DR WINER SUPPLEMENT:

DR NEIL LOVE: Dr Osborne commented on the clinical management of women with metastatic breast cancer and the increasing emphasis on treatment strategies that maximize quality of life. However, the Miami meeting Patterns of Care study documents considerable variations in how practicing oncologists choose systemic therapy. I met with Dr Eric Winer who's had a major research leadership role in defining regimens with improved tolerability for women with metastatic breast cancer, and he began by reviewing how his interest in this area evolved.

DR ERIC WINER: Throughout the 1990's the emphasis was more is better, or on looking to see if more is better. Throughout that period of time when much of the focus was on high-dose therapy and more intensive regimens, at times I felt like a bit of a lone ranger trying to work toward better-tolerated regimens. I think clearly the pendulum has swung in a different way, or swung away from that. As a result of learning over the course of the last decade that more isn't always better, there has been a tremendous interest in trying to identify schedules of treatment that are more tolerable, sometimes more effective and at the same time, focusing on therapies that are more targeted. Of course, the hormonal therapies have been targeted therapies for decades and decades. So, along those lines, I've conducted a number of different trials where we've tried to take advantage of oral-dosing schedules and lower-dose, weekly schedules. In general, programs that allow a patient, both to have her cancer under control and to lead as normal of life as possible.

DR LOVE: Where did this interest come from?

DR WINER: Oh, I think the interest came from the fact that the first and foremost thing we would like to do is cure everyone's cancer. Even better than that, we would like to prevent cancer from happening to begin with. But, if we can't do those things, and if a woman is stuck living advanced breast cancer, then the very least we can do is try to figure out ways that she can live a long time, and live a long time not suffering from terrible side effects from treatment.

DR LOVE: What are some of the things that you see being done by other physicians or trends in the community that may be improved in that regard?

DR WINER: Fortunately, I think we have come a long way in the direction of making life more tolerable for women with advanced breast cancer. There was a time not that long ago, when women would spend far more time in the hospital either getting chemotherapy regimens or recovering from side effects that they had. I think a number of things have been very positive. Number one, although I do believe that there maybe be some small number of women who really benefit from high-dose therapy, we have failed to show that overall it is beneficial, so we have really moved away from that as a general approach.

Second, I think that proving that single-agent therapy is, in the long run, as effective as combination therapy was a major step forward. Of course, there are combination regimens that are associated with higher response rates. But the fact of the matter is, in general, I think most of us believe that sequential single-agent therapy is probably associated with the same overall results in terms of survival as combination therapy. What that has allowed us to do, is tailor treatment programs to a much better extent for individual patients. The other big plus of single-agent therapy is that as we think about combining all of these chemotherapy agents with some of the newer biologic therapies, and many of these newer therapies won't be used as single agents, but will be used in combination with other agents. It is just much easier to do.

Finally, I think that there has really been a greater awareness in the past few years that hormonal therapy in breast cancer is an incredibly powerful therapy, and of course it was one of the first therapies we had. Again, throughout this whole era of more is better, there was a bit of a tendency on the part of many medical oncologists to move a little more quickly towards chemotherapy than might have been necessary. In the past few years, at the same time that we have seen people move away from high-dose therapy, we have seen them focus more on single agents and lower doses given in a more chronic schedule. In general, these treatments are associated with a better quality of life, and I think there has also been a focus on hormonal interventions.

DR LOVE: I want to get back to your point of combination chemotherapy because a lot of people have made that statement and I would guess most people are using single-agent sequential therapy in the metastatic setting. But, Dan Budman made an interesting point to me recently. He had some data on quality of life on the Xeloda-Taxotere study, which, at least in their hands, showed better "quality of life" in the combination arm. Of course, there is more toxicity, but the point he was making was that even without a survival advantage, which you have at least in that study, the key determinant for quality of life in the metastatic setting is control of tumor.

