Tamoxifen trial begins amid new concerns.

Last week, the National Cancer Institute (NCI) officially launched its long-awaited, drug-based breast cancer prevention trial. At 119 medical centers and some 300 related satellite institutions in the United States and Canada, physicians have begun formally recruiting 16,000 healthy women at high risk of developing breast cancer. The trial aims to evaluate whether prophylactic doses of tamoxifen, the most widely prescribed drug for treating breast cancer, will safely prevent breast cancer (SN: 4/25/92, p.266).

"Tamoxifen certainly is not miracle cure" or without risks, said NCI Director Samuel Broder at a press briefing in Bethesda, Md., last week.

Indeed University of Pittsburgh surgeon Bernard Fisher, the NCI trial's principal investigator, acknowledged that the synthetic hormone poses some increased risk of endometrial cancer and blood-clot-producing phlebitis. Other recently reported studies have indicated that tamoxifen may also spawn liver tumors, a type of breast cancer resistant to therapy and perhaps even malignancies of the gastrointestinal system.

Taken together, Fisher says, these adverse effects are "really relatively rare and infrequently severe enough to require discontinuation of treatment."

Nonmalignant liver disease appears to be the newest adverse effect associated with tamoxifen. In the April 11 LANCET, Richard G. Long and his co-workers at City Hospital in Nottingham, England, report the death of a 58-year-old patient receiving 20 milligrams of tamoxifen daily -- the same dose that women will receive in the NCI prophylactic trial. Five months after the woman began taking tamoxifen, she appeared jaundiced and complained of lethargy, nausea and vomiting. Though her doctor immediately took her off the drug, she died soon thereafter. Autopsy revealed "acute hepatic necrosis -- pure liver-cell damage," Long says, and suppression of neutrophils, white blood cells important in fighting bacterial infection.

An inquiry to the U.K. Committee on Safety of Medicines regarding other reports of tamoxifen-associated liver problems "revealed four similar cases of hepatic failure, three fatal, and five other cases of tamoxifen-associated hepatitis (one fatal)," the Nottingham doctors note. The committee also cited 11 other reports of liver complications.

Calls to NCI, the Food and Drug Administration and tamoxifen's maker -- ICI Pharmaceuticals of Wilmington, Del. -- found no similar reports of liver disease associated with U.S. tamoxifen use. Even in Britain, these liver problems remain rare, Long observes. However, he adds, "people are throwing this drug around like sweets, suggesting that it's totally safe and that large numbers of women should have it.... I now have doubts about that."