rather than purely descriptive subclinical damages, just like neuropathy and renal insufficiency. The present study has also the advantage of including a high number of consecutive adult cases (n = 401), which is actually more than three times the number of the largest study including pre-treatment audiogram published so far (n = 124)⁶². Additionally, the chosen hearing loss criteria are conservative and objective, applying to symptomatic patients only, making the incidence and severity reported pragmatic.

The present study shows that at least 1 out of 5 patients treated with cisplatin chemotherapy develops symptomatic significant hearing loss, adding morbidity to this already suffering population. To prevent ototoxic hearing loss through molecular or pharmacological intervention would be of interest for thousands of patients world-wide and to this end, translational research projects aiming at otoprotection by different methods are currently underway in our own and many other institutions. We believe that a strong collaboration between clinicians and basic scientists will significantly increase the chances of developing an effective preventive therapy against cisplatin ototoxicity tailored to the patient’s need and with a meaningful mode of application for otologists.

This large retrospective analysis of consecutive adult cancer patients treated with cisplatin-based chemotherapy showed a symptomatic hearing loss in 20% of the cases. In order to improve early detection, the systematic application of a thorough audiological examination before, during and after completion of cisplatin chemotherapy is mandatory. Early detection of ototoxic hearing loss is a prerequisite for a multidisciplinary discussion and a potential modification of the treatment regimen aiming at maximizing anticancer action while minimizing morbidity for each individual patient. In addition, rapid, accurate and early detection of ototoxic hearing loss lays a sound base for imminent clinical trials aiming at prevention of cisplatin-induced ototoxicity.

ACKNOWLEDGMENTS

None.

DISCLOSURE

All authors have no financial disclosure nor conflict of interest to declare.

DATA AVAILABILITY

The datasets generated and analyzed during the current study are not publicly available due to restriction from the Oncology Department, referring to sensitive oncological matters but are available from the corresponding author on reasonable request.

AUTHOR CONTRIBUTIONS

FV: Conceptualization. Collection of the data. Writing – original draft preparation.

AV: Writing – Review & Editing.

DM: Writing – Review & Editing.

GN: Writing – Review & Editing.

FR: Writing – Review & Editing.

TD: Writing – Review & Editing.

PS: Conceptualization. Writing – original draft preparation.

DATA AVAILIBILITY STATEMENT

All data are fully available without restriction.

COMPETING INTERESTS

The author declare no competing interests.

