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Executive Summary

ICI Pharma's Nolvadex (tamoxifen citrate) significantly expanded its approved patient population with a June 21 okay from FDA for adjuvant use in treating node-negative breast cancer. Previously, only node-positive patients were considered candidates for adjuvant or postoperative therapy with Nolvadex. "Since between 50 and 60% of newly diagnosed breast cancer patients are node-negative," ICI Pharma said in a June 21 press release, "this indication will significantly affect a majority of women faced with this disease." A double-blind trial of Nolvadex versus placebo involving 2,644 women with primary node-negative breast cancer, who had surgery, "supported the fact that patients at lower risk would benefit from at least five years of follow-up with tamoxifen therapy," ICI noted. FDA's Oncologic Drugs Advisory Committee recommended Nolvadex use in the node-negative breast cancer following lumpectomy or mastectomy at its Feb. 2 meeting ("The Pink Sheet" Feb. 5, T&G-5). Revised labeling for the drug lists the new indication: "Nolvadex is effective in delaying recurrence following total mastectomy and axillary dissection or segmental mastectomy, axillary dissection, and breast irradiation in women with axillary node-negative breast cancer." The labeling adds: "Data are insufficient to predict which women are most likely to benefit and to determine if Nolvadex provides any benefit in women with tumors less than 1 cm." Discussion of the approval criteria for Nolvadex as a cancer chemopreventative will begin in earnest at the June 29 meeting of FDA's Oncology Drugs Advisory Committee, where an IND application for the indication will be discussed. The sponsor of the proposed study, which would be the first of its kind in the U.S., is Phillip Bretz, MD, a surgeon at the Desert Breast Institute in Rancho Mirage, California. Bretz's proposed 10-year, multi-center trial would accrue about 14,000 post-menopausal U.S. women at risk for breast cancer who had one or two first-degree relatives with the disease, plus an undetermined number from the U.S.S.R. who were exposed to irradiation during the Chernobyl nuclear accident. According to Bretz, the health minister of the Ukraine plans to meet with FDA officials soon to discuss the proposed trial. The study would randomize women to receive either tamoxifen, an anti-estrogen, or placebo. According to Bretz, the trial might have three arms, in order to study two different dosages of tamoxifen. The estimated cost of the 10-year trial, with follow-up until death, will range from $65-$100 mil., Bretz said, adding that "it depends on what the drug company does." According to an ICI spokesperson, the company "is willing to support prevention trials if that is the way the scientific community wants to go." Also attending the FDA meeting will be Trevor Powles, MD, of the Royal Marsden Hospital in Sutton, Surrey, England. Powles recently completed a pilot chemoprevention study using tamoxifen, and is now proposing a major randomized prevention trial, in which 10 centers would each recruit 200 women a year for five years; follow-up would be 10 years. Another speaker, Richard Love, MD, University of Wisconsin/Madison, will present results of an ongoing four-year study designed to look at the effects of tamoxifen on cardiovascular risk factors and bone disease. Love is working on an alternative proposal for a tamoxifen/chemoprevention study. Another researcher, V. Craig Jordan, director of the breast cancer program for the Wisconsin Clinical Cancer Center, favors doing a "chemosuppression" trial, in which tamoxifen would be administered to post-menopausal women who have had a previous mastectomy but no further therapy. In a letter in the June 20 issue of the Journal of the National Cancer Institute, Jordan stated, "there are probably several hundred thousand women with ER-positive [estrogen receptor] node-negative breast cancer who are at risk for recurrence and at risk for a second primary tumor." Because no IND would be needed, "a clinical trial organization could initiate a randomized study quickly. A single trial, with rapid enrollment, could address the issue of the efficacy of delayed adjuvant therapy and could act as a benchmark study to evaluate the efficacy of tamoxifen as a chemosuppressive (preventive) therapy in women at high risk for primary breast cancer." Bretz has reportedly met with several congressional staffs, including those of Sen. Wilson (R-Calif.), Rep. Vucanovich (R-Nev.) and Rep. Myers (R-Ind.). Rep. Myers testified about his family's experience coping with breast cancer at a May 16 hearing before the Subcommittee on Health and Long-Term Care. Congresswoman Vucanovich, who has also had breast cancer, was treated with a modified radical mastectomy, but did not receive tamoxifen. Both representatives would favor the kind of study that Bretz is proposing, according to their staffs. An NIH consensus conference on early stage breast cancer (June 19-21) also addressed the expanding use of tamoxifen. The panel's concluding statement found that "there is clear evidence that the rate of local and distant recurrence is decreased by both adjuvant combination cytotoxic chemotherapy and by adjuvant tamoxifen." The conference statement notes that data from 10 randomized trials reviewed show that "adjuvant systemic therapy reduces the rate of recurrence by approximately one-third with a broad range. For example, among a group of women with a recurrence rate of 30%, adjuvant therapy would decrease the rate of recurrence to about 20%."

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