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© Oxford University Press 2006.
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Raloxifene Prevails in STAR Trial, May Face Easier Road to Acceptance Than Previous Drugs
Raloxifene seems to have won the contest with tamoxifen to prevent breast cancer in high-risk postmenopausal women, providing equal cancer-preventing benefits with fewer serious side effects. The finding clears the way for possibly wider use of the osteoporosis drug.
Results from the 20,000-woman Study of Tamoxifen and Raloxifene (STAR) were released in April, more than a year ahead of schedule. Raloxifene's greatest advantage appears to be fewer serious side effects, including uterine cancer, blood clots, and cataracts.
"The study was designed to compare the drugs head to head, and raloxifene was the winner," said Larry Wickerham, M.D., associate director of the National Surgical Adjuvant Breast and Bowel Project, which announced the results with the National Cancer Institute
"This is good news for women," added Leslie Ford, M.D., associate director of clinical research for NCI's Division of Cancer Prevention. Roughly the same number of women taking each drug developed breast cancer—167 in the raloxifene group and 163 in the tamoxifen group, a difference that wasn't statistically significant.
The findings have prompted raloxifene maker Eli Lilly to petition the Food and Drug Administration for permission to market raloxifene for breast cancer prevention. Now physicians across the country are anticipating an influx of requests from postmenopausal women for raloxifene.
"I absolutely think prescribing patterns will change—are already changing," said Isaac Schiff, M.D., chief of obstetrics and gynecology at Massachusetts General Hospital in Boston, citing the widespread media attention generated by the announcement. "Women will be coming in to see their doctor to take raloxifene for breast cancer prevention."
However, reaction to raloxifene has not been universally upbeat. Barbara Brenner, executive director of Breast Cancer Action, reiterated the concerns her group expressed about tamoxifen.
"Women should remember that these drugs are about risk reduction, not prevention. We're concerned that treating risk as a disease will encourage women to take a powerful drug that has its own risks."
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Some 500,000 women in the United States already take raloxifene for osteoporosis treatment and prevention, generating more than $1 billion in annual sales for Eli Lilly. An Eli Lilly spokeswoman said the company is diligently collating data from STAR and several earlier studies and will complete the paperwork by the end of the year.
Raloxifene was approved by the FDA for osteoporosis prevention in 1997 and for osteoporosis treatment in 1999. The trials that led to those approvals indicated that raloxifene might also reduce the risk of breast cancer, a finding that directly led to STAR.
The announcement marks a milestone for the ongoing placebo-controlled STAR trial, which began in 1999. Although the data were originally scheduled to be presented at the American Society of Clinical Oncology annual meeting in June, NSABP spokeswoman Lori Garvey said that the results "ethically compelled" the group to spread the word as quickly as possible. In April, after completing its data analysis, the NSABP told the 500 STAR recruiting centers to notify trial volunteers which drug they had been taking. Women who had been receiving tamoxifen can now switch to raloxifene for the rest of their trial enrollment.
The trial was designed to monitor each volunteer for 5 years, and the announcement came after women had been enrolled for an average of just under 4 years. Wickerham said the NSABP will continue to monitor the women "as long as they let us, at least several more years." Extending the $88 million trial will tell researchers whether the preventive effects of raloxifene continue after women stop taking it and give them "more robust" data on adverse events, Wickerham said.
Fewer Adverse Events
In September 1998, the Journal of the National Cancer Institute published results from STAR's predecessor, the landmark Breast Cancer Prevention Trial (BCPT), which found that tamoxifen cut the risk of breast cancer by 49% in high-risk postmenopausal women. The results marked the first time a drug had been shown to reduce the risk of breast cancer, and it was heralded as a breakthrough.
"The BCPT should be viewed not only as the first study that demonstrates that breast cancer can be prevented but also as a beginning of a paradigm shift" in women's health, said Bernard Fisher, M.D., first author of the report and principal investigator for the trial.
However, in the intervening 7 years, tamoxifen "got little use" for preventing breast cancer, Ford said. Wickerham agreed and listed two major reasons. First, physicians knew tamoxifen mainly as a cancer treatment drug, which had been its primary use since the 1970s. "Primary-care physicians, who are absolutely critical for prevention efforts, weren't familiar with it," Wickerham said.
