DR NEIL LOVE: Earlier in the program, Dr Burstein reviewed several posters his team presented at San Antonio and another interesting poster was submitted by the breast cancer team at Northwestern University. One of the most important trial reports at last year's San Antonio meeting by Dr Joyce O' Shaughnessy, was of a large randomized trial in metastatic breast cancer that demonstrated a statistically significant response rate and survival advantage for the combination of capecitabine and docetaxel compared to docetaxel alone. Hoping to identify a regimen with similar efficacy and perhaps improved tolerability, the Northwestern trial reported at this year's San Antonio meeting was a Phase II study of the combination of paclitaxel and capecitabine. I met with the Dr William Gradishar to learn more about this important new trial.

DR WILLIAM GRADISHAR: As a way of background, a pivotal trial in this area has been presented that showed that Taxotere-Xeloda is better than Taxotere as a single agent, looking at not only response rate, but ultimately the end point of survival. That trial has actually generated a great deal of interest on the part of clinicians who are treating patients because there have been relatively few trials that actually have demonstrated a benefit in terms of survival for patients with metastatic disease. One of the issues in that trial is, although there was a survival advantage, the cost, in a sense, of achieving that was toxicity. It was somewhat higher than the single-agent arm. As a result, many of the patients who participated in that trial had to have dose reductions in terms of Xeloda. All that said, there's going to be a poster presented, I believe tomorrow, that actually critically looks at a number of different issues related to that trial.

There are several concerns: Is that trial a fair assessment of the effect of single-agent Taxotere? Is it a fair assessment of the combination? Would the same thing have been achieved if patients got sequential Taxotere followed by Xeloda? As it turns out, not an insignificant fraction of patients who got single-agent Taxotere were ultimately put on Xeloda at the time of disease progression. I think DR Miles is presenting those results tomorrow in poster form. I think what that's going to demonstrate is that a significant fraction of patients did get sequential therapy. If you were to extrapolate or tease out, if one could, those patients who got Taxotere followed by Xeloda, took them out of the mix, the Taxotere single-agent arm would probably have done even worse in terms of ultimate outcome compared to the combination. So, I think there is probably clearly something real about the combination of Taxotere and Xeloda in terms of enhancing survival.

DR. LOVE: The other thing is, there's a biologic-pharmacologic basis to think that.

DR GRADISHAR: Yes. One of the enzymes clearly critical for converting Xeloda into an anti-cancer drug within a tumor cell is upregulated by the Taxanes, and specifically Taxotere. So, there's a rationale for looking at that combination that's borne out, actually, in the clinic.
So, with all that as background, the trial that was started a couple of years ago in a community setting was looking at the natural other question: Would you achieve similar results if you looked at a combination of paclitaxel and Xeloda? Although it was a relatively small Phase II trial, what we've been able to demonstrate is response rates just above 50 percent, and a significant fraction of complete responses -12 percent, which is very good for a metastatic disease trial, admittedly a small trial.
The other thing that's interesting is the tolerability was somewhat better than was observed in the Taxotere-Xeloda treatment arm in the randomized trial. I think that comparing a small Phase II trial to a large randomized trial is not necessarily fair, but the results of our trial demonstrate, or at least suggest, that it might be worth pursuing the combination of paclitaxel and Xeloda in patients with metastatic disease. It's active. It seems to be pretty well tolerated. I think it raises other questions about whether you could make that combination even more tolerable perhaps looking at weekly schedules of the taxanes, be it Taxotere or Taxol. Because of the interest in the Taxotere-Xeloda combination and the results that came from that trial, the combination is now being moved into the adjuvant setting in a number of large Intergroup, international trials. I think the biologic basis of putting those two drugs together has been demonstrated in the metastatic disease setting. Ultimately where we want to see these things really make their mark is in patients with earlier-stage disease, where we hope we can affect, in much larger numbers, the outcome of these patients.

DR. LOVE: So, what were the doses used?

DR GRADISHAR: The dose of Xeloda in the trial was 825 milligrams per meter squared, days one through fourteen. The dose was given twice a day. And the dose of paclitaxel was 175 milligrams per meter squared on day one.

DR. LOVE: So, the dose of capecitabine was a lot less then?

DR GRADISHAR: Right.

DR. LOVE: And you still saw activity?

DR GRADISHAR: We saw activity. And, as a result probably of dose reduction in general, the therapy was pretty well tolerated.

DR. LOVE: What about hand-foot syndrome?

DR GRADISHAR: We did see some patients that experienced that, and it occurred in roughly about 10-12 percent of patients, at least Grade III-IV hand-foot syndrome that we worry about. So, it was not the majority of patients, it was the minority of patients.

