The largest-ever clinical trial of breast cancer prevention drugs will begin early next year at cancer centers in Southern California and nationwide.
The $75-million study will compare two drugs for their toxicity and ability to prevent cancer in 22,000 post-menopausal women who have a high risk of breast cancer.
Advocates say the study's results could save many women from more drastic cancer-fighting measures: mastectomies, chemotherapy and radiation.
The trial is not without controversy, however, because one of the drugs has potentially serious side effects, and some contend that its recent approval was premature.
That drug, tamoxifen, has long been a potent treatment for already-diagnosed breast cancer and was approved last month by the Food and Drug Administration for preventive use by women at high risk of developing the disease.
Because of tamoxifen's side effects, though, patients and their doctors are cautioned by the FDA to weigh the gamble of taking the drug when they are healthy against the risk of developing cancer.
The other drug in the upcoming trial is raloxifene, which was approved a year ago as an osteoporosis prevention drug for post-menopausal women. During tests as a bone-loss therapy, researchers noted that those taking it also showed a decreased incidence of breast cancer.
The new study of tamoxifen and raloxifene is designed to weigh the strengths and risks of both.
"This study will give us not only the comparative information about the two drugs--their side effects and the efficacy in reducing the risk of breast cancer--but also more information about tamoxifen itself," said Dr. Randall Holcombe, chief of the division of hematology/oncology at UC Irvine Medical Center in Orange, which is taking part in the coming study.
Learning more about tamoxifen is important, according to a number of scientists, because its side effects include a markedly increased risk of uterine cancer and blood clots in lungs and large veins.
The first tamoxifen trial was cut short 14 months before the end of a five-year study period. Scientists ended that research because they found that taking the drug markedly reduced the risk of developing breast cancer. Researchers thought that it was unethical to continue giving a placebo to the control group of more than 6,000 women.
Critics of that study and the upcoming one, both funded by the National Cancer Institute, say that neither effort will determine whether women taking the drugs have reduced their long-term risk of developing or dying from breast cancer, because the studies do not have adequate follow-up.
In particular, they question the first trial because the placebo subjects--those who for comparison purposes unknowingly received no treatment--eventually were offered the option of taking tamoxifen or joining the new study. This step made it impossible to clearly identify the drug's long-term effects, critics say.
"The problem is they won't answer the long-term issue and that is the most important issue," said Cynthia Pearson, executive director of the National Women's Health Network, an advocacy group. The National Cancer Institute should pursue the latest study but commit to follow-up research, she said.
Dr. Patricia Ganz, a professor in UCLA's schools of medicine and public health, agreed that neither study adequately addresses the mortality issue and that the earlier study's ultimate results could be affected by how many placebo patients opt for therapy.
Ganz, who is a key researcher on both studies, said the upcoming trial will include follow-up to produce mortality data, but that it will fall short of the typical 100,000 subjects needed to draw valid conclusions about whether taking the drugs extends a patient's life.
Regardless, the research has the potential of changing the lives of women at high risk for the disease, she said, in part by creating more options.
"We used to take the breast off of some high-risk patients, such as those whose biopsy showed precancerous cells," she said. "We don't do that any more because it is an extreme intervention. Now, in addition to screening and early detection, they have a choice [tamoxifen] that will reduce their risk by 50%."
The studies are important, said cancer researchers, because they will strengthen the data so that doctors can talk with more authority about therapies and because patients can make informed decisions based on a broader menu of choices.
"I have spent the last 15 years studying cancer survivors, and their lives change after they get the disease," Ganz said. "I can tell you it is better to not get it."
The study will be launched in early 1999 at 193 centers nationwide and in Canada.
Eligible for the trial are post-menopausal women 35 or older who are at increased risk for developing breast cancer. Factors that raise a woman's risk include age, the number of close relatives who have had breast cancer, having no biological children, and giving birth to a first child when older than 30.