More Research Is Needed in Cisplatin-Induced Hearing Loss in Pediatric Patients With Cancer

Bruce Carleton, PharmD, FCP, FISPE

Children with cancer aged 5 years of old or younger receiving treatment with cisplatin may be at a higher risk of hearing loss, according to results of a study published in Cancer. Consequently, close audiological monitoring may be necessary for children who are very young in age, according to Bruce Carleton, PharmD, FCP, FISPE.

Specifically, an assessment of 368 pediatric patients with cancer and 2052 audiological tests demonstrated that the highest level of cisplatin-induced hearing loss was associated with children under 5 years (75%; 95% CI, 66%-84%). At a follow-up of 1 year, the increase in hearing loss among children under 5 had increased to 61% compared with 48% in children over the age of 5 (95% CI, 37%-62%; P < .001).

In an interview with Oncology Nursing News®, Carleton, University of British Columbia, Department of Pediatrics, Division of Translational Therapeutics, discussed these research findings, and the need for focused research in this area.

Oncology Nursing News®: Could you provide some background on the research and a brief overview of the study findings?

Carleton: Cisplatin is one of the critical medications that we use to save children's–and adult’s–lives with cancer. Cisplatin is actually a heavy metal, like lead; it's made from platinum. Just like lead has toxicity associated with its exposure, so does cisplatin. It has therapeutic benefits, [but] it also has harm that can be induced by its use. It’s balancing the beneficial effects of cisplatin with [the] potential for it to cause permanent hearing loss, which is irreversible, that we try to do with every [patient with cancer]. This study was about looking at children who have cancer and [determining] who is at the highest risk of hearing loss.

The part that we were trying to answer in this question was: is age important? Are young children at higher risk of hearing loss from cisplatin than older children? In pediatric medicine, people think we treat children. But in fact, we treat humans from birth, age 0 to 18, which is [an] adult. We treat an entire spectrum of patients. As we develop across that age spectrum, our bodies develop, our defense mechanisms develop, our toxicity for certain agents, for example, develops and that's exactly what this study showed; children who are younger actually face a higher risk of hearing loss than children who are older.

We know that about 60% of children who get cisplatin to save their lives, end up with some degree of hearing loss. Sixty percent. [It is more] common that you get hearing loss than not. About 40% of children who get cisplatin will actually need hearing aids the rest of their lives as a result of treatment.

One of the things we were interested in doing was following many patients for a long period of time to see what happens with this heavy metal exposure of cisplatin. We collected 368 [pediatric patients with cancer] who received cisplatin, and then followed their hearing assessments or audiological assessments, and we looked at more than 2000 of them. The idea was to see what happened to their hearing in patients based on age. Three years after starting therapy, 75% of patients aged 5 years and younger, and 48% of patients aged older than 5 years had experienced cisplatin-induced hearing loss.

The findings of this research suggest that audiological assessments in between cycles of cisplatin may be necessary for children under the age of 5. Could you elaborate on the importance of these assessments and comment on its feasibility?

The international communities have been divided on this issue. The [current] standards are: [conduct] a hearing assessment at the end of therapy. To some extent, that makes sense. At the end of therapy, lifesaving therapy, we look at hearing and we help to manage the patient with hearing aids or whatever other enhancements they're going to need as a result of damaged hearing. Again, the, the rate of hearing loss or the degree of hearing loss—and when it occurs—is different in children. Therefore, what [we’re] trying to understand is the biology about why those differences exist. For children who go deaf quite early, what makes them different than children who may take 1 year or more to have significant hearing loss?

At the end of every cycle, we should [conduct] a hearing assessment, and we should follow the toxic course of this drug. I think the legitimate concern among some clinicians is that if patients or parents know that their child is developing hearing loss, they're more likely to say, “Do we really have to give them this cisplatin?”

I completely agree that parents would be more likely to say that if they could see the pattern developing. That doesn't mean that it's not a legitimate question. The issue is, what can that pattern analysis of following these children in their hearing loss tell us about the rates of hearing loss and the differences between us as humans? It’s through seeing those patterns over time that we'll be able to better make decisions about what to do in the future, to illuminate why these children are more vulnerable to hearing loss, and how best to protect their hearing while administering this lifesaving therapy.

Similarly, the study notes that there was an interesting connection between concomitant treatment with vincristine and the development of cisplatin-induced hearing loss over time. What did the findings reveal about that association?

This is something that only perhaps those of us in clinical pharmacology think a lot about, but it's the question about whether other medications that are being used at the same time might increase, often referred to as drug interactions.

The first question is: are other drugs that are co-administered to treat cancer make cisplatin more toxic to the years? It turns out that vincristine does. That’s very helpful for us to understand who is at higher risk of hearing loss, is getting chemotherapy, and then what to do about that. These are lifesaving therapies, but at the same time, if we know who's likely to lose their hearing, we can plan and support these children better in the future.

What are your expectations for future research in cisplatin-induced hearing loss?

First of all, genetics are critically important in all of this, and genetics can help us predict who is more likely to have hearing loss. We have been doing that in Canada for more than 10 years now; we have tested more than 1000 patients. We do have some genetic markers that we have published, and that we use to determine who's more likely to have cisplatin induced hearing loss. It's not the whole story. We don't know, every patient why every patient gets hearing loss. However, we do know that there are some genetic markers that put patients at higher risk. Using those genetic markers to screen patients can help us identify who are at higher risk.

The next step is, if they're at higher risk, what do we do? Do we not use cisplatin? Can we administer it at a lower dose? All of those things need to be studied. Our focus right now is in using a compound that would essentially reduce hearing loss through a genetic strategy by enhancing what we have found to be a protective effect from a given gene. That's what we're working on right now.

As we continue to develop, take in more patients, and better understand the mechanisms of the genetic markers that we find, I think that's really critical. The reason genetic markers are important is because we're all different as individuals. We are 99.9% identical on this planet, as members of the human race, but that one-tenth of 1% difference equals about 5 million base pairs of different genetic code. That's where to focus, in my opinion, when you see some patients who tolerate cisplatin without any evidence of hearing loss, and others who have profound hearing loss. Is there a way that we can [utilize] the genetics of those patients who do not experience having hearing loss [to support] those who that end up with hearing loss? These are the strategies that my labs are currently working on.