WHO. WHO fact sheets - Cancer. 2020 3 february 2020; Available from: https://www.who.int/news-room/fact-sheets/detail/cancer.
Miller, K.D., R.L. Siegel, C.C. Lin, A.B. Mariotto, J.L. Kramer, J.H. Rowland, K.D. Stein, R. Alteri, and A. Jemal, Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin, 2016. 66(4): p. 271 – 89.
Arnold, M., M.J. Rutherford, A. Bardot, J. Ferlay, T.M. Andersson, T.A. Myklebust, H. Tervonen, V. Thursfield, D. Ransom, L. Shack, R.R. Woods, D. Turner, S. Leonfellner, S. Ryan, N. Saint-Jacques, P. De, C. McClure, A.V. Ramanakumar, H. Stuart-Panko, G. Engholm, P.M. Walsh, C. Jackson, S. Vernon, E. Morgan, A. Gavin, D.S. Morrison, D.W. Huws, G. Porter, J. Butler, H. Bryant, D.C. Currow, S. Hiom, D.M. Parkin, P. Sasieni, P.C. Lambert, B. Moller, I. Soerjomataram, and F. Bray, Progress in cancer survival, mortality, and incidence in seven high-income countries 1995–2014 (ICBP SURVMARK-2): a population-based study. Lancet Oncol, 2019. 20(11): p. 1493–1505.
Di Maio, M., C. Gallo, N.B. Leighl, M.C. Piccirillo, G. Daniele, F. Nuzzo, C. Gridelli, V. Gebbia, F. Ciardiello, S. De Placido, A. Ceribelli, A.G. Favaretto, A. de Matteis, R. Feld, C. Butts, J. Bryce, S. Signoriello, A. Morabito, G. Rocco, and F. Perrone, Symptomatic toxicities experienced during anticancer treatment: agreement between patient and physician reporting in three randomized trials. J Clin Oncol, 2015. 33(8): p. 910–5.
Simon, M.V., Neurophysiologic intraoperative monitoring of the vestibulocochlear nerve. J Clin Neurophysiol, 2011. 28(6): p. 566–81.
Mujica-Mota, M., S. Waissbluth, and S.J. Daniel, Characteristics of radiation-induced sensorineural hearing loss in head and neck cancer: a systematic review. Head Neck, 2013. 35(11): p. 1662–8.
Roland, P.S. and J. Rutka, Ototoxicity. 2004, BC Decker Inc.
Prayuenyong, P., A.V. Kasbekar, D.A. Hall, and D.M. Baguley, Audiovestibular clinician experiences and opinions about cisplatin vestibulotoxicity. Eur Arch Otorhinolaryngol, 2020. 277(12): p. 3283–3293.
Prayuenyong, P., J.A. Taylor, S.E. Pearson, R. Gomez, P.M. Patel, D.A. Hall, A.V. Kasbekar, and D.M. Baguley, Vestibulotoxicity Associated With Platinum-Based Chemotherapy in Survivors of Cancer: A Scoping Review. Front Oncol, 2018. 8: p. 363.
Brummett, R.E. and K.E. Fox, Aminoglycoside-induced hearing loss in humans. Antimicrob Agents Chemother, 1989. 33(6): p. 797–800.
Ariano, R.E., S.A. Zelenitsky, and D.A. Kassum, Aminoglycoside-induced vestibular injury: maintaining a sense of balance. Ann Pharmacother, 2008. 42(9): p. 1282–9.
Roland, P.S. and J. Rutka, Ototoxicity. 2004, BC Decker Inc. p. 76–78.
Cazals, Y., Auditory sensori-neural alterations induced by salicylate. Prog Neurobiol, 2000. 62(6): p. 583–631.
Cuffel, C. and J.P. Guyot, [Aspirin ototoxicity: a rare situation today]. Rev Med Suisse, 2013. 9(400): p. 1785–8.
Seaman, B.J., E.A. Guardiani, C.C. Brewer, C.K. Zalewski, K.A. King, S. Rudy, C. Van Waes, R.A. Morgan, M.E. Dudley, J.C. Yang, S.A. Rosenberg, and H.J. Kim, Audiovestibular dysfunction associated with adoptive cell immunotherapy for melanoma. Otolaryngol Head Neck Surg, 2012. 147(4): p. 744–9.
Johnson, L.A., R.A. Morgan, M.E. Dudley, L. Cassard, J.C. Yang, M.S. Hughes, U.S. Kammula, R.E. Royal, R.M. Sherry, J.R. Wunderlich, C.C. Lee, N.P. Restifo, S.L. Schwarz, A.P. Cogdill, R.J. Bishop, H. Kim, C.C. Brewer, S.F. Rudy, C. VanWaes, J.L. Davis, A. Mathur, R.T. Ripley, D.A. Nathan, C.M. Laurencot, and S.A. Rosenberg, Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood, 2009. 114(3): p. 535 – 46.
Roland, P.S. and J. Rutka, Ototoxicity. 2004, BC Decker Inc. p. 33.
Curhan, S.G., R. Eavey, J. Shargorodsky, and G.C. Curhan, Analgesic use and the risk of hearing loss in men. Am J Med, 2010. 123(3): p. 231–7.