DR WINER: Well, it is and it isn't. Clearly, in patients who are symptomatic, the key determinant is controlling the tumor if that can be done with reasonable toxicity. The two things that we care about in treating women with metastatic breast cancer, ultimately, are how long someone lives and what their quality of life is. In terms of quality of life issues and patients getting chemotherapy, it's a balance. It is a balance between controlling disease-related symptoms and not inducing terrible symptoms with treatment. The whole issue with the Taxotere-Xeloda vs. Taxotere study, that study showed a survival benefit for the combination. My understanding was that quality of life in the combination arm was at least as good. In my mind, what that study says is that capecitabine is a really good breast cancer drug. It doesn't necessarily say anything about combination vs. single-agent therapy because, in fact, the majority of patients on the single-agent docetaxel arm never got capecitabine. But, it unquestionably says that capecitabine is a really good drug.

DR LOVE: How do you use capecitabine in your practice?

DR WINER: I actually use capecitabine a lot in my practice. Typically I use it as a single agent, and in fact, outside of a trial, I exclusively use it as a single agent. I use it fairly early on in a lot of patients. In my mind there isn't any magic order in which one has to give chemotherapy agents in the metastatic setting. As a general rule, patients stay on their first- or second-line treatments longer than they are going to be on their third- and fourth-line treatments. In my mind, that means it makes sense to use an agent that is better tolerated earlier rather than later. So, outside of a trial, I frequently give capecitabine either as a first- or a second-line agent these days. I try to dose it in such a way, usually starting at about 2000 milligrams per meter squared, but dose it in such a way that there are really fairly minimal side effects.

DR LOVE: Has that been your experience?

DR WINER: I know there has been tremendous fear of hand-foot syndrome, diarrhea and other problems with capecitabine. But my sense is that if you are attentive to doses and you're careful about telling patients to stop if they run into side effects, then it is an amazingly well tolerated regimen.

DR LOVE: Generally speaking, what is your initial chemotherapy regimen in a patient that, let's say, has had an adjuvant anthracycline-Cytoxan (CA) for example.

DR WINER: I really don't practice this one size doesn't fit all kind of approach. Of course, we do a lot of trials and we often have a number of different trials going on in a first-line setting. So, for the patient who is not going to be in a trial, in a first-line setting, who has had an anthracycline in the adjuvant setting, on any given day or week, I could give that patient either of the taxanes - docetaxel or paclitaxel - capecitabine or Navelbine. Those are really the choices that I would most often choose between. I'd really make that decision talking to the patient and getting some sense of the kinds of side effects she would prefer to put up with or avoid, and really try to tailor it for her.

DR LOVE: Do you have any impressions in terms of response rates for those four?

DR WINER: Sure. Of course they have not been compared in head-to-head comparisons. There have been small, randomized studies of paclitaxel vs. capecitabine and Capecitabine vs. CMF. There was a docetaxel vs. paclitaxel that has never been reported. Navelbine, in general, has been looked at in lots of single-arm studies, but not in randomized studies compared to any of those agents. My general sense is that the response rates tend to be fairly similar. There are many people who would tell you that of all of those they think that docetaxel is perhaps the most active. I'm not convinced that any of those agents are more active than any of the others. So for me, in making a decision with a patient, it's not so much am I going to use a taxane ever, it's a question of whether I'm going to use the taxane as a first, second or third-line agent.

DR LOVE: How would you compare the side effects and toxicity profiles of those approaches?

DR WINER: Well, I like oral, and most patients like oral. Let me explain that a little more. Patients like oral as long as it doesn't give them more side effects or compromise efficacy. There was a nice patient preference study done by Geoffrey Liu - who's actually a fellow at our institution - when he was an intern up in Canada asking patients about their preferences for IV vs. oral chemotherapy. What they said was exactly what I think most of us would expect, if they could have the same degree of efficacy with fewer side effects, if I remember right, 9 to 1 they would pick oral. Who wants to sit with an IV in your arm or a tube attached to your portacath if you can avoid it? So, of those regimens, given my choice, I'd prefer to take the oral one. Which is, again, why I very frequently, in a non-study setting, particularly in a patient who isn't having rapidly progressive disease where I think the decisions are perhaps a bit different, I would use capecitabine.

