Section 5
Combination Endocrine Therapy

LHRH AGONISTS PLUS TAMOXIFEN

Combination endocrine therapy is a conceptual change for us. We eliminated that approach a couple of decades ago,perhaps because of small, inadequately powered trials that were clearly unable to detect the type of differences we can identify today with larger studies. The reality is that combination endocrine therapy may be more effective than single agent treatment. With better tools now available, we are returning to the concept of complete estrogen blockade — a strategy that started several decades ago with hypophesectomy and adrenalectomy. Studies of chemical ovarian suppression plus tamoxifen suggest greater efficacy than either alone.

—Gabriel Hortobagyi, MD

The combination of an LHRH agonist and tamoxifen would be interesting to study in premenopausal women with large tumors that are strongly ER-positive. We found that Zoladex plus tamoxifen in the neoadjuvant setting produce better and longer-lasting responses than either agent alone or in sequence. So, it ’s something that deserves further exploration. We are also planning to study the mechanism of action of Faslodex ® (fulvestrant) using microarray and also combining it with other agents. The combination of Faslodex and Arimidex looks very interesting because of the different mechanisms of action.

—J Michael Dixon, MD

ARIMIDEX PLUS TAMOXIFEN OF THE ATAC TRIAL: ANTITUMOR EFFECTS

On the basis of emerging data in premenopausal women with chemical ovarian ablation and tamoxifen, one would expect that the combination arm of ATAC would be superior to the other two arms. On the other hand, there is some preclinical data suggesting that the combination of tamoxifen and anastrozole will not be advantageous, so we ’ll have to wait for the data. In terms of the single agent ATAC arms, I am impressed by the data from the large aromatase inhibitor trials in first-line metastatic breast cancer, and on that basis, we have the hypothesis that the same type of comparison in the adjuvant setting will have a similar or magnified outcome.

—Gabriel Hortobagyi, MD

From the data in the metastatic and neoadjuvant setting, it’s quite clear that aromatase inhibitors are superior to tamoxifen. I would expect that superiority to carry through into the adjuvant setting, although it may take some time to observe.The use of aromatase inhibitors in the adjuvant setting is not currently approved, but for high-risk, ER-positive, postmenopausal patients with a previous stroke or DVT, we consider substituting an aromatase inhibitor.

The combination arm of ATAC is more difficult to predict, but the in vivo effects of Arimidex and tamoxifen are very different — they work through different mechanisms — and this is the major background basis to believe that the combination arm might be better.

— J Michael Dixon, MD

ARIMIDEX PLUS TAMOXIFEN ARM OF ATAC TRIAL: BONE, LIPID, ENDOMETRIAL EFFECTS

I expect some impact of Arimidex on the bones, but probably not a major effect. Many of our neoadjuvant patients have taken anastrozole or letrozole for five years, and we have not seen major problems as far as side effects are concerned. One reason that the UK prevention study decided not to have a combination arm is that there ’s not enough information yet on the safety profile of combining Arimidex and tamoxifen. Everybody’s waiting with baited breath to see the results of the ATAC study. In the combination arm, there are competing effects of Arimidex lowering estrogen levels and
tamoxifen’s estrogen-mimicking action on bone and lipids.The hope is that any adverse effects of Arimidex will be countered by the positive effects of tamoxifen. So, from a theoretical point of view, you ’d expect either no effect or perhaps even a positive effect. In terms of the endometrium, theoretically the combination should be no worse than tamoxifen alone. Arimidex causes less vaginal problems than tamoxifen and no leukorrhea.

— J Michael Dixon, MD

The ATAC trial has subprotocols looking at bone,lipids and the endometrium that are appropriately powered to answer those important questions. However, in the first-line trials of aromatase inhibitors, there was no increase in bone-related complications such as compression fractures. I would expect a higher fraction of patients to remain disease-free in the anastrozole arm, and the main question is the combined arm — where you may have greater antitumor activity plus some of the benefits of Tamoxifen, for example, on bone. We don’t have many patients in the metastatic setting exposed to aromatase inhibitors for extended periods of time. If ATAC looks positive, I would have serious reservations about substituting another aromatase inhibitor for long-term adjuvant therapy, particularly because of safety concerns.

— Aman Buzdar, MD

AROMATASE INHIBITORS IN WOMEN MADE MENOPAUSAL BY LHRH AGONISTS

There is one limited metastatic study in ER-positive patients demonstrating that Zoladex plus anastrozole yielded similar responses to what has been seen in postmenopausal patients, but we need to design appropriate trials to address this issue.It is very important to consider that aromatase inhibitors as monotherapy should not be used in premenopausal patients. But it would be a very interesting and logical approach to design trials of complete estrogen blockade in ER-positive premenopausal patients, using an LHRH agonist and anastrozole.

—Aman Buzdar, MD

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