Fulvestrant

DR CARLSON: For a patient whose disease is progressing on an aromatase inhibitor, I wouldn’t currently consider the addition of fulvestrant a reasonable option outside of a clinical trial. In general, two concurrent hormonal maneuvers, at least in postmenopausal women, don’t appear to add dramatically to antitumor efficacy.

Premenopausal women receiving ovarian suppression and an aromatase inhibitor or ovarian suppression and tamoxifen might derive a benefit from the dual hormonal maneuver. For postmenopausal women, however, data supporting dual hormonal maneuvers are effectively nonexistent.

SWOG-S0226 will help to address this issue to some extent. It’s a randomized, Phase III trial evaluating anastrozole versus anastrozole with fulvestrant. If that trial shows superiority of the dual hormonal maneuver, then adding fulvestrant in this situation will make a lot more sense.

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Fulvestrant Loading Dose

DR CARLSON: The pharmacokinetic studies provide a strong rationale for using a loading dose of fulvestrant. Without a loading dose, it takes several months to reach fully efficacious estrogen receptor downregulating levels of fulvestrant. So I’m a strong advocate of it.

If we’d had the pharmacokinetic data when the first-generation trials were conducted, we never would have used fulvestrant without a loading dose. The real difficulty with the loading dose is that it is sometimes difficult to obtain reimbursement for because it’s not part of the FDA label. Whenever I can obtain reimbursement for it, however, I’m using the loading-dose strategy.

If we extended the endocrine therapy section of the NCCN breast cancer guidelines to include the dose and schedule of agents, then we would be required to incorporate a loading-dose strategy based on the pharmacokinetic data.

Breast Cancer Update 2007 (4)

DR PRITCHARD: Good pharmacokinetic data indicate that without a loading dose, it takes three to four months to reach steady-state levels of fulvestrant. I believe most of us are using a loading dose, and there doesn’t seem to be any real problem with that. A number of trials have been using the loading dose, and no safety problems are apparent.

Breast Cancer Update 2007 (3)

DR BUZDAR: We don’t know whether using the loading dose of fulvestrant is the best approach. We can only say that it was the way fulvestrant was administered when we compared it to exemestane, and the efficacy was similar. If I have to use fulvestrant in clinical practice in this type of setting, I will use the drug as it was administered in the protocol.

Breast Cancer Update 2007 (2)

DR ANDREW D SEIDMAN: The EFECT study employed a loading schedule for fulvestrant, which is what I tend to use in my practice. When using fulvestrant, one should probably follow the design of this trial, starting with the 500-mg loading dose followed by a subsequent dose of 250 milligrams two weeks later and then 250 milligrams monthly.

Breast Cancer Update 2006 (6)

DR C KENT OSBORNE: I have utilized a loading dose of fulvestrant with some patients — the issue is how fast you need to reach therapeutic levels. I may take that approach with a patient who has more aggressive disease and the therapeutic levels need to be reached faster. However, for a patient with bone-only indolent disease, I’d probably utilize the once-a-month schedule.

TAnDEM: Trastuzumab/Anastrozole

DR CARLSON: The TAnDEM trial was a prospective, randomized trial evaluating anastrozole alone versus anastrozole with trastuzumab in women with ER-positive, HER2-overexpressing metastatic breast cancer. Patients receiving the combination of anastrozole and trastuzumab had a higher rate of response and a longer time to progression, with no difference in overall survival at the current analysis.

The results are reminiscent of the single-agent versus combination chemotherapy studies that have been reported. The combination chemotherapy generally shows higher rates of response, longer times to progression, no differences or very small differences in overall survival and greater toxicity.

With the aromatase inhibitors and trastuzumab, the toxicity is modest. So differences in toxicity are much less of a concern than with the cytotoxic agents. I believe that without a survival difference or randomized trials evaluating sequential hormonal therapy followed by trastuzumab or trastuzumab followed by hormonal therapy versus the combination, it’s hard to be dogmatic in terms of which strategy is preferable.

In a woman like this, who’s moderately symptomatic, I believe obtaining a good response with confidence is important. This is a woman for whom I would typically use an aromatase inhibitor in combination with trastuzumab. I do that because the added toxicity for most women is usually minimal.

If the patient is asymptomatic, then the rationale is much less compelling for using combination therapy. In that situation, I would typically start with a hormonal agent alone and hold the trastuzumab for use down the road, most likely in combination with cytotoxic therapy.

I would tend to delay chemotherapy. The studies with trastuzumab, which show a survival benefit, have included primarily hormone-responsive disease only after the application of hormonal therapy. Women with ER-positive or PR-positive breast cancer who had not received hormonal therapy were excluded from most of those studies.

