INTERVIEW WITH DR DANIEL R BUDMAN

Like most contemporary oncology conferences, one of the unstated themes of the chemotherapy foundation meeting was targeted systemic therapy. Dr Perez commented on trastuzumab in this regard, Dr Carlson described the intriguing effects of fulvestrant, and another presenter, Dr Dan Budman, continued with this theme as it relates to cytotoxic agents, and particularly the oral fluoropyrimidine, capecitabine, and the potential synergy with other agents that upregulate thymidine phosphorylase, which promotes the formation of 5 fluorouracil. Dr Budman began our discussion by noting the potential of new research advances in molecular biology to improve the therapeutic index of cytotoxic therapy.

DR. LOVE: Like most contemporary oncology conferences, one of the unstated themes of the chemotherapy foundation meeting was targeted systemic therapy. Dr Perez commented on trastuzumab in this regard, Dr Carlson described the intriguing effects of fulvestrant, and another presenter, Dr Dan Budman, continued with this theme as it relates to cytotoxic agents, and particularly the oral fluoropyrimidine, capecitabine, and the potential synergy with other agents that upregulate thymidine phosphorylase, which promotes the formation of 5 fluorouracil. Dr Budman began our discussion by noting the potential of new research advances in molecular biology to improve the therapeutic index of cytotoxic therapy.

DR. BUDMAN: The whole methodology is changing so rapidly and, with the whole genome project, where we have a greater understanding of what we're dealing with, all these techniques will be adopted to the clinic to allow us to better treat our patients.
One of the major objections I have to cancer chemotherapy is we're very indiscriminate. We know that the drugs are not particularly good, that there's a small subset that does spectacularly well with whatever disease you have, but there's a lot of toxicity and we haven't been able to adequately distinguish how to treat these patients. And perhaps the physicians who treat lymphomas have the greatest advancement, and that's why I sort of see that as a paradigm to follow. Because it's an easier tissue to work with, they've been able to better analyze what these diseases really are to subset them and to set up treatment plans that are appropriate.

The advantage of targeted therapy is that having a better defined target, you can then design drugs, as we've seen with Gleevec, you've seen with Iressa, and a whole bunch of other drugs, where you have a rational development of knocking out a specific function that you believe, hopefully, that will impact on that tumor. The critical issue, as far as metastatic disease, as far as I see it, is several. One is obviously palliation, which we all want. Secondly would be complete remissions. And one of the frustrating areas is that you will have some patients who are exquisitely sensitive and, with virtually no therapy, will go into a complete remission. And you have other patients who may have very minimal tumor bulk, so you'd say, "Well, these are good-performance patients. They have everything going for them," and nothing works. So that, ideally, again, we need to know what is the difference. At the present time, it's still unknown.

DR. LOVE: Can you talk a little bit about some of the information that you presented yesterday at the meeting?

DR. BUDMAN: Sure. I've worked over several years at trying to look at methods of increasing therapeutic index. Therapeutic index is basically the toxicity to the tumor versus toxicity to the host. Again, I think it's an outcome of my dissatisfaction that we use many toxic regimens for very marginal benefit, and it's very nice to see a P value. But for the actual treating clinician or the patient, a tiny benefit is very frustrating and, indeed, if these were antibiotics, we would be laughing at the use of these drugs, because the benefit is so small, whether it be in the adjuvant setting or trying to prolong life.
One of the areas that we've been particularly interested in is a very intriguing novel, chemically synthesized drug, and that was capecitabine. And the basis of the synthesis actually goes back to the 1980s, when various researchers described a technique called retro metabolic engineering. What this was, was to take an active drug, and then to modify it into a non-toxic drug by one of two mechanisms. Either to modify it into what's called a pro drug, that has to be metabolized into the active drug, or to modify it into what's called a soft drug, which means that the active drug is rapidly broken down by normal tissue, but is not broken down by, let's say, malignant tissue. In both cases, the objective was to keep being a very high concentration of the active drug in the tumor, and hopefully lessening host toxicity, so that one would get increased therapeutic index. And basically, that's what capecitabine is. It's a pro drug which undergoes enzymatic activation and has been shown both in animals and in humans - the doctors in the U.K. studied a whole bunch of colon cancer patients and treated them, then looked at what happened in the tumors versus normal tissue, and you can concentrate fluoropyrimidines three to tenfold, so that you have potential higher efficacy and selectivity by the basis of this very clever engineering of the chemistry.

DR. LOVE: I think maybe in some cases, there might be the misconception that capecitabine is just "oral 5FU."