Ikeda, A.K., A.A. Prince, J.X. Chen, J.E.C. Lieu, and J.J. Shin, Macrolide-associated sensorineural hearing loss: A systematic review. Laryngoscope, 2018. 128(1): p. 228–236.
Rybak, L.P., Ototoxicity of loop diuretics. Otolaryngol Clin North Am, 1993. 26(5): p. 829–44.
Jourde-Chiche, N., J. Mancini, N. Dagher, S. Taugourdeau, G. Thomas, C. Brunet, C. Bornet, M.J. Pastor, and L. Chiche, Antimalarial ototoxicity: an underdiagnosed complication? A study of spontaneous reports to the French Pharmacovigilance Network. Ann Rheum Dis, 2012. 71(9): p. 1586.
Shine, N.P. and H. Coates, Systemic ototoxicity: a review. East Afr Med J, 2005. 82(10): p. 536–9.
Tuknayat, A., G.P. Thami, P. Gogia, and M. Bhutani, Cyclophosphamide-Induced Hearing Loss: Reversibility and Preventive Strategies. Am J Ther, 2018. 25(6): p. e692-e695.
Cummings, C.W., Experimental observations on the ototoxicity of nitrogen mustard. Laryngoscope, 1968. 78(4): p. 530–8.
Tampio, A.J.F., S. Dhanireddy, A. Sivapiragasam, and B.D. Nicholas, Bilateral Sensorineural Hearing Loss Associated With Nivolumab Therapy for Stage IV Malignant Melanoma. Ear Nose Throat J, 2021. 100(3_suppl): p. 286S-291S.
Rosner, S., Y. Agrawal, D.Q. Sun, N. Aygun, M.D. Schollenberger, E. Lipson, and J. Naidoo, Immune-mediated ototoxicity associated with immune checkpoint inhibitors in patients with melanoma. J Immunother Cancer, 2020. 8(2).
Hultcrantz, M., R. Simonoska, and A.E. Stenberg, Estrogen and hearing: a summary of recent investigations. Acta Otolaryngol, 2006. 126(1): p. 10–4.
Formann, E., R. Stauber, D.M. Denk, W. Jessner, G. Zollner, P. Munda-Steindl, A. Gangl, and P. Ferenci, Sudden hearing loss in patients with chronic hepatitis C treated with pegylated interferon/ribavirin. Am J Gastroenterol, 2004. 99(5): p. 873–7.
Stenner, M., K. Sturmer, D. Beutner, and J.P. Klussmann, Sudden bilateral sensorineural hearing loss after intravenous cocaine injection: a case report and review of the literature. Laryngoscope, 2009. 119(12): p. 2441–3.
Khan, A.S., Z. Sheikh, S. Khan, R. Dwivedi, and E. Benjamin, Viagra deafness–sensorineural hearing loss and phosphodiesterase-5 inhibitors. Laryngoscope, 2011. 121(5): p. 1049–54.
Roland, P.S. and J. Rutka, Ototoxicity. 2004, BC Decker Inc. p. 128–130.
Roland, P.S. and J. Rutka, Ototoxicity. 2004, BC Decker Inc. p. 130–132.
Moellering, R.C., Jr., Pharmacokinetics of vancomycin. J Antimicrob Chemother, 1984. 14 Suppl D: p. 43–52.
Bruniera, F.R., F.M. Ferreira, L.R. Saviolli, M.R. Bacci, D. Feder, M. da Luz Goncalves Pedreira, M.A. Sorgini Peterlini, L.A. Azzalis, V.B. Campos Junqueira, and F.L. Fonseca, The use of vancomycin with its therapeutic and adverse effects: a review. Eur Rev Med Pharmacol Sci, 2015. 19(4): p. 694–700.
Roland, P.S. and J. Rutka, Ototoxicity. 2004, BC Decker Inc. p. 78–79.
Kelland, L., The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer, 2007. 7(8): p. 573–84.
Dasari, S. and P.B. Tchounwou, Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol, 2014. 740: p. 364–78.
WHO, WHO Model List of Essential Medicines. 2015.
Yanfang Dong, L.Z., Qinfen Tian, Yi Zheng, and Léon Sanche, Chemoradiation Cancer Therapy: Molecular Mechanisms of Cisplatin Radiosensitization. The Journal of Physical Chemistry C, 2017. 121 (32): p. 17505–17513.
Bajorin, D.F., G.J. Bosl, N.W. Alcock, D. Niedzwiecki, E. Gallina, and B. Shurgot, Pharmacokinetics of cis-diamminedichloroplatinum(II) after administration in hypertonic saline. Cancer Res, 1986. 46(11): p. 5969–72.
Paken, J., C.D. Govender, M. Pillay, and V. Sewram, Cisplatin-Associated Ototoxicity: A Review for the Health Professional. J Toxicol, 2016. 2016: p. 1809394.
van As, J.W., H. van den Berg, and E.C. van Dalen, Platinum-induced hearing loss after treatment for childhood cancer. Cochrane Database Syst Rev, 2016(8): p. CD010181.
