By Lisa Seachrist
SILVER SPRING, Md. - A drug born of Cold War radiation concerns gained a recommendation for approval for a new indication by an FDA advisory panel.
The Oncologic Drugs Advisory Committee voted 11-to-1 to recommend U.S. Bioscience Inc.'s cytoprotective drug, Ethyol, for reducing the incidence of severe dry mouth, or xerostomia, in postoperative patients undergoing radiation treatment for head and neck cancer. The drug received FDA approval in October 1995 for use in preventing the cumulative renal toxicity caused by repeated administration of cisplatin in the treatment of ovarian and non-small cell lung cancer.
The supplemental indication recommended by the panel was narrower than what the company had requested, because the panel was unsure whether Ethyol would protect the tumors in patients who were receiving only radiation for their cancers.
"I think we are very happy with the recommendation," said Wolfgang Oster, executive vice president of worldwide clinical research for U.S. Bioscience. "It's a very important new indication and it opens up the opportunity to use it in the clinic and for new studies. It's really a beautiful thing for us."
Ethyol (amifostine), which was given orphan drug status and an accelerated review by FDA, would be marketed by Alza Corp. of Menlo Park, Calif., which sells it in the U.S., and co-promoted by West Conshohocken, Penn.-based U.S. Bioscience. Ethyol is a cytoprotective agent that limits the damage to cellular DNA by mopping up radiation-induced free radicals and reactive molecules formed by certain chemotherapy molecules. Its origins go back to attempts to protect soldiers from radiation fallout.
Xerostomia is a common and often permanent toxicity associated with radiation to the head and neck caused by the destruction of salivary glands. Unfortunately, radiation is the treatment of choice for cancers of the head and neck. About 40,000 cases of head and neck cancer are diagnosed annually in the U.S.
Far from simply being an inconvenience, xerostomia places patients at increased risk of oral infection, dental cavities and loss of teeth. In addition, patients can have extreme difficulty speaking, swallowing and eating as a result.
The company conducted an open-label Phase III clinical study comparing the incidence of xerostomia in 303 patients treated with either Ethyol and radiation therapy or radiation therapy alone. Patients receiving Ethyol had an infusion of the drug 15 minutes before undergoing radiation therapy.
Seventy-eight percent of patients treated with radiation therapy alone had moderate to severe dry mouth following therapy compared to only 51 percent of patients who received Ethyol prior to radiation. In addition, 40 percent of patients treated with radiation alone developed late xerostomia as compared to 24 percent of those treated with Ethyol.
"I was personally surprised by the magnitude of the effect found in this study," said Walter Curran, a radiation oncologist at Thomas Jefferson University in Philadelphia, who reviewed the data for the Radiation Therapy Oncology Group and presented data for the company. "It's my view that the company has presented convincing evidence that amifostine reduces the incidence of xerostomia."
Side effects associated with Ethyol include mild to moderate nausea and vomiting, some of which must be managed with anti-emetics. In addition, some patients developed hypotension while being infused with Ethyol. Because Ethyol protects cells from cancer therapies, there was concern that Ethyol would reduce the radiation therapy's efficacy in killing tumors. However, the company demonstrated that there was no reduction in tumor control as a result of Ethyol therapy.
Determining clinical benefit for a symptom such as dry mouth is difficult because in large part it is a quality-of-life issue. The FDA and the company chose different ways of analyzing information, such as difficulty in speaking and swallowing and using palliative oral products. As a result, the agency claimed that a patient benefit questionnaire administered to trial participants can be considered only descriptive in nature because the open-label design of the trial created a potential for significant bias.
In addition, the agency called into question the drug's effect on tumor control, noting that the most stringent analysis of the data can't rule out the possibility that Ethyol treatment results in 30 percent less tumor control.
"I'm in favor of some sort of limited approval, not the blanket approval that was given in the U.K.," said panel member Andrew Harwood, a radiation oncologist at Romogosa Radiation Center in Lafayette, La. "I'm concerned that the drug may protect tumor in patients who've not [had surgery to remove their tumors]."