DR. BUDMAN: Well, I don't think it is. The only way that capecitabine would be oral 5FU is if you ignore the chemistry, where you have the ability to concentrate in a tumor and lessen the host toxicity and give so much of the drug that you have active drug throughout the system. And, indeed, that can happen. If one gives a very high dose of the drug, that you can overwhelm the clever chemistry. But if you look both in the pre-clinical models, especially the pre-clinical models, where you take breast cancer xenograft models and you look at what's happening in the tumor, first, as I mentioned, it's concentrated. Secondly, combined with other drugs, such as taxanes, which up-regulate the regular emitting enzymatic step for the drug, which it thymidine phosphorylase, you can get curative potential, while if you use 5 fluorouracil under the same conditions, you do not. So, this is not 5FU unless you give too much of it. It's sort of like, if you make a person waterlogged, obviously, it has a different effect than if you give a glass of water. There has to be a defined range that you want to use, so that you don't get untoward toxicity. And, indeed, that's what we do in Phase I's. We back off that horrible toxicity and try to go below it and hope that that's the reasonable dose level.

DR. LOVE: Any biological or biochemical explanation for why we see the hand-foot syndrome?

DR. BUDMAN: Well, again, that's dose-related. And it may be, in part, due to polymorphism of DPD, which is the enzyme that degrades 5FU. It's, in part, if one uses capecitabine or uses any fluoropyrimidine as a continuous exposure, you see it. And if you're using high doses of capecitabine, where you're basically saturating the normal host tissue, because you've abrogated everything that the clever chemistry does, then you would be more apt to see it. In my own practice, I see very little of that. That's because I pay attention to the dose. I'm much more careful.

DR. LOVE: How exactly do you approach dosing?

DR. BUDMAN: The dosing is two levels. One is, I think, based upon the retrospective data that we have from Texas, from Joyce O'Shaughnessy, that two grams per meter squared daily, given with food. And that's the way all the studies were done, and perhaps absorption time is important, also - but given with food, was an acceptable dose. And noting, at least in my own practice, that very elderly patients, I would start at 1500 per meter squared. For whatever reason, they're more sensitive. There has been some literature discussion that there may be a difference in DPD levels between females and males, and I deal mainly, obviously, with a breast cancer population, with females, and they may be more sensitive. But with those caveats, I really have had very little problems with this drug.

DR. LOVE: That's interesting. You're the first person I can remember who's talked about giving it with food. Maybe I didn't think to ask people.

DR. BUDMAN: If you look at the initial studies and they were very arbitrary, quite frankly. We were involved in the original Phase I in the United States, which was a continuous exposure, which I still think is probably very attractive for combining with radiation and combining with other agents that one is going to give on a chronic basis. The intermittent schedule with the European schedule that was adopted. But the initial way of giving it, it was unclear, quite frankly. One didn't know, and it was arbitrarily chosen to give it twice a day and to give it with food, so that people would not have stomach upset and would hold it down. That was a very simplistic view, but that's how the studies evolved.
Some pharmacology has been done since that time to show that the area under the curve in the plasma really doesn't change. The only thing that changes when you give it with food is the P concentrations. And perhaps P concentrations are in some way also related to toxicity. That, I don't know.

DR. LOVE: That's interesting. Do you ever use it on a continuous basis?

DR. BUDMAN: No. I haven't used it. I've used it - the FDA approved two weeks on, one week off. The only time we used it on a continuous basis was the initial trial, the Phase I trial. I think it would be very attractive, for example, for rectal cancer or cervical cancer, to give it continuously. I don't treat those patients, so, since I don't give that bimodality treatment, I would have to wait for studies that show that it, indeed, works that way.

DR. LOVE: And what has been the dose when it was looked at in a trial setting for on a continuous basis?

DR. BUDMAN: My knowledge of it is limited, but I know that you can get 875 per meter squared in continuously with radiation, and I'm sure that one can go higher. Meeting with various physicians around the country at various times, they have told me that because of the problems of infusional therapy, they have adopted on an ad hoc basis. There are formal trials evolving. I'd like to see the results of those, so we know that it can be given. It would be nice to see exactly what is the reasonable dose to use.

DR. LOVE: That's interesting that you mention that you don't see very much hand-foot syndrome, and Joyce O'Shaughnessy told me the same thing. In addition to the dosing approach that you talked about, what else do you think is important in terms of minimizing toxicity? And I guess I'm particularly thinking about patient education and follow-up, at least Joyce mentioned that to me.

DR. BUDMAN: Absolutely. When we see these patients, we're very frank. I think that medicine has evolved over the past 10 to 15 years, where patients are much better educated and they have a much better sense of both the potential benefit and the toxicities. We try to sit down with them and go through what is expected with a drug and what to watch out for. Our patients, at least, I think, are very cognizant that, if they have diarrhea or they have redness of the hands or feet, to stop the drug. That has been rare in my experience that one has actually needed to do that with the doses we're talking about. Especially in the elderly population, occasionally you do see that. You don't get into trouble if you're aware of it. You know, I try to emphasize that more is not better. Just because you're having toxicity doesn't mean that you're going to have a response. In fact, some of the patients that I've had best responses have had no symptoms at all. I've had one patient who has been on just single-agent capecitabine for six months, whose husband works for the airlines, and she travels between Europe, Florida and New York. We see her intermittently since, thank God, she's doing well, approximately every two months. She takes the drug and she hasn't had any toxicity. And so, for her, it's been a godsend.

