What is the relationship between the use of chemotherapeutic (chemotherapy) agents and ototoxicity?

From the Guidelines

The relationship between chemotherapeutic agents and ototoxicity is significant, with certain drugs posing substantial risk to hearing function, particularly platinum-based compounds like cisplatin, which can cause permanent, bilateral, high-frequency sensorineural hearing loss in 20-75% of patients, as reported in the most recent and highest quality study 1.

Key Findings

• Cisplatin is the most notorious ototoxic chemotherapeutic agent, with a higher risk of ototoxicity associated with high cumulative doses 1.
• Carboplatin has a lower ototoxic profile but can still cause damage at high doses, especially when used in combination with cisplatin 1.
• Other ototoxic chemotherapeutic agents include aminoglycoside antibiotics, loop diuretics, and vinca alkaloids like vincristine 1.
• Risk factors that increase ototoxicity include cumulative drug dose, young age (especially children under 5), pre-existing hearing loss, renal impairment, concurrent cranial radiation, and genetic predisposition 1.

Mechanism and Prevention

• The mechanism of ototoxicity involves damage to outer hair cells in the cochlea through oxidative stress and DNA damage, progressing from high to lower frequencies with continued exposure 1.
• Monitoring audiometric testing before, during, and after treatment is essential, and protective strategies include dose limitation, extended infusion times, and investigational otoprotective agents like sodium thiosulfate, N-acetylcysteine, and amifostine, though these must be used cautiously to avoid interference with anti-tumor efficacy 1.

Clinical Recommendations

• Systemic sodium thiosulfate is recommended for administration in non-metastatic hepatoblastoma, and its use in other non-metastatic cancers may be considered, but further research is needed to determine its safety in patients with metastatic cancer 1.
• Amifostine, sodium diethyldithiocarbamate, and intratympanic therapy should not be routinely used to prevent cisplatin-induced ototoxicity 1.
• Cisplatin infusion duration should not be altered as a means to reduce ototoxicity 1.

From the FDA Drug Label

Ototoxicity has been observed in up to 31% of patients treated with a single dose of cisplatin 50 mg/m 2, and is manifested by tinnitus and/or hearing loss in the high frequency range (4,000 to 8,000 Hz). The prevalence of hearing loss in children is particularly high and is estimated to be 40 to 60%. Decreased ability to hear normal conversational tones may occur Deafness after the initial dose of cisplatin has been reported. Ototoxic effects may be more severe in children receiving cisplatin. Hearing loss can be unilateral or bilateral and tends to become more frequent and severe with repeated cisplatin doses.

The relationship between the use of chemotherapeutic agents, specifically cisplatin, and ototoxicity is that cisplatin can cause ototoxicity, which may manifest as tinnitus and/or hearing loss. The risk of ototoxicity may be increased by factors such as:

• Prior or simultaneous cranial irradiation
• Use of other ototoxic drugs (e.g., aminoglycosides and vancomycin)
• Renal impairment
• Genetic factors (e.g., variants in the thiopurine S-methyltransferase [TPMT] gene) 2

From the Research

Relationship Between Chemotherapeutic Agents and Ototoxicity

• The use of chemotherapeutic agents, such as cisplatin, has been linked to ototoxicity, which can result in hearing loss and tinnitus 3, 4, 5, 6, 7.
• Studies have shown that the prevalence of ototoxicity in patients receiving cisplatin-based chemotherapy can be as high as 74%, with 68% of patients experiencing tinnitus and 59% experiencing hearing loss 3.
• The risk factors for ototoxicity include age, cumulative cisplatin dose, cardiovascular risk factors, and family history of hearing loss 3, 6.

Mechanism of Ototoxicity

• Cisplatin-induced ototoxicity is closely related to the accumulation of reactive oxygen species (ROS) and subsequent death of hair cells (HCs) and spiral ganglion neurons (SGNs) 7.
• The death of these cells can lead to sensorineural hearing loss (SNHL) and tinnitus 7.

Prevention and Treatment of Ototoxicity

• Early detection of ototoxicity is crucial in minimizing or preventing its consequences 4.
• Regular audiologic evaluations are recommended for patients receiving cisplatin-based therapy, regardless of the cumulative cisplatin dose 6.
• Gene therapy approaches, such as the use of lentiviral vector-mediated ectopic expression of anti-apoptotic proteins, have shown promise in protecting against cisplatin-induced ototoxicity 7.
• Referrals to audiologists before, during, and after cisplatin treatment are recommended to monitor and manage ototoxicity 3.