DR SMITH: This is a 91-year-old lady with Stage II breast cancer, diagnosed in 1990. At the time, her tumor was 2.4 centimeters, estrogen receptor-positive, but lymph node-negative. She underwent mastectomy and took adjuvant tamoxifen for seven years.

Since that time she’s developed mild to moderate dementia and, according to her family, she may forget to take her pills from time to time. The patient herself is not aware of this.

She did quite well until September 2004, when she presented with right hip pain. A bone scan showed diffuse bone metastases, mostly involving the hips and femurs, bilaterally, with a right superior pubic ramus fracture.

A CT scan showed multiple liver metastases, five in number, with the largest one being three centimeters in size, and no other sites of disease.

The pubic ramus fracture was irradiated, which resolved her pain, and she was started on pamidronate and fulvestrant, with stabilization of her disease for eight months.

DR LOVE: You mentioned that the patient has dementia. Were you able to discuss treatment with her in a way that she understood?

DR SMITH: She did understand that her cancer had returned and that she needed some treatment.

DR LOVE: Did her symptomatology improve on the fulvestrant?

DR SMITH: Yes, her pain resolved and that was the only symptom she was having.

DR LOVE: Dr Osborne, what are your thoughts on the use of fulvestrant?

DR OSBORNE: Two clinical trials were conducted comparing fulvestrant versus anastrozole for second-line therapy in patients who had received tamoxifen in the adjuvant or metastatic setting (Pippen 2003; Robertson 2003; [4.1]). One study was conducted in North America and the other in Europe and the rest of the world. The data from both trials were very similar. The complete response rate was slightly higher with fulvestrant, whereas the partial and objective response rates were very similar. In terms of stable disease and clinical benefit, fulvestrant was a tiny bit better than anastrozole. In one of the trials, duration of response favored fulvestrant, but by and large, the drugs were very similar.

How does fulvestrant compare with tamoxifen in the front-line setting? All the preclinical data suggested that fulvestrant would be significantly better than tamoxifen, so a trial was conducted comparing these two endocrine agents. In the receptor-positive group, fulvestrant and tamoxifen were similar in response and time to treatment failure, but overall, tamoxifen looked slightly better in some of the parameters.

DR LOVE: Would you have used fulvestrant in this patient?

DR OSBORNE: Because of the data showing superiority of aromatase inhibitors relative to tamoxifen, in a previously untreated patient I would tend to go with an aromatase inhibitor first. However, in this patient, who has received tamoxifen and suffers from dementia and may not be taking her pills correctly, I think she’s a perfect candidate for fulvestrant, and I totally agree with its use in this situation.

DR GRADISHAR: One of the issues is whether there’s a particular sequence of endocrine therapy that’s optimal, in terms of prolonging time to disease progression or overall survival. The EFECT trial is one effort to look at patients who have progressed through a nonsteroidal aromatase inhibitor, be it anastrozole or letrozole, and are then randomly assigned to receive either fulvestrant or the steroidal aromatase inhibitor exemestane. There are no data from that trial yet; it’s probably three quarters of the way to its accrual goal at this point.

DR LOVE: Kent, the SoFEA trial in Europe is evaluating another strategy in patients who are progressing on aromatase inhibitors. Those patients are randomly assigned to fulvestrant, exemestane or fulvestrant plus anastrozole. I know there are oncologists in practice who have continued an aromatase inhibitor and added fulvestrant. What do you think of that strategy in the clinical setting?

DR OSBORNE: I think it’s a good idea, but as you know, there are no data. I have to say I have done it in a few patients based on two preclinical studies that have evaluated this: my own and Angela Brody’s. Fulvestrant seems to work much better when there’s no estrogen around. Even though postmenopausal women have lower estrogen levels in the blood, their tumors don’t necessarily have lower estrogen levels, and fulvestrant seems to be more effective when estrogen is low.

It would be interesting to see the results of a clinical trial evaluating that.

DR LOVE: A lot of people have talked about the issue of how to dose fulvestrant. My simplified understanding of it is that since it’s a competitive inhibitor for estrogen, you could increase dose or get rid of the estrogen.

DR OSBORNE: Yes, you could do it either way, but I am concerned that in premenopausal women, it doesn’t work very well. Obviously, they have a lot of estrogen in their blood, and we know it doesn’t work well for conditions like benign endometriosis. I think the estrogen in the premenopausal woman is too much to be competitively inhibited with the fulvestrant dose that we’re now using. Plus it takes three to six months to get the dose to steady state when you start at 250 mg a month, and that’s a problem. Some patients may be taken off fulvestrant after only two months of therapy, before the blood levels are even high enough to make a difference.

Ongoing trials are evaluating fulvestrant at doses of 500 mg on day one, 250 mg on days 14 and 28, and then once a month. That’s based on a computer model of the pharmacokinetics of the drug. Whether insurance companies will pay for that loading dose outside of that trial is another issue.

DR LOVE: Do you use that strategy in a clinical setting?

DR OSBORNE: Yes. I do.

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