INTERVIEW WITH DR. ROBERT LIVINGSTON

DR. LOVE: What actually is metronomic chemotherapy and what's the history of it?

DR. LIVINGSTON: The definition that I understand of metronomic chemotherapy is based largely on pre-clinical studies. I think a lot of these have only been presented. They've not yet been published. But basically, those studies demonstrated that, if you had continuous exposure, in particular to either cyclophosphamide or vinblastine, you could demonstrate a greater degree of anti-angiogenic activity and also a greater degree of anti-tumor activity, than if you gave the agents in the classic intermittent fashion.

DR. LOVE: So, the initial randomization is between this regimen. Does it have a name?

DR. LIVINGSTON: We call it continuous AC.

DR. LOVE: Okay.

DR. LIVINGSTON: AC plus G.

DR. LOVE: Okay. Versus?

DR. LIVINGSTON: Versus standard AC.

DR. LOVE: Four cycles?

DR. LIVINGSTON: Six.

DR. LOVE: Six cycles.

DR. LIVINGSTON: As you know, there's a growing opinion, at least in this country, that four cycles of AC is probably an inadequate duration of treatment. It was the opinion of the other Intergroup chairs, as well as myself, that we ought to give the same duration of treatment in both arms. So, the patients will receive six cycles at 60 milligrams per square meter per cycle. They will receive a total dose of 360 milligrams per square meter, which is still below the generally accepted safe limit. The time it will take to give that treatment and recover from it is 18 weeks. It'll be given once every three weeks. Our regimen will be given also for 18 weeks.

DR. LOVE: So, you're cutting back on the duration.

DR. LIVINGSTON: We're going to cut back so that the total amount of Adriamycin given in the randomized trial will be 360 milligrams per square meter in both arms, including our arm, as opposed to the 480 milligrams per square meter that we gave in the earlier trial.

DR. LOVE: And then there's a second randomization?

DR. LIVINGSTON: Then there's a second randomization that's based on the Phase III randomized trial that was done by Joyce O'Shaughnessy and her colleagues for the U.S. Oncology group. It was actually updated at this meeting, comparing Taxotere at 100 milligrams per square meter to the combination of Taxotere at a lower dose and Xeloda in patients with anthracycline-refractory Stage IV disease, so a different target population.

What that trial showed and continues to show is a statistically significant higher response rate for the combination. But more importantly, the trial showed a statistically significant longer time to progression and a statistically significant improvement in survival for patients receiving the two-drug combination as opposed to Taxotere alone.

Now, this is a very unusual finding in metastatic disease. In fact, the only other Stage IV trial that I can bring immediately to mind, that shows that kind of an advantage for a form of chemotherapy, is the combination of Taxol and Herceptin versus Taxol alone in HER2/neu positive patients. It would seem very logical that, if you have a drug combination that shows a survival advantage in Stage IV disease, it ought to show the same advantage in spades when you're talking about the adjuvant setting, where you have a lower tumor burden. Nevertheless, it needs to be proven. We can't just accept it at face value in the adjuvant setting. So, the purpose of the second randomization is, in fact, to determine whether the combination of Taxotere and Xeloda does give us a superior result to the use of Taxotere alone.

DR. LOVE: Some have criticized that study in terms of the interpretation of survival, because not that many women crossed over from Taxotere to capecitabine. Any thoughts on that?

DR. LIVINGSTON: Well, I think that all you can say is that we don't know absolutely that doing an initial design of Taxotere alone followed by capecitabine would not be as effective as giving them together up front. But we know that, in certain other settings, even when a crossover design is built in, there turns out to be superior survival. For example, take the Taxol-Herceptin versus Taxol alone trial. There was a built-in crossover in the trial, and the majority of patients, did cross over. Yet, ultimately, there was a survival advantage that was statistically significant for the combination.

DR. LOVE: Are you actually using that combination of Xeloda and Taxotere in your practice?

DR. LIVINGSTON: Yes. We're using it in our practice. We are using it primarily in patients who have had previous anthracycline treatment and are not candidates for one of our own investigational studies.

DR. LOVE: In what situations are you using that as opposed to single agent?

DR. LIVINGSTON: If the patient has not had previous exposure to either a fluorinated pyrimidine or a taxane, but has had previous exposure to an anthracycline, that would be the regimen that we would offer outside the context of a clinical trial.

