. "Other Therapeutic Uses of Antiprogestins." Clinical Applications of Mifepristone (RU486) and Other Antiprogestins: Assessing the Science and Recommending a Research Agenda. Washington, DC: The National Academies Press, 1993.
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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda
One partial response in a patient with lymph node metastases was observed, but the response lasted for only five months. Disease did not progress in six patients for periods of three to eight months. The appearance of toxicities was delayed; these included weight loss in ten patients, fatigue, anorexia, nausea, malaise, somnolence, and one grand mal seizure. A rise in serum creatinine and an increase in eosinophil counts were also observed. Of interest is the fact that 3 of the 11 patients responded to third-line treatment with the progestin megestrol acetate. This included the one patient who had also responded to mifepristone.
A number of endocrine levels were evaluated in this study. Increases were noted in estradiol, ACTH, cortisol, and androstenedione, but sex hormone-binding globulin levels decreased with treatment. The authors attributed increases in estradiol in these postmenopausal women to increased adrenal stimulation secondary to antiglucocorticoid effects of mifepristone and subsequent peripheral conversion of adrenal androgens to estrogens in these postmenopausal women. This increase in estrogens, which could be potentially deleterious to the treatment of breast cancer, hypothetically could be overcome by combining the antiprogestin with an antiestrogen or aromatase inhibitor. Preclinical data supporting the utility of such an approach are mentioned above (Kian et al., 1989; Bakker et al., 1990).
Adjuvant Therapy and Chemoprevention
Potential uses for antiprogestins in adjuvant therapy (postoperative therapy undertaken when no detectable tumor is present to reduce the risk of recurrence) or chemoprevention (treatment of well women to lower the risk of initial development of cancer) arose at the committee's workshop during the discussion of Horwitz's presentation, undoubtedly stimulated in part by the experience with the use of the antiestrogen, tamoxifen, for these indications. However, given the current status of the clinical development of antiprogestins, specifically mifepristone, such applications to chemoprevention are purely speculative at present. Although a number of interesting theoretical applications have been identified, clinical experience with these compounds is too limited at present. In addition, the potential for agonist as well as antagonist activity (discussed in several papers in Appendix B) and the preclinical observation of tumor stimulation (Bowden et al., 1989) suggest that cautious observation will be required prior to clinical trials in early breast cancer or prevention. Substantial clinical activity and acceptable toxicity in advanced disease patients would be required before one could seriously consider using antiprogestins as an adjuvant treatment for breast cancer and certainly prior to their introduction for the chemoprevention of breast cancer. In addition, antiprogestin therapy would need