Tserga, E., T. Nandwani, N.K. Edvall, J. Bulla, P. Patel, B. Canlon, C.R. Cederroth, and D.M. Baguley, The genetic vulnerability to cisplatin ototoxicity: a systematic review. Sci Rep, 2019. 9(1): p. 3455.
Jereczek-Fossa, B.A., A. Zarowski, F. Milani, and R. Orecchia, Radiotherapy-induced ear toxicity. Cancer Treat Rev, 2003. 29(5): p. 417–30.
Sheth, S., D. Mukherjea, L.P. Rybak, and V. Ramkumar, Mechanisms of Cisplatin-Induced Ototoxicity and Otoprotection. Front Cell Neurosci, 2017. 11: p. 338.
Knight, K.R., D.F. Kraemer, and E.A. Neuwelt, Ototoxicity in children receiving platinum chemotherapy: underestimating a commonly occurring toxicity that may influence academic and social development. J Clin Oncol, 2005. 23(34): p. 8588–96.
Gietema, J.A., M.T. Meinardi, J. Messerschmidt, T. Gelevert, F. Alt, D.R. Uges, and D.T. Sleijfer, Circulating plasma platinum more than 10 years after cisplatin treatment for testicular cancer. Lancet, 2000. 355(9209): p. 1075–6.
Breglio, A.M., A.E. Rusheen, E.D. Shide, K.A. Fernandez, K.K. Spielbauer, K.M. McLachlin, M.D. Hall, L. Amable, and L.L. Cunningham, Cisplatin is retained in the cochlea indefinitely following chemotherapy. Nat Commun, 2017. 8(1): p. 1654.
Breglio, A.M., A.E. Rusheen, E.D. Shide, K.A. Fernandez, K.K. Spielbauer, K.M. McLachlin, M.D. Hall, L. Amable, and L.L. Cunningham, Cisplatin is retained in the cochlea indefinitely following chemotherapy. Nature Communications, 2017. 8.
Brock, P.R., S.C. Bellman, E.C. Yeomans, C.R. Pinkerton, and J. Pritchard, Cisplatin ototoxicity in children: a practical grading system. Med Pediatr Oncol, 1991. 19(4): p. 295–300.
Schmidt, C.M., E. Bartholomaus, D. Deuster, A. Heinecke, and A.G. Dinnesen, [The "Muenster classification" of high frequency hearing loss following cisplatin chemotherapy]. HNO, 2007. 55(4): p. 299–306.
Chang, K.W. and N. Chinosornvatana, Practical grading system for evaluating cisplatin ototoxicity in children. J Clin Oncol, 2010. 28(10): p. 1788–95.
Institute, N.C., Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. 2017.
Theunissen, E.A., W.A. Dreschler, M.N. Latenstein, C.R. Rasch, S. van der Baan, J.P. de Boer, A.J. Balm, and C.L. Zuur, A new grading system for ototoxicity in adults. Ann Otol Rhinol Laryngol, 2014. 123(10): p. 711–8.
Brock, P.R., K.R. Knight, D.R. Freyer, K.C. Campbell, P.S. Steyger, B.W. Blakley, S.R. Rassekh, K.W. Chang, B.J. Fligor, K. Rajput, M. Sullivan, and E.A. Neuwelt, 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(19): p. 2408–17.
Landier, W., Ototoxicity and cancer therapy. Cancer, 2016. 122(11): p. 1647–58.
Nagy, J.L., D.J. Adelstein, C.W. Newman, L.A. Rybicki, T.W. Rice, and P. Lavertu, Cisplatin ototoxicity: the importance of baseline audiometry. Am J Clin Oncol, 1999. 22(3): p. 305–8.
Schultz, C., M.V. Goffi-Gomez, P.H. Liberman, and A.L. Carvalho, Report on hearing loss in oncology. Braz J Otorhinolaryngol, 2009. 75(5): p. 634–41.
(ASHA), A.S.-L.-H.A., Audiologic Management of Individuals Receiving Cochleotoxic Drug Therapy [Guidelines]. 1994.
Davis, H. and S. SR Silverman, Hearing and Deafness, ed. H. 4th ed. New York, Rinehart & Winston. 1978.
Fernandez, K.A., P. Allen, M. Campbell, B. Page, T. Townes, C.M. Li, H. Cheng, J. Garrett, M. Mulquin, A. Clements, D. Mulford, C. Ortiz, C. Brewer, J.R. Dubno, S. Newlands, N.C. Schmitt, and L.L. Cunningham, Atorvastatin is associated with reduced cisplatin-induced hearing loss. J Clin Invest, 2021. 131(1).
Esfahani Monfared, Z., A. Khosravi, A. Safavi Naini, G. Radmand, and K. Khodadad, Analysis of Cisplatin-Induced Ototoxicity Risk Factors in Iranian Patients with Solid Tumors: a Cohort, Prospective and Single Institute Study. Asian Pac J Cancer Prev, 2017. 18(3): p. 753–758.
Niemensivu, R., K. Saarilahti, J. Ylikoski, A. Aarnisalo, and A.A. Makitie, Hearing and tinnitus in head and neck cancer patients after chemoradiotherapy. Eur Arch Otorhinolaryngol, 2016. 273(9): p. 2509–14.