DR. LOVE: So, you tend to do that rather than give single-agent therapy?

DR. LIVINGSTON: Yes.

DR. LOVE: What's your experience been in terms of how it's tolerated?

DR. LIVINGSTON: Well, one definitely has to start at a lower dose than initially prescribed in the randomized Phase III trial. And actually, the design of the study that I described to you - the Phase III Intergroup study that's going to go forward in the adjuvant setting - has taken advantage of the toxicity data that was obtained from that earlier Phase III trial. Joyce O'Shaughnessy and the people at Roche in the Statistical Department made the data available to us about tolerance over time to the doses administered. The short version of this is that when the 25 percent dose reduction that was necessary in most patients for both Taxotere and Xeloda was employed, most of the patients were then able to tolerate that combination at that dose for the remainder of their treatment. So, what we've done, essentially, is to take that 25 percent dose reduction as our initial dose for the adjuvant trial, and we're proposing Taxotere at 60 milligrams per square meter and Xeloda at a total daily dose of 1,875 milligrams per square meter in that trial.

DR. LOVE: And what's the other arm?

DR. LIVINGSTON: The other arm is Taxotere alone at 100 milligrams per square meter. And we get four cycles of Taxotere, and when we get four cycles of Taxotere in the combination of Taxotere and Xeloda, so the total duration of either of those arms will be 12 weeks.

DR. LOVE: It's interesting that you're starting at 100 because that XT trial also showed that they needed to reduce the dose of Taxotere. I think it was about an average of 80 milligrams.

DR. LIVINGSTON: Yes. You must realize that this protocol hasn't yet been written. What I can tell you is that it's been approved unanimously in concept by the cooperative group chairs and by NCI. It's possible that we might decide to go with a lower dose of Taxotere. But I think if we accept that 100 milligrams per square meter is still the dose recommended by Aventis and the one that is FDA-approved, and if we look at the fact that the advantage of the combination was shown in the context of the comparison to 100 milligrams per square meter, it's probably good science to keep that same comparison.

DR. LOVE: When do you guess that this trial actually will be open?

DR. LIVINGSTON: If we're lucky and things proceed as rapidly as they can, the trial might be open within a year.

DR. LOVE: Wow. That long.

DR. LIVINGSTON: I suppose it could happen as swiftly as six months. In general, when you're talking about the activation of a study through the Intergroup mechanism, from the time everybody agrees to do it, to having it actually on line, entering patients, tends to be about a year.

DR. LOVE: This is going to happen for sure?

DR. LIVINGSTON: Well, it's as sure as anything I can tell you that's still in the future. But at the Intergroup chairs' meeting on Sunday, just before this meeting, it was re-discussed, re-presented, and there was unanimity to proceed.

DR. LOVE: What total number of patients are you looking for?

DR. LIVINGSTON: I wish I could tell you exactly. I haven't had an opportunity to meet with my own biostatistician for the group to give you a hard answer. When we were talking about a two-arm study, and basically the design of that would have been continuous AC plus G versus AC alone followed by Taxotere in both arms she told me 900 patients per arm. I think it's probably going to continue to be about 900 patients per arm. So, I think we're looking at a total need for about 3,600 patients.

DR. LOVE: One thing that's interesting about this trial is that you said high-risk node-negative patients are going to be eligible, and here we're talking about a taxane. What has your practice been in terms of using adjuvant taxanes off protocol in the adjuvant setting?

DR. LIVINGSTON: If the patients have ER-negative disease, we have tended to use a taxane in consolidation, if they fall into the high-risk category. I think that's probably not different from what many people are doing in community practice. We're going to use the same criteria for high-risk disease that are being used in the current E-1199 study that is ongoing now for patients with node-positive disease as an Intergroup study.

DR. LOVE: When is that study going to be completed?

DR. LIVINGSTON: That study actually will complete its accrual within one to two months.

DR. LOVE: What are the randomization arms in that?

DR. LIVINGSTON: The patients get AC as up-front treatment. They are then randomized to Taxotere or to Taxol and, within Taxotere and Taxol, they're randomized to q three week versus weekly administration.

Previous | Continue

Page 2 of 5

Home · Search