1. Tumolo, Jolynn

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As if the cancer isn't enough. Families preparing for certain types of chemotherapy at Montefiore Health System in the Bronx meet early on with an audiologist, tasked with delivering even more unwelcome news: The treatment that could save your child's life may also cause hearing loss.

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"We often receive the patients and their families when they're still in shock. We very compassionately offer that information," said Laura Tocci, AuD, Director of Audiology


How? Tocci sighed, "The best way we can."


For many patients with cancer, platinum-based chemotherapy agents like cisplatin and the less-common carboplatin can be literal lifesavers. However, a significant number of survivors (estimates range from about half up to nearly two-thirds) experience permanent hearing deficits.


"Essentially, the chemotherapy and chemotherapy byproducts seem to injure the hair cells within the ear, and patients initially lose very high-frequency hearing," said Adam Levy, MD, Pediatric Oncologist at the Children's Hospital at Montefiore. "Then, as the chemotherapy is given further, more damage occurs to the hair cells, and lower-frequency hearing is lost."


Depending on the patient and the treatment protocol prescribed, oncologists can sometimes adjust chemotherapy if hearing loss occurs, Levy explained. That's why audiologists and pediatric oncologists work so closely at Montefiore-children receiving cisplatin get regular audiograms, and Levy receives the results via email within the hour. Unfortunately, though, lowering the cisplatin dose or holding off on the agent completely isn't an option for every patient. "There's such a great fear of the cancer not being cured when you lower the dose," he said.


While survival trumps hearing in cancer treatment, chemo-induced hearing loss is by no means getting a free pass. Scientists are making advances in efforts to quell the ototoxic effects of chemo while preserving its tumor-fighting power. Hearing professionals, meanwhile, are coaching patients and other health care providers on how, in the wake of chemo-caused hearing deficits, to maintain as much function as possible.


"It's a very active area of interest," Levy said, "how to prevent long-term side effects from the chemo that we give."


Latest Drug Advancements

Although platinum-based chemotherapy can cause hearing loss in adults and in children, drug developers investigating ways to reduce cisplatin ototoxicity are zeroing in on younger patients. "It is well-established that large, cumulative cisplatin doses and younger age increase the risk of ototoxicity," explained Jonas Dyhrfjeld-Johnsen, PhD, Head of Pharmacology at French biopharmaceutical company Sensorion, which focuses on inner-ear diseases. "Because childhood cancers can often be successfully treated with longer courses of cisplatin as principal therapy (whereas adult cancers often have shorter cisplatin treatment durations, require more complex treatments, and have lower success rates), this puts children at higher risk for ototoxicity."


In a recently published preclinical study, R-azasetron besylate prevented cisplatin-induced hearing loss in rats by more than half through significantly reducing the loss of outer hair cells in the inner ear (Otol Neurotol 2017;38(9):1355). When tested on in vitro human cancer cells at concentrations nearly 30 times the expected therapeutic dose, the drug candidate notably did not hamper the cytotoxic effect of cisplatin either. Since an earlier phase I trial showed no adverse events of R-azasetron besylate in healthy adults, phase II testing is set to begin in 2018.


"We are very encouraged that [R-azasetron besylate] has demonstrated significant treatment benefits in two distinct preclinical models of sensorineural hearing loss-cisplatin-induced ototoxicity and acute, severe acoustic trauma-involving sensory hair cell death," noted Dyhrfjeld-Johnsen. "This suggests a robust mechanism of action allowing [R-azasetron besylate] to significantly reduce damage to the inner ear."


In the fall of 2017, researchers shared promising results from a phase III study at the International Society of Pediatric Oncology meeting in Washington, D.C., leading them to seek FDA approval for sodium thiosulfate. Among 99 children who received cisplatin for standard risk hepatoblastoma, hearing loss occurred in 37 percent who also received sodium thiosufate-compared with hearing loss in 67 percent who received cisplatin alone. The trial found no evidence of tumor protection with the addition of sodium thiosufate.


A previous phase III trial published in The Lancet Oncology produced similar positive findings: Sodium thiosufate safely reduced cisplatin-induced hearing loss by about half in children receiving treatment for hepatoblastoma, germ cell tumor, medulloblastoma, and other cancer diagnoses (2017;18(1):63-74).


Other potential game-changers include ORC-13661, which in preclinical studies prevented cisplatin-induced hair cell damage in animals. Researchers plan to apply to the FDA's Investigational New Drug program to conduct clinical trials in humans.


