Implications of the ATAC trial for clinical practice

The ATAC trial is very important. It rejuvenates interest in hormonal therapy. Many of us were educated believing that "a hormone is a hormone." In postmenopausal women, it appears that the aromatase inhibitors are superior to tamoxifen. I believe that treatment with an aromatase inhibitor ought to be presented to those patients as an option in the adjuvant setting, and I only utilize anastrozole because that’s the drug for which we have data. I tell patients that it appears that anastrozole may be superior to tamoxifen, but with tamoxifen we have a much longer track record. Then, I describe the differences in the toxicity profiles.

In premenopausal women, there is a rejuvenation of interest in ovarian ablation in combination with tamoxifen. Is ovarian ablation in addition to tamoxifen or in combination with an aromatase inhibitor superior to tamoxifen alone in a premenopausal woman? Right now that is the $64-million question that is being addressed in the Suppression of Ovarian Function Trial (SOFT) and the Tamoxifen and Exemestane Trial (TEXT).

Sequential single-agent versus combination chemotherapy in metastatic disease

The trial recently published by George Sledge, comparing doxorubicin and paclitaxel given sequentially to the combination, is quite interesting. It indicates that, in the long run, sequential single-agent chemotherapy may be just as effective as combination chemotherapy in terms of survival.

This harkens back to studies done in the 1970s. Dr Chlebowski compared sequential single agents to combination chemotherapy. He found that sequential single agents provided an equivalent survival, but seemed to be inferior in patients with liver metastases.

That trial was done at a time when liver metastases referred to patients with bulky liver metastases who had a very poor prognosis; if they did not respond to frontline therapy, they would likely expire from their disease. In the majority of patients, I think single-agent chemotherapy is quite acceptable.

On the other hand, we have the trial comparing docetaxel with or without capecitabine. However, the majority of the patients who received docetaxel did not receive capecitabine as second-line treatment.

In terms of decision-making for metastatic disease, combination chemotherapy is optimal in a patient who needs a response in order to have a good outcome. In patients for whom you have the luxury of waiting to see if there is a response to treatment, then sequential single agents are quite acceptable.

Selecting the order of single-agent chemotherapy

In hormone-refractory disease, patients will be on chemotherapy indefinitely. We have to consider their lifestyle, figure out what’s important to them and be able to accommodate their needs, consistent with good medical practice. Patients must consider the schedule, how frequently they need to come to the clinic and the toxicities of the particular agents.

It’s hard to say that any individual single agent is the gold standard. We have the taxanes and the anthracyclines, but the newer agents, such as capecitabine, are also perfectly reasonable to use as frontline agents. In some patients, I would see no problem in doing that. I’m not sure that the sequence in which you use agents makes a difference; therefore, we tend to use the agent with the least toxicity or the toxicity profile most consistent with the patient’s needs.

Use of fulvestrant in patients with ER-positive metastatic disease

In postmenopausal women, I tend to use fulvestrant following an aromatase inhibitor. That is generally my practice, although we really are lacking data in that situation.

There are some Phase II studies and anecdotal reports; however, I believe that there are Phase III trials that are being launched comparing fulvestrant to a steroidal aromatase inhibitor.

In my mind, aromatase inhibitors are the treatment of choice as frontline therapy, based on the bulk of evidence in the majority of postmenopausal women who have received adjuvant tamoxifen. Fulvestrant is certainly an alternative because it was shown to be at least equivalent to anastrozole. From a practical point of view, I tend to use the oral agents initially and then go to fulvestrant as a second-line treatment.

In my experience, fulvestrant is well tolerated. Many of these patients receive a bisphosphonate on a monthly basis anyway, so it really doesn’t involve an additional trip to the clinic. The injections tend to be well tolerated, and most patients have not complained about hot flashes. I have seen results that are consistent with what I would expect for an active hormonal agent in that patient population.

First-line therapy for patients with HER2-positive metastatic disease

There is a survival advantage with the use of trastuzumab up front in a woman with HER2-positive metastatic disease, and giving an anthracycline may inhibit the ability to receive trastuzumab in the future. I think it’s inexplicable to use an anthracycline as first-line therapy in this situation.

If I were a patient, I would certainly prefer to receive a trastuzumabcontaining regimen. With trastuzumab and chemotherapy as first-line therapy, there is the option of giving the combination for a period of time, then stopping the chemotherapy and maintaining the remission with trastuzumab.

Phase II trial of liposomal doxorubicin and trastuzumab

We currently have a clinical trial looking at liposomal doxorubicin and trastuzumab as frontline therapy. Some preclinical studies suggest that this combination might be synergistic, and liposomal doxorubicin seems to have less cardiac toxicity than the parent anthracycline.

It is very early in the development of this combination. Thus far, we have not seen any cardiac toxicity, and it's quite active. I certainly would not recommend it outside of a clinical trial in which the patient is given appropriate informed consent. In the statistical design, we are looking for either cardiac events or lack of efficacy to stop the trial early. We are looking at efficacy and safety, so that we will get a response rate and some notion of the cardiac toxicity.

Trastuzumab monotherapy

I use trastuzumab monotherapy in some situations; however, I tend to use it in combination with chemotherapy because the combination offers a survival advantage compared to chemotherapy alone. Certainly there are patients who do not wish to take chemotherapy, have disease that might not warrant chemotherapy or in whom a single-agent regimen would certainly be reasonable.

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