DR. LOVE: Is this now going to be taken into a Phase III setting?

DR GRADISHAR: Yes. It was a relatively small study that we have end-point results on. The discussion that we've had since these results are available is a great deal of enthusiasm about the response rate and tolerability. The decisions going forward is whether we want to look at this in a randomized fashion, whether there's a commitment to do that, and whether there are resources to do that. As I said earlier, the Taxotere-Xeloda combination has generated enough interest that it's now gone into the adjuvant setting.

DR. LOVE: It seems like a logical thing to look at. Has anyone else looked at this combination?

DR GRADISHAR: No, not exactly as we conducted this trial. No.

DR. LOVE: What are you doing right now in terms of your practice in terms of patients with metastatic breast cancer and the use of either one of these combinations?

DR GRADISHAR: This trial just closed, but what we had been doing is trying to encourage them to go on the trial. Off of the study, what we generally recommend to patients with metastatic disease, unless they have rapidly progressing visceral disease, is that we have a practice of generally trying to optimize single agents in a sequential manner. I think that there is a rationale for considering combination chemotherapy, and it's perfectly reasonable in a patient who has rapidly progressing visceral disease, where your need to get high response quickly is important. We also recognize that when you use combination therapy, although you may be able to increase the response rate somewhat, depending on the combination you use, almost inevitably there are greater side effects with that combination. And that's not untrue with either of the trials that I spoke about earlier, paclitaxel-Xeloda or Taxotere-Xeloda. There are higher toxicities with those combinations, but at the same time, higher response rates.
Now, the Xeloda-Taxotere combination has been demonstrated to have a superior survival outcome, and it's one of the very few trials that have ever demonstrated that. So, I'm not trying to minimize that. But if you look at other combinations or other treatment approaches, few of them if any, have ever shown a survival advantage. So, for the select patient who has a good performance status, I think the combination of Taxotere-Xeloda or paclitaxel-Xeloda is perfectly reasonable. But, again, I think an alternative option is to be using optimal single agents sequentially until the time of disease progression. There have been numerous studies that have looked at that question of combination versus single agent, generally showing similar outcomes and better tolerability with single agents in terms of quality of life. So, I think, it's still somewhat of a philosophical difference on how people approach patients with metastatic disease.

DR. LOVE: You mentioned the issue of toxicity. I've heard people say, "Well, by adding in the Xeloda, you're really not - and being careful about the dose and informing patients about hand-foot syndrome - that you really aren't increasing the toxicity." What's your actual clinical experience with either one of these combinations? Do you think that they actually are more toxic than single-agent taxane therapy?

DR GRADISHAR: Well, I think they are somewhat more toxic, at least as they're prescribed in the original clinical trial. There is an excess of side effects that you wouldn't see with either single agent alone. I think they're manageable. I think that if you know how to dose adjust, you can make patients better in terms of their side effects. I think the question is: How much of the side effects are worth paying for, in a sense, to achieve a somewhat higher response rate? And I'm not, again, minimizing the survival advantage. It's real. It's there. But there's a cost to it.

DR. LOVE: Another point of view I've heard is: Even in a patient who doesn't have rapidly progressive disease, the key determinant to quality of life is tumor control. Even if in the long run there isn't a survival advantage - although at least in this one case there was - but even if there weren't, by having a higher response rate, greater tumor control earlier on, that, in fact - and I think even in the Xeloda-Taxotere study they've actually tried to do some quality-of-life measurements - even bringing in the increase in side effects because you get greater tumor control, that overall balances out to having a better quality of life.

DR GRADISHAR: That's a reasonable argument. I think it has to be looked at critically, and there are people who do that for a living, where they actually try and measure the time with symptoms versus the time without, which would hopefully reflect the therapy controlling the disease or making it better. And if the cost in terms of side effects exceeds the time where you're free of symptoms because of the therapy, then I think it's a net loss for the patient, in a sense. But, if the time without symptoms related to the disease or improvement in symptoms that can be attributed to the therapy outweigh the side effects of the therapy, then I think that argument is valid.

DR. LOVE: Let me bring in one final issue that I think ties in. If you're going to take the philosophy of, let's try to find a therapy that has the least side effects, but still reasonable tumor control. Why not use capecitabine first if you're going to use sequential therapy, and then follow it by a taxane?