DR LOVE: Putting aside oral vs. IV, how do you describe the regimens?

DR WINER: Again, I actually think, from a side effects stand point, the best agents there are probably capecitabine and vinorelbine. Hair loss, is often a big deal for people. Capecitabine, in particular, is associated with virtually no hair loss. While the side effects with capecitabine can be a problem if you're not careful with the dosing, if you are careful with the dosing, you can get by with virtually no side effects. Some patients, over time, will get some chronic changes in their hands and feet, but that's really about it.

DR LOVE: You talked about the rapidly progressing patient. What would be a typical clinical scenario and how does that affect your thinking?

DR WINER: The one time that I do think combination therapy may make more sense is in the patient who has rapidly progressive disease and the feeling that this is your one and only opportunity. I might add parenthetically that this is also the situation where if ever I was to combine a chemotherapy agent or more than one chemotherapy agent with a hormonal therapy in a patient with a hormone receptive-positive tumor. Feeling like, this is my patient's one chance to improve, if she is not better in the next six weeks, she is going to be dead, or her cancer is going to be so far advanced that there is not going to be any hope of trying anything else. In that kind of setting, I would be a bit more inclined to use combination therapy although even there, my worry about combination therapy is often times that patient may have a poor performance status and may not tolerate it as well. But, there I would probably use it.

While I haven't done it yet, that is actually the situation where if I ever were to give capecitabine and Taxotere, I would use it in that kind of situation. I also think that that's the kind of situation where given the fact that agents like doxorubicin and the taxanes are more typically considered first-line agents, I would be more comfortable doing the more standard thing, using one or more of those agents.

DR LOVE: You say the standard thing?

DR WINER: The standard thing meaning that, at this point in time, if you go out and survey US oncologists, what they think the usual first-line agents are. Most are still going to tell you that the most active agents, in general, are going to be an anthracycline and a taxane. That's what you are going to hear from many people. In the patient that has very rapidly progressive disease, I guess I'm a little less comfortable stepping outside of what I perceive to be the way that most people would approach the problem. Truth be told I'm not sure that either of those agents, the anthracycline or the taxanes are necessarily better than any of the other things on the list. But again, if I have one opportunity and I have to pick an agent in that patient with very rapid progressive disease, assuming that she had not had a prior anthracycline or a prior taxane, I'd probably use one of those agents.

DR LOVE: There are a couple other types of situations or questions that enter into this, and another one is choosing between hormone therapy and chemotherapy in the ER-positive patient in the metastatic setting. I think the same kinds of principals enter into it. How do you approach those patients?

DR WINER: In my mind, a patient who has a hormone receptive-positive tumor with metastatic breast cancer, the default position should be to use hormonal therapy. It is far better tolerated than even the best tolerated chemotherapy. Often times responses can be very durable. In my mind, the longer we put off the more toxic therapy the better off that patient is. Then the question is what are the exceptions? In my mind, the exceptions are really largely the patient, where it seems that she has very rapidly progressive disease or even moderately rapid, and where for whatever reasons, I think that the chance that she will respond to hormonal therapy is less than average.

DR LOVE: Is it the issue of the chance or the time to response?

DR WINER: I'm less convinced about this time to response issue. People in the past have talked a lot about the fact that it takes longer to get a response to hormonal therapy than chemotherapy. I'm not entirely sure how well we've studied that. Certainly you can see responses to hormonal therapy quickly at times, certainly with some chemotherapy agents it can take a while to see a response. Probably you can see a little faster response with chemotherapy than with hormonal therapy, but I think we have probably made more of that than we should.

