Cancer, Cancer Treatments & Ototoxicity

Author: Michelle McElhannon, Pharm.D

One in three Americans will be diagnosed with cancer at some point in their lifetimes (National Cancer Institute, 2018). The good news is that deaths from cancer have decreased by 25% since 1990. By 2026, there will be an estimated 20.3 million cancer survivors in the United States (National Cancer Institute, 2018). As patients present with cancer, or having survived cancer, health care professionals are called upon to integrate, communicate and educate on how cancer and cancer treatments affect audiologic health.
What Is Cancer?
The body consists of trillions of cells. Cells are DNA encoded to specialize, replicate and die when no longer functioning as needed. Cancer cells have genetically mutated, and can ignore signals for apoptosis, or cell death. Cancer cells begin to divide without stopping and can spread into the surrounding tissues. Cancer cells are less specialized than healthy cells, and damaged or old cells survive or new cells form when not needed. Since cancer cells are a mutated form of the host’s own cells, the immune system may not recognize cancer cells as foreign. Cancer cells can influence healthy cells, molecules and blood vessels. By releasing angiogenic factors, a cancerous tumor can promote capillary development to supply nutrients and remove waste. Cancer cells can also access blood supply to metastasize, or spread to other organs. (NIH, 2015)

Neoplastic treatments such as surgery, radiation and chemotherapy may cause or worsen otoxicity.
Tumors may place pressure on or infiltrate the auditory organs. Surgery may further damage the ear or auditory nerve. (Simon, 2011) Central nervous tumors may cause rapid changes in intracranial pressure. Other procedures affecting intracranial pressure include lumbar puncture, tumor resection, ventriculostomy and cerebral spinal shunts (Guillaume DJ, 2012).
Radiation therapy uses high energy particles or waves, such as x-rays, gamma rays, electron beams or protons to destroy or damage cancer cells. Radiation causes small breaks in the DNA inside cells, stopping growth and replication to cause cell death. Radiation can be external, using high energy rays, or internal. Internal radiation, or brachytherapy, is the placement of a radioactive source in or near the tumor, such as in prostate cancer radioactive seed implants. Radiation can also be given systemically, via mouth or IV.

The risk of radiation induced ototoxicity is increased with increased dosing, at greater than 30 grays (Hua C, 2008). Risks are also increased if given with other ototoxic therapies, such as ototoxic chemotherapy (Warrer R, 2012). Radiation of the posterior nasopharynx and mastoid can cause serious otitis media and conductive hearing loss. External auditory canal radiation can lead to soft tissue infections as well as increased/dry cerumen production (JA, 1984). Cochlear radiation is associated with sensorineural hearing loss, which is generally permanent and progressive.

Sensorineural hearing loss affects a third of patients, typically having a late onset of 3-5 years post-treatment. Hearing loss is generally more severe in the high frequencies, and poor word discrimination is common (Mujica-Mota M, 2013).
The cell cycle goes through the resting phase, active growing phases, and then mitosis (division). The efficacy of chemotherapy depends on its ability to stop cell division. Cancer drugs usually work by damaging the RNA or DNA that instructs the cell how to replicate and divide.

Chemotherapy-induced side effects occur when the chemotherapy also damages healthy cells. Rapidly dividing cells are generally affected, accounting for the side effects of hair loss and mucosal irritation, for example.

Drug-induced ototoxicity is increased based on several factors: susceptibility of the tissue to the drug, accumulation of the drug within the organ, inhibition of normal physiologic functions, direct toxic effects on the sensory end organs, central effects, and ototoxic synergism.

