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Vol. 05 Issue 4, Late Fall 2000

Activist Perspective: The Dark Side of the STAR Trial
The Ribbon 

Andrea R. Martin
Founder and Executive Director
THE BREAST CANCER FUND

The promise is dazzling: not one but two pills to prevent breast cancer. Which one does a better job? That's the spin from the National Cancer Institute (NCI) about their multi-million dollar STAR trial (Study of Tamoxifen and Raloxifene) for breast cancer prevention. The goal: enroll 22,000 healthy "high risk" women, half of whom will take tamoxifen for five years, the other half will take raloxifene for the same time period.

During the first 18 months since the study was announced, only 6,139 women have signed up. So the NCI is revving up recruitment, particularly among African American women and other women of color, using scare tactics that distort the risk/benefit ratio of taking either of these drugs. The reality is that every woman in the trial is being exposed to drugs with potentially life-threatening side effects.

Therein lies the dark side of the STAR trial, the failure to ask the question: which drug does a better job than a placebo (i.e. a dummy pill which is like taking no drug at all)? The absence of a placebo group in the STAR trial is not just a design flaw; it is a lapse in ethics and a callous disregard for women's health. It is also an unconscionable misuse of public funds.

The Breast Cancer Fund has been concerned about STAR since its inception, just months after the premature termination of the Breast Cancer Prevention Trial (BCPT), also known as the tamoxifen trial. Women in the BCPT took either tamoxifen or a placebo to see if tamoxifen could prevent breast cancer in healthy women at increased risk for the disease. Dr. Richard Klausner, Director of NCI, ended the trial and declared that answer "an unequivocal yes," heralding results that showed there were &wuot;45% fewer cases of invasive breast cancer in women who took tamoxifen compared to women who took a placebo."

The tamoxifen trial was halted prematurely, 14 months before its scheduled conclusion, to allow women in the placebo group the option of taking tamoxifen. Because the BCPT failed to recruit enough women (the study design called for 16,000, but only 13,388 were recruited) and was stopped too soon, it did not show a difference in mortality, that is, whether taking tamoxifen actually saved lives. Nor did the brief trial determine long-term risks versus benefits, or the optimal length of time a "high risk" well woman should remain on tamoxifen.

Scientists from Britain and Milan criticized the NCI findings and decision to halt the BCPT early, citing their own large, longer-term studies that failed to show that tamoxifen prevented breast cancer in healthy women. The U.S. Food and Drug Administration also disagreed with NCI and refused to allow Zeneca (now AstraZeneca), the manufacturer of tamoxifen, to use the term prevention in advertising the drug. Nevertheless, many media reports still refer to tamoxifen as a preventive drug.

The Breast Cancer Fund, The National Breast Cancer Coalition and other leading breast cancer and women's health organizations are strongly opposed to the STAR trial not only because of its lack of ethics in failing to have a placebo arm, but also because its predecessor trial (BCPT) left too many unresolved issues. Most importantly, during the BCPT approximately 96% of the women taking a placebo did not get breast cancer and 98% of the women taking tamoxifen did not get breast cancer. This means there was only a 2% absolute reduction in risk, which leads to the second major issue with STAR: whether tamoxifen's small reduction in the absolute risk of breast cancer outweighs the risks it poses to healthy women. The most serious of these risks include uterine cancer, blood clots in the legs and lungs, and strokes.

The third unresolved issue of STAR is the definition of "high risk." Women at greatest risk for breast cancer are those believed to have inherited defects in either of the two breast cancer susceptibility genes. However, experts agree that less than 10% of all women diagnosed with breast cancer carry these defects, and very few women have ever been tested for these genes. The reality is that the vast majority of women with breast cancer have no family history of the disease. Yet, NCI now offers a computer "risk disk" to women interested in taking tamoxifen even though there are fundamental questions about the criteria, including family history, used for determining an individual's risk. Using NCI's criteria would classify 29 million American women at increased risk of getting breast cancer, creating a $6 billion market for AstraZeneca.

The fourth serious issue with STAR is its zealous recruitment of ethnic women despite the fact that only 3% of the BCPT participants were African American. Again, undaunted by the inadequate information provided by its first tamoxifen trial, the STAR trial is targeting African American, Native American and other under-represented women, suggesting that it provides a long-awaited opportunity for women of color to take part in clinical trials. Is this truly an effort about women and breast cancer prevention, or is it about amassing numbers to satisfy research statistics and to market drugs? Once again, NCI is underestimating just how savvy many women have become about issues related to their health, perhaps as evidenced by the slow accrual of STARlets.

Despite these major unresolved issues about tamoxifen, NCI has hitched their wagon to STAR, hyping it as "the largest breast cancer prevention study in North America." It might also be called the largest wholesale exploitation of healthy women since DES and the Dalkon Shield. Without a placebo group, STAR will expose 22,000 women to one of two drugs with potentially life-threatening side effects.

The most serious risks of tamoxifen, outlined above, are most common in women over 50, the women at greatest risk for breast cancer and therefore most likely to take the drug as a preventive measure. Raloxifene, manufactured by Eli Lilly and marketed as Evista, is another story. Evista is a synthetic hormone with both estrogenic and anti-estrogenic effects, advertised as "a new way to prevent osteoporosis" (while admitting that "its effect on fractures is not yet known") and reduce the levels of LDL (the "bad" cholesterol).

The reported risks of Evista are similar to tamoxifen's risk but, according to a professor of environmental medicine at the University of Illinois School of Public Health, one unreported risk -- ovarian cancer -- could prove even more deadly. Writing in the Chicago Tribune (April 19, 1998), Dr. Samuel Epstein says: "Lilly's pre-market clearance study clearly shows that Evista induces ovarian cancer in both mice and rats...at dosages well below the recommended therapeutic level." While effects in rodents are not proof of human risk, there is strong scientific consensus that carcinogenic effects in two rodent species constitutes significant evidence of human risk.

Eli Lilly also claims that Evista poses no risks of breast and uterine cancers. However, the pre-market trials of Evista lasted less than four years, too short a time to measure such risks. Epstein called Lilly's suppression of its own evidence about ovarian cancer risk "reckless and threatening to women's health and life." He also termed the FDA's marketing approval of the drug without the ovarian cancer warning "equally reckless." The Breast Cancer Fund agrees.

The STAR trial could have been used to address many of the unanswered questions from the BCPT tamoxifen study. It could have tested each drug against a placebo to properly evaluate the risk/benefit ratio compared to nothing or to a vegetarian diet or to a diet containing soy products or to other factors. But instead of advancing research in the direction of breast cancer prevention, STAR is exposing healthy women to toxic drugs in a way that will ultimately provide no new information.

This trial, which gives a whole new meaning to "star quality," reminds us of one breast cancer activist's summary of the tamoxifen trial: "Bad drug. Bad science. Bad news for women."

©The Breast Cancer Fund 2000.

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