In my mind, it's really asking the question, what's the likelihood that this patient is going to respond to hormonal therapy, number one. And number two, what's the likelihood that if she doesn't respond to hormonal therapy she will be in dramatically worse shape in two or three months or that waiting could possibly compromise how she would do with chemotherapy at that point. Then more importantly, or as importantly, if she doesn't respond to hormonal therapy and she is symptomatic now, we have allowed her to live with those symptoms for a couple of extra months. Back to your point earlier, much of the quality of life benefit with treatment is controlling symptoms. If we are allowing someone to live with symptoms for an extra few months that's not doing a good thing for her quality of life.

DR LOVE: Do you have the impression that just the presence of visceral metastases makes it less likely to respond to hormone therapy?

DR WINER: That again, has been a long held assumption that is probably time to challenge. I do have the sense that patients who have extensive visceral metastases respond less well to hormonal therapy. That's, of course, where I start worrying about the fact that if, and again it's a big if, there is a difference in time to response then it may make a difference. But, visceral metastases of 1975 are not the same, in general, as visceral metastases of 2002. In 1975, a woman who had liver metastases had a great big liver and often times abnormal liver function tests and an elevated bilirubin. In 2001 and 2002, women who are found to have lesions seen on a spiral CT that sometimes may be sizeable, but frequently may be a centimeter or two centimeters and the women may be entirely asymptomatic with normal liver function tests. I actually don't think that someone like that should necessarily be channeled towards chemotherapy instead of hormonal therapy.

DR LOVE: What about the HER2-positive patient in the metastatic setting? How do you approach that woman?

DR WINER: The HER2-positive patient, we now think of as a little different. First, when we say HER2-positive patient, let's assume that that means it is either a tumor that is amplified by FISH or at a minimum 3+ on IHC. In terms of that patient, the way I would change the algorithm is really in a couple of ways. Number one, my threshold for moving away from hormonal therapy is just a bit different. In a patient who has HER2-positive and ER- or PR-positive breast cancer, I still would strongly consider hormonal therapy. But I think there is at least suggestive evidence, that patients with HER2-positive disease may have somewhat less benefit from hormonal therapy and may be somewhat less likely to respond to hormonal therapy. So, a patient with HER2-positive disease, if I were on the fence about hormonal therapy versus moving on towards something else, I would be more likely than in the HER2-negative patient to move away from hormonal therapy. Again, I don't think at all that HER2-positivity is a contra-indication to give hormonal therapy and in many patients I would do it as the first treatment.

But then, when it's time to move to chemotherapy in HER2-positive patients, I believe, and most of us believe, that Herceptin is really the standard in care. The only question there is whether you're going to use Herceptin plus chemotherapy or in some patients Herceptin alone.

DR LOVE: How do you make that determination?

DR WINER: I think in the US, and certainly in my own practice, I've more commonly given Herceptin plus chemotherapy in many of these patients. Based on the fact that comparing across trials, there's a sense that response rates, and therefore control of tumor related symptoms, is higher when chemotherapy is added. Of course, we don't know that the strategy of giving Herceptin followed by chemotherapy or followed by Herceptin and chemotherapy is inferior.

I guess the one other thing I would add is that the survival benefit seen with Herceptin in the randomized trial was done when chemotherapy and Herceptin were given up front. So, if we are going to be totally true to the randomized data, the data that demonstrate that Herceptin helps people live longer, then, at least at the moment, Herceptin and chemotherapy probably is the most standard.

DR LOVE: What are the kinds of situations where you would use Herceptin alone?

DR WINER: I think they fall into a few different categories. One would be in a patient who very much wanted to avoid any side effects associated with chemotherapy. I should add, that we now have a number of different chemotherapy regimens that at least in Phase II studies have been tested in combination with Herceptin. So, there is more of a choice for a woman then perhaps there was a few years ago. We've got more experience with different agents that have a different range of side effects, so that's number one.

The second situation would be the patient who has HER2-positive breast cancer, but really has fairly minimal disease or disease that's really changing slowly. In that situation, I see little harm in going with Herceptin alone and watching what's going on, and potentially adding chemotherapy at some point later.