Patient factors also increase ototoxic risk from chemotherapy and adjunct therapies. Age, co-morbid conditions, cumulative dose, concurrent ototoxic medications and radiation treatment can all contribute to chemotherapy-associated ototoxicty.
Children are at greater risk for developing cisplatin-induced ototoxicity than adults. Children less than five are 21 times more likely to develop ototoxicity from cisplatin than at 15 years old, with an odds ratio of 21.17. The incidence of cisplatin-induced hearing loss in children ranges from 22-77%. (Knight et al. 2005; Kushner et al., 2006; Coradini et al., 2007)
Co-Morbid Conditions
Renal failure decreases clearance of the ototoxic medication, increasing organ exposure. Individuals presenting with high serum creatinine are at greater risk. (Bokemeyer, 1998) Chemotherapy may also induce nephrotoxicity in patients with previously normal renal function.

Hypertension was significantly associated with impaired overall hearing in analyses adjusted for age and cisplatin dose (Frisna RD, 2016).

Dose, Increasing Number of Cycles
The degree of hearing loss is often related to the dose. The larger the dose, the more significant the hearing loss. Cumulative cisplatin doses exceeding 400 mg/m2 (Bokemeyer, 1998)and carboplatin administered in high, myeloablative doses have been shown to increase the risk of irreversible hearing loss.

Co-administration of ototoxic agents can create a synergistic or additive effect. Aminoglycosides, loop diurectics, quinine, nonsteroidal anti-inflammatory drugs and antiretroviral therapy have ototoxic potential and can increase risk of hearing loss when given concurrently with platinum compounds. (Verdel BM, 2008)
Concurrent or Past Cranial Irradiation
Hearing loss associated with concurrent cisplatin and radiation treatment may be progressive beyond the conclusion of chemotherapy. Audiologic monitoring may be appropriate for as long as 10 years following the completion of treatment. (Bass JK, 2016) (Sweetow, 1983)

Ototoxic chemotherapies include: Platinum compounds, nitrogen mustard, methotrexate, vincristine, dactinomycin and bleomycin.
Platinum Compounds
Platinum compounds are highly ototoxic, with cisplatin being one of the most ototoxic drugs in clinical use. Carboplatin and Oxaloplatin are less ototoxic, but still have ototoxic potential. Cisplatin is used in the treatment of solid tumors of head, neck, lung, ovary, testicle and bladder cancer in adults. In children, cisplatin is used to treat neuroblastoma, osteosarcoma, hepatoblastoma, germ cell and CNS tumors. Cisplatin ototoxicity is variable in adults and children, but has been reported to occur in up to 50 % of adults and up to 77% of children (Bokemeyer, 1998).
Cisplatin is a planar complex of a bivalent platinum cation with two cis-standing chloride and two cis-standing ammonia ligands. A highly reactive aquo complex is formed when the chloride anions of the cisplatin complex are exchanged by water molecules intracellularly. This complex then binds to nucleophiles in DNA, RNA, proteins, and peptides. The DNA is the main target of cisplatin in proliferating tumor cells (Wang, 2005). Cisplatin can enter cells by passive diffusion or via active transporters. Copper transporter 1 (CTPR1) and organic cation transporter 2 (OCT2) have been shown to mediate the cellular uptake of cisplatin (Howell SB, 2010) (Cianfrone G, 2011). Cisplatin blocks DNA replication and transcription and induces DNA repair. Cisplatin exposure in the mitochondrial DNA and proteins affect cell respiration and induces reactive oxygen species (ROS) formation, causing addition harm to cells. Irreversible damage causes cell death (apoptosis) in the affected cells. (Wang, 2005)

In most organs, cisplatin is eliminated in days to weeks. The half-life of cisplatin is prolonged in the ear, and may take months to years to be eliminated. Cisplatin is also dosed in cycles, resulting in a larger cumulative dose. Research shows that for every 100 mg per m2 increase in cumulative dose results in a 3.2 decibel hearing impairment. Cumulative doses >400 mg/m2 increase irreversible ototoxic risk. (Frisna R, 2016)

Cisplatin ototoxicity is characterized by the production of reactive oxygen species (ROS) in the cochlea, resulting in destruction of cochlear hair cells, stria vacularis damage, and spiral ganglion cell destruction. (Ding D, 2012)