DR. LOVE: Any reason to think that maybe lower doses, even lower than this, you know, 1200 milligrams, for example, would be effective? Has that been looked at?

DR. BUDMAN: No. This is a chronic problem with oncology drugs. There are two ways of looking at it. One would be to look for a surrogate marker, whether it be a serum level threshold that you have to reach or some other surrogate marker, a biologic function, or to just back off the maximum tolerated dose, which we've classically done, and give a dose below that and hope that it's reasonable. Ideally, one would expect with a drug that's rationally derived, such as this, that perhaps we could even go lower and get the same efficacy. Unfortunately, at the present time, we don't have dose-finding studies. So, everybody has their own little empirical experience, but you don't have large numbers to know for sure whether or not there's any compromise. All you know for sure is the retrospective data that 2 grams per meter squared gives you the same result as a more toxic 2.5 grams per meter squared daily. But beyond that, we really don't know the lower limits. I wouldn't be surprised. On the Phase I, we had responses at a gram per meter squared. But, again, it was continuous. I would not be surprised that one would see responses at that level and perhaps much less toxicity. But, it hasn't been done.
One of the criticisms I have of medical oncology is that, for a great degree, pharmacodynamics and pharmacogenetics to this point in time have been neglected. Pharmacodynamics in the sense that one may have threshold levels just the way we see with cardiac drugs, or we see antihypertensives or antiinfectives, that it's most likely the same. And we haven't really done that except for a topicide. There is some data suggesting that there's a certain threshold for a topicide and, beyond that, there's just toxicity. It would be nice to see for other drugs. We haven't done that. It's a major issue, really, of rational drug development.

DR. LOVE: I want to explore with you a little bit more, some of the things that you were talking about in your presentation, but before I do, since you brought up the issue of clinically how you use capecitabine in terms of dosing, I'm curious how you integrated into your clinical algorithm for management of women with metastatic breast cancer. When you look at a woman who has metastatic breast cancer, how do you separate out the chemotherapy algorithm?

DR. BUDMAN: Well, I think it's gotten much more complicated over the last two or three years, than it was before. Before, it was sort of a no-brainer. One would use an anthracycline and an alkylating agent and, when they failed that, you would sort of pick off the shelf whatever you had. I think now, with the realization that with the current modalities, we're not curing these patients. Then you have two issues. One is the quality of life and the other is the duration of response. And most of us have still used an anthracycline for visceral disease. And, ideally, if a person has hormonally responsive disease, do that, and try to withhold, if at all possible, cytotoxics.
But there is evolving evidence, which I presented yesterday, now from a large randomized Phase III trial at 75 centers, over 500 patients, that if you're in anthracycline failure, that you can maintain quality of life and, indeed, increase both disease free and overall survival with using both docetaxel and capecitabine. So, that, I think, now is a standard of care that we have to look at carefully. And perhaps one of the questions to ask is to even move it up further. Now, have I done that? I've done that in an ad hoc manner, where I've taken patients who I did not want to give anthracyclines to, because they had underlying cardiac disease or other co-morbid conditions, and I've used this as a regimen. But I have not done it in a rigorous fashion. I've sort of individualized patients for that.

There is data, which is evolving from Italy, of using a triple, as I mentioned, which was presented at the last ASCO, suggesting that one can use docetaxel, epirubicin, and capecitabine and, in small numbers of patients, had a very high response rate. So, the field, again, is in evolution. But I think the critical issue is quality-of-life issues. If we prolong duration, but we haven't given a reasonable quality of life, we're kidding ourselves. And in many clinical trials, the only end point people have talked about is response rate or duration, and not quality of life. That's why the trial that I presented yesterday was of interest, because one of the major end points was quality of life, which was maintaining - in fact, was higher - with the combination of docetaxel and capecitabine, than it was with full dose docetaxel alone.

DR. LOVE: Can you draw that out a little bit? I guess one of the big issues that everybody brings up about that study is the fact that there wasn't a crossover. Any thoughts on that?

DR. BUDMAN: A crossover for that type of study would be very difficult. The reason is, when you look at the patients, these were patients who had failed anthracyclines either in the adjuvant setting or in the metastatic setting, and, indeed, two-thirds of them had failed it in the metastatic setting. So, this was a tough group of patients. They had all received alkylating agents. Three-quarters of them had already received fluoropyrimidines, so that this was a group of patients that already had failed, to a great degree, 5FU. And then to go back and think about crossover after that, I guess the doctors were reluctant.