Malgonde, M.S., P.S. Nagpure, and M. Kumar, Audiometric patterns in ototoxicity after radiotherapy and chemotherapy in patients of head and neck cancers. Indian J Palliat Care, 2015. 21(2): p. 164–7.
Greene, J.B., R. Standring, F. Siddiqui, and S.F. Ahsan, Incidence of Cisplatin Induced Ototoxicity in Adults with Head and Neck Cancer. Advances in Otolaryngology, 2015. 2015: p. 4.
Whitehorn, H., M. Sibanda, M. Lacerda, T. Spracklen, L. Ramma, S. Dalvie, and R. Ramesar, High prevalence of cisplatin-induced ototoxicity in Cape Town, South Africa. S Afr Med J, 2014. 104(4): p. 288–91.
Arora, R., J.S. Thakur, R.K. Azad, N.K. Mohindroo, D.R. Sharma, and R.K. Seam, Cisplatin-based chemotherapy: Add high-frequency audiometry in the regimen. Indian J Cancer, 2009. 46(4): p. 311–7.
Dell'Aringa, A.H., M.L. Isaac, G.V. Arruda, M.C. Esteves, A.R. Dell'aringa, J.L. Junior, and A.F. Rodrigues, Audiological findings in patients treated with radio- and concomitant chemotherapy for head and neck tumors. Radiat Oncol, 2009. 4: p. 53.
Zuur, C.L., Y.J. Simis, R.S. Verkaik, J.H. Schornagel, A.J. Balm, W.A. Dreschler, and C.R. Rasch, Hearing loss due to concurrent daily low-dose cisplatin chemoradiation for locally advanced head and neck cancer. Radiother Oncol, 2008. 89(1): p. 38–43.
Low, W.K., S.T. Toh, J. Wee, S.M. Fook-Chong, and D.Y. Wang, Sensorineural hearing loss after radiotherapy and chemoradiotherapy: a single, blinded, randomized study. J Clin Oncol, 2006. 24(12): p. 1904–9.
Dutta, A., M.D. Venkatesh, and R.C. Kashyap, Study of the effects of chemotherapy on auditory function. Indian J Otolaryngol Head Neck Surg, 2005. 57(3): p. 226–8.
Waters, G.S., M. Ahmad, A. Katsarkas, G. Stanimir, and J. McKay, Ototoxicity due to cis-diamminedichloroplatinum in the treatment of ovarian cancer: influence of dosage and schedule of administration. Ear Hear, 1991. 12(2): p. 91–102.
Reddel, R.R., R.F. Kefford, J.M. Grant, A.S. Coates, R.M. Fox, and M.H. Tattersall, Ototoxicity in patients receiving cisplatin: importance of dose and method of drug administration. Cancer Treat Rep, 1982. 66(1): p. 19–23.
Aguilar-Markulis, N.V., S. Beckley, R. Priore, and C. Mettlin, Auditory toxicity effects of long-term cis-dichlorodiammineplatinum II therapy in genitourinary cancer patients. J Surg Oncol, 1981. 16(2): p. 111–23.
Helson, L., E. Okonkwo, L. Anton, and E. Cvitkovic, cis-Platinum ototoxicity. Clin Toxicol, 1978. 13(4): p. 469–78.
Piel, I.J., D. Meyer, C.P. Perlia, and V.I. Wolfe, Effects of cis-diamminedichloroplatinum (NSC-119875) on hearing function in man. Cancer Chemother Rep, 1974. 58(6): p. 871–5.
Flamme, G.A., M.R. Stephenson, K.K. Deiters, A. Hessenauer, D.K. VanGessel, K. Geda, K. Wyllys, and K.D. McGregor, Short-term variability of pure-tone thresholds obtained with TDH-39P earphones. Int J Audiol, 2014. 53 Suppl 2: p. S5-15.
Kujawa, S.G. and M.C. Liberman, Synaptopathy in the noise-exposed and aging cochlea: Primary neural degeneration in acquired sensorineural hearing loss. Hear Res, 2015. 330(Pt B): p. 191–9.
Council on Physical Therapy, American Medical Association. JAMA, 1942. 119: p. 1108–1109.
Roland, J.T., Jr., B.J. Gantz, S.B. Waltzman, and A.J. Parkinson, Long-term outcomes of cochlear implantation in patients with high-frequency hearing loss. Laryngoscope, 2018. 128(8): p. 1939–1945.
Joo, Y., K.J. Cruickshanks, B.E.K. Klein, R. Klein, O. Hong, and M. Wallhagen, The Contribution of Ototoxic Medications to Hearing Loss among Older Adults. J Gerontol A Biol Sci Med Sci, 2019.
Weiss, A., R. Kuonen, H. Brockmeier, M. Grotzer, C. Candreia, R. Maire, P. Senn, C. Stieger, J. Rosenfeld, D. Veraguth, M. Kompis, K. Scheinemann, C.E. Kuehni, and G. Swiss Pediatric Oncology, Audiological monitoring in Swiss childhood cancer patients. Pediatr Blood Cancer, 2018. 65(3).

