The STAR Trial: Tamoxifen vs. Raloxifene for Preventing Breast Cancer
A huge clinical trial conducted by the NSABP was launched by the National Cancer Institute in July 1999 to see which of two major breast cancer drugs-tamoxifen or raloxifene-works better to actually prevent breast cancer. As many as 500 medical institutions nationwide and in are participating in the study, which plans to eventually enroll more than 22,000 postmenopausal women at an increased risk for the disease.
The trial is called the Study of Tamoxifen and Raloxifene (STAR) trial. And its implications are immense.
History
The predecessor to the STAR trial was the Breast Cancer Prevention Trial (BCPT), which was launched in April 1992 and is still ongoing. The BCPT was designed to determine whether the drug tamoxifen (Nolvadex) could prevent breast cancer in women who are at increased risk for developing the disease. For more than two decades tamoxifen has been used to treat breast cancer, but because of that success some researchers began to ask if it could also be effective in preventing the disease in the first place.
The trial was prematurely halted in March 1998 when interim results showed that tamoxifen dramatically reduced breast cancer incidence-in fact, tamoxifen had resulted in a remarkable 49 percent reduction in breast cancers among women at the highest risk for the disease. The findings were so impressive that the lead investigators notified all of the 13,388 participants so that those women who had been taking the placebo could consider starting tamoxifen therapy.
Tamoxifen
Tamoxifen is a drug taken in pill form that interferes with the activity of estrogen, effectively countering that hormone's cancer-promoting effects. Tamoxifen has been used to treat both early and advanced stage breast cancers for more than 20 years
Tamoxifen was first developed in 1962 as a morning-after birth control pill that was successful in experiments with laboratory rats. In humans, however, tamoxifen had the opposite effect. It was found to be a fertility drug. Luckily, a British doctor, Arthur Walpole, thought to test tamoxifen on women with breast cancer. It was known that many cancers were responsive to estrogen, and he hypothesized that an anti-estrogen agent might help. Indeed it did.
Doctors then proved that it worked in women with advanced breast cancer, and eventually in women with newly diagnosed breast cancer as well.
As its use increased in the early 1990s, clinicians were surprised again by this "anti-estrogen," which they had assumed blocked estrogen throughout the body. Instead, they found that it blocked estrogen in the breast and brain but conversely seemed to act like estrogen in a beneficial way in the bones and liver. This observation led them to identify a new category of drugs called "selective estrogen receptor modulators" or SERMS.
The goal of SERMS is to achieve the positive effects of traditional estrogen therapy, such as protecting against heart disease and osteoporosis, while avoiding the negative effects, including an increased risk of uterine cancer.
Raloxifene
Researchers then set out to design a drug that would be even better than tamoxifen; one that would not cause uterine cancer but would prevent osteoporosis and heart disease as well as breast cancer. The first of these designer SERMS to be developed was raloxifene.
Raloxifene (Evista) is a drug similar to tamoxifen, taken by mouth as a pill. It is being included in the STAR trial based on a surprise finding in a separate study on osteoporosis in postmenopausal women.
The Multiple Outcomes of Raloxifene Evaluation (MORE) examined the use of raloxifene to prevent fractures in postmenopausal women with osteoporosis. But during the course of the study, the investigators noted an initial 74 percent reduction in the risk of breast cancer in women taking raloxifene compared with a placebo. After an average follow-up of just over three years, a 65 percent relative risk reduction was seen in the postmenopausal women studied. (The need to conduct the STAR trial is to answer the effectiveness of breast cnacer prevention with Raloxifene since women in the MORE trial were not evaluated based on breast cancer risk and may possibly have been at lower risk for breast cancer since their actual diagnosis to trigger being placed on the drug was osteoporosis.)
Risks and Side Effects
Like most medications, tamoxifen and raloxifene can cause adverse effects in some women. The symptoms experienced most often include hot flashes and vaginal discharge, dryness or itching. It is possible that some women may experience leg cramps, constipation, pain with intercourse, sinus irritation or infection, or problems controlling the bladder upon exertion. Treatments are available to minimize or eliminate most of these side effects.
In the early Breast Cancer Prevention Trial, women taking tamoxifen were found to have an increased chance of developing three relatively rare conditions: endometrial cancer (cancer of the lining of the uterus), pulmonary embolism (blood clots in the lung), and deep vein thrombosis (blood clots in a major vein).
Women taking raloxifene in clinical trials demonstrated a similarly increased chance of developing a pulmonary embolism or deep vein thrombosis. However, the drug did not increase the risk of endometrial cancer as it did in women taking tamoxifen.
Importantly, a number of recent studies have found that tamoxifen may have a limited time period of positive benefit-up to five years. An NSABP trial showed 5 years of treatment was as good as 10 years for prevention of breast cancer but showed an increase in rare side effects with longer use.
Signing Up for STAR
As of July 23, 2000, 6,385 women had been enrolled into the STAR trial, with more than 17,000 additional participants being sought over the next several years. The National Cancer Institute is especially interested in reaching out to minority women, who traditionally have been underrepresented in major clinical trials.
Women at increased risk for developing breast cancer, who have gone through menopause, and are at least 35 years old can participate in the STAR trial. Increased risk of breast cancer is determined in one of two ways. The risk for most women is determined by a computer calculation based on age, number of first-degree relatives with breast cancer, number of suspicious breast biopsies, and other factors. Also, women diagnosed as having lobular carcinoma in situ (LCIS), a condition that is not cancer but indicates an increased chance of developing invasive breast cancer, are eligible based on that diagnosis alone.
STAR is limited to postmenopausal women because the drug raloxifene has yet to be adequately tested for long-term safety in premenopausal women. The National Cancer Institute recently launched a separate study to evaluate the safety of raloxifene in premenopausal women, at an increased risk for breast cancer.
Women who are interested in getting more information about the STAR trial can call the NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237). To locate the nearest STAR center via the Internet, you can visit the NSABP's Web site at http://www.nsabp.pitt.edu or NCI's clinical trials Web site at http://cancertrials.nci.nih.gov. To get information about the STAR trial being conducted at Johns Hopkins call 410-614-STAR .
SOURCES:
National Surgical Adjuvant Breast and Bowel Project (http://www.nsabp.pitt.edu)
National Cancer Institute clinical trials Web site (http://cancertrials.nci.nih.gov)
Abstracts from the 36th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, May 25, 2000, (www.asco.org)
Drug Benefit Trends, 1998; 10(10): 54-57, 59
Abstracts from the 17th Annual Miami Breast Cancer Conference, Miami, FL, March 3, 2000
American Cancer Society (www.cancer.org)
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