- Anticancer agents can cause ototoxicity, which is a side effect that can lead to hearing loss.
- Ototoxicity criteria for diagnosis include specific decreases in hearing frequency levels and loss of response in consecutive frequencies.
- The aetiological agents of ototoxicity can lead to temporary or permanent hearing loss and can be cochleotoxic or vestibulotoxic, depending on the type and dose of the toxin.
- Aminoglycosides are a group of antibiotics that are known to be ototoxic, especially when serum levels are elevated above 2µg/ml.
- The mechanism of aminoglycoside ototoxicity involves cellular injury in the inner ear, particularly affecting the sensory neuroepithelium.
- There are various risk factors that can predispose individuals to ototoxicity, including genetic susceptibility, impaired renal or liver function, and longer durations of treatment.
- Loop diuretics can also potentiate the toxicity of aminoglycosides and increase permeability in the stria vascularis.
- Topical therapy with aminoglycosides via ear drops rarely causes ototoxicity, especially when combined with steroids to reduce toxicity.
- Cisplatin, another chemotherapeutic agent, can also lead to ototoxicity through the generation of reactive oxygen species and oxidative stress, resulting in cellular apoptosis in the inner ear.
- Clinical features of ototoxicity caused by cisplatin can include gradual, progressive hearing loss, tinnitus, and vestibular impairment.
- Investigations for ototoxicity may include early high-frequency audiometry, otoacoustic emission testing, and speech discrimination threshold assessments.
- New treatment modalities, such as injections with gel and epinephrine, have been explored to mitigate cisplatin-induced hearing loss in patients.- Cochlear hair cells are sensitive cells in the inner ear responsible for hearing.
- Ethacrynic acid, frusemide, and bumetadine are diuretic medications that can potentiate the ototoxicity (toxicity to the ear) of aminoglycosides.
- Renal failure and low albumin levels can increase the risk of ototoxicity from these medications.
- Frusemide should be infused at a rate of less than 15mg/min, with serum levels monitored to be below 50 μg/ml to reduce the risk of ototoxicity.
- Clinical features of ototoxicity include reversible hearing impairment, permanent hearing loss, flat sensorineural hearing loss (SNHL), tinnitus, and ataxia.
- Salicylates affect the ionic conductance of outer hair cells in the cochlea without causing structural damage to spiral ganglion cells or the myelin sheath of the 8th nerve.
- Salicylates can lead to reversible hearing loss and tinnitus, with serum concentrations between 20-50 mg/dl causing a 30dB hearing loss.
- Quinine affects the motility of outer hair cells and can cause reversible hearing loss, tinnitus, nausea, and vomiting, with prolonged use potentially leading to permanent hearing loss.
- Cinchonism is a set of symptoms associated with quinine toxicity, including deafness, vertigo, tinnitus, headache, nausea, and visual loss.
- Chloroquine, a synthetic drug, may cause permanent sensorineural hearing loss (SNHL).
- Erythromycin can be toxic to outer hair cells, leading to symptoms such as tinnitus, hearing loss, vertigo, and flat SNHL. Recovery may occur within 1-2 weeks after stopping the medication.
- Management of ototoxicity involves identifying risk factors, modifying drug doses, and employing otoprotective approaches such as using iron chelators and antioxidants.
- Monitoring for ototoxicity may involve baseline audiometric evaluations, otoacoustic emissions testing, auditory brainstem response (ABR) testing, and vestibular monitoring.
- Management of ototoxicity may include withdrawing the offending drug, repeated hearing tests, hearing aid or cochlear implant use, vestibular rehabilitation, and genetic counseling.
Anticancer agents and Ototoxicity
Aim:
Cure or prolonged remission : Primary modality
Palliation : shrinkage of evident tumour, alleviation of symptoms, prolongation of life
Phase specific chemotherapy: (kinetic scheduling)
Proliferating /dividing cells or resting cells
Drug administration- timing such a way that cells are synchronized into a phase sensitive to the chemotherapy (Short courses of treatment)- Pulses
Cell cycle specific chemotherapy:
Actively dividing cells
Dose-related plateau
Duration of exposure should be increased
Cell cycle-nonspecific chemotherapy:
Proliferating and resting cells
Linear dose-response curve
Tumour growth:
Kinetics is regulated by:
Doubling time- (cell cycle time)
Time taken by tumors to double its volume; varies considerably between tissue types
Growth fraction-
Percentage of tumor cells passing through the cell cycle at a given point in time, greatest in early stages
Cell loss-
Unsuccessful division, death, desquamation, metastasis and migration
Reduced apoptosis – major factor
Classification according to mechanism of action
Alkylating agents: melphalan, cyclophosphamide, busulphan, lomustine, dacarbazine, mitomycin C.