Table 1: Ototoxic drugs are classified according to their ototoxic potency, with a summary of the main ototoxic characteristics of each compound. Legend: +++ often, ++ sometimes, + rare, (+) very rare.

Drug	Ototoxicity	Characteristics
Aminoglycosides^{10, 11}	+++	Up to 41%, permanent
Platinum derivatives	+++	At least 20%, permanent
Deferoxamine¹²	+++	Around 20%, partial reversibility
Salicylates¹³	++	Dose-related and reversible, but rare nowadays¹⁴
T-cell receptors gene therapy^{15, 16}	+++	Up to 50%, mostly reversible
NSAIDs^{17, 18}	+
Macrolides¹⁹	+	Dose-related, mostly reversible
Loop diuretics²⁰	+	Reversible or permanent. Potentiate aminoglycosides’ ototoxicity
Antimalarials^{7, 21, 22}	+	Mostly reversible
Cyclophosphamide²³	+
Nitrogen mustard²⁴	+
Bleomycin²⁴	+
Immune checkpoint inhibitors^{25, 26}	+	Not clear
Estrogens²⁷	(+)
Interferon-a²⁸	(+)
Cocaine²⁹	(+)
Phosphodiesterase-5 inhibitors³⁰	(+)
Polymyxin³¹	(+)
Chloramphenicol³²	(+)
Vancomycin^{33, 34}	(+)
Vinca alkaloids³⁵	(+)

