Head and Neck Cancer Clinical Trial
Official title:
Randomized Controlled Trial to Test the Efficacy of Trans-tympanic Injections of a Sodium Thiosulfate Gel to Prevent Cisplatin-induced Ototoxicity in Patients With Head and Neck Cancer
This study evaluates whether a gel containing sodium thiosulfate deposited via a trans-tympanic injection on the round window of the middle ear could reduce the ototoxicity caused by the drug Cisplatin among patients with head and neck cancer treated by chemoradiation. One ear selected randomly will be treated while the other will serve as control.
Background
Cisplatin (cis-DiammineDichloridoPlatinum, DDP) is an antineoplastic agent used in the
treatment of solid malignant tumors in adults and is also a key part of treatment for many
children and adolescents with cancer. However, treatment with Cisplatin carries the risk of
serious dose-limiting adverse effects. Ototoxicity is of major concern since the associated
hearing loss greatly impairs patients' quality of life and no preventive treatment is
presently available. Cisplatin ototoxicity is an important problem for patients treated for
head and neck squamous cell carcinoma (HNSCC) who receive repeatedly high doses.
Cisplatin causes an accumulation of reactive oxygen species (ROS) in the cochlea, triggering
damage to the outer hair cells of the organ of Corti. Sulfur-containing antioxidants can
neutralize ROS following Cisplatin intoxication, and thus represent a potential preventive
measure. A few sulfur-containing molecules have been studied. Experimental and human studies
have shown that sodium thiosulfate (STS) can protect against Cisplatin-induced ototoxicity.
However, when administered through the blood stream, STS interfere with Cisplatin treatment
efficacy. To counter the ototoxic effects of Cisplatin treatment without impairing its
efficacy, a local pharmacology approach directly aiming at the cochlea, would represent a
powerful clinical strategy.
The proposed study is the first to test the efficacy of STS administered locally in the
middle ear to prevent Cisplatin-induced ototoxicity in humans.
Objective
The objective of this study is to test the efficacy of trans-tympanic injections of a sodium
thiosulfate-hyaluronate gel prior to cisplatin treatments to prevent cisplatin-induced
ototoxicity in patients with locally advanced head and neck cancer.
The principal objective is to test the efficacy of the trans-tympanic injections of the gel
at pure tone high frequencies. Exploratory analyses for secondary objectives will assess 1)
cochlear damage, specifically hair cell function and 2) hearing loss at frequencies used for
speech perception. Other outcomes considered are the severity of ototoxicity and the adverse
effects of the trans-tympanic injections.
Methods
The proposed study is a randomized controlled trial. For each participant, one randomly
selected ear will receive the treatment while the other ear will not. For ethical reasons,
the control ear will not receive a placebo injection.
Participants to the trial will be recruited at the radiation therapy department of the CHU
de Québec. Eligible participants are patients newly diagnosed with a locally advanced
squamous cell carcinoma of the head and neck scheduled to be treated with concomitant
chemoradiation. This treatment includes Cisplatin 100 mg/m2 on days 1, 22, and 43 after the
first radiation fraction.
At the end of the first day of radiation therapy, the pharmacy department of the CHU de
Québec will prepare the sodium thiosulfate hyaluronate gel by mixing 0.55 ml of a 25%
solution of sodium thiosulfate pentahydrate (Seacalphyx, Drug identification number (DIN)
02386666, Seaford Pharmaceuticals Inc.) and 0.55 ml of a hyaluronate gel (Healon 10 mg,
Abbott Medical Optics Inc.). After a local anesthesia of the tympanic membrane, the
otologist will deposit 0.1 ml of the gel exactly on the round window of the middle ear. From
there the STS should diffuse towards the cochlea. The same procedure will be repeated on the
eve of the subsequent Cisplatin treatments on days 22 and 43.
To assess the effect of the trial intervention, a complete audiologic evaluation will be
conducted before and one month after the end of chemoradiation therapy. The CHU de Québec
audiologists will perform audiograms at frequencies ranging from 0.5 to 14 kHz. Sound
intensity will be measured as dBHL(decibel hearing level). Speech reception thresholds will
also be assessed. In addition, distortion product otoacoustic emissions (DPOAEs) recording
will also be performed. Otoacoustic emissions measurements could detect hair cell damage due
to Cisplatin early. The final audiologic evaluation will be conducted by an audiologist
blinded to the ear assignment who would not have access to the trial and hospital records.
Adverse effects of the transtympanic injection will be documented according to the Common
Terminology Criteria for Adverse Events v4.0 (CTCAE). In addition, to identify unexpected
adverse effects of the trial intervention on hearing, a shorter unblinded audiogram will be
conducted before proceeding to the second and third transtympanic injections. Data from
these audiograms will not be used in the main analysis.The follow-up for audiologic safety
monitoring will be continued for one year after the end of the trial.
The principal outcome is the hearing loss defined by the difference between the average
permanent threshold shift (PTS) in dB (decibel) at four pure tone high frequencies (9, 10,
12.5 and 14 kHz) using the data from the audiograms done before and after Cisplatin therapy,
for each patient and for each ear. The average PTS in dB at these pure tone high frequencies
will be compared between the treated and the control ears using a t-test for paired data. A
planned interim analysis will be conducted when half of the anticipated participants would
have completed the follow-up. In the interim analysis, the test for superiority will be done
with two-sided alpha=0.01 and the results shown only to the Data and Safety Monitoring
Committee (DSMC). If the DSMC recommendation is to continue the trial as planned, the final
analysis will be done with two-sided alpha=0.045 in order to keep the trial overall
statistical significance level to 0.05.
Exploratory analyses for secondary outcomes will assess 1) cochlear damage, specifically
hair cell function obtained from the results of DPOAEs, ands 2) the difference between the
PTS in dB at pure tone averages (0.5 to 8 kHz), which represent frequencies for speech
perception. Other outcomes considered are ototoxicity severity according to CTCAE, and
adverse effects of the transtympanic injections.
The investigators have established an independent DSMC to overview the conduct of the trial
comprising experts in biostatistics, audiology, and haemato-oncology.
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