Heavy metals: cisplatin, carboplatin, oxaliplatin.
Antimetabolite: methotrexate, 5 fluorouracil, cytarabine, 6-mercaptopurine, thioguanine.
Cytotoxic antibiotic: bleomycin, doxorubicin, actinomycin-D.
Spindle poison: vincristine, vinblastine
Topoisomerase inhibitor: irinotecan, topetecan, etoposide.
Alkylating agents
Highly reactive compounds
Covalently linked group (R–CH2)
Crosslink between DNA strands
Interfere with enzymes involved in DNA replication
Most severe damage in S phase
Cyclophosphamide
Orally or i.v.
Single dose of 500 – 1000 mg/m2 every 3 or 4 weeks
Well hydration
S/E: bone marrow suppression, hemorrhagic cystitis, nausea/vomiting, alopecia, infertility, ridging of nails
Ifosfamide
Structurally related to cyclophosphamide
7-10 gm/m2 i/v infusion over 5 days or over 3 to 5 days in equally divided dose
S/E: haemorrhagic cystitis (MESNA administration), myelosuppression, nausea, vomiting, hyponatraemia, CNS toxicity
Heavy metals
Cisplatin
Inorganic heavy metal complex
DNA cross linking- to guanine group
80 – 100mg/m2 every 3 - 4 weeks or by intravenous infusion
Standard treatment in concomitant chemo radiotherapy either as a mono or polychemotherapy in combination with 5-FU in HNC (Pignon et al., 2009)
S/E: nausea, vomiting, neutropenia, thrombocytopenia, anaemia, renal toxicity (not used if creatinine clearance <40 ml/min), ototoxicity, peripheral neuropathy
Carboplatin
Cisplatin bonded to organic carboxylate gp.
More soluble & slower hydrolysis (less nephrotoxic and neurotoxic)
400mg/m2 i.v. ≈ 100 mg/m2 of cisplatin – safe
Can be given as mono or polychemotherapy with 5-FU
S/E: myelosuppression
Antimetabolites
Methotrexate:
Folic acid analog, S phase specific
i/m, s/c, i/v
40–60mg/m2 i/v bolus, weekly.
70mg/m2 require folinic acid rescue action
Relatively nontoxic, inexpensive and convenient
S/E: stomatitis, gingivitis, bone marrow depression, maculopapular rash, renal toxicity (hydration and alkalinization of urine)
5- Fluorouracil:
Fluorinated pyrimidine similar to uracil
Inhibits formation of thymine, factor for DNA synthesis
10-15 mg/kg i/v weekly or,
400-500mg/m2 i/v daily for 5 days followed by 400-500 mg/m2 weekly
Continuous infusion with improved response rate
In combination with cisplatin (PF), given as induction chemotherapy
Beneficial when given as polychemotherapy with either platins than monotherapy for concomitant chemoradiation (Pignon et al., 2009)
S/E: myelosuppression, nausea, vomiting, diarrhoea, stomatitis, alopecia, rash
Cytotoxic antibiotics
Bleomycin: Anti-neoplastic antibiotic derived from Streptomyces sps
Break DNA strand by binding and producing O2 free radicals
10-20 U/m2 i/m or i/v once or twice weekly by infusion
S/E: fever, chills, stomatitis, hyperpigmentation, pulmonary fibrosis, anaphylaxis
Adriamyin (Doxorubicin)- Anthracycline antibiotic – Streptomyces sps
Interfere with nucleic acid synthesis (DNA gyrase)
60 – 75 mg/m2 i/v every 3 weeks
S/E: stomatitis, nausea, vomiting, diarrhoea, alopecia, neutropenia, thrombocytopenia, cardiomyopathy congestive heart failure (in 10% of patients; cumulative dose of 550 mg/m2)
Actinomycin D : interacts between C;G base pairs
Mitomycin C : Crosslinks DNA (like alkylating agents)
Spindle poisons
Vinca alkaloids:
cause mitotic arrest by disrupting microtubular spindle formation
Vinblastine, Vincristine
Vinblastine 5 mg/m2 i/v weekly or by continuous infusion
Vincritine 1.0-1.5 mg/m2 i/v once or twice monthly
Single dose should not exceed 2 mg
S/E: sensory motor peripheral neuropathy, alopecia, constipation
Taxanes:
Palcitaxel: bark of pacific yew (Taxus brevifolia)
promotes assembly of microtubules and inhibits their disassembly
Cause cell cycle arrest at G2 phase by binding to tubulin and preventing microtubule depolymerization
Paclitaxel: 135-250 mg/m2 i.v. infusion over 3-24 hours
Docetaxel: 60-100 mg/m2 i.v. bolus every 3 weeks
S/E: neutropenia, infection
TOPOISOMERASE INHIBITORS
Inhibit topoisomerase enzyme (responsible for DNA replication, chromatid segregation and transcription)
Topoisomerase I inhibitors : Camptothecin, derived from Camptotheca acuminate (a Chinese tree)
