OHSU study shows platinum-based ototoxicity in children prevalent, but new drugs offer prevention hope
(December 8, 2005) Portland, Oregon - By 14, Peter Johnson had survived brain cancer and a relapse of the disease in his shoulder. But it was treatment for the last tumor that would create his life's greatest challenges.
Johnson, now 33, has suffered since 1986 from the effects of ototoxicity, a condition in which platinum-based chemotherapy drugs, such as carboplatin and the more common cisplatin, damage the tiny hair cells in the inner ear that vibrate in response to sound waves. This leads to progressive, irreversible hearing loss and reduced quality of life for patients.
Despite surgery and intense radiation therapy to remove the brain tumor, Johnson says the hearing loss resulting from the chemotherapy for the shoulder tumor has been the most disabling.
"The hearing loss is difficult," said Johnson, a Portland resident who started losing his hearing in 1986, about a year after his chemotherapy treatment for the shoulder tumor ended. "What I don't think the general public understands is that surviving cancer isn't the same as a broken leg. Once the leg is healed, you're pretty much back to normal. Once you survive cancer, the after-effects are numerous and you just keep discovering them."
To scientists at Oregon Health & Science University, Johnson's experience is not surprising. A new study published in the current edition of the Journal of Clinical Oncology found that ototoxicity's frequency and severity, as well as its long-term effects on development, have long been underreported by the medical community.
The research found that a well-known classification system doctors use for reporting toxicities in patients, the National Cancer Institute's Common Terminology Criteria for Adverse Events, or CTCAE, doesn't consider high-frequency hearing loss, allowing the magnitude of ototoxicity in children treated with platinum agents to be miscalculated.
The purpose of the study is "to make people aware that this is more common than people think and we need to follow this issue," said Kristy Gilmer Knight, M.S., a pediatric audiologist at OHSU's Doernbecher Children's Hospital and the study's lead author.
Knight said a major problem for doctors trying to diagnose hearing loss from ototoxicity is that it's not that obvious. "The way it manifests itself is not that children lose all their hearing," she said. "The way it manifests itself is tricky. The typical presentation is high-frequency hearing loss, and so it may not look like they're having a problem, especially when communicating one-on-one in a quiet room. And kids won't complain about not understanding what was said when they're really little."
And that can lead to development issues for children. A 1998 study that evaluated the educational performance and social-emotional functioning of about 1,200 children with minimal hearing loss found that 37 percent failed at least one grade in school compared with the normal rate of 3 percent. They also had more problems with behavior, energy, stress, self-esteem and social support.
OHSU researchers tested the hearing of 67 patients, ages 8 months to 23 years, who received platinum-based chemotherapy. Data was analyzed to determine the length of time to hearing loss using criteria from the American Speech-Language-Hearing Association, or ASHA, and the effects of treatment and patient characteristics on the incidence and severity of ototoxicity.
According to the study, hearing loss was found in 61 percent of patients, with average onset beginning 135 days after chemotherapy. This included 55 percent of children treated with cisplatin; 38 percent of children treated with cisplatin's less-toxic derivative, carboplatin; and 84 percent of children treated with both agents. Children treated for osteosarcoma, neuroblastoma and medulloblastoma, the form of brain cancer Johnson had, experienced greater incidence and severity of hearing loss.
But researchers say many of these children are falling through the cracks. The study found that while the ASHA criteria and CTCAE grading scale were similar in how they defined hearing loss progression, results from clinical trials often focus only on CTCAE grade 3 toxicity, which represents hearing loss requiring therapeutic intervention, and grade 4, which requires a cochlear implant and additional speech and language development services. The study said agreement between the CTCAE and ASHA criteria was "inadequate."
"By tradition, many published clinical trials report only grade 3 and 4 CTCAE toxicities," the study explained. "In the case of hearing loss, this would leave grades 1 and 2 ototoxicity unreported, thereby underestimating the magnitude of ototoxicity in children treated with platinum agents. We believe that CTCAE grade 1 and 2 hearing losses are significant in children and should therefore be considered and reported." The study found that 36 percent of patients who were examined would not have been reported as having ototoxicity if only CTCAE grades 3 and 4 were considered.
Scientists want to boost awareness of ototoxicity because it may soon be preventable. Nancy Doolittle, Ph.D., associate professor of neurology, OHSU School of Medicine, and a researcher in the Blood Brain Barrier Program, which studies methods for breaching the brain's natural defense system to deliver chemotherapy compounds to tumors, has shown that sodium thiosulfate (STS) decreased hearing loss in patients with malignant brain tumors who were treated with carboplatin chemotherapy, which is given with the blood-brain barrier disruption technique. When STS was given four hours after carboplatin, ototoxicity decreased from 84 percent of patients to 29 percent.
The OHSU study team is developing protocols for a clinical trial of a second potential chemo-protectant called N-acetylcysteine, or NAC. The drug, typically used to treat people with Tylenol poisoning, prevented platinum-induced ototoxicity in rats in a study published in mid-2004. NAC may prevent hearing loss by binding to cisplatin's platinum molecules, inactivating them. And as a free radical scavenger, it hunts down highly reactive atom clusters believed to cause similar hearing loss caused by noise trauma.
The main aim is to determine a safely tolerated dose of NAC in humans. Once the safe dose is determined, Phase 2 efficacy testing begins to see if NAC, combined with STS, will protect hearing.
"One of the strategies for improving survival is increasing doses of chemotherapy," Doolittle said. "Because larger doses may cause more toxicity, we have to be able to address the toxicity. Maintaining quality of life by maintaining hearing is really important."
While the damage has been done to his own hearing, Johnson hopes drugs, such as STS and NAC, can help prevent the hearing loss in other cancer survivors. He also hopes to use his law degree and his experience as a law librarian and paralegal to advocate for others who've experienced hearing loss, which required Johnson to learn lip reading, relish television shows and movies with closed captioning, dread telephone calls and, ultimately, get a cochlear implant for his right ear.
"The fact of the matter is I could put out the same quality of work everybody else could, but I needed a half hour longer," said Johnson, who developed dyslexia as a result of the radiation treatment and chemotherapy. In his professional experiences, Johnson notes that "the real world doesn't want to give you an extra half hour to do what needs to be done, though."
Other study co-authors included; Dale Kraemer, Ph.D., associate professor, Department of Pharmacy Practice, Oregon State University; and Edward Neuwelt, M.D., professor of neurology and neurological surgery, OHSU School of Medicine and the Portland Veterans Affairs Medical Center, and director of the OHSU Blood Brain Barrier Program. The study was funded by the National Institute of Neurological Disorders and Stroke, the National Institutes of Health and the U.S. Department of Veterans Affairs.
Dr. Neuwelt, OHSU, Portland Veterans Affairs Medical Center and the Department of Veterans Affairs have a significant financial interest in Adherex, a company that may have a commercial interest in the results of this research and technology. This potential conflict was reviewed and a management plan approved by the OHSU Integrity Program Oversight Council and the Portland Veterans Affairs Medical Center Conflict of Interest in Research Committee was implemented.
