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Executive Summary

TAMOXIFEN BREAST CANCER PREVENTION STUDY SHOULD "PROCEED," with modifications, FDA's Oncologic Drugs Advisory Committee decided at its July 2 meeting. The committee voted 6-1 in favor of allowing the National Surgical Adjuvant Breast and Bowel Project (NSABP) to go ahead with the long-term, large-scale study but asked that certain changes be made in the eligibility criteria "to ensure that the study population is at a high enough risk for the development of invasive breast cancer or cardiovascular disease to justify five or more years of [tamoxifen] therapy." "This is an experiment that needs to be done . . . but we want higher risk groups to justify" the long-term treatment, committee member David Ahmann, MD, Mayo Medical School, commented. While the committee expressed strongly its wish that only women at very high risk of breast cancer be included in the trial, the advisory group did not offer specific suggestions on how to narrow the entry criteria. NSABP's trial is intended to be the first controlled-clinical study of the prophylactic effects of tamoxifen on healthy women. According to the draft protocol, 16,000 women with "a defined high risk of breast cancer" will be enrolled in the 70-center trial and randomized to treatment or placebo arms for five years of therapy. Although the study's primary outcome is breast cancer prevention, the number of cardiovascular episodes that occur and the incidence of osteoporosis also will be compared. Jointly sponsored by the National Cancer Institute and the National Heart, Lung and Blood Institute, NSABP's trial already has received approval from NCI's board of scientific counselors and the National Cancer advisory Board. Once the FDA advisory committee's recommendations have been incorporated into a final protocol, NSABP expects to resubmit its proposal to the FDA for formal IND approval. NCI says the study is on schedule to begin enrolling patients by the late fall. NSABP currently plans to enroll any woman over the age of 60 or any premenopausal woman whose "relative risk of developing breast cancer is the same as that of the average 60 year old," principal investigator Bernard Fisher, MD, explained to the committee. Premenopausal relative risks will be determined using a risk measurement system known as the GAIL scale and computerized epidemiological programs developed by the statisticians at NSABP. Most of the committee members agreed that the general mechanics of the protocol were "thoughtful and elegant." Committee chair Craig Henderson, MD, Harvard School of Medicine expressed unease about the wisdom of exposing "a large, heterogeneous . . . healthy population to treatment with a potentially harmful drug." For example, Dean Brenner, University of Michigan School of Medicine, commented: "Treating healthy people is not the same as treating sick people . . . I'd be much more comfortable treating somebody with a defined higher serious risk, like a pre-maligrant lesion, where one can justify it [tamoxifen treatment(BRACKET)." The panel's desire to "tighten" the study's eligibility requirements was fueled by the results of several recent studies suggesting that tamoxifen may produce serious adverse events in a small percentage of patients. In the recently completed NSABP/B-14 trial involving 1,400 patients on tamoxifen for five years or more, 1.5% of the active therapy patients experienced serious thromboembolic reactions. Three of these patients had embolic episodes resulting in death. In addition, a recently published study from Sweden also has shown a 1% incidence of endometrial cancer in tamoxifen patients. Committee member Ahmann pointed out the NSABP is predicting they will avert cancers in less than 2% of their trial participants. "What is the likelihood that adverse events could outweight clinically significant benefits" in healthy patients, he asked. "You need a closer look at a more focused population to show benefit." The alleged risks involved in tamoxifen therapy also provoked some committee members to recommend that an especially detailed and objective informed consent document be prepared for the trial. "Nobody wants an infomercial," said Grace Monaco, JD, Chairman of the Candlelighters Childhood Cancer Foundation. The committee nonetheless decided to endorse the protocol as a whole, because they believed it to be "an excellent and interesting study . . . from a good group." Nancy Kemeny, MD, Memorial Sloan-Kettering, summed up the committee's opinion, saying, "I'm not against the study; I just want to modify certain things. . . ." The advisory committee previously had expressed conceptual support for a tamoxifen chemoprevention trial at a meeting last June ("The Pink Sheet," July 9, 1990, T&G-2).

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