DR. LOVE: That was something I hadn't seen before, the fact that so many of them had gotten 5FU. Again, the study basically randomized between docetaxel-capecitabine and docetaxel alone. And you also, I think, presented some sort of updated information, but it kind of looked like we were seeing the same basic phenomenon in terms of response and survival.

DR. BUDMAN: The curves, if anything, were better than when Joyce presented them six months ago. So that, if anything, it shows a greater benefit than it did then. Of the patients, only 17 percent crossed over. And it's difficult to do crossover studies, but the take-home message that I see from the study is that, if you have a higher response rate, a better quality of life, and a longer duration of survival with a combination, you probably can't do as well with any sequential, because you're going to have a higher tumor burden. You're going to have more morbidity. And then, perhaps you prolong life, but, at what cost? There will be a greater cost. So, we know that patients who you can reduce their tumor burden as a group usually have a better performance and a better quality of life. And a higher response rate with a longer survival is obviously an advantage.

DR. LOVE: And, again, when we're talking about crossover, we're talking about the patients who were initially randomized to docetaxel being crossed over to capecitabine.

DR. BUDMAN: To capecitabine.

DR. LOVE: And in terms of quality of life, I guess I hadn't quite picked up on that before. Those are objective measurements?

DR. BUDMAN: Yes. Yes.

DR. LOVE: What was actually seen?

DR. BUDMAN: This was a rigorous quality-of-life measurement that was used before the study and sequentially during the study, and showed that the patients receiving the combination actually had a better quality of life than the patients having single-agent. And that may seem paradoxical, but the way I interpreted it is, if you're having a response and your fungating tumor is gone, where you can get out of bed and you can walk around much more easily and, you know, you can go to work and things like that, obviously, it's a benefit. And knowing that the combination had a better chance of doing that, you have obviously a better chance of getting a higher quality of life.

DR. LOVE: Of course, the other thing that comes in when you look at quality of life is toxicity from the therapy. Can we dissect that out? Was the combination more or less, or about the same toxicity as just Taxotere alone?

DR. BUDMAN: Well, the toxicities were different. The combination arm had a lower dose of docetaxel, so that the neutropenia was less. That was less than half, while it was predominant using docetaxel at 100 per meter squared. If you look at actually what do these patients receive, in both arms it was dose reduction. So that what happened was that, in the doublet arm, the capecitabine was actually dose-reduced to 2 grams per meter squared, which is, as we said previously, is probably the correct dose.
When the trial was set up, it was felt to be mandated at that point in time, that the FDA-approved dose be used. So that if I would extrapolate from this, I would say that the actual delivered dose was 2 grams per meter squared, which we know is much more rational, and if I were to use this type of treatment, I would be using 2 grams per meter squared.

DR. LOVE: And 75 of docetaxel?

DR. BUDMAN: And 75. Now, when one looks at toxicities at the combination arm, we saw two things. One was some neutropenia, which is expected with the docetaxel, and hand-foot syndrome and some diarrhea. And, again, this is expected and happens commonly at 2500, less so at two grams per meter squared, and these patients, obviously, this was the toxicity seen early. They were dose-reduced and they were able to be maintained on study.

DR. LOVE: I guess maybe from a global perspective, having used this combination, do you think that it's more toxic, less toxic or about the same as using docetaxel alone?

DR. BUDMAN: I think that if one's careful, the capecitabine is sort of extra, without much baggage. The toxicities are very manageable. Toxicities, as I mentioned, I think are very much dose-related and, therefore, if one is careful, you won't have a problem. Docetaxel at 100 per meter squared, quite frankly, I think, is too much for anybody, and in that study, they were actually, again, dose-reduced so that the actual delivered was about 80 per meter squared. But I think you can get benefit. Because we know it upregulates thymidine phosphorylase, which is the rate-limiting step for activation of capecitabine in the tumor, that you can see this benefit with very little cost by using the combination.

DR. LOVE: Now, there are a number of agents that have been identified, that up-regulate TP. Where does, sort of, docetaxel fit in? Is it one of the more active in terms of doing that?

DR. BUDMAN: Docetaxel is known to be one of the most active agents seen in breast cancer. The down side is that it has a significant amount of toxicity. What I thought was intriguing and what I showed from the pre-clinical models is that, first of all, alkylating agents upregulate. That, second of all, vinorelbine, which is sort of a drug that is known to have activity in breast cancer, but has really never gone anywhere, but has a lot less toxicity than the taxanes, also up-regulates it. There is potential, therefore, to look at other combinations, such as, potentially, an oral combination of Alkeran with capecitabine, which could be used in elderly patients. We've treated two patients that way in their nineties, who demanded treatment, without much toxicity, and I would love to see a formal trial done by a group. Or to use vinorelbine, which is currently being done at the Dana Farber with capecitabine, in an attempt to try to minimize toxicity. One of the major problems that we see is body image. And women who lose their hair have a loss of body image, which is sort of a loss of control, and it becomes superimposed upon the disease process, an emotional process which, obviously, feeds on it. And if one can work around the hair loss, ideally, that may make these people feel better and function better.