DR GRADISHAR: Well, I think that's an interesting question, and one that I just left a discussion about. I think it's very reasonable. As you know Xeloda was approved more or less as a salvage therapy. And it showed activity in patients who were refractory to more conventional therapies. I have absolutely no reason to think it wouldn't be effective up front as an initial therapy, certainly, in select patients. It may be the best reasonable choice for somebody who's not going to be able to come in, who's reliable enough to take a pill, who just doesn't want IV chemotherapy, whatever the rationale. There are probably some patients in who that would be a perfectly reasonable issue or patients who've progressed after having adjuvant anthracycline-taxane therapy. So, it sort of fits that position, as well.

DR. LOVE: The other issue would be side effects. With the aromatase inhibitors, the original reason - the actual, initial second-line studies didn't even show an advantage compared to megestrol acetate, but it was the side effects. You would expect that capecitabine would have fewer side effects than taxanes.

DR GRADISHAR: Right. And again, I suppose that depends on the dose that's selected. And I think that if you start out at the approved dose and make an effort to try and maintain the patient there, some will be able to do it. Many patients will have to have a dose reduction. And at a reduced dose, they may tolerate it very well and the outcome, quite frankly, may be very similar to a taxane. But I think the issue in first-line therapy is: Can you make it equally effective with fewer side effects than some of the other alternatives available? Certainly, with the taxanes, there are numerous ways of giving them. You can give them weekly. You can get away with a lot fewer side effects, perhaps. But there is a big advantage in many patients' minds about getting an oral agent, if you can demonstrate it's effective.

DR. LOVE: You mentioned there are some situations where you use capecitabine first-line. What kinds of clinical situations?

DR GRADISHAR: Well, I think for a patient who has progressed on anthracycline-taxane adjuvant therapy that would be a perfectly reasonable choice for a patient who is adverse to the idea of getting IV chemotherapy. There are a few that may be that way, patients who just like the idea of something oral as opposed to IV. I think there are select patients.

DR. LOVE: One other issue I wanted to ask you about is, at your meeting, the Lynn Sage Breast Cancer Symposium, you gave a lecture reviewing where we are in aromatase inhibitors. That was only a couple of months ago. Things have changed.

DR GRADISHAR: Yeah. It's an interesting time, actually. There's been a lot of interest in the ATAC trial, which was presented just yesterday. And my guess is, as a result of those results, there are patients all around the country asking their doctors what they should be doing today. And there are numerous different scenarios that one can envision. First of all, I think it's important to emphasize - and I'm sure others have - that although the results are extremely interesting, they're still early. They really looked at postmenopausal patients, not premenopausal patients. They looked at patients largely who did not get chemotherapy, although there were some in the trial, about 20 percent that did. And we don't know anything about that subset yet. We don't know anything about patients who may have been on tamoxifen. The trial was designed for patients who were essentially naïve of any other adjuvant therapy.
So, the scenario that I'm describing is today, women who have been on tamoxifen for six months, two years, three years, are now asking their physicians if they should switch. And the results we have based on the ATAC trial don't address anything of that nature. So, I think we have to be very cautious in extrapolating early results from the ATAC trial, which are very interesting, and I was impressed by, quite frankly, and then applying those results to every single woman that we're seeing in practice right now.
Tomorrow I may see a woman who's getting chemotherapy, who will ultimately go on tamoxifen. Should I extrapolate that by giving her an aromatase inhibitor, the results will be identical to the ATAC trial? I don't know, because relatively few patients in the ATAC trial actually got chemotherapy, and we haven't heard the results of that subset yet. We don't know anything about patients who've been on one, two, three or four years of tamoxifen. I think the issue is more relevant and more germane if we see a new patient who's postmenopausal who walks through the door and is destined for adjuvant hormonal therapy. How would you apply those results to that woman? And I think it would be fair and honest that we should discuss them with all the caveats. I think it would be a consideration to put a patient on an aromatase inhibitor. If we were using evidence-based medicine, if you were ultimately going down that path, I would likely use the drug that was used in the ATAC trial, Arimidex.

DR. LOVE: I want to dissect out a few of the things that you've just talked about. Let's start with the scenario that you first mentioned, which is the issue of the woman who's on adjuvant tamoxifen. I'm hearing a lot of people say the same thing that you're saying, in terms of we don't really know what's going to happen. On the other hand, even before the ATAC trial, there were women who were having problems with tamoxifen, hot flashes, whatever kinds of symptomatology, or maybe they get a deep vein thrombosis. Do you think that now you'd be more likely to switch those patients over?

DR GRADISHAR: Those patients, even in a very limited fashion, I have put on an aromatase inhibitor as adjuvant therapy prior to yesterday's presentation. And the rationale before yesterday was simply that looking at all the data from the metastatic disease trials, it was clear that the aromatase inhibitors were very effective, at least as good if not superior to tamoxifen as first-line therapy. So, although somewhat of a leap, somewhat of an extrapolation, it was at least rational for the women who's not tolerating tamoxifen and you felt she needed adjuvant therapy, to put her on an aromatase inhibitor. So, I had no qualms about that. And I think, going forward, there's even more basis for doing it, if you had that kind of patient. Because now we have a 9,000-patient trial that's at least showing early on that there is a clear advantage for Arimidex.