In the final situation where I think it is worth thinking about Herceptin alone, although in the end I probably wouldn't do it, and probably most people wouldn't; is the patient who's had AC followed by Taxol as an adjuvant regimen and three months later has recurrent disease. She's someone who's been demonstrated to have fairly chemotherapy-resistant disease. She's not the kind of patient who was ever in the randomized trial that led to the approval of Herceptin. In that patient, I think that her chance of doing well is primarily dependent on her chance of responding to Herceptin itself. I'm not sure how much chemotherapy is going to add. While I probably, in that patient, given her very poor prognosis would end up adding chemotherapy, I'm not sure that it's not a rational to think about just trying Herceptin alone there. Again, giving the demonstrated resistance to chemotherapy.

DR LOVE: How would you sort through the options of which chemotherapy?

DR WINER: I think some of those decisions are easy, and at least for the time being, none of us should be giving Herceptin with an anthracycline given the cardiotoxicity. I think there are an adequate number of choices based on studies that have been done. I think we can use one of the regimens that's already been tested so that there is at least some toxicity and efficacy data. Clearly the standard of care remains Herceptin and paclitaxel based on the FDA approval. But, there are lots and lots of physicians who give Herceptin and docetaxel given the clear activity of docetaxel in patients with metastatic breast cancer and the fact that there is preclinical synergy in laboratory models. Finally there have been a number of small Phase II trials that have looked at every three-week docetaxel with Herceptin and weekly docetaxel with Herceptin. All of which suggest that the side effects are very similar to what you would expect to docetaxel alone, and with very reasonable efficacy data.

The other regimen is one that we have been very involved, and that we started studying about three years ago, which is Herceptin and vinorelbine. We've now actually completed two trials with that regimen. The first trial was a trial in 40 women where half of them received prior chemotherapy in the metastatic setting, half of them hadn't. None had received prior Herceptin. But, in that study the regimen was extraordinarily well tolerated, with an overall response rate of 75 percent. That is really an example of a study where we were so pleased with the results that when it was over, we, all the physicians in our group, just kept giving the regimen because we felt very comfortable with the side effect profile and with the effectiveness. We have just completed and have submitted to ASCO an abstract of the results of a Phase II trial of Herceptin and vinorelbine in 55 patients done in 15 centers across the US. It is probably a little premature to talk about those results, but we've been comfortable again with both the safety results and with the preliminary efficacy assessment.

DR LOVE: Why hasn't that been taken to a Phase III setting, or is it being taken?

DR WINER: Funny you should ask that because in fact it is in a Phase III setting. There is an on-going multi-center study, involving about 50 sites in the US comparing Navelbine-Herceptin with a taxane-Herceptin regimen. The taxane-Herceptin regimen is left to the choice of the physician. They can either pick weekly Taxol or weekly Taxotere. It's a study that will accrue a total of 250 patients hopefully over the course of the next 12 to 18 months. The reason we are doing it is because in general Navelbine has not been one of the first-line agents in the treatment of patients with metastatic breast cancer. We think that Navelbine-Herceptin has been a very promising regimen. However, if people are going to take this regimen seriously, and even possibly consider incorporating it into an adjuvant program in the future, we really feel that it has to be compared head-to-head with the taxanes.

DR LOVE: Who is actually doing that study.

DR WINER: It is an investigator-initiated study with pharmaceutical support from GlaxoSmithKline. We are running the study with support from GSK, and we have a CRO who is helping us with all the sites.

DR LOVE: When did that get up and running?

DR WINER: It opened up in September. I can't tell you exactly the number of sites that have opened yet, but we have a total of about 50 sites that will be participating. There are probably at least 15 or 20 that have it through their IRBs now.

DR LOVE: I guess the natural question would be what happens when they progress?

DR WINER: That is a good question, and it's something that we've been struggling with. At least at this point in time, there's no clear evidence that continuing Herceptin after a patient progresses is something that is necessarily a very useful strategy, but the data are quite thin.

DR LOVE: Do you do it?

