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09-15-2007, 08:50 AM
An FDA advisory panel in July gave its stamp of approval for the osteoporosis drug raloxifene to be used as an oral chemopreventive agent for invasive breast cancer in older women at high risk for the disease and those with osteoporosis.

However, that recommendation came with several qualifications.

While panelists said that the drug should be available as an alternative to tamoxifen-the only agent with FDA-approved labeling to reduce the risk of breast cancer in women at high risk for developing the disease-many members of the Oncologic Drugs Advisory Committee urged regulators to impose safeguards on raloxifene's use.

Results of three placebo-controlled studies indicated that raloxifene, an estrogen agonist - antagonist indicated for the treatment and prevention of osteoporosis in postmenopausal women, reduces the risk of estrogen-receptor (ER)-positive breast cancer, said FDA clinical reviewer Bhupinder Mann.

But, he said, that benefit comes with certain risks, such as deep venous thrombosis (DVT), pulmonary embolism, and death due to stroke. Mann also noted that raloxifene does not appear to reduce the risk of ER-negative breast cancers.

Results of a study comparing raloxifene with tamoxifen in nearly 20,000 postmenopausal women at high risk for invasive breast cancer indicated that raloxifene is comparable to tamoxifen in reducing the incidence of the disease, said FDA clinical reviewer Patricia Cortazar.

In that study, known as the Study of Tamoxifen and Raloxifene (STAR), higher rates of DVT were observed in women receiving tamoxifen than in women receiving raloxifene, she noted, adding that higher rates of endometrial cancers and cataracts were also observed in the tamoxifen-treated group.

Panelists at the July 24 meeting were asked to advise FDA on whether the chemopreventive benefits of raloxifene, marketed by Eli Lilly as Evista, outweighed the serious risks associated with the drug.

Compared with tamoxifen, which is also associated with uterine cancer, raloxifene is a "more attractive" choice of drug in preventing breast cancer because it has fewer risks of toxicity, argued Larry Wickerman, project officer for the National Surgical Adjuvant Breast and Bowel Project, the group that conducted STAR.

Because of the serious adverse effects associated with tamoxifen, said panelist Michael Perry, director of the Division of Hematology and Medical Oncology at the University of Missouri at Columbia, many physicians have shied away from using the drug as a chemopreventive agent in women at risk for breast cancer.

And, he added, since tamoxifen went off patent, "there is no manufacturer pushing the drug."

Despite recent improvements in breast cancer research, said George Sledge, Balive Lantero Professor of Oncology at Indiana University School of Medicine, the disease remains a major cause of cancer mortality.

More than 178,000 women will be diagnosed with invasive breast cancer in the United States in 2007, according to the American Cancer Society, and more than 40,000 of those women will die from the disease this year. Breast cancer is second only to lung cancer as a cause of cancer death among women.

Women, Sledge told the committee, "should have a choice" in chemopreventive agents to combat breast cancer.

Since it was first approved in 1997, more than 22 million women worldwide have received raloxifene to prevent or treat osteoporosis, he noted.

Therefore, Sledge asserted, "It is a well-established agent."

But panelist James Couch, associate chairman of the Neuroscience Service at the University of Oklahoma Health Sciences Center, urged caution about the use of raloxifene and expressed particular concern about the potential for stroke in patients taking the drug.

Committee member Aman Buzdar, professor of medicine at the University of Texas in Houston, agreed, stating that "If you develop a stroke, your life is changed forever. If you develop breast cancer, you can be cured."

Many on the advisory committee expressed unease that Eli Lilly had not proposed the duration for which patients should take raloxifene to prevent breast cancer.

If a woman starts taking the drug in her 50s, asked committee chairman Maha H. A. Hussain, is she expected to take it well into her 80s?

"I think that some restrictions should be on duration. I don't think it should be left to the primary care physician," said Hussain, professor of medicine and urology at the University of Michigan.

To limit the potential for harm, said panelist Curt D. Furberg, professor of public health sciences at Wake Forest University School of Medicine in Winston-Salem, North Carolina, raloxifene should be restricted for use in women where the drug has been shown to be effective.

He called on FDA to require the inclusion of a black-box warning in the product's labeling "to bring to people's attention that there are risks involved."

Furberg urged regulators to also require Eli Lilly to develop a patient-friendly medication guide. FDA, he added, should also monitor the drug's use by creating a patient registry.

If regulators approve the breast cancer indication, Furberg said, FDA should "re-review" its approval decision in five years to ensure patients are being kept safe from unnecessary adverse events.

He noted that patients in STAR took raloxifene for only five years; therefore, no long-term data regarding the use of the drug as a chemopreventive agent is available.

Also missing, many panelists noted, are survival data for patients taking the drug to prevent invasive breast cancer.

Pharmacist Jennifer Thompson, an oncology clinical specialist at the University of Maryland Marlene and Stewart Greenebaum Cancer Center in Baltimore, said it is important for researchers to continue following STAR participants long-term to determine the proper duration of therapy for raloxifene as a chemopreventive agent.

"Maybe in five years, we will have that answer," she said in an interview.

Another limitation of the three placebo-controlled studies and STAR, Thompson noted, is that the trials included postmenopausal women only, leaving premenopausal women at high risk for the disease with only tamoxifen as a therapy choice.

If FDA approves raloxifene as a chemopreventive agent, Thompson said, clinical pharmacists will play a vital role in educating patients with breast cancer about the risks and benefits of the drug and in monitoring those patients for adverse events.

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