Table 2: Literature reporting cisplatin-induced ototoxicity in adults with baseline audiometry are listed. Different criteria were used in the studies, they are detailed hereafter, with their limitations⁵⁸.

CTCAE criteria⁵³: Minimum ≥15 dB HL averaged at 2 contiguous frequencies at least in one ear relative to baseline audiogram, or subjective change in hearing. Ordinal 4-scale depending of the severity. Disadvantage: Includes subjective change.

ASHA criteria⁵⁹: Minimum ≥20 dB HL in one frequency or ≥10 dB HL in two adjacent frequencies. Disadvantage: A 10 dB HL loss can be due to experimental error. Doesn’t provide quantification.

Brock criteria⁵⁰: Minimum ≥40 dB HL at 8 kHz. Ordinal 4-scale depending of the lower frequencies. Disadvantage: Lacks of sensitivity due to the minimal 40 dB HL hearing loss.

Davis and Silverman criteria⁶⁰: Minimum >20 dB HL of mean value at 0.5,1 and 2 kHz. Ordinal 4-scale from mild to profound. Disadvantage: Doesn’t include high frequencies typically affected in cisplatin-induced ototoxicity.

Study	Methodology	Population	Chemotherapy	Outcome
Fernandez 2021⁶¹ USA	Combined prospective and retrospective	277 adults (54-66 years, 85% male) with head and neck squamous cell carcinomas. Baseline audiometry (0,250-12,5 kHz). Follow up max 90 days.	Cisplatin-based (median dose 200 mg/m²)	49% hearing loss among non-statin users and 38% in statin users (CTCAE criteria).
Esfahani 2017⁶² Iran	Prospective	124 adults (18-78 years, 65% male). Baseline audiometry (1-8 kHz).	Cisplatin (mean dose 454 mg/m²) + cyclophosphamide and adramycin in 6% + methylprednisolone in 6%	26% hearing impairment (>10 dB HL in at least one frequency). 3% tinnitus.
Niemensivu 2016⁶³ Finland	Prospective	22 adults (40-74 years, 77% male. Baseline audiometry (0,125-8 kHz).	Cisplatin (mean dose 205 mg/m²) + radiotherapy in pharyngo-laryngeal region	50 % hearing loss (≥10 dB at 4 or 8 kHz). Tinnitus 40%.
Malgonde 2015⁶⁴ India	Prospective	34 patients (age not specified) with head and neck malignancies. Baseline audiometry (frequencies not specified).	Cisplatin (cumulative dose not specified) + radiotherapy	100% hearing loss at 1 year
Greene 2015⁶⁵ USA	Retrospective	30 adults (17-81 years, 47% male) with head and neck, brain, lung, bladder, uterus, pelvic, ovarian cancers, unknown primary cancers. Baseline audiometry (0,25-10 kHz).	Cisplatin (mean dose 148 mg/m²), 20% received cranial radiation	63% hearing loss (≥40 dB HL at ≥1 kHz or >20 and <40 dB HL at <4 kHz or >20 and >40 dB at 4 kHz)
Whitehorn 2014⁶⁶ South Africa	Retrospective	107 mostly adults (14-75 years, 74% male) with head and neck cancers, lymphoma, osteosarcoma and others. Baseline audiometry (0,5-8 kHz).	Cisplatin (cumulative dose median 180 mg/m² in group without ototoxicity and 236 mg/m² in group with ototoxicity)	55% ototoxicity (≥20 dB HL at any frequency or 10 dB HL at any two adjacent frequencies)
Arora 2009⁶⁷ India	Prospective	57 adults (19-76 years, 64% male) with cancer types not specified. Baseline audiometry (0,5-16 kHz). Follow-up 3 months.	Cisplatin groups low-dose ≤60 mg/m², middle-dose 61-80 mg/m², high dose ≥81 mg/m²	100% hearing loss in middle- and high-dose groups (>10 dB HL of mean value of hearing thresholds at 0.5, 1 and 2 kHz or >20 dB HL at individual frequency)
Dell’aringa 2009⁶⁸ Brazil	Prospective	17 adults (40-75 years, 88% male) with head and neck cancers. Baseline audiometry (0,25-8 kHz).	Cisplatin (mean dose 299 mg/m²) + concomitant radiotherapy including skull base	70% of hearing loss (≥20 dB HL in an isolated frequency or of ≥10 dB HL in two or more successive frequencies)
Shultz 2009⁵⁸ Brazil	Prospective	31 mostly adults (7-66 years, 51% male) with cancer types not specified. Baseline audiometry (frequencies not specified).	Cisplatin (mean dose 299 mg/m²)	29%-61% of hearing loss depending of criteria (CTCAE, Brock, ASHA, David and Silverman)
Zuur 2008⁶⁹ Netherlands	Prospective	60 adults (mean age 62 years, 68% male) with sinus, oral, oropharynx, hypopharynx, larynx, neck, lung and esophagus cancers. Baseline audiometry (0,125-16 kHz).	Cisplatin (median cumulative dose 220 mg/m²) + radiotherapy reaching the inner ear field in 96% of patients	31% in low-dose group (CTCAE criteria up to 8 kHz) 47% hearing loss (CTCAE criteria up to 16 kHz)
Low 2006⁷⁰ Singapore	Prospective	58 mostly adults (15-74 years, 88% male) with nasopharyngeal carcinoma. Baseline audiometry (0,5-4 kHz). Control group of 57 adult (30-70 years, median 43, 77% male) with same disease. Follow up 2 years.	Radiotherapy followed by cisplatin (median dose 160 mg) and fluorouracil, control group treated with radiotherapy only	Hearing threshold worse at all frequencies comparing to the control group.
Dutta 2005⁷¹ India	Prospective	60 adults (83% male) with cancer types not specified. Baseline audiometry (frequencies not specified).	Cisplatin low dose in 51 patients (100 mg/m² in three doses) and high dose in 9 patients (120 mg/m² in two doses)	33% hearing loss in high dose group
Nagy 1999⁵⁷ USA	Retrospective	53 adults (40-75 years, 77% male) with esophagus, lung, or head and neck cancers. Baseline audiometry (0,25-8 kHz).	Cisplatin at doses either 160 (87%) or 240 mg/m² (13%). Possibly until 38% received concurrent radiation therapy to the head and neck	36% hearing loss (>10 dB HL for any pure tone average or >20 dB HL for any frequency)
Waters 1991⁷² Canada	Retrospective	60 adults (18-71 years) with ovarian carcinoma. Baseline audiometry (0,25-8 kHz).	Cisplatin at different doses (50 -100 mg/m²) + adramycin	92% hearing loss in high dose treatment (>15 dB HL at any frequency)
Reddel 1982⁷³ Australia	Prospective	32 adults (16-64 years) with germ cells tumors, ovary carcinoma and others. Baseline audiometry (0,25-8 kHz).	Cisplatin (mean cumulative dose 203 mg/m²)	47% hearing loss (≥15 dB HL in one or more frequencies)
Aguilar-Markulis 1981⁷⁴ USA	Prospective	50 adults (100% male) with genitourinary cancers. Baseline audiometry (0,5-8 kHz).	Cisplatin 1 mg/kg 1/week 6x and every 3 weeks thereafter for at least 12 months	64% ototoxicity (≥15 dB HL at any frequency)
Helson 1978⁷⁵ USA	Prospective	104 children and adults (8-78 years) with cancer types not specified. Baseline audiometry (0,5-8 kHz).	Cisplatin median dose 430 mg/m^{2 for} age 8-20, 255 mg for age 21-45, 220 mg for age >46	91% hearing loss (>20 dB HL at 2 any frequency)
Piel 1974⁷⁶ USA	Retrospective	30 adults (11-62 years, 60% male) with cancers types not specified. Baseline audiometry (0,25-8 kHz).	Cisplatin (dose not specified)	60 % hearing loss (≥15 dB HL at 8 kHz in one ear or ≥10 dB HL in both ears). 6% tinnitus.