DR WINER: I do it sometimes. I don't do it all the time. I'll get back to that in a minute. But, as part of this study, we may be able to get a little data there. First, for patients that are on the taxane-Herceptin arm of that study, some of the investigators may actually choose to open up the on-going study that MD Anderson is running that's looking at Navelbine vs. Navelbine-Herceptin. It would be a very natural extension from the first study into that second study. The other thing is that we will probably try to look at least one or more regimens that contain Herceptin in patients that progress on the first regimen. While that won't definitively answer any question, it will at least give us some sense of the activity of Herceptin containing regimens in the second-line setting. Which at least, at the moment, the only real data out there is from the extension study that was done after the pivotal trial.

DR LOVE: It sounds like you are going to run into the old compulsive, well, you didn't cross them over?

DR WINER: We've talked about crossing people over as part of the study. In general, the investigators participating in the study had some interest in it, but didn't want to be locked into a cross over. Survival isn't the end point of the study. The primary point of the initial randomization between Navelbine- Herceptin and taxane-Herceptin is response rates.

DR LOVE: Any gut prediction on what you are going to see?

DR WINER: My gut prediction is that the efficacy between the two arms will end up being fairly similar. If our experience with Navelbine-Herceptin holds up, and that is still a big if, I suspect that the toxicity will be less with the Navelbine-Herceptin arm than with the taxane-Herceptin arm, but we're just going to have to see.

DR LOVE: How often are you using Navelbine-Herceptin before taxane-Herceptin in a non-protocol setting?

DR WINER: Again, we have now completed two Phase II trials. It is a regimen we are very comfortable with, and it is a regimen that certainly seems to be very effective and well tolerated. We use it a fair amount.

DR LOVE: What about capecitabine-Herceptin?

DR WINER: My understanding, and I don't know all of this data, my understanding is that there are studies both in the US and in Europe looking at those two agents together. I haven't seen any results reported. Capecitabine, or 5FU, is one of the agents that in the preclinical models have not been synergistic, but that should not stop anyone from looking at it. Potentially, it could be a very well tolerated regimen. On an entirely anecdotal level, I will say, that I have certainly seen a number of very fine responses with capecitabine, not with Herceptin, but as a single agent in HER2-positive patients who have been on Herceptin in the past.

DR LOVE: You were going to say when you continue Herceptin on progression.

DR WINER: The rule of thumb that I've used - I don't know if this is right or wrong, and I don't think there really is a right or wrong answer - is that in a non-protocol setting, in a patient who has disease progression on Herceptin, I tend to use it once more. You might say that there is really no justification for doing that given the absence of data, but often patients feel very strongly about continuing or having the security of coming back to it. That is particularly the case when a patient has responded to a Herceptin-containing regimen. They have this idea, rightly or wrongly, that it is their lifeline. Particularly in a patient who has responded to a Herceptin-containing regimen, when she develops disease progression, I typically will move to another agent, and try one more chemotherapy agent with the Herceptin. Or I will stop Herceptin, but then often times come back to it with one other agent down the road.

There is one exception to this and this is unfortunately not an uncommon situation. The exception is the patient that is responding to a Herceptin containing regimen and develops CNS metastases. In that patient, I don't consider her to have progressed or to have disease that is refractory. I consider her to have progressive disease in the brain, but I don't consider her to have refractory disease to Herceptin. Typically there I would continue the same regimen and take the appropriate steps in treating her CNS disease obviously usually giving her cranial irradiation.

DR LOVE: You mentioned the fact that you consider Herceptin part of first-line therapy, and then the chemotherapy becomes the question. That for example, is the NCCN guideline and that's what you hear from most research leaders. Is that what you think is happening in the community?

DR WINER: I think for the most part that is happening in the community, but I think there are still some community oncologists who may be giving Herceptin not as a first-line therapy, but as a second- or third-line therapy. To a large extent that is changing as more people are comfortable with Herceptin, and as the concerns about cardiac toxicity have come down a little bit I think we're seeing that more and more.