Scientists announced in September 2017 that its noninvasive method of drug delivery, which uses magnetic fields to push steroid-covered iron nanoparticles directly into the inner ear, reduced cisplatin-induced hearing loss in mice by 50 percent (Front Cell Neurosci 2017;11:268).


Empowering Through Support

Once chemo-induced hearing loss occurs, it is unlikely to improve. Thankfully, children and adults can benefit from a vast array of interventions to help them adjust. Depending on the level of hearing loss, options range from counseling on communication and lip-reading strategies to obtaining high-tech hearing aids complete with noise-reduction processing and directional microphones (some stream calls directly from the wearer's smartphone) or cochlear implants. Even everyday modern technology used by the masses can assist people with hearing loss.


Levy cited a young patient who uses a dictation app on her smartphone to translate speech to text.


"She suffered her hearing loss when she was a teenager, so she speaks fine. What she does is asks her question, then hits the microphone button. You speak into the phone, and she reads your response," Levy said. "This is actually, to me, a very poignant example of how commonly available technology really made her life a lot better. Now, on the other hand, I do encourage her to join a group that would help her learn how to read lips and offer her support for hearing impairment in more conventional ways, but the app is a really nice bridging mechanism for her to feel connected.


"Teenagers often communicate via texting anyway," he added, "so this is a way for her to be able to communicate almost in real-time that works quite well for her."


FM systems, in which the speaker uses a microphone and the listener hears the message through a receiver, can help students in the classroom or even patients still in the hospital who haven't yet had opportunity to obtain hearing aids but for whom communication is essential.


"These patients may have had a fairly sudden onset of their hearing loss as opposed to somebody whose hearing loss happens gradually over time, and there's an emotional impact to that," said Erica Williams, PhD, Clinical Associate Professor in the Department of Speech and Hearing Science at Arizona State University, Tempe. "It's important to keep in mind the cause of their hearing loss and what they're dealing with medically. They may have some pretty high communication needs in terms of dealing with multiple physicians and family members about everything going on with their care."


Don't underestimate the importance of coaching patients to speak up when others fail to meet their communication needs, Williams advised. To the physician who might be looking down at her notes while she speaks, to the spouse who might be addressing his comments to the sink of dirty dishes he's tackling, to the staff at a restaurant where the music is too loud and obstructing communication, people with hearing loss should feel empowered to advocate for themselves-to remind people to face them when talking, for instance, or to request a more quiet table at a noisy restaurant.


"Advocating for yourself doesn't come as naturally as people might think, even with patients who have had hearing loss for a good amount of time," Williams said. "Many people tend to hide things like hearing loss instead of seeking help for it."


Preventing Further Damage

The Children's Oncology Group recommends youngsters treated with cisplatin or carboplatin have their hearing tested when they begin long-term cancer follow-up and, if deficits are identified, at least annually thereafter until stable. When Robert Frisina, PhD, Professor and Director of the Global Center for Hearing and Speech Research at the University of South Florida in Tampa, looked for similar recommendations for adult cancer survivors, he found none. Yet, according to a study he and colleagues recently conducted, one in five men treated with cisplatin for testicular cancer had a resulting hearing loss that was severe to profound. Another 37 percent had moderate or moderate-to-severe hearing loss (J Clin Oncol 2016;34(23):2712).


"Most of the clinical delivery of chemotherapy does not involve sensory measurements like hearing," Frisina said. Consequently, for many adults, the possibility of chemo-induced hearing loss isn't even on their radar. "They're thinking, 'I've got cancer. I want to beat cancer. And I'm not going to worry about other things until I beat the cancer.' And then, over time, hearing loss may start to interfere with job productivity, relationships, and quality of life. With oncologists being so successful with many of these cancers, the other problems that develop get worse with age and become more important."


Frisina recommended that health care providers ask adults under cisplatin treatment about their hearing status at least annually. Patients who do incur hearing loss should be educated on how to prevent further hearing damage, like avoiding excessive noise exposure, wearing hearing protection, and staying away from aminoglycoside antibiotics and other ototoxic drugs. Additionally, patients should understand that since high blood pressure, diabetes, and thyroid issues have all been linked with hearing loss, keeping in overall good health is important to avoid further hearing loss.


"The theme is, if you already have a hearing loss that's above normal, then you want to be extra careful about doing these other things that will make your hearing loss worse," Frisina noted. "Everybody should really follow that advice. But if you already have a hearing loss, then you should really be motivated to do it."


Jolynn Tumolo is a contributing writer.