INTERVIEW WITH DR. ROBERT LIVINGSTON

DR. LOVE: What other trials are out there in the adjuvant setting, looking at these two questions that you're talking about?

DR. LIVINGSTON: There are no other trials. This would be the first trial, actually, to address either of these questions in the adjuvant setting. That is, continuous chemotherapy versus intermittent with the AC regimen or any other, and the combination of a taxane with Xeloda versus taxane alone.

DR. LOVE: I thought that U.S. Oncology was going to be doing an adjuvant study?

DR. LIVINGSTON: Yes. They have proposed a trial. And I'm sorry. My answer to your question was in the context of ongoing studies. I don't know the exact nature of their trial, and that hasn't really been divulged to me. But I do know that both U.S. Oncology and the NSABP intend to have trials in which one arm would involve the combination of Taxotere and Xeloda. I think that's actually a good thing rather than a bad one, because at least that will be a more or less common arm, depending on the doses that are chosen for the three different randomized studies.

DR. LOVE: Getting back to the adjuvant trial that you mentioned, what are you going to specify in terms of the ER-positive patient?

DR. LIVINGSTON: The ER-positive patient will not be included in this trial. This trial will be for estrogen receptor-negative patients only.

DR. LOVE: That's interesting. In your own practice in a non-protocol setting when you have a node-positive, ER-positive patient, are you using taxanes?

DR. LIVINGSTON: No, we're not. In fact, our own practice we don't use Adriamycin in the patient, either. We're still giving CMF if the patient has ER-positive disease, has fewer than four positive nodes, and does not have HER2/neu overexpression. Because, we're not impressed that anyone has been able to show that for those "garden-variety" patients, anthracycline-based therapies are any better.

DR. LOVE: So, you're giving CMF and tamoxifen, presumably?

DR. LIVINGSTON: We're giving CMF followed by tam.

DR. LOVE: Interesting. And then, in the HER2-positive patient?

DR. LIVINGSTON: In the HER2-positive patient, we've been routinely using anthracycline-based therapy and we've been routinely using taxane-based consolidation.

DR. LOVE: In ER-positive?

DR. LIVINGSTON: In ER-positive or ER-negative patients, if they are HER2-positive.

DR. LOVE: That's interesting. So, if they're HER2-positive and ER-positive, you are giving a taxane.

DR. LIVINGSTON: We're treating them the same way we treat the ER-negative patient.

DR. LOVE: Why?

DR. LIVINGSTON: Well, as you know, there are data to show that in HER2/neu-positive disease, there is a reasonable response rate to taxanes. It's probably the same as the response rate in HER2/neu-negative disease that has become anthracycline-refractory.

DR. LOVE: I guess what I was wondering about is, do we know from the Intergroup ACT study, the issue of ER-positive, HER2-positive patients? Because I don't remember seeing that.

DR. LIVINGSTON: We do not have data that I know about from any completed randomized trial that speaks to the value of a taxane in HER2-positive patients. The CLGB study run as an Intergroup that we've referred to already seems to show an advantage in retrospective analysis for ER-negatives and not for ER-positives, has, to my knowledge, never been presented with respect to HER2/neu. So, there is no data. They must have some data. They clearly had data in their previous study, of course, but that data has never been made available and, as you know, there's no published manuscript.

DR. LOVE: Why is it that you are approaching the ER-positive, node-positive patient differently, based on HER2 status?

DR. LIVINGSTON: Because we think that HER2 overexpression confers a much greater probability of resistance, even to an anthracycline-based combination, and certainly confers a greater probability of resistance to hormonal therapies as we have used them, namely tamoxifen.

DR. LOVE: What are some of the other trials that you're involved with or that you see out there that you think are interesting or asking new and different questions?

DR. LIVINGSTON: Well, our group for a long time has been very interested in anti-tubulin combinations. And by that, I mean primarily taxanes and vincas. Since the most useful vinca to treat breast cancer is by far Navelbine, or vinorelbine, our trials have all involved that drug. We've done a series of studies using a dose-dense and dose-intense approach to the administration of Navelbine, first alone and then in conjunction with taxanes, and always in the setting of anthracycline-refractory Stage IV breast cancer.

The first of those trials with me as the first author in JCO involved Navelbine alone combined with GCSF, and this actually was fourth-line chemotherapy. All these patients had previous anthracycline and previous taxane exposure. We saw a 25 percent response rate in that trial, and we had a median survival of eight months. We thought both of those were encouraging in the setting of fourth-line chemotherapy. So, we went from that to a study that's been published with Dr. Ellis from my group as the first author, also in JCO, where we looked at a four-day infusion of Taxol followed on days 8 and 15 by Navelbine, followed at the third week by the Taxol again. So, it was weekly treatment, but the taxane was given at the beginning of the first week. The Navelbine was given on the second and third weeks. In that study, the patients were all anthracycline-refractory, but some had not received a previous taxane. The overall response rate in that trial was 60 percent, and we had a 23-percent complete response rate, something we've never seen before in a salvage setting.

We then went on from that to a trial with Taxotere and Navelbine, where Taxotere is given on day one at 60 milligrams per square meter, and the Navelbine is given at 27.5 milligrams per square meter on days 8 and 15. The cycle is repeated every three weeks. Julie Gralow in my group has presented this at ASCO. A manuscript is being submitted. And that has actually gone forward as a group-wide study in the Southwest Oncology Group. That study in our institution was also a salvage protocol. It was done for patients with anthracycline-refractory disease. We again had a high response rate, about 60 percent, and in that study we had a 27-percent complete response rate. The median survival in that study is quite remarkable. It's actually in the range of 16 months.

So, we've been encouraged by those results to take the Taxotere-Navelbine combination in conjunction with GCSF support into the cooperative group setting as front-line treatment. We're giving it now as front-line treatment in the setting of Stage IV disease. Obviously, if the study confirms or almost confirms our results from the pilot, we would then be encouraged to take that anti-tubulin combination into the adjuvant setting.

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