Outer hair cells have both copper transporter 1(CTPR1) and organic cation transporter 2 (OCT2) molecules and therefore cisplatin can enter the cells via active transport, causing initial hearing impairment at the higher frequencies. Inner hair cells contain only OCT2. Over time and with increased exposure, cisplatin will also enter the inner hair cells via OCT2, causing hearing impairment at the lower frequencies. (Lanvers-Kaminsky C, 2017)
Cisplatin-induced hearing loss usually presents as progressive and bilateral high-frequency sensorineural hearing loss with tinnitus. (Sakamoto, 2000) Hearing loss can occur rapidly or gradually, from multiple or singular doses. Most cisplatin-induced hearing loss is permanent, but some cases have demonstrated a partial recovery when the patient has received lower cumulative doses (<400 mg/m2) (Bokemeyer, 1998). The associated hearing loss may not be symmetrical. Women receiving cisplatin chemotherapy for breast cancer displayed an asymmetry of hearing thresholds of at least 10 dB between ears posttreatment. (Jenkins, 2009) Tinnitus may occur with or without hearing loss. Tinnitus may be permanent or temporary, alleviating a few hours after treatment or persisting after treatment.
Adjunct ototoxic therapies
Other drug classes that are known to induce hearing loss include aminoglycosides, loop diuretics, quinine, non-steroidal anti-inflammatory drugs, and antiretroviral therapy (Cianfrone G, 2011). Supportive treatment with aminoglycosides and loop diuretics in patients with cancer is well documented to increase risk of ototoxicity from cisplatin significantly.
Chemotherapy can result in decreased immune functions, and patients may need to be treated for serious infections. Aminoglycosides are used to treat Gram-negative infections by Pseudomonas, Salmonella, and Enterobacter species. (Forge and Schact, 2000) Aminoglycoside ototoxicity is usually irreversible. Of all ototoxic drugs, the aminoglycosides are the most vestibulotoxic, although they vary within the class in the effects on the vestibular and cochlear systems. Kanamycin, amikacin, neomycin, and dihydrostreptomycin are preferentially cochleotoxic. Gentamicin affects both cochlear and vestibular systems, although most authors include gentamicin as primarily vestibulotoxic. Streptomycin, tobramycin, and netilmicin are also primarily vestibulotoxic. (Monsell EM, 1993)Aminoglycosides show a decreased clearance from inner ear fluids. The half-life is 10-13 days from a single dose and up to 30 days from multiple doses Damage occurs to cochlear hair cells, stria vascularis, marginal cells, and the spiral ganglion. Aminoglycosides mechanism of toxicity involves the creation of reactive oxygen species (ROS) leading to cell death. Increased risk of aminoglycoside-associated ototoxicity has been seen in patients with a genetic A1555G mutation. A1555G codes for mitochondrial 12SrRNA. Mutated 12SrRNA resembles bacterial 16SrRNA, and can be targeted by aminoglycosides. (Prezant TR, 1993)