Topoisomerase II inhibitors: etoposide are semisynthetic derivatives of Podophyllum peltatum, the American mandrake
Chemotherapy regimen in ENT
Side effect : anticancer drugs
Side effect : anticancer drugs
Side effect : anticancer drugs
Prevention of chemotherapeutic side effects
Adequate hydration, diuresis
Anti oxidant drugs
Allopurinol and ebselen reduces cisplatin-induced nephrotoxicity and ototoxicity in a rat model (Lynch et al.,2005)
Anti inflammatory drugs : salicylates
Intracellular Distribution : Procainamide protects against the nephrotoxicity of cisplatin (Viale.,2000)
Novel Therapies
Monoclonal antibodies against epidermal growth factor receptors: Cetuximab (c225)
Targeted small molecule against EGFR : Geftinib, erlotinib
Monoclonal Ab against VEGF receptor : Bevacizumab
Trastuzumab (Herceptin) : Humanoid Mab against HER-2 receptor
Ritiximab : monoclonal Ab against CD20
Bortezomib: proteasome inhibitor
Ototoxicity
Ototoxicity
Chemical injury to the labyrinth occurring as a side effect of pharmacotherapy (Scott Brown 7th ed.)
Criteria for diagnosis of ototoxicity
(a) ≥20 dB decrease at any one test frequency
(b) ≥10 dB decrease at any two adjacent frequencies, or
(c) loss of response at three consecutive frequencies where responses were previously obtained confirmed by repeat testing, generally within 24 hours
(ASHA guidelines,1997)
Cochleotoxic/ vestibulotoxic depending upon type of toxin and dose
Reversible/ irreversible
Aetiological agents
Temporary hearing loss : Quinine, Aspirin, Ethacrynic acid/furosemide, Erythromycin, azithromycin, clarithromycin
Permanent hearing loss : Aminoglycosides, Cisplatin/Carboplatin,Vancomycin,Toluene, Benzene
Both cochleo/vestibulotoxic : Aminoglycosides, Cisplatin/Carboplatin , vancomycin
Isolated reports of ototoxicity: Arsenicals, bromides, chloramphenicol, chlorhexidine, mercurials, polymixinB, tetracycline, vinblastine, vincristine
Aminoglycosides
Mechanism of aminoglycoside ototoxicity
Major target : sensory neuroepithelium of inner ear
Cellular injury by binding with iron to form toxic metabolite – ROS and free radicals, Free radical formation apoptotic cell death
In cochlea, outer > inner hair cells
In vestibule, type I > type II hair cells
crista ampulli > utricular or saccular maculi
Genetic predisposition : mutation 12S rRNA (0.5 % in caucasians) - maternally transmitted
Time and concentration dependent, serum level of > 2µg/ml
Risk factors
Genetic susceptibility
Impaired renal and liver function
Bacteremia
Elevated temperature
Longer duration of treatment
Critically ill, debilitated, malnourished condition, elderly>65
Foetus susceptible at 18-20 wks of gestation
Loop diuretics : potentiates toxicity
increase permeability of stria vascularis
Ototoxicity with topical therapy
Ear drops containing aminoglycosides rarely cause ototoxicity even with perforation of TM, but vestibular toxicity has been reported in several series. (Marais et al.,1998)
Incidence of topical aminoglycoside–associated ototoxicity may be about 1 per 10,000 patients (Roland et al.,2004)
Humans : Thicker round window membranes; a deeper round window niche antibiotics without any known ototoxic potential (fluoroquinolones), they should be used as a first-line treatment
(AAO HNS recommendation 2004)
combining aminoglycoside ototopicals with steroids, as with results in significantly less ototoxicity than using the aminoglycoside alone (Park et al.,2004)
Clinical feature and natural history
Gradual progressive hearing loss,
usually symmetrical bilaterally
Permanent
May occur even weeks following cessation of drug
Sudden profound SNHL - reported
High low frequency hearing loss ( basal turn of cochlea affected first)
+/- tinnitus
B/L vestibular impairment
Cisplatin
Reactive oxygen species and free radicals oxidative stress apoptosis
Loss of outer hair cells > inner hair cells
Spiral ganglion cells + cochlear neurons degeneration
Mammalian vestibule less sensitive to cisplatin toxicity than aminoglycoside
Risk factors:
High cumulative dose >200mg/m2
Previous noise exposure (3 fold increase)
Low serum albumin levels, low RBC levels
Renal or liver dysfunction
Patient with NPC (cranial RT + Cisplatin Chemotherapy)