Second, and perhaps more important, several consumer groups opposed the concept Fisher heralded as a paradigm shift—giving a drug with known adverse effects to healthy women. The National Breast Cancer Coalition "urged caution." Breast Cancer Action called it "a bad trial of a bad drug." And Public Citizen found the FDA's approval of tamoxifen for breast cancer prevention "incredible."
"I have great concern that otherwise healthy women may be injured or killed from tamoxifen, thinking that it was going to prevent them from dying from breast cancer," said Larry D. Sasich, Pharm.D., a pharmacist at Public Citizen, at the time of the FDA's announcement in October 1998. "After all, it is a known carcinogen."
The reaction arose in part when the initial BCPT results showed an increased risk of uterine cancer in the group that took tamoxifen: 1.4% of participants developed the disease, compared with 0.2% of women in the placebo arm. The risk for potentially fatal blood clots also increased, as did menopausal symptoms such as hot flashes and vaginal discharge.
"The uterine cancer was a concern—it was a rare but serious side effect," Schiff said. "But the other issue that affected many more women ... was the reemergence of hot flashes months and months after her last period." Hot flashes are also an issue with raloxifene.
The STAR data place raloxifene on much better footing, said Victor Vogel, M.D., the protocol chair of the STAR trial. "It causes fewer (uterine) cancers, (fewer) pulmonary and deep vein emboli, and fewer cataracts," he said during a teleconference announcing the results. Of the women in STAR with a uterus—about half had previous hysterectomies—36 women taking tamoxifen developed uterine cancer, compared with 23 taking raloxifene, a 38% risk reduction in both arms. However, the results are only "borderline statistically significant," Wickerham said.
The reduction of other adverse effects, however, was statistically significant: Women taking raloxifene were 36% less likely than their tamoxifen-arm counterparts to develop pulmonary emboli (54 versus 35); 21% less likely to develop cataracts (394 versus 313); and "somewhat less likely" to develop menopausal symptoms, Vogel said. More complete data will be presented June 5 at the ASCO meeting.
"The side effect profile makes raloxifene a very good alternative to tamoxifen" for breast cancer prevention in postmenopausal women, Ford said.
A Running Start
Other factors also favor raloxifene, Schiff said. The public is now used to the idea of chemoprevention, and primary-care physicians already prescribe raloxifene regularly for prevention and treatment of osteoporosis. Also, from 1998 to 2000, Eli Lilly promoted raloxifene for breast cancer prevention: an unapproved use, drawing heat from the FDA and from tamoxifen maker Astra-Zeneca.
Just weeks after the FDA approved raloxifene for the prevention of osteoporosis, the agency sent a warning letter to Eli Lilly chastising the company for a press release and other materials claiming that data from the Multiple Outcomes of Raloxifene Evaluation trial proved the drug could reduce the risk of breast cancer. In 1999, the agency issued another warning letter, telling the company to rein in its sales force, which had been pushing physicians to prescribe raloxifene for breast cancer prevention. Astra-Zeneca sued and in 2000 won an injunction against Eli Lilly that severely restricted how that company could market raloxifene.
Combined, these factors give raloxifene a running start as a breast cancer chemopreventive. "Many obstetrician/gynecologists already prescribe raloxifene off-label for breast cancer prevention," Schiff said. "I give seminars all the time where colleagues come up and tell me they use it to prevent both osteoporosis and breast cancer."
But the expanded use of raloxifene comes with caveats, Wickerham said. The STAR trial excluded women at risk for blood clots and strokes—namely, those with a history of vascular events, heart attacks, hypertension, and diabetes. "This was a highly selected group," Wickerham said. "Not only were the participants at high risk for breast cancer, we worked to minimize the risk of adverse events."
Physicians who prescribe raloxifene for breast cancer prevention should follow STAR's example, he said. "If we're going to begin using raloxifene outside of STAR, the same group of patients should avoid it."
Related Article in JNCI
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J Natl Cancer Inst 2007 99: 1282-1289.
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