Increased risks of aminoglycoside ototoxicity include: increased serum concentrations, decreased renal function (Lerner SA, 1986), multiple daily doses (Wu WJ, 2001), noise exposure, and concurrent ototoxic medications. Patients’ serum aminoglycoside levels and serum creatinine should be monitored for safety. Once daily dosing is preferable over multiple daily dosing. Optimally, patients should have hearing evaluations before, during, and after therapy. Patient counseling should include the avoidance of noisy environments for at least 6 months following aminoglycoside therapy and the avoidance of other ototoxic medications.
Loop Diuretics
Loop diuretics are given to reduce edema and blood pressure. Furosemide, bumetanide, ethacrynic acid, and torsemide have been indicated in causing reversible, self-limiting ototoxicity, although irreversible effects have been reported in neonates. Loop diuretic-induced ototoxicity can occur when changes in the ionic gradients between the perilymph and endolymph cause edema of the epithelium of the stria vascularis. Blood flow reduction also can impair the barrier function of the endothelium, allowing entry of other ototoxic medications. Minimization of the ototoxic risk includes using the lowest possible dose, avoiding rapid infusion rates, avoiding co-administration of other ototoxic agents, and using caution in patients with renal failure.
Many patients are unable to relay the name or dose of their chemotherapy. Cisplatin is known by different names such as Platinol®, Platinol- AQ®, CDDP, DDP. Cisplatin may be combined with another medications: CT (cisplatin/topotecan), Herceptin® (cisplatin/capecitabine/trastuzumab), Gemzar ® (cisplatin/gemcitabine), Taxotere® (cisplatin/docetaxel), for example. Interdisciplinary communication with the patient’s oncologist, pharmacist, and family physician is important to identify a patient’s comprehensive risk profile.
Clinical Pearls
  • High blood pressure can worsen cisplatin-induced ototoxity
  • Dehydration can increase ototoxic risk
  • Renal failure, increased serum creatinine, can increase ototoxic risk.
  • Cisplatin is also nephrotoxic. Nephrotoxicity increases risks of ototoxicity. Serum creatinine should be monitored before, during and after therapy
  • Irreversible ototoxicity risk is higher at cisplatin doses >400 mg/m2
  • Children <5 are 21 times more likely to experience hearing loss
  • Radiation can worsen the risk of ototoxicity, and may be progressive in nature even up to 10 years post radiation
  • A comprehensive list of patient medications is necessary to screen for additive ototoxic and nephrotoxic potential
Patient Counseling
As chemotherapy induced ototoxicity can be progressive, extending past the date of initial exposure, patients require self-monitoring and protective counseling. More than a third of adults are in the basic (47 million) and below basic (30 million) health literacy groups (U.S. Department of Education, 2003), so educational material should be literacy appropriate and provided in both verbal and written forms.

Patient counseling points to include:
  • Signs and symptoms of cochlear damage and potential effects on communication ability
  • Symptoms such as tinnitus, fullness, loss of balance, or changes in hearing sensitivity
  • How and how often to assess for hearing loss
  • Potentiating effects such as exposure to noise during or following treatment
  • If the patient lives or works in an environment with high noise levels, the possible synergistic effect of noise and cochleotoxic damage must be considered, and both the patient and family should be made aware of this increased risk.
  • Audiological follow-up may be required long term
Per the “Guidelines for the Audiological Management of Individuals Receiving Cochleotoxic Drug Therapy” developed by the American Speech-Language-Hearing Association, prospective audiological evaluations remain the only reliable method for detecting ototoxicity before the patient becomes symptomatic. (American Speech-Language-Hearing Association, 1994) An interdisciplinary ototoxicity health care team ideally would involve oncologists, nurses, audiologists, and a pharmacist. Early referral to the audiologist can allow for early identification of ototoxic hearing loss, patient counseling, and prescription for amplification devices, and/or hearing loss strategies. Pharmacists can identify drug and disease state interactions and alert the oncologists and audiologists of other ototoxic medications that may worsen cisplatin-induced ototoxicity, as well as provide patient counseling. Early identification of an ototoxic hearing loss or drug interaction provides oncologists with an opportunity to adjust the chemotherapy/medication regimen and/or increase patient monitoring. (American Academy of Audiology, 2009) Applying a team-based approach to clinical, audiological and pharmacological identification of ototoxic risks in the oncology patient can serve to improve patients’ hearing outcomes and quality of life.    
Michelle McElhannon received her B.S. and Doctor of Pharmacy from the University of Georgia. She completed a residency in pharmacy practice at The Ohio State University Medical Center and has specialized in ambulatory care pharmacy for over 20 years. Currently, Michelle is a Public Servant Assistant in the Division of Experience Programs at the University of Georgia College of Pharmacy. At her practice site she provides diabetes education and medication management to patients at a Federally Qualified Health Center while simultaneously providing introductory pharmacy practice experiences to second year UGA pharmacy students. At her home site, she is a wife, and a mother to three children, 11 dogs (3 dogs plus 8 puppies), 5 chickens, 3 birds, 5 fish, 1 turtle and 1 very ferocious black cat.
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