Clinical feature:
B/L, symmetric, progressive, high frequency SN hearing loss
Sudden SNHL- reports of spontaneous recovery
Otalgia
Transient tinnitus (2-36%)
Vestibular symptom less common than aminoglycoside , occur at >400mg/m2
Investigations
Early high frequency audiometry
Otoacoustic emission
Speech discrimination threshold may be markedly decreased
New t/t modality
Injection as gel along with epinephrine, weekly for 4 weeks
100% of patients who receive high-dose cisplatin (150 to 225 mg/m2) may show some degree of hearing loss in ultrahigh-frequency audiometry (Mynatt et al 2006)
Loop diuretics
Mechanism of injury :
Oedema of stria vascularis
Loss of endocochlear potential (driving force for cochlear hair cells)
Ethacrynic acid> Frusemide>Bumetadine
Potentiate the ototoxicity of aminoglycosides
Renal failure, low albumin increase risk
Ototoxicity of frusemide - reduced by infusing @ <15mg/min and serum level < 50 mg/ml
Incidence ~ 6%
Clinical feature:
Reversible hearing impairment, permanent profound, mid and high frequency hearing loss
Flat SNHL, tinnitus, ataxia may be associated
Salicylates
Affects ionic conductance through OHC (alters function of protein prestin)
No structural damage to spiral ganglion cells/ myelin sheath of 8th nerve reported
In dose of pyrexia treatment, protects cochlea against Gentamycin toxicity (Chen et al., 2007)
Linear relationship with serum drug concentration
Clinical feature: Reversible tinnitus, hearing impairment (flat SNHL), permanent rarely
Animal experiment- salicylates rapidly enter perilymph
Serum concentration of 20-50 mg/dl - 30dB of hearing loss
Quinine
Affects motility of outer hair cells
Reversible hearing loss and tinnitus, nausea and vomiting
High frequency, notch 4kHz
Prolonged treatment- permanent hearing loss
Cinchonism – deafness, vertigo, tinnitus, headache, nausea, visual loss
Congenital deafness and hypoplasia in cochlea – 1st trimester
If hearing loss occurs in speech frequency – permanent
Chloroquine, synthetic drug may lead to permanent SNHL
Erythromycin
Toxic to outer hair cells
Blowing tinnitus, loss of hearing, and vertigo
flat type of SNHL, although some patients manifest a high-frequency loss
recovery within 1 to 2 weeks after stopping erythromycin
Can also occur with azithromycin, clarithromycin
Approach to the management of ototoxicity
Identification of risk factors
genetic susceptibility – positive family H/O aminoglycoside ototoxicity
deranged renal and liver function test
longer period of treatment – cumulative effect
bacteremia
administration of multiple ototoxic drugs
Modification of drug dose
Close monitoring
Otoprotective approach
Iron chelators: deferoxamine and dihydroxybenzoate
Antioxidants: lipoic acid, d-methionine, Glutathione (Rybak et al., 2007)
N acetylcysteine (Tepel M, 2007)
p53 inhibitor, pifithrin-alpha, caspase inhibitors, and gene therapy
( inhibition of cell death pathway) – in research
Spin-trapping agents: Alpha-phenyl-N-tert-butyl-nitrone can effectively trap and inactivate ROS and other free radicals (Ekborn et al.,2002)
Ototoxicity monitoring : American academy of audiology guidelines 2009
Baseline audiometric evaluation : PTA, Tympanogram
Ultra-high frequency PTA up to 16-20kHz HFA permits detection of aminoglycoside-induced or cisplatin-induced ototoxic losses well before changes become evident in the conventional range (Fausti et al.,1992)
Otoacoustic emission: TEOAEs or DPOAEs responses tend to change before hearing thresholds in the conventional frequency range, but not before changes in HFA thresholds (Knight et al. 2007)
ABR :
High-frequency ABR testing
Elongation of latency
Disappearance of click-evoked wave V
Vestibular monitoring-
Electronystagmography (ENG)
Rotational chair testing and caloric testing – VOR
Vestibular evoked myogenic potentials (VEMPs)
Computerized dynamic posturography (CDP) – Platform posturopathy
Management of ototoxicity:
Withdrawal of the drug
Hearing test – several times (possibility of spontaneous recovery)
Hearing aid/cochlear implant
Vestibular rehabilitation
Genetic counselling
Perinatal exposure – parental counselling, hearing evaluation
