INTERVIEW WITH DR. ROBERT LIVINGSTON

DR. LOVE: I'm curious about how all these research advances that we've talked about have affected the way you actually take care of patients in a non-protocol setting. And I'm curious about the algorithm and the thought process you go through when you see a woman presenting with metastatic breast cancer. So, maybe I could dissect that out a little bit with you. Why don't we start out with the ER-negative, HER2-negative patient with metastatic breast cancer. How do you sort that through in terms of your decisions?

DR. LIVINGSTON: Well, if the patient's estrogen receptor-negative, it's my belief that that patient, in the metastatic setting as well as the adjuvant setting, should be offered anthracycline-based therapy, if she's not already had it in the adjuvant setting with relatively recent relapse. That is, relapse within a year of receiving the anthracycline. That's based on observations that actually go back 20 years, that there is an advantage for the use of anthracycline-based combinations in ER-negative disease. These correlations were made before we knew about HER2/neu. So, I can't show you absolutely irrefutable data that ER-negative, HER2-negative patients do better with an anthracycline-based regimen. But I would be very hesitant to give them a non-anthracycline-based regimen.

DR. LOVE: What would be a typical regimen that you would give them?

DR. LIVINGSTON: Well, as I say, in our place, we're looking at an anti-tubulin combination, and we're doing that in an institutional study, as well as doing it in the SWOG. Outside the context of SWOG, I think that a reasonable first-line treatment for these folks would be a combination of Adriamycin and Taxotere. I think one could argue for the combination of Taxotere and Xeloda, but it hasn't yet been studied, as you know, in the first-line metastatic disease setting.

DR. LOVE: So, you generally start out with combination therapy?

DR. LIVINGSTON: We generally start out with combination therapy, unless there's some reason due to the patient's condition, not to employ a combination.

DR. LOVE: And if the patient's had a prior anthracycline?

DR. LIVINGSTON: If the patient's had prior anthracycline, again, at our place, we still tend to use the anti-tubulin combination. If the patient's had a prior anthracycline in the outside world or if, for some reason, that patient is not eligible for our anti-tubulin combination, today we would recommend and use the combination of the Xeloda and Taxotere.

DR. LOVE: What about for the patient who has had prior adjuvant ACT and relapsed recently?

DR. LIVINGSTON: Right. Well, again, that patient who's had ACT and relapsed recently has not had exposure to Navelbine. So, we would tend to use Navelbine as part of the treatment. And what we tend to do right now in an off-study situation - although I hope we're going to get a study going pretty soon - is we tend to combine the Navelbine with weekly administration of a taxane. As you know, there's reasonably good evidence that weekly administration of either Taxol or Taxotere after q three week administration, will recapture responses. In other words, if metastatic disease, somewhere in the range of 20 to 30 percent of patients will achieve a useful objective response when they have had previous exposure to that taxane once every three weeks. So, our rationale is, we can take Navelbine, give it at almost full dose, and combine it, for example, with Taxol, which has very little myelosuppression on a weekly schedule, and get both drugs in at reasonably close to a full dose.

DR. LOVE: Why would you choose that regimen, or Navelbine alone, compared to capecitabine?

DR. LIVINGSTON: Basically, I think it has to do with our research interest in Navelbine and the fact that we're pursuing anti-tubulins. I think there are patients who would be better candidates for single-agent Xeloda and that you have to individualize what you're going to do with the patient based on what you see in that individual. If I was very worried about myelosuppression, or if the patient already had neurotoxicity, that would push me in the direction of single-agent Xeloda.

DR. LOVE: It's really interesting, talking to different research leaders and physicians in community practice, to hear how they respond or what their typical algorithms are. I'm sure you see a lot of second opinions, you do lectures to the community?

DR. LIVINGSTON: Oh, yeah.

DR. LOVE: You probably are exposed to a wide breadth of how people practice. How do you characterize your own approach compared to others?

DR. LIVINGSTON: Well, I guess that I have to begin by saying that I think a very well informed and rational medical oncologist can make a good case for any of several algorithms. There aren't one or even two algorithms for the management of a typical case that has overwhelming evidence to support it in the context of newly-diagnosed metastatic disease. I think that my own personal approach is colored by the things that have driven our research directions. Those have been primarily two notions. One of them is the notion of continuous drug exposure and the other is the attempt to determine whether combined anti-tubulin therapies are better. So, the answers that I give to you about hypothetical cases are related to what I've been immersed in, in terms of clinical research.
Having said that though, I think I do have empirical evidence right now based on Phase II studies that continuous chemotherapy with the AC regimen may be better. And I think we have reasonable evidence based on a Phase II series of pilots, that combined anti-tubulins may be better. One could obviously take either of those regimens and potentially add a drug like Xeloda. I think you'd run into problems with the continuous AC, for the same reason we ran into the problem with 5FU, because of the hand-foot situation. But you might be able to combine Xeloda very easily with a regimen where you use a taxane and Navelbine. Neither taxanes nor Navelbine are likely to produce hand-foot. Weekly taxane is not likely to produce myelosuppression and neither is Xeloda.