DR. LOVE: You mentioned the fact that the combination showed greater response rate and survival, and you updated, I think, some of those numbers - what do the current numbers look like?

DR. BUDMAN: Well, it's obviously easier to see on a graph, but what we're talking about now is that the differences that one sees between single-agent and the doublet is virtually identical to what was seen with the Saltz regimen for colon cancer. Again, we had what amounts to almost a single agent, as 5FU/leucovorin, compared to a doublet. And you see that the curve is moving about the same amount. Around the country, as you know, except for now some concerns with toxicity, the 5FU/leucovorin regimens have been adopted very rapidly, because it did show significant difference. And you see the same type of significant difference here. The differences become more marked - and, again, unfortunately, it's easier to see with a graph - if one looks back at the old Nabholtz data, which is, I believe, accepted by most people, comparing older combinations of drugs to Taxotere, showing that Taxotere was higher efficacy, and then showing that you can superimpose the control arm - that's the docetaxel arm of this study - and get even more efficacy with the new doublet, which is the capecitabine-docetaxel.

DR. LOVE: That's an interesting approach. It kind of reminds me of the Bernie Fisher sequential, you know, adjuvant, you know, superimposing different trials and, as we move forward, you know, pushing the curves out a little bit.

DR. BUDMAN: Ideally, that's what you will see at some point by these.

DR. LOVE: What about taking this combination into the adjuvant setting? I know there are a couple of trials now. The NSABP is going to be doing a neoadjuvant trial with docetaxel and capecitabine. I think U.S. Oncology is doing an actual adjuvant trial. Do you think that that's a rational next step?

DR. BUDMAN: I think it's a very active combination, so it's reasonable. I also know that the NCI-Bethesda is looking at it in an adjuvant setting, taking patients with locally advanced disease and trying to downstage them using this compound. And then, obviously, biopsying before and afterwards to look at enzymatic levels and everything else. Yes, I think it's reasonable.
We are a member of the Cancer and Leukemia Group B. I sit on the Breast Committee there. And our particular interest with capecitabine actually was to look at using this drug in an elderly population that we wanted to give adjuvant treatment to, where the options of the physician now are either to use CMF or AC or compounds like that, rather toxic for the elderly population. Knowing that capecitabine, at least in more advanced disease, has activity at least equivalent to CMF, and therefore, could potentially offer a minimally toxic of not toxic regimen with benefit in a population of patients that we all are somewhat reticent to treat, although we treat.

DR. LOVE: And that's Hy Muss' study? You know, one of the things I wonder about - I guess there are situations, although I'm not sure how often it's happening, anymore - where people do use CA in younger women. And I guess the question is, if you feel ethically comfortable enough to do it in older women, why not do it in younger women?

DR. BUDMAN: It may at some point advance to that. I think that what we're taking is a group of patients that many physicians have been a little bit hesitant to treat aggressively with chemotherapy, because the benefit, although it's there statistically, is small in this patient population. In fact, if you look at the Europeans, they've been very strong in using hormonal therapy in this population, not even using cytotoxics. So, we're talking about using cytotoxics with hesitancy, looking for a more gentle but reasonably active drug combination, or, in this case, a single drug. And if it shows, indeed, that it's efficacious, then one would use it earlier. Or, as you've mentioned, what may turn out for the younger population is that, since there's activity of at least a doublet - Taxotere with capecitabine - or even a triplet, if epirubicin turns out to be beneficial, that in the younger population what one would do is try to get away from the alkylating, agent with the sterility and all the other problems of the alkylating agent, and use one of these other combinations. So, there's a lot of evolution now, and there's a lot of, I think, excitement that there's a new way of thinking of these diseases, which, for the last 15 years, has basically been adriamycin cytoxin plus or minus 5FU combinations.

DR. LOVE: When you see a woman who has relapsed shortly after receiving an anthracycline-containing adjuvant regimen, for example, how do you sort through the various options? You mentioned docetaxel and capecitabine. Another option might be a single agent taxane that a lot of people would use in that situation. And then there's also the issue of single-agent capecitabine or one of the other agents. How do you sort through that and what are the factors you consider in coming to that decision?

DR. BUDMAN: I really think it depends upon where the disease is. If one had a lot of visceral disease, I would be more apt to use the doublet, which would be the docetaxel-capecitabine. If one has relatively indolent disease, I might try a single agent first, again, for quality of life. Because, unfortunately, none of these treatments are curative.