DR. LOVE: The other issue that you brought up was the question of chemotherapy and a woman who's getting adjuvant chemotherapy. It's true that at this point we don't have data. I think we have to see pure data to make pure decisions. But, on the other hand, we know from having seen with tamoxifen, that there seemed to have been an independent effect. Is there any reason you think that that would be different with an aromatase inhibitor?

DR GRADISHAR: There's nothing I know. And there's certainly no data that was presented from Professor Baum's presentation yesterday, that would suggest anything to the contrary. But I think that we have a snapshot of the data. And 20 percent of the patients in each of the treatment arms in the ATC trial received chemotherapy, which really reflects about 600+, 600-700 patients per treatment arm. And if we look at the overview analysis, chemo-hormonal therapy in receptor-positive patients, there was almost an additive effect. One would hope that we would see a similar finding in the chemo-Arimidex arm. But I think, because all of our data is with tamoxifen, it is a bit of leap to know that it will be exactly the same with Arimidex. I don't have reason to think otherwise biologically, but we just don't know.

DR. LOVE: Right. And you'd like to see the data, which is completely understandable. The other issue that you mentioned, which is certainly going to be a question, is the patient who's just about to start adjuvant therapy, or adjuvant hormonal therapy. And you said that you have to present the data to them. But on the other hand, I think most people are going to turn to their physician and say, "Well, what do you think?" And what do you think their answer is usually going to be?

DR GRADISHAR: Well, I think the caveat is that we have thousands and thousands and thousands of patient years' experience, decades of follow-up in many of the patients who have been on tamoxifen trials. We have - I don't remember if it's 2.2 years, something of that nature, follow-up of this single trial that's large. So, that's sort of a hedge. But I'd always reinforce that point. I think, if the woman was otherwise appropriate, postmenopausal, ER-positive, that Arimidex would be a consideration in such a patient.

DR. LOVE: What about the patient who starts out adjuvant chemotherapy, being premenopausal, and is postmenopausal by the time she finishes her chemotherapy and ready to start hormonal therapy?

DR GRADISHAR: That's the same sort of patient I think we've just described. If you know for sure that she's postmenopausal by her hormonal profile, I would view her as postmenopausal. And then I think the same discussion I just had with the other lady, who clearly is by age, postmenopausal, would apply. I think there are some other issues we don't know about in the ATAC trial, as well. And that is: What are the long-term effects on bone? And the patient you just described, if she's quite young and is rendered postmenopausal by chemotherapy, her long-term may be 30-40 years. And what would be the consequence of depleting calcium from her bones at that much earlier age, compared to somebody who's 70? So, I think we need more information about bone fractures, et cetera, from the ATAC trial, to know exactly what we're doing.
There was another presentation just as an aside looking at the use of bisphosphonates. This has been raised as a natural progression of the ATAC trial, or the ATAC strategy. If it does look like the aromatase inhibitors truly are a step forward then we have to start looking at, perhaps, aromatase inhibitors plus a bisphosphonate to try and not only provide benefit in terms of risk reduction for cancer, but maintaining their overall quality of health.

DR. LOVE: Right. You're talking about Trevor Powles's clodronate presentation.

DR GRADISHAR: Right.

DR. LOVE: Where there were actually fewer bone mets and greater survival seen?

DR GRADISHAR: Right.

DR. LOVE: And, of course, the NSABP is studying that right now.

DR GRADISHAR: Right.

DR. LOVE: In a trial setting.

DR GRADISHAR: So, not only looking at bisphosphonates for the purpose of potentially reducing disease progression or recurrence, but also just maintaining bone density, if you happen to be depleting bone density with an aromatase inhibitor.

DR. LOVE: There were a number of presentations by different people that I started to see connections to in terms of questions that came up or would come up because of the ATAC data. And another presentation was Nancy Davidson updating her Intergroup study of adjuvant chemotherapy, ovarian ablation and tamoxifen. Has that been a strategy that you've been using in women who are premenopausal, get chemotherapy, and are still menstruating afterwards, using ovarian ablation?