DR LOVE: What about the schedule of Herceptin?

DR WINER: Of course, the approved schedule is weekly. The data from our colleagues in Canada are looking at an every three-week schedule, both as a single agent, and in combination with Taxol. And those data have been encouraging. There has been discussion although no final action to my knowledge in terms of changing the Intergroup adjuvant trial to an every three-week schedule based on those data. I still typically give Herceptin on a weekly schedule when I'm doing it with chemotherapy. What I've done off-study in a number of patients is, at a point in time when perhaps I'm stopping chemotherapy and continuing Herceptin alone, I'll often move to an every three- week schedule to make life a little bit easier for patients. In my limited experience, it has been entirely well tolerated. I suspect that this is something that we will be seeing more and more of.

In the early days of Herceptin, once Herceptin had been approved, there was a great interest in looking at weekly chemotherapy schedules with Herceptin because Herceptin was already being done on a weekly basis. I think we're now probably going to see a proliferation of new regimens that go back to an every three-week dosing schedule where both the chemotherapy and the Herceptin are given every three weeks.

DR LOVE: You have a great interest in physician/patient communication. What are some of the things you have observed or learned about? Lets start with the metastatic setting.

DR WINER: When people are healthy, it doesn't matter all that much to them, what their healthcare team looks like and acts like, and what the texture of that relationship is. One of the things that happens when people are sick and in need of more medical care, or even when they're not very sick but they need more chronic medical care, is that the piece of one's quality of life that is affected by the relationship with the healthcare team gets bigger. So, if you think of quality of life as a pie that's divided up into your work, your family, and assorted other things, that piece that is the relationship between your doctor, your nurse, the social worker and everyone else there, becomes much bigger. So, from the standpoint of taking care of women with advanced breast cancer, I tend to think it's pretty important that patients have good, strong and open relationships with the people who take care of them. That's not just the doctor that's the whole team. It sounds a bit trite, but it does take a village to take care of someone. It's not just the doctor alone. I try hard to make decisions with patients, and to give people options and to have them guide me.

Having said that, both in the care of women with metastatic breast cancer and in the care of patients with early-stage disease, I think that ultimately taking into account a patient's preferences, and her individual medical and psychological issues, that we have to make a recommendation to people. I think a lot of decision making is not about giving a patient a choice between A, B, C and D, but it's about describing those options, knowing your patient and then with her trying to pick the best one, together.

I could go on and on, but I really think that these communications are very important. By communicating well and helping to set and reset patients expectations over time, we can really help people dealing with a chronic illness. What I mean by set and reset expectations is that I think one of the hardest things that we all have to deal is, when we are taking care of someone who expects to be having a guarantee of responding to a treatment, and she doesn't. I think that the challenge we all face is, on the one hand, being realistic so that people don't have unrealistic expectations. On the other hand combining that with a real sense of hopefulness, so that we allow patients to feel hopeful, but at the same time not allowing them to have false expectations.

DR LOVE: I'm sure you're involved in teaching oncology fellows. So, how do you teach this?

DR WINER: I think that you teach most of this by example. I think you have to teach it by living it, and you have to teach it by having oncology fellows see patients with you, and give them an opportunity to do it on their own, with some amount of supervision. I think the way you also do it, and it's something that we think about less, but we do it by the way we talk about patients not only while we're in their presence, but also by the way we talk and think about them when the they aren't with us. So, in all of those discussions in the workroom, and wherever else. I think that a lot of the teaching really is setting an example, and allowing people to model after you. By no means do I think that I don't have plenty to learn in this area. Part of the challenge here is always recognizing that you can be a lot better than you are.

DR LOVE: Any thoughts about what actually plays out in clinical practice?

