New Treatments for Endometrial Cancer. Part 6
The last part of the mythology is that the higher the dose of the progestins the better the response rate and duration. Now this myth came from some breast cancer studies that suggested that if you gave high dose progestins to breast cancer patients you get a higher response. One particular study that comes to mind was a Piedmont Oncology Association study that suggested that. So we tried to look at this in endometrial carcinoma. Two hundred milligrams a day of medroxyprogesterone acetate, which is really a standard oral dose of this, yielded an overall response rate of 26% complete plus partial response rate. Five times that dose, 1,000 mg per day, yielded a response rate of 17.9%, actually lower, with a statistically significantly shorter progression free survival and a much higher incidence of toxicity, such as fluid retention and thromboembolic phenomenon. So there is no evidence that you need to go to extremely high doses of this.
Cancer treatment
If we sum up what we know about progestins in endometrial cancer, both parenteral and oral agents will yield response rates that range from 17-16%, relatively short durations of response, and an overall survival of less than a year. The results with progestins are better in grade I or receptor positive tumors where we get response rates of around 40%, progression free survival of roughly nine months, and overall survival of around 14 months. The results are very poor in higher grade or receptor negative tumors; response rate 12%, progression free survival 3 months, overall survival 10 months. Doses higher than 200 mg per day orally of medroxyprogesterone acetate, or its equivalent, is 160 mg per day, all for no advantage.
Now what about tamoxifen? These are the four series that have been reported in the literature. There were two smaller series that suggested significant activity. The GOG then tested tamoxifen first to a 25 patient study then in a larger 63 patient study, in patients who had had no prior hormonal therapy. And what we found was very little activity. Much lower than what we saw with progestins. The bottom line on tamoxifen is that the larger trials show little or no activity. Even in those with prior hormonal responses – we did a subset that had responded to progestins and then later relapsed – and we tried tamoxifen in that group as we do with breast cancer, with successive hormonal therapies, we found no activity. So tamoxifen appears to have a relatively little role in treating endometrial cancer, a bigger role in causing it.
We can summarize hormonal therapy; progestins are clearly active. I think if you want to put a handle on one response rate, 20% is a good number to quote. Response correlates with grade and receptor status and is high only in grade I tumors. The duration of response is brief as is survival, except in those patients with grade I or receptor positive tumors. And no other hormonal agent other than progestin has really demonstrated significant activity. The GOG has tested a whole series of other agents looking for other agents that have reasonable activity.
Our recommendation is; when you choose hormonal therapy for your endometrial cancer patient use progestin. It should be the first line of systemic therapy in patients with grade I or receptor positive tumors. It should not be your first line of treatment in grade II, III tumors or known receptor negative tumors. Salvage hormonal therapy after chemotherapy failure can be considered because it has relatively little cost and toxicity and occasionally might work.