Risk Estimate Raised for Those in Breast Cancer Study : Medicine: Move revives controversy over government-funded trial of preventive use of tamoxifen. But doctors involved in work say revisions are minor.

Leaders of a highly anticipated study examining the drug tamoxifen’s ability to prevent breast cancer say they are changing the consent form provided to the 16,000 women enrolled in the trial because of new data that confirms the drug may cause other cancers.

Although the revisions are considered minor by most doctors involved, the move revives a longstanding controversy over the $68-million, government-funded study, called the Breast Cancer Prevention Trial.

The study is one of the first to examine whether it is beneficial to give healthy people a potentially toxic drug to prevent disease. Outside of the study, tamoxifen is only given to women who have had breast cancer to thwart a recurrence. The new data on risks is collected from studies on breast cancer patients that began in 1981.

In the prevention study, which began two years ago, healthy women at high risk for breast cancer are randomly assigned to take either a daily 20-milligram dose of tamoxifen or a placebo for at least five years.

Study leaders have always acknowledged that the drug may increase a woman’s risk of developing uterine or liver cancer and blood clots but they do not know whether the benefits of the drug outweigh the risks. The revised consent form nudges estimates of those risks up a notch.

The revisions are based on data from a long-term, nationwide study of breast cancer patients taking tamoxifen, said Dr. Bernard Fisher, a University of Pittsburgh surgeon who collected the data. Fisher, who is also a principal investigator in the prevention trial, said the new data will be published in full later this year in the Journal of the National Cancer Institute.

But the data have already translated into a change in the consent form given to women in the prevention trial.

According to Fisher, the risk of developing uterine cancer is similar to what was originally predicted: about two cases per 1,000--a rate that, while small, is still three times higher than that faced by women in the general population.

Moreover, study leaders say that data on the breast cancer patients already taking the drug shows there have been a few deaths from uterine cancer. Participants in the preventive study were previously told that the cases of uterine cancer that have occurred were caught at an early stage and were thought to be curable.

The risk of developing thrombosis or phlebitis, both of which can produce life-threatening blood clots, has been adjusted slightly from 1.3% to 1.5%. (Similar-aged women not taking tamoxifen have a 0.4% chance of developing blood clotting disorders.) The risk of developing liver cancer has also been changed. Previously, study leaders said liver cancer had been reported in rats receiving tamoxifen but not in humans. Now, researchers say two women in a Swedish study of tamoxifen have developed liver cancer.

But, Fisher said: “I think this (potential risk) has been blown out of proportion. . . . In the thousands of women we’ve given tamoxifen, we have never seen liver cancer.”

Overall, Fisher said, he believes the risks are still considered to be worth the potential benefits. About 180,000 American women are found to have breast cancer each year and about 46,000 die of the disease, according to the American Cancer Society.

The consent form revisions, Fisher said, “are part of an educational update to keep our investigators and patients informed. This is not a situation where we suddenly found something that frightened us.”

Although study participants will be told of the changes, the revisions are not significant, said Dr. Patricia Ganz, who is conducting part of the study with a group of women at UCLA.

But critics of the study say that the changes reflect a deep uncertainty about the risks and benefits of the drug.

“This is definitely a shift in the risk-benefit ratio, way into this study,” said Arthur Caplan, director of the Center for Biomedical Ethics at the University of Minnesota. “It gets at the general question of, ‘Is this thing too risky to do?’ ”

And in a paper published in September, Johns Hopkins University epidemiologist Trudy Bush predicted nearly twice the risk of uterine and liver cancer as that predicted by the study organizers.

Tamoxifen is also known to sometimes cause less severe side effects, such as hot flashes, menstrual irregularities and nausea. In the new consent form, women are also informed that the drug may cause ovarian cysts and hair thinning.

Moreover, the revised form contains a more detailed warning to women of child-bearing age to use effective contraceptives during the trial due to the risk of fetal damage if the drug is taken during pregnancy.