DR GRADISHAR: We talk to women about that, and our discussion is based to a large extent on the results of that trial. I think it's still not the standard of care. But I think if you have a woman who's young - and Nancy actually showed some of this data yesterday in the youngest cohort of patients - and they have a high risk of recurrence, then I think it's at least worth discussing the potential of doing ovarian ablation in that trial. She was also careful to say that one of the perhaps, flaws of the trial was there was not a CAF followed by tamoxifen alone arm. We don't really know what might have been achieved with that, short of performing ovarian ablation. Sort of continuing along that theme, if you have a very young woman that you render postmenopausal decades before, or ten years before, she was intended to become postmenopausal, we also have to take into account what other health problems she might develop; again, issues like bone density, cardiovascular risk, et cetera. So, I think if you're going to do ovarian ablation, or suggest it in a woman, you want to make sure her risk of that recurrence is high enough to justify that. If you have somebody with a low-risk, node-negative disease situation, chemotherapy may be adequate to reduce her risk. And adding additional maneuvers onto that may be outweighed by the side effects down the line.

DR. LOVE: Yeah. I think this whole discussion that we're having in terms of the ATAC trial and ovarian ablation, as always for the last 10-15 years, in the background is the risk of recurrence. And as you just mentioned being concerned about some of the other side effects is less of an issue when a patient's at very high risk, node-positive, et cetera. The one thing that I saw, that I hadn't seen before and I thought was really striking was the disease-free survival curves in the CAF-only arm, comparing the women who became menopausal to those who did not. There was really an interesting separation. Maybe there's some other explanation for it, but I hadn't seen that before. That was kind of impressive.

DR GRADISHAR: And if I'm correct, what it showed is those that became amenorrheic had a better outcome than those that did not.

DR. LOVE: Exactly

DR GRADISHAR: That mirrors other reports that have been in the literature for the last 20 years. It also builds on the theme that if you can potentially render those women postmenopausal and make them amenorrheic with some of the maneuvers in the other arms, that you may change the curves. That's actually what she sort of showed in the subsequent slides.

DR. LOVE: Right. It was kind of a consistent theme.

DR GRADISHAR: Right.

DR. LOVE: As you mentioned, there are other - she talked about other sources of data in the same direction. And I think she alluded to the question of where the ATAC trial's going to fit in right now. But, the natural question that popped into my mind as I was watching her presentation is the young patient with multiple positive nodes, strongly ER-positive, who does not become amenorrheic after chemotherapy, where you very well might want to use an LHRH agonist or ovarian ablation. Normally, you would follow that up with tamoxifen.

DR GRADISHAR: Right. And I think in that setting, based on what we know, at least theoretically it makes sense to consider an aromatase inhibitor based on all the trials, metastatic, adjuvant now, that we've heard about.

DR. LOVE: It seems like there are a lot of people who have used that kind of strategy of an LHRH agonist, particularly plus an aromatase inhibitor in the metastatic setting. Is that something you've done?

DR GRADISHAR: Yes, I have. And, again, for a better tolerated therapy with potential - meaning an endocrine approach - with no clear compromise on outcome. That's a very reasonable thing to consider.

DR. LOVE: You talked about "an aromatase inhibitor" earlier. You said that we have the data for Arimidex. Can you talk a little bit more about your thoughts on that? I assume that you use other aromatase inhibitors in the metastatic setting. There are three on the market.

DR GRADISHAR: Right. I use all three: Arimidex, Femara and Aromasin - anastrozole, letrozole, and exemestane. And the data is strongest, clearly - or most compelling - for letrozole and anastrozole, certainly as first-line therapy in metastatic disease. I think they all can make a strong argument as second-line therapy. There's some data that I actually pay attention to that suggest that the classes aren't completely cross-resistant. A patient, who's gotten a non-steroidal Arimidex or Femara, and then progresses, I think it'd be reasonable to consider exemestane to follow. Going forward into the adjuvant setting, if you're driven by data, the data is with Arimidex. And I can envision, and I imagine, that physicians will extrapolate the metastatic disease data and consider letrozole as an alternative to Arimidex as an adjuvant. It may turn out to be exactly similar to Arimidex in the ATAC trial, but we just don't have the data yet.
One of the most important trials that's ongoing - and we actually had a long discussion about this last night in a separate venue - is one of the trials in the adjuvant setting that's incorporating letrozole. It is tamoxifen alone versus letrozole alone versus a sequence of either tamoxifen followed by letrozole or letrozole followed by tamoxifen. That trial's probably critical because it's going to mirror, in a sense, what I envision happening tomorrow around the country. Meaning that people are going to start, after a couple of years of tamoxifen, just putting their patients on an aromatase inhibitor and we don't really have any data to tell us whether that's good, bad or the same as the ATAC trial. So all of a sudden it is important that that trial gets done because it's going to reflect a treatment arm of what's actually going on in the community I bet.

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