DR WINER: In terms of the relationship issues, I think it is incredibly variable from doctor to doctor and from patient to patient. In general, most patients like their doctors, in general most cancer patients like their oncologists. I think that patients adapt to different styles. I suspect that most doctors actually do less adapting then they think they do to individual patients, and that we all tend to have a certain style. It's a little more fixed than we like to believe that it is. I do believe when those relationships aren't working - when you as the doctor feel like you're just not communicating with the patient, and the patient is making you feel crazy, and you're not serving her needs - I think that is really the time, and I don't think we do this enough, that we really have to address it head on, and figure out whether it is time to make some sort of a change.

DR LOVE: Do you think that most oncologists make the same recommendations for their patients, that they would want to have in the same situation?

DR WINER: At some level I hope they do, but on another level, I hope they don't. Let me explain. When we choose between similar treatments with different side effects, what we should be recommending to patients isn't necessarily what we would do for ourselves, but what - after talking to that patient - fits best with that patient's preferences. Often times the recommendation may be not be what we would choose for ourselves. For example, I might be terrified of neurotoxicity, but my patient isn't. Maybe, playing the piano is everything to me. I think more often than not, we do recommend what we would choose ourselves, and more often than not, there isn't such variability in people's preferences and they go along with that.

DR LOVE: What are your thoughts on the ATAC trial data that was just presented?

DR WINER: The ATAC trial data is not what I expected. I was expecting and predicting that the three arms, in short term follow up, would be equivalent, and that perhaps there would be differences in toxicity. I think the results are interesting, in their own way exciting, and not terribly surprising. I think there has been a sense on the part of many of us, based on data in the advance disease setting that aromatase inhibitors may be a little bit better than tamoxifen. Of course, the data only apply at this point in time to postmenopausal women. The ATAC trial is a large trial and would suggest that at least with early follow up and with a first preliminary presentation that Arimidex was, in fact, better from the standpoint of basically disease-free survival compared to tamoxifen and compared to the combination.

The challenge, of course, is figuring out how to put those finding into practice in the next week or two and in the next year or two. There have been a number of conversations over the past 24 hours about that issue, and a lot of different points of view. I guess my feeling is that first I wouldn't switch any woman who has been on tamoxifen for more than a month or two to an aromatase inhibitor based on that study.

I think the more pressing issue is whether I'm going to go back, and in every postmenopausal woman who I would have given tamoxifen to am I going to give Arimidex to, or an aromatase inhibitor to, instead. And, there I haven't really come to an answer. I'm a little hesitant, based on one trial reported at one meeting that has not gone through peer review of any sort yet, to say that that's going to change my entire practice. Although, I suspect that it is very likely in the next 6 to 36 months that that practice will change. I do feel that I'm going to discuss this with patients, although, I have to say that for the past year I have been telling whenever I put them on tamoxifen who are postmenopausal that tamoxifen has been the standard of care, but there are drugs that are moving up to challenge it, and things may change.

DR LOVE: You mention other aromatase inhibitors. Would you use one of the other ones if you were going to use it in the adjuvant setting?

DR WINER: I'm pretty data driven and personally, if I were going to use an aromatase inhibitor in the adjuvant setting at this point in time, I would use the results of the trial, and I would write for Arimidex. There will, undoubtedly, be a lot of discussion about whether these data can be applied to other aromatase inhibitors and I suspect that this is just the beginning of a big debate on this issue.

Of course one of the consequences of if we all decide that the new standard of care is an aromatase inhibitor based on this trial and that's it, we also have to be ready to amend all the trials where tamoxifen is presently required. That's actually easy because in an adjuvant chemotherapy trial where tamoxifen is an add-on and it's not part of the question, it is easy enough to add on Arimidex. The bigger challenge though is in the studies that are asking tamoxifen vs. aromatase questions. If in fact, we decide that this is the new standard of care, all of those studies are essentially bankrupt. If we've made that decision then we shouldn't be doing those studies, but if we do make that decision we simply aren't going to have more data.

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INTERVIEW WITH:

- Dr. Kent Osbourne

- Dr. Nicholas Robert

- Dr. Aman Buzdar

- Dr. Eric Winer

Full interview transcripts from audio program with relevant links

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