Mifepristone (RU486) in Refractory Ovarian Cancer
Abstract & Commentary
Synopsis: Forty-four patients with ovarian cancer refractory to cisplatin and paclitaxel were treated with mifepristone. A response rate of 26.5% was seen with minimal toxicity.
Source: Rocereto TF, et al. Gynecol Oncol 2000;77:429-432.
For most patients with refractory ovarian cancer, palliation means receiving systemic chemotherapy. Rocereto and colleagues from Cooper Hospital/University Medical Center in New Jersey report on 44 refractory ovarian cancer patients treated with mifepristone 200 mg/day. All of these patients were resistant to both cisplatin and paclitaxel defined as progressing while on treatment or developing recurrent tumor within six months of completing chemotherapy. Of the 34 patients evaluable for response, the use of mifepristone was associated with a response rate of 26.5%.
All patients in this study had previously received cisplatin and paclitaxel either sequentially (such as cisplatin-cyclophosphamide followed by paclitaxel) or in combination. The median number of prior treatment regimens was two (range 1-6). The median time from the initial cancer diagnosis to treatment with mifepristone was 23.5 months (range 6-123 months). Patients with potential poor risk features were allowed to enter this study. For example, one-half of the serous-type tumors were grade-3, and one patient had clear cell histology. In addition, patients could be enrolled with a performance status up to two.
Responses required either a 50% reduction in a measurable lesion or a 50% reduction in the CA-125. Although six patients achieved a partial response, none of these responses lasted longer than two months. However, there were three complete responses lasting two, four, and over 32 months. The patient with the longest response was taken off therapy after 32 months and remains disease-free more than a year later. Survival for the responders was not reported, but for the 25 non-responders, the median survival from onset of treatment with mifepristone was seven months (1.5-35 months or more).
Toxicity was evaluated in all 44 patients in the study. Only nine patients were reported to have had an adverse event. The principal toxicity was dermatologic; two patients with a grade-3 rash were taken off study and the other five patients had a grade-1 rash. Two gastrointestinal events included a case of gastroenteritis and one patient had antiemetic-responsive nausea.
COMMENT by Kenneth W. Kotz, MD
A hormonal agent that is effective in ovarian cancer would be of great interest to all physicians who treat ovarian cancer. Older trials of hormonal agents such as progestins, estrogens, androgens, aromatase inhibitors, gonadotropin-releasing hormone analogs, and anti-estrogens have shown occasional responses1 but only tamoxifen seems to be currently used. Published series of tamoxifen suggest a complete response rate of 4.6%, a partial response rate of 7.4%, and stabilization of disease in 30.5%.1 In the largest of these series, 10 of 105 patients treated by the Gynecologic Oncology Group had a complete response lasting a median of 7.5 months.2 Mifepristone, a progesterone receptor inhibitor, has been shown to have activity against ovarian epithelial cancer cell lines in vitro.3 Its activity in vivo, as reported by Rocereto et al, may be comparable to that reported for tamoxifen, an estrogen receptor inhibitor. It is not known whether a positive progesterone receptor result predicts for a response to mifepristone, although the estrogen receptor status does not predict the likelihood of responding to tamoxifen.
Because the only proven adjuvant therapy is chemotherapy, hormonal therapy is a palliative maneuver usually offered to patients who relapse. One common clinical situation is what to do for an asymptomatic patient with a rising CA-125. While there is no proof that early intervention prolongs survival in this situation, hormonal approaches are particularly reasonable for the patient who does not want to simply watch the CA-125 rise and wait for symptoms to develop. This would be an area in which to explore the activity of tamoxifen, mifepristone, or even the combination of the two. Unfortunately, combinations of other hormonal approaches have not proven superior to any single agent alone.1
All patients in this study were on estrogen replacement therapy. Despite theoretical concerns, there is no clinical evidence that patients diagnosed with ovarian cancer are harmed by receiving estrogen replacement therapy.1 On the other hand, one wonders whether the results of inhibiting the progesterone receptor with mifepristone could be compromised by the simultaneous stimulation of the estrogen receptor by hormone replacement therapy. It will be interesting to see whether the progesterone receptor inhibitor mifepristone will find a role in the treatment of ovarian cancer or other progesterone-receptor-expressing cancers.
References
1. Schwartz P, et al. In: Ovarian Cancer: Controversies in Management. Gershenson D, McGuire W, eds. New York, NY:Churchill Livingstone;1998;325-341.
2. Hatch KD, et al. Cancer 1991;68:269-271.
3. Rose F, Barnea ER. Oncogene 1996;12:999-1003.
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