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Indian Journal of Cancer, Vol. 46, No. 4, October-December, 2009, pp. 262-263 Guest Editorial Cisplatin ototoxicity Malhotra H Division of Medical Oncology, Birla Cancer Center, SMS Medical College Hospital, Jaipur Code Number: cn09067 PMID: 19749455 Today, with effective state-of-the-art treatment, many more cancer patients are either being cured of their disease or are enjoying many years of near-normal life. As a result of this, long-term toxicities and complications of cancer therapy are being recognized and are becoming important. Cisplatin, although discovered in the 1970s, continues to remain one of the most commonly used anti-cancer drugs, with proven efficacy in a variety of tumors. Most clinicians are aware of the potential nephrotoxicity of cisplatin and invariably check the renal functions (blood urea and serum creatitnine) before administering the drug, and also institute measures to minimize nephrotoxicity during and after administration (hydration, diuretics, etc.). Similarly, most oncologists would anticipate, evaluate, and intervene to minimize, if possible, common toxicities of commonly used anti-neoplastic agents, for example, cardiotoxicity with anthracyclins, neurotoxicity with paclitaxel, oxaliplatin, thalidomide, and bortezomib, pulmonary toxicity with bleomycin, and bone marrow suppression with multiple chemotherapeutic agents. Somehow, most oncologists do not anticipate or look for ototoxity in patients receiving cisplatin, even though this is a well-known toxicity of the drug and may be irreversible if not detected and managed in time. In this issue of the Journal, Arora, et al. [1] evaluated hearing loss, in a prospective fashion, in patients receiving cisplatin for various indications. They divided the study group into three according to the dose of cisplatin received: low-dose, n = 10 (= / < 60 mg/sq. m of drug every three weeks), middle-dose, n = 35 (61 - 80 mg / sq.m), and high-dose, n = 12 (> 81 mg / sq.m). In the overall cohort, subjective decrease in hearing was reported by only seven patients, while six patients complained of tinnitus. However, on audiometery, even in the low-dose cisplatin group, more than 50% of the patients had significant hearing loss, especially in the higher frequency range (> 8 KHz). In the middle-dose and the high-dose groups, almost 100% of the patients reported having hearing loss in the 8 - 12 and> 16 KHz range. Cisplatin is an effective cytotoxic agent that is currently used as standard treatment for a variety of human neoplasms. The incorporation of cisplatin into combination regimens has resulted in high cure rates, for example, in the case of advanced testicular cancer. However, clinical application is limited because of serious and sometimes irreversible toxicity, including Gastro-inetestinal, neurotoxicity, nephrotoxicity, myelosuppression, and ototoxicity. Forced diuresis and pre- and post-infusion hydration, limits nephrotoxicity; with current supportive medication, GI toxicity is manageable in a majority of the patients. However, despite extensive research, no therapeutic intervention of proven benefit has been found to prevent neuro- and ototoxicity. Cisplatin is the most ototoxic drug known. Ototoxicity is one dose-limiting side effect of the drug. It is normally manifested as a sensorineural hearing loss beginning in the high frequency ranges and successively progressing toward the speech frequency range. It is often accompanied by transient or permanent tinnitus. Radiation to the ear may enhance ototoxicity. There is high interindividual variability in ototoxicity, where some individuals may get considerable hearing loss even after the first course. The cause of the high interindividual variability is not known, but the possible explanations are pharmacokinetic differences, genetic factors, and the metabolic status of the patient at the time of drug administration. It is not possible yet to identify susceptible individuals before treatment. Early diagnosis may be aided by monitoring of high-frequency audiograms. A mean ototoxicity incidence of 33% has been reported when patients received a single dose of 50 mg/m 2 of cisplatin. [2] Investigations using audiometric techniques revealed a frequency of cisplatin-induced ototoxicity of approximately 20 to 40%, after a high cumulative dose of cisplatin of 400 mg/m 2 . [3] However, this percentage is not observed by all investigators and there is considerable variation in the incidence of ototoxicity across studies. Ototoxicity is probably caused by some damage to the organ of Corti by cisplatin, including the destruction of auditory sensory cells, which is manifested as hearing loss and / or tinnitus in the high frequency range (beyond 4 kHz). [4] Platinum ototoxicity has been reported to also include otalgia, and in rare cases, vestibular alterations. [5],[6] Sometimes these problems can be severe, and ototoxicity and vestibular toxicity are usually irreversible. Ototoxicity affects the inner ear, which is essential for both hearing and balance. Auditory function must be monitored carefully because the toxicity can become disabling. Other than higher dosage and longer duration of cisplatin therapy, the risk factors useful for predicting the risk of ototoxicity and its reversibility remain undetermined. The cumulative dose of cisplatin applied, its infusional rate, the combination with other drugs, the age of the patient, concomitant radiotherapy, and pre-existing inner ear hearing impairment may enhance the risk for development of ototoxicity. [4],[5],[6],[7] However, the influence of the schedule of cisplatin administration on the severity of ototoxicity is largely unknown. Continued high-dose cisplatin chemotherapy necessitates the investigation of strategies to decrease the dose-limiting ototoxicity. Lowering the dose-intensity would not be a preferred option because this might reduce the efficacy of cisplatin and subsequent control / cure of the underlying cancer, especially in children. [8] There is a need for drugs that prevent cisplatin-induced ototoxicity. Nearly all the candidate agents are sulfur- or sulfhydryl-containing compounds (thio compounds), known as antioxidants, and potent heavy metal chelators. [9] The administration of these potential inhibitors could preserve normal glutathione levels and antioxidant enzyme activities during or after cisplatin treatment, which in turn could prevent ototoxicity. The radio- and chemoprotector, Amifostine, has also been tried as a protective agent. However, from a clinical perspective it is important that preventive inhibitors do not interfere with the antitumor activity. Even though there have been studies with multiple oto-protective agents, none of these agents have been found to be unequivocally beneficial in preventing cisplatin ototoxicity and no agent is currently recommended for routine use. At present, the only way to prevent cisplatin-induced ototoxicity is a limitation of the total dose per cycle, the cumulative dose, and the dose-intensity. [10],[11] Obviously, this might reduce the efficacy of this cytotoxic agent. Audiometric monitoring may help to provide early evidence of decreased hearing ability, leading to the possible limitation of the severity of ototoxicity. Moreover, for some patients, it is possible that the drug dosage may be modified or cisplatin be substituted with other oto-safe platinums like carboplatin or oxaliplatin. Despite these efforts, ototoxicity will still occur after cisplatin administration. Oncologists need to be aware and start anticipating and looking for cisplatin ototoxicity in patients receiving the drug. As pretreatment and periodic cardiac assessment (ECG, echocardiogram, MUGA scans) is done in patients receiving anthracyclins, and repeated blood counts are done in patients receiving myelotoxic chemotherapy; similarly pretreatment and periodic assessment for ototoxicity should be planned for patients receiving cisplatin. This can be done by careful questioning of the patient or by high-frequency audiometery. Such assessments would be especially important if the patient is a child, is receiving high-dose cisplatin or has tinnitus or decreased hearing after the first cycle of treatment. References
Copyright 2009 - Indian Journal of Cancer |
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