Hearing Loss Clinical Trial
Official title:
Does Aspirin Have a Protective Role Against Chemotherapeutically Induced Ototoxicity?
Aspirin (ASA) has been shown, in an animal model, to attenuate the ototoxic properties of
cisplatin. The researchers plan to investigate this in patients undergoing cisplatin
chemotherapy.
The researchers hypothesise that low-dose aspirin can prevent cisplatin induced ototoxicity
in the clinical setting.
Cisplatin has the highest ototoxic potential of all platinum containing compounds. It is
used in the treatment of squamous cell carcinoma of the head and neck, germ cell tumours of
the testis and bladder carcinoma.
42% of 400 patients receiving high-dose cisplatin (70-85 mg/m2, median cumulative dose
420mg) experienced common toxicity criteria (CTC: appendix 1) grade 3 or 4 symptoms (De
Jongh 2003). Ototoxicity is dose related: 75-100% of patients receiving a very high dose and
20-40% with a low dose regime will develop significant ototoxic symptoms. In one study, 50%
of head and neck cancer patients treated with cisplatin develop ototoxicity (Blakley 1994).
Cisplatin ototoxicity can present as a variable collection of symptoms and signs. These
include bilateral and symmetrical hearing loss that is permanent and irreversible. High
frequency sensorineural hearing loss with progression towards lower frequencies. Tinnitus,
that is also permanent and irreversible.
There are a number of known factors that can predispose to cisplatin ototoxicity. They
include: Dose, duration and mode of administration, age extremes, previous or concurrent
cranial irradiation, previous history of hearing loss, renal disease, concomitant use of
other ototoxic drugs, noise exposure with concomitant cisplatin administration, decreased
serum albumin level, low hemoglobin level, low red blood cell count and a low haematocrit.
Interestingly, cisplatin ototoxicity is considered to be exclusively confined to the
cochlear, the vestibular system is unaffected (Myers 1993).
Ototoxicity from chemotherapeutic agents is due, in part, to reactive oxygen species.
Reactive oxygen species can be attenuated by antioxidants. Salicylates are antioxidants that
can be administered as aspirin.
It has been shown, in an animal model, that aspirin can protect hearing from cisplatin
induced ototoxicity (Li 2002). In this set of experiments, the rat was used to evaluate the
protective role of aspirin in both the acute and chronic setting. Auditory evoked brain stem
responses were used to determine pre- and post-intervention hearing thresholds. In the acute
experiments (n=23), one dose of cisplatin (16mg/kg) was administered and the animals were
given aspirin (100mg/kg) starting the day before cisplatin treatment and continuing 4 days
thereafter. There was a significant difference in hearing thresholds between the treatment
and control groups at 3, 8 and 14kHz.
In the chronic experiments cisplatin was given on days 1, 4 and 7 (5mg/kg). Aspirin was
given from 2 days before to 3 days after cisplatin treatment (100mg/kg bd). The hearing
thresholds were compared before the first dose and 10 days after the last treatment. In
those animals treated concurrently with aspirin, their hearing did not differ form control
animals at 16 and 24 kHz. This was correlated to a significant reduction in inner hair cell
loss from 20% (cisplatin) to 8% (cisplatin and aspirin).
Salicylates also protected renal function as determined by both plasma blood urea nitrogen
and creatinine levels.
Salicylates did not affect tumour mass or metastasis. The rats were inoculated with
malignant breast cancer cells (metastatic mammary adenocarcinoma). Aspirin protected against
cisplatin-induced ototoxicity, without affecting the oncolytic action of the cisplatin.
Gentamicin and cisplatin both have a similar ototoxic mechanism of action. Aspirin has been
shown to prevent gentamicin-induced hearing loss without compromising its anti-bacterial
efficacy in both animal models and the clinical setting (Sha 2006, Chen 2007). Sha's group
reported a prospective, randomized, double-blind trial with 200 patients. The patients all
required gentamycin for clinical indications. In the 'treatment' arm of the study, the
patients also received aspirin (1g tds for 14 days). A significant difference in hearing was
shown at 6 and 8kHz of >15dB if aspirin was not given.
;
Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention
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