DR. LOVE: I think there are quite a few people who I've talked to, whose approach to chemotherapy with metastatic breast cancer is something like the following: We're dealing with a situation where we can't eradicate the disease. We're in a palliative mode.

DR. LIVINGSTON: Mm-hmm.

DR. LOVE: And that there's maybe not as - perhaps there's not very much evidence that treating aggressively or using combinations, for example, as opposed to the sequential single agent is going to change the long-term outcome. And so that type of thinking leads to an algorithm of sequential agents with a lot of focus on which ones would be least toxic. It sounds like your approach is a little bit different. I'm curious why?

DR. LIVINGSTON: Well, I think you have to see what the patient practice that someone deals with is like. The median age of the patients I see is the early forties. These are patients, generally, who come to us because they want something aggressive done. They have small children. They have a lot of people who are relying on them. Obviously, I have some patients who are 75 years old and who have bone-dominant disease and they've relapsed on a hormone, that I'm not going to give one of these combinations. Okay? But I probably have a much smaller proportion of those women than a person who's out in community practice. In other words, my practice represents a funnel. I'm getting a lot of young women who've got visceral-dominant disease, have failed some kind of initial treatment, and want to be part of an aggressive approach. I think if my practice was largely composed of postmenopausal women, many of whom have a single site of disease like chest wall recurrence or bone-dominant, I would choose - and, in fact, do use - the sequential single-agent approach.

DR. LOVE: Just to draw out that line of thinking a little bit more, because, again, that type of person who would have presented the approach I just described to you, would say, "Well, you have a 41-year-old woman. You still have a situation that's not curable." Even though the patient may be asking for aggressive therapy, we're really doing her a disservice by giving it to her.

DR. LIVINGSTON: Well, I disagree with that. But I can't prove that that point of view is wrong. I guess the main reason that I disagree is based on two things. One of them has to do with the quality of life and the other has to do with the quality of response. I think, in general, if you have a young and relatively healthy patient and you can achieve an objective response without major toxicity, that individual's quality of life is likely to improve. And I think you're more likely to achieve an objective response with a combination, than you are with a single agent.
The second thing has to do with complete response. I mentioned the complete response rate that we have seen on these anti-tubulin combinations as something of interest. I think it's something of interest because we know that complete remission in metastatic breast cancer can be associated with very long survival. The best series on this is out of M.D. Anderson Hospital and was published several years ago. Basically what they did was to look at hundreds of patients who had received some variation on FAC as chemotherapy for Stage IV disease. They looked at a subgroup of patients who had achieved a complete remission, and that subgroup was something like 12 to 15 percent of the total. Well, the five-year disease-free survival of those patients was 19 percent. Almost a fifth of those patients actually had remissions going on for long enough that you'd be wondering if that patient was cured. The median duration of the remission was about 30 months. Well, this is obviously much longer than we typically see with a salvage hormone or a salvage single agent. So, it's my bias that, if one has the potential of achieving, and especially if one has the potential of achieving a complete response, it's worthwhile to give more aggressive treatment.

DR. LOVE: That's interesting. Sometimes I kind of go back and forth. And that argument that you just made is one that Dan Budman actually brought up to me. Very interesting. He was talking about the Xeloda-Taxotere study. And apparently they did some quality-of-life measurements, and his point was that if you can manage the toxicity, exactly as you say, the key issue in terms of quality of life becomes control of the tumor.

DR. LIVINGSTON: Exactly. Yeah. I think that's really the most important distinction. If your regimen is so toxic that it makes everybody sick - if for example, they had insisted on continuing to give everybody 75 per meter of Taxotere and 2.5 grams per square meter Xeloda, well, of course, that's unacceptable. But if you start with a regimen that's acceptable or you're ready to move very quickly to an acceptable dose, then, in general, people who've got metastatic breast cancer will have a quality of life improvement. Because most people have symptoms from their cancer and if they don't have them now, they're going to have them in three-six months.

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