July 13, 1998 Reporting in the July issue of the Journal of Pharmacology and Experimental Therapeutics, researchers with the Portland U.S. Department of Veterans Affairs Medical Center and Oregon Health Sciences University have found that they can prevent or sharply reduce hearing loss caused by one of the most effective therapies for brain tumors.
The VA/OHSU team found that treatment with sodium thiosulfate (STS) significantly reduced hearing loss in 29 brain tumor patients receiving the chemotherapy agent carboplatin delivered by opening the blood-brain barrier.
"These findings are very encouraging," said study leader Edward A. Neuwelt, M.D., a neurosurgeon and professor of neurology and neurosurgery at the Portland VA Medical Center and OHSU. He also directs the Blood-Brain Barrier Program located at both the VA and OHSU.
"Not only did we see fewer patients suffer severe hearing loss, but patients who did experience some hearing loss were able to undergo more courses of carboplatin treatment before any loss occurred."
Before the STS trials began, 15 (79 percent) of 19 similar patients suffered profound hearing loss caused by carboplatin treatment. These patients had an average hearing loss of 20.8 decibels after one treatment with carboplatin, while the STS-treated patients lost only 3.7 decibels.
The Portland researchers previously had paved the way for brain tumor treatment with carboplatin and similar agents by pioneering methods to open the "blood-brain barrier" in order to enhance drug delivery (Neurosurgery, May 1998). This natural barrier normally serves as a wall between the blood and brain, helping protect brain tissue.However, it also prevents large-molecule drugs such as carboplatin from reaching a tumor inside the brain.
Using a sugar solution to temporarily shrink the barrier cells, thereby creating spaces between them, Neuwelt and his colleagues literally "opened the gate" for drugs such as carboplatin to enter the brain.
They subsequently found that carboplatin was one of the most effective therapies for brain tumors (Cancer Journal/Science American, March/April 1998), but it unexpectedly caused major hearing loss when given across an open blood-brain barrier.
Approximately a third to one-half of cancer patients treated with the platinum-based chemotherapy agent cisplatin develop some degree of communication difficulty due to hearing loss, Neuwelt pointed out. The related drug carboplatin, however, previously had caused only modest hearing loss when used to treat patients with cancers in other parts of the body.
"We were surprised to find that our carboplatin-treated patients experienced profound high frequency hearing loss," Neuwelt said.Many of the brain-tumor patients treated with carboplatin prior to the STS trials required hearing aids following their therapy he noted.
"If you're in a quiet room, hearing loss in the high frequency range is not a big problem, but if you have background noise, high frequency hearing loss significantly impairs communication."
After an exhaustive Internet search, the husband of one of Neuwelt's patients suggested that STS might help prevent the hearing loss. The VA/OHSU team eventually confirmed that STS could preserve hearing in animals treated with carboplatin (Cancer Research, February 15, 1996) and proceeded with clinical trials.
Using a "two-compartment system," the researchers first opened the blood-brain barrier, administered carboplatin chemotherapy by artery to attack the patient's brain tumor and then waited two hours before giving intravenous STS.
"You have to open the gate to let the drug in and then wait until the gate is closed to give STS," Neuwelt said. Studies have shown that STS can cause seizures if given to animals when the blood-brain barrier is open.
STS apparently protects hearing by binding to the platinum in carboplatin before it has a chance to harm the inner ears, Neuwelt said.
"The take-home message is that sodium thiosulfate is the first drug shown to prevent chemotherapy-induced hearing loss. These results with STS may prove useful in combating the hearing loss associated with platinum-based chemotherapy treatment for other types of cancer such as cancer of the ovary and lung."
Neuwelt's co-authors of the JPET paper include Robert E.Brummett, Ph.D., Nancy D. Doolittle, Ph.D., Leslie L. Muldoon, Ph.D., Robert A. Kroll, D.V.M., Michael A. Pagel, Rhonda Dojan, Victoria Church, Laura G. Remsen, Ph.D., D.V.M., and Joseph S. Bubalo.
Their work was supported by the Department of Veterans Affairs Merits Review Program and the National Institutes of Health.
VA research provides improved medical center care for veterans, as well as the general population.Through its unique affiliation with medical schools such as OHSU, VA plays a crucial role in educating future physicians in research and clinically oriented areas.
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