DR. LOVE: When you say single agent, which one?

DR. BUDMAN: Depending upon what the patient's received before. If the patient's received, for example, an anthracycline and a taxane, let's say, then one might want to use just an alkylate at first, if they have minor disease. Or, if they have evidence of hormone responsiveness, use an aromatase inhibitor or a different hormone. It depends. If one has rapidly advancing disease or a visceral disease, where you're obviously more concerned that the drug you're giving may end up being inactive, then I would go to a combination.

DR. LOVE: Do you use capecitabine as a single agent in that situation, say even before they've had a taxane?

DR. BUDMAN: Yes. If a woman has receptor-negative disease, has mainly subcutaneous or cutaneous disease, which, again, can be a major morbidity. Having an ulceration on your chest is no fun. Or you have mainly bony disease in these circumstances, again, being receptor negative or having failed hormonal therapy, where quality of life issues are important. The disease is progressing, so it needs some sort of treatment, but one doesn't necessarily want to hit them over the head with a sledgehammer. Then I think it's imminently reasonable. I've done it many times, to use single-agent. And as I mentioned before, the one woman that I have whose husband works with the airlines. And her disease is mainly bony and cutaneous, and it allows her functionality, which she wouldn't have with many of these other regimens.

Unfortunately, with capecitabine, it's taken several years for people to realize that they don't have to get burned by the dose, that if you use a reasonable dose, it's a good drug. And there'll be a learning curve with this, too. It's a matter of using it, seeing that it is efficacious, and then deciding in their practice where they really feel it should be integrated.

DR. LOVE: I'm curious about - you've been involved in some of the classic adjuvant trials in the past - what your current approach is to adjuvant therapy and what are some of the adjuvant trials right now, that you're very excited about in terms of seeing some results in.

DR. BUDMAN: We're a member of CLGB and, as such, we accrue to the CLGB adjuvant trials. And what I've already mentioned is, for the elderly, the current trial which is going through our IOB and should be open this month, is the AC versus capecitabine. For younger patients -

DR. LOVE: I think, also, you can have CMF in that one, too?

DR. BUDMAN: Correct. Most of our practice has actually migrated to AC for several reasons. One is perhaps a little higher efficacy. Secondly, it's easier to give, because it's once every three weeks, rather than classical CMF, which Aaron Goldhersh has commented on as the way one should give CMF. And it's over on four doses, so that if you're going to use it in a population, at least you can get it done quicker, and it's easier for those patients.

For the younger patients, there are several trials ongoing. Again, these are intergroup trials which one can access on the web. But are basically using classical AC up front for four cycles, and, for HER2/neu negative patients, are then looking at the two taxanes that are currently available. And that is both taxol and Taxotere. In those trials, the consideration really is, first, which taxane is better. And we really don't know. We know in tissue cultures, as I mentioned, that docetaxel is tenfold more active, but does that correlate, then, with humans? And that, we don't know.

And second of all, the schedule. The data on the schedule is really still incomplete. We know that if one gives taxanes weekly, there are responses of patients who have failed it every three weeks. On the other hand, perhaps they weren't absolutely resistant to every three weeks. And it's asking a question of weekly taxane versus every three weeks. The difficulty, obviously, with a weekly taxane is it chains the patient to the hospital or to the doctor's office, and quality of life isn't as good. But it's an important study, because if there's a major difference, obviously - the adjuvant difference we see now is very small. In fact, what was also shown by Larry Norton for 9344, which was Craig Henderson's study, that the actual benefit from paclitaxel after AC was very small and was much less than was initially hoped.

DR. LOVE: I'm curious about what you do right now in a non-protocol setting in terms of your general approach to adjuvant therapy, and particularly as it relates to the use of taxanes.

DR. BUDMAN: What we follow, to some degree, has still been 9344, because, as I said, our allegiance has been to CALGB, and therefore, we feel most comfortable with their studies.
For the estrogen receptor-positive patient, we have dropped the taxane, because 9344 has not shown any benefit. And the NSABP, which was not completely - it was a different group of patients and slightly different treatment, and you have to remember they also received the anti-estrogen, not sequentially, and there is some suggestion that perhaps there may be an antagonism in tissue culture. But since receptor-positive patients, there seems to be at the present time no benefit for taxane. We've been withholding it, because we really don't know the long-term side effects of taxanes.

For the receptor-negative, where in 9344 there still is some benefit, we have been using the classical 9344, which is four cycles of AC followed by four cycles of paclitaxel. Several members of our group have also, based upon the Canadian experience with a FEC, gone to a FEC regimen, giving six cycles of FEC, which is better than CMF. The whole area is, again, in flux. I would suggest, if possible, that patients do go an adjuvant study, because we really don't know the best adjuvant treatment by any means, and it would be nice to answer it. The Canadians are looking at the 9344 AC-taxol versus FEC. So, eventually, we'll get it answered, but that will be several years from now.

