(Case #1, continued) The lesion is excised and found to be 0.8 cm. An axillary dissection is negative. Generally, what systemic therapy would be appropriate for this woman?

Commentary by Drs Morrow and Davidson

Dr Love: So, most of the audience would recommend tamoxifen alone, probably because of the tumor size. And there is not too much interest in chemotherapy.

Select, Recent Publications

Let's review two clinical trials that would be relevant to a patient in this situation; one that has recently started (NSABP B-34) and another that's being discussed (NSABP B-35). NSABP B-34 is a very interesting trial based on the concept that increased bone resorption and loss may lead to the growth of bone metastasis. The NSABP, in the background of the protocol, noted that in seven of their previous adjuvant trials, half of first recurrences were only in bone, and that, of patients who eventually develop metastases, 70 percent had bone metastases at some point, and of course, we all know that bone metastases are a major problem in breast cancer.

Select, Recent Publications

Dr Love: Bisphosphonates have an anti-osteolytic effects and reduce the rate of fractures and hypercalcemia in patients with metastases. There have already been three reported randomized trials looking at bisphosphonates in the adjuvant setting. Dr Diel, a speaker at this meeting, reported one study showing not only fewer bone mets, but also fewer non-bone mets and improved survival. Dr Powles' study reported fewer bone mets only during the clodronate treatment period. And finally, a third study by Saarto showed no effect on metastasis, and actually decreased survival. This last study was small, and the lack of effect is possibly related to statistical power.

Clodronate is an oral second-generation bisphosphonate that is generally very well tolerated, other than occasional GI disturbances. The objectives of NSABP B-34 is to evaluate whether or not clodronate improves disease-free survival. Secondary aims are to evaluate whether the agent reduces the incidence of skeletal and nonskeletal mets, improves overall survival, recurrence-free survival, and reduces the incidence of skeletal morbidity.

The trial allows women to receive other systemic therapy at the discretion of the investigator. So, for those of you who answered the previous question that you would give a patient like this tamoxifen, you could do so and then randomize her to also receive clodronate or placebo. Interestingly, the patients continue the clodronate or placebo treatment until they develop the first bone metastasis. If they develop a non-bone recurrence, they continue treatment.

Let's go to the next interactive question. Based on the information that I've presented, how you would feel about randomizing a woman like this to the NSABP study?

How would you feel about offering this patient participation in the NSABP B-34 (adjuvant clodronate vs placebo study)?

Commentary by Drs Morrow and Davidson

Dr Love: Dr Vogel can you share your thoughts about how you would feel about putting a patient like this on this study?

Dr Vogel: This study offers a number of attractive features. First of all, it allows some choice for the oncologist, which is very important. We all have some different thoughts about what the optimal management is of sub-centimeter tumors in the older postmenopausal population. On one hand, this lady — at age 67 — can probably expect 14 to 18 years of additional life. Interventions that are minimally noxious but highly effective are very prudent. What I like about B-34 is that for those of my colleagues who feel that this patient should receive tamoxifen, they can do that. For those who believe that she should not receive tamoxifen, they can do that. Clodronate is a relatively innocuous agent, and the biology behind the use of bisphosphonates in this study is very good. I would encourage such a patient to consider this trial.

Dr Margolese: In keeping with the theme of exploring how the panel and the audience think about clinical trials, I want to point out that in the previous question there was almost unanimity that everyone would treat with tamoxifen. Here, as in the earlier questions on the ongoing trials, we see a phenomenon — when trials have been completed, reported and the evidence is clear, the audience is close to unanimous in saying, "Okay, I'm going to do that." When the trial is ongoing, and people want this information, they're not unanimous in saying, "Let's work together to find it." So, we're learning something about ourselves as therapists.

When B-06 — the lumpectomy trial — was accruing much slower than its predecessor, the mastectomy trial, I wrote an article about clinical trial accrual . We sent out questionnaires asking surgeons why they accrued so rapidly for the first trial, and very slowly for the randomized lumpectomy trial. One of the things we found in their comments on that questionnaires was that people tended to believe that they were either therapists or investigators. We are seeing exactly the same thing here. People will wait for the results and be anxious to use them, but may not participate in the trials. As a group, we should be more willing to speed up the process of obtaining the results.

Dr Love: Getting into this idea of the treaters versus non-treaters, let me follow up on Richard's point here with a quick yes or no interactive question. Based on the information I presented to you and what you may have heard about bisphosphonates, I'd like to know whether or not you would consider or suggest using this drug off protocol if it were available?

If clodronate were available in the U.S., would you be inclined to use it as adjuvant therapy outside a protocol setting?

Commentary by Nancy Davidson, MD

Dr Love: It is very interesting that 42 percent of the audience say that they would use this drug off protocol.

Professor Baum: Richard Margolese and I share the same mindset, and throughout our parallel careers, we have agreed with each other — until this point. I think he's been perhaps a little less than generous to the audience here. This interaction is brilliant! This is research into medical education, and I think it's phenomenal! If this audience represents a cross-section of therapists, then the fact that half of them would enter one of these trials is brilliant. And it's probably far better than in the United Kingdom. I suspect that those not willing to enter trials may be non-trialists or may have legitimate reasons for being unhappy about that particular trial. So, perhaps contrary to Richard, I am encouraged rather than discouraged by the responses.

Dr Margolese: I think we're still really in agreement, because I do share that point of view. What I'm really saying is that although the NSABP is comprised of some large academic institutions, it is really made up of many small institutions. The bulk of our patient accrual comes from private practitioners and CCOPs. This shows that you can do high-quality science if you organize through this kind of mechanism. There are very few people in a place like North America who can't participate in clinical trials if they want to.

Dr Love: Let's move on to talk about the other proposed trial that the NSABP is currently discussing, and hopefully we can provide some input to the NSABP about how you would feel about a patient on a trial that they're now actively considering. This trial would focus on node-negative, receptor-positive women comparing the standard that most of you said you would use, tamoxifen, to a newer agent not yet on the market, Faslodex® (fulvestrant), which has a unique mechanism of action and recently has had some very encouraging trial data.

Faslodex has a chemical structure very similar to that of estradiol with the addition of a side chain; however, it has a very different effect. It's a pure estrogen antagonist with strong binding affinity to the estrogen receptor, similar to estradiol, and 100 times greater than tamoxifen. It impairs ER dimerization, blocks AF-1 and 2 activation, and it's being termed an "estrogen receptor downregulator," because the receptor levels actually decrease in the breast cancer cells.

The agent is administered by monthly intramuscular injections, which seems to be very well-tolerated. In contrast to the SERMs, it inhibits the uterotrophic effects of estradiol and tamoxifen. It is not thought to cross the blood-brain barrier, and it is hoped that it will not cause hot flashes like other antiestrogens. It is also effective in tamoxifen-resistant patients.

Dr Love: At the 2000 San Antonio meeting, two trials (20 and 21) were reported comparing Faslodex to what at this point is the gold standard in hormonal therapy - an aromatase inhibitor, in this case Arimidex® (anastrozole). These trials were large randomized studies in patients with metastases who had progressed on tamoxifen. The two randomization arms — Faslodex and Arimidex — had similar outcomes and similar low rates of thrombosis and hot flashes. The North American trial (21) showed a significantly greater duration of response for Faslodex, which had been predicted from laboratory research.

There is also a preoperative study that was recently launched by the EORTC, looking at neoadjuvant Faslodex versus placebo in women with early breast cancer.

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