So the survival advantage was evident despite the fact that the women with hormone-responsive disease had initially been treated with, presumably, a sequence of single-agent hormones. I would not use chemotherapy early on, especially for the asymptomatic woman with a hormone-responsive tumor.

In this context, the more difficult issue is whether the use of single-agent trastuzumab would be reasonable without endocrine therapy. For such a woman, I would typically use endocrine therapy first, but Chuck Vogel and Melody Cobleigh have presented data evaluating single-agent trastuzumab that include rates of response that are not too bad and, again, are associated with minimal toxicity.

Breast Cancer Update — Think Tank Issue 1, 2007

DR MACKEY: The TAnDEM data didn’t change my approach for the average woman who comes in at age 60 with visceral metastases, particularly since we performed an unplanned subgroup analysis of the women with liver metastases and they did not appear to benefit from the addition of trastuzumab to anastrozole in terms of overall survival.

It was the women without liver metastases who might have had a survival advantage associated with the addition of trastuzumab. If she were not willing to go through chemotherapy, I would talk to her about the TAnDEM trial and trastuzumab with an aromatase inhibitor.

DR DICKLER: In the TAnDEM trial, the median progression-free survival went from 2.4 to 4.8 months with the addition of trastuzumab to anastrozole. Some patients derive most of that benefit, and others don’t derive any.

Without being able to select those patients, I will probably use the combination of trastuzumab and an aromatase inhibitor up front because some people will derive a great benefit. Until I know who those patients are and I can select them when I’m starting therapy, I will administer the combination initially.

I also feel that using hormonal therapy is important. I’ve had patients in my practice with metastatic disease for eight to 10 years. It’s important to be able to delay the onset of chemotherapy because it has a big impact on quality of life.

Breast Cancer Update 2007 (2)

DR SEIDMAN: The important question is, if you use the combination of an aromatase inhibitor and trastuzumab early on for a patient with hormone-sensitive, metastatic breast cancer, what will be the implication of having already played your trastuzumab card when that patient ultimately develops hormone-refractory disease? We know that adding trastuzumab to chemotherapy, either paclitaxel or docetaxel, provides a survival advantage, so I’m not ready to change my practice based on the TAnDEM data.

Having said that, there are patients who come to me who are on antiestrogen therapy and trastuzumab, but usually their clinical story has some strange, unique aspect that makes me feel it’s an appropriate thing to do.

One example in which applying the TAnDEM data would make sense would be for the occasional patient who’s received adjuvant tamoxifen but not an aromatase inhibitor and then develops metastatic disease and is treated with chemotherapy and trastuzumab. Most of us are in the habit of stopping the chemotherapy at a certain point and just continuing trastuzumab, but in this case the patient has not received an aromatase inhibitor.

For me it would be a “no-brainer” at that point to use the chemotherapy and trastuzumab to maximum response, or to the point at which toxicity begins to accumulate, and then discontinue the chemotherapy and add the aromatase inhibitor.

Also, there are those patients who present with metastatic disease who have never received adjuvant therapy, yet you feel you should first treat them with chemotherapy and trastuzumab, even if they have ER-positive disease. This would be another example in which, perhaps, after administering the chemotherapy and trastuzumab, you should put the chemotherapy aside and use the aromatase inhibitor out back instead of up front.

Breast Cancer Update 2007 (4)

DR EDITH A PEREZ: The data with nab paclitaxel versus once every three-week paclitaxel justify the FDA approval. Data from the randomized Phase II trial, which evaluated nab paclitaxel or docetaxel once every three weeks, are tantalizing. I’m happy that there will be a formal, randomized Phase III trial of nab paclitaxel weekly versus docetaxel once every three weeks.

The study comparing nab paclitaxel to docetaxel was a 300-patient, randomized Phase II study with four arms. In three of the arms, the patients received nab paclitaxel, and the fourth group received docetaxel. The three nab paclitaxel arms received 300 mg/m² once every three weeks or one of two weekly regimens — either 100 or 150 mg/m² three weeks out of four. The docetaxel arm received 100 mg/m² of docetaxel once every three weeks.

The response data were fascinating: 33 percent for the once every three-week nab paclitaxel and 36 percent for the once every three-week docetaxel, which is what I would expect from a single-agent taxane in the first-line treatment of metastatic disease.

However, the responses for the two weekly nab paclitaxel arms were about 58 and 62 percent — beautiful response rates for these weekly regimens. That’s why investigators will use 100 mg/m² weekly as the appropriate comparator against docetaxel for the Phase III study.

This randomized Phase II study was telling, not only because of the response rate — the progression-free survival rates are still premature, although the numbers are starting to look interesting — but also because the tolerability was good for the weekly nab paclitaxel, 100 mg/m² three weeks out of four.

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