DR. LOVE: Now, you talked about the ACT and 9344, which, of course, is node-positive patients. What about node-negative patients? Do you ever use it in them, higher-risk, node-negative?

DR. BUDMAN: No. I mean, at the present time, I don't think there's information, at least that will satisfy me, that node-negative patients benefit in any way from taxanes. And the difficulty being, again, that you're exposing patients to drugs that we really don't know the long-terms risks. Node-negative patients do well, in general, and have a much better outlook, and I'd be very reluctant, off of protocol, to use taxanes.

DR. LOVE: When you do use adjuvant chemotherapy in node-negative patients, what regimen do you tend to use?

DR. BUDMAN: We tend to use AC quite a bit. For the reasons of convenience for the patients, and it's over quickly. Four cycles, and it's over.

DR. LOVE: There has been a lot of debate, and I think Gabe Hortobagyi, particularly - and he brought this up at the consensus conference last year, about the question of AC and whether it's as efficacious as FAC or some of the six-cycle regimens. Any thoughts on that?

DR. BUDMAN: May not be. Larry Norton mentioned a little bit about this yesterday. I sort of differ with the history, how I remember it. When we set up the 8541 study that I ran, when the discussions were done at that point in time and we wanted to do a dose-intensity trial, we looked around at what was known. And Craig Henderson had finished a short four-cycle FAC combination at the Farber and felt that it was equivalent to anything that was available elsewhere. And the MD Anderson had some data, also, on FAC. So, based upon that, we decided that the high-dose arm, which may or may not be tolerable - and this was before cytokines and the fact I was criticized when we did the high-dose arm - that we had to go back and do a pilot study to show we wouldn't hurt patients. We did a study called 8443, to show that it was feasible. This was before people had good antibiotics and before we had cytokines, that we limited it to four cycles based upon Craig's data and some of the data from the MD Anderson. And then decided to make the standard arm the six months, which was fairly traditional anyway, so we felt more comfortable with that.

The difficulty is that it was small amounts of data and it was a leap of faith. And, you know, many times in medicine, unfortunately, we base whatever we do on very little and do a leap of faith. And once it was in the word processor and once one showed that the high-dose arm was statistically equivalent or better, better in the ERB-2 positive patients, that it was much better, it got engrained in the word processor, and that's the way everybody's giving AC. I was asked at the plenary session at ASCO when I originally presented the date, "What does 5FU do in that setting?" And my answer was, "I don't know."

What I think people did is that they went then to the NSABP data, said, "Gee, AC is a little bit easier than FAC. Why not go with AC?" Everybody's adopted AC. The word processor said "four cycles." And things get engrained. In medicine, unfortunately, things get engrained. So, I think it's an open question whether using this higher dose than we used in the study that I ran, 8541, we only used it for four months. And using it for six months at this higher dose, whether or not there's any benefit, there may indeed be. There is some suggestion maybe, from the FEC trials, that there will be. It's an open question and needs to be resolved. It may be an easy way of increasing efficacy, by just giving two more cycles.

DR. LOVE: But you're saying that right now in the non-protocol setting, you're using four cycles?

DR. BUDMAN: Because that's the standard. And, again, unless there's further evidence that there's a difference, you're asking for potentially increased toxicity somewhere down the road. In the trial that we ran with the four cycles of FAC as 6600, we didn't - I believe, thinking back, I think there were four cardiac events, and that was it. So, out of 1600 patients, that wasn't very much. But, again, the cumulative effects of these drugs and these patients are relatively healthy otherwise, there was potential toxicity over time. So, I would feel more comfortable if we had concrete evidence based upon trials to show, indeed, that the six cycles are actually better.

DR. LOVE: I'm curious where you think hormonal therapy is going in breast cancer, particularly in the adjuvant setting. Hopefully, next month we're going to find out about the ATAC trial, Arimidex versus tamoxifen or versus the combination of the two. And then, of course, the other big, I think, adjuvant hormonal issue has been the question of ovarian suppression. Where do you think we are right now and where to you think we're heading in the next few years?

DR. BUDMAN: Well, it's amazing how this field can turn around and they sort of come back to where they've been. There's no question that you can get a high response, whether it is in the adjuvant setting or in the metastatic setting, with a hormonal responsive patient with minimal toxicity. And that can be quite durable. So that hormones are really, since ovarian ablation was described in the late 1890s, hormones are really a basis of what we do today.