Table 3: Overview of pertinent patient-related data

Patient characteristics	N (%)
Total number of patients included	401 (100)
Males	236 (59)
Females	165 (41)
Smokers	141 (35)
Patients with hypertension	88 (22)
Patients with diabetes	37 (9)
Patients with dyslipidemia	49 (12)
Patients with vasculopathies	31 (8)
Patients with 2 risk factors	80 (20)
Patients with ≥3 risk factors	45 (11)
Cisplatin only	127 (31)
Cisplatin + docetaxel	75 (19)
Cisplatin + etoposide phosphate	65 (16)
Cisplatin + pemetrexed	38 (10)
Cisplatin + gemcitabine	32 (8)
Cisplatin + bleomycine + etoposide phosphate	20 (5)
Other chemotherapeutics	44 (11)

Table 4: Correlation between cisplatin-related hearing loss incidence and proposed risk factors in n=401 patients.

Risk factor (number of patients) - hearing loss incidence in %	Risk ratio [95% CI]	Difference [95% CI]	p-value
Male gender (236) - 23	1.5 [0.1, 2.3]	0.08 [0, 0.2]	0.06
Smoking (141) - 22.5	1.2 [0.8, 1.8]	0.04 [-0.05, 0.1]	0.35
Diabetes (37) - 16	0.8 [0.3, 1.7]	-0.04 [-1.7, 0.08]	0.5
Hypertension (88) - 14.5	0.7 [0.4, 1.1]	-0.07 [-0.2, 0.02]	0.15
Vasculopathy (31) - 9.5	0.5 [0.2, 1.3]	-0.1 [-0.2, 0]	0.1
Dyslipidemia (49) - 26.5	1.3 [0.8, 2.3]	0.07 [-0.06, 0.2]	0.2
2 risk factors (80) - 22.5	0.7 [0.3, 1.5]	-0.05 [-0.16, 0.06]	0.4
≥3 risk factors (45) - 15.5	1.1 [0.7, 1.8]	0.03 [-0.7, 0.1]	0.5

No competing interests reported.

Download PDF

Version 1

posted

You are reading this latest preprint version

Cisplatin-induced ototoxicity in 401 consecutive Geneva cancer patients

Status:

Version 1

Abstract

Objective

Methods

Results

Conclusion

Figures

Introduction

Materials And Methods

Design

Participants

Hearing assessment

Statistical analysis

Results

Risk factors

Discussion

Conclusion

Declarations

References

Tables

Additional Declarations

Status:

Version 1