Now, how to improve upon that? The ATAC trial may be a little too early. And, you know, we're all anxiously waiting to know whether there's a difference. We don't know.
And the mechanisms of action are really different, with the realization that some of these breast cancer calls can actually synthesize their own estrogen and, therefore, have autochrome properties and, by using an aromatase inhibitor, you can turn that off, may offer another dimension beyond an anti-estrogen. So, the aromatase inhibitors, unless they prove to cause tremendous osteoporosis, are very attractive. They're not particularly toxic. In the metastatic setting they're more active than the anti-estrogens. They're very well tolerated. So, as you know, there are several other trials, but all these trials are, I think, very important, and they're almost all starting to mature.

The other area that I think is sort of fascinating is now still pre-clinical, and that is, by the use of some of the tyrosine kinase inhibitors epidermal growth factor. One can reverse anti-estrogen resistance in vitro, so that, ideally, what we might end up doing at some point is using a hormone with a so-called targeted therapy and be able to get more benefit, because it will either impede the development of resistance, or since most tumors are felt to be heterogeneous, perhaps suppress that clonal population that would be innately resistant to anti-estrogens. So, there's a lot of movement now in the hormone field.

DR. LOVE: What about in your clinical practice in terms of a non-protocol setting? Have you now moved to using aromatase inhibitors before tamoxifen as first-line therapy?

DR. BUDMAN: In the metastatic setting, these are exceedingly well-tolerated drugs. The quality of life is good. The responses are superb. They can be very durable. And, yes, I think that they really will end up replacing the anti-estrogens, unless some of the new anti-estrogens turn out to have some other nuance we're not aware of at this time. The only downside, as I said, is we really don't know the long-term risks as far as osteoporosis.

DR. LOVE: What about in the premenopausal receptor-positive patients? Have you used, for example, LH-RH suppression plus an aromatase inhibitor?

DR. BUDMAN: Up to the present time, really, what we've done more in clinical management has been to base our treatment on what the ORTC has done. And what they basically showed was that in a premenopausal woman, that combined blockade using an LH-RH agonist with an anti-estrogen gave you a better response rate and more duration of response. So, I haven't migrated in that direction. When the trials show benefit in that section, then we probably will migrate. But right now, as I said, we've been following the ORTC data.

DR. LOVE: One final thing I wanted to ask you is that I think that because of the exciting things that have been seen in adjuvant therapy, I think a lot of our hopes have been shifted towards that arena, and with good reason. But I think, also, we've maybe started to discount a little bit, the potential for what we can accomplish in women with metastatic disease. And the idea of, you know, not eradicating the disease, but keeping a patient in a comfortable state and functional for a very long period of time. Do you think that realistically that's an end point that maybe we might get to in the next five or ten years?

DR. BUDMAN: I think that we're tending in that direction. I see it almost as nihilism, because what I hope is, as we are understanding molecular biology, it gets better. And as our understanding of gene expression gets better, that we could look for eradication of these illnesses. We know that some tumors spontaneously resolve and, therefore, there's something there. Whether or not it's immunologic or whether it has some other basis, God knows. But it's sort of frustrating to think that the best we can do is a holding action. And I think that's more where we are now, quite frankly. We have a bunch of drugs. Some of them are good. Some of them are marginal. We're trying to enhance quality of life without hurting people, and yet we're not curing very many people in the metastatic setting. Ideally, as I said, one reason that keeps me in this field is I hope that there will be a change, that the knowledge will impact on it. And it may be that we will never reach the point where we really understand this diseases well enough to eradicate them, and the best we can do is suppress them.

DR. LOVE: Well, my take on it wasn't anywhere near as pessimistic, and that is if you can, for example in breast cancer, bring a woman to a state where she's asymptomatic, even if she has lesions on her bone scan or chest x-ray, and she lives a normal life expectancy, in a sense it's sort of a functional cure.

DR. BUDMAN: That may occur. I mean, to some degree, that's sort of analogous to what you're really doing now with some hormonal treatments, where there's a paucity of side effects and people are functioning. Perhaps I'm an optimist, or whatever. I'd like to feel that we can do better than that and, at some date, we'll really eradicate these diseases.
One of the major issues in drug development that people don't really realize, is to bring a drug to market is taking over 10 years. And the pre-clinical development may be only three or four years. But the majority of that time now is the clinical development, and it's becoming more and more difficult in our society to do clinical research, for several reasons. One is obviously regulatory, and part of this is appropriate, because you do want to protect people and, unfortunately, there are always problems. There's always somebody who's going to do the wrong thing. But the accrual to trials nationally is running about three percent. And it's dismal in the sense that one has to wait ten years or, more optimistic, maybe seven to eight years, to get a result, and then to look that even to introduce a new drug, that we're talking about was conceived over ten years ago, because the clinical trials mechanism is working so slowly. And that I would urge physicians to think about at least appropriate patients, to consider them for clinical trials.

DR. LOVE: This concludes our program special thanks to our speakers, and thank you for listening. I'm Dr Neil Love for Breast Cancer Update.

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