DR. LOVE: Welcome to Breast Cancer Update, this is Dr Neil Love, and later on in the program, we are going to take what should be a very interesting departure for this series, a multifaceted exploration of an actual breast cancer case. First, from the perspective of the treating oncologist, Dr Kevin Fox, and then from a variety of other physicians, both in the community and tertiary care setting. As usual on our series, the accompanying print web guide and breastcancerupdate.com contain a great deal of additional information on the topics discussed on the audio program, including additional comments from our speakers. Breast Cancer Update has always focused on the interface of clinical research and patient care, and for several decades, Dr Steven Jones, has been at the center of many of the major steps forward that have been made in the adjuvant and advanced disease setting. During our conversation, Dr Jones reflected on some of major research advances that have impacted daily practice, and he began by commenting on the use of bisphosphonates in patients with metastatic disease.

DR. JONES: That's made a huge difference, and it's not really talked about a lot. They're commonly used, but I see patients, too, with bone disease, where they're not used. I basically use IV bisphosphonates in every single patient with metastatic breast cancer to bone, whether it's lytic or blastic, primarily because most patients have some lytic component. When those studies were done, they were done just arbitrarily on patients with potentially major lytic lesions. But my experience is, that really has been a big difference. The end result is for the patient with metastatic breast cancer, who has bone disease, after they've been on IV bisphosphonates for two to three years, what I see happening now, which you never saw it before, is that they progress in other organs. They don't progress in bone. Bone disease is well controlled. Liver metastases might progress. You might have to change therapy based on that. But I think that's a major advance.

DR. LOVE: How does that translate into the kinds of symptoms that people have as they move towards the end?

DR. JONES: Well, there are two aspects. First, I virtually never see hypercalcemia in breast cancer patients these days, because they get IV Aredia from the beginning, unless they presented with hypercalcemia. But once they've been on IV Aredia, you just don't see hypercalcemia. So, that's an important thing. Because in the past when you didn't have this, if they progressed, they'd come in, have more pain, have hypercalcemia, might end up being in the hospital. So, that keeps patients out of the hospital. And the second thing is, they have much less overall bone pain. Now, some patients still have bone pain and have fractures and things, but really less morbidity from the bone disease. So, that's a real plus.

DR. JONES: The second area where I've seen really major development has been in hormonal therapy. We have some great new agents based on very good science. There's some very good agents soon to be approved or probably in the next couple of years. This is going to be one of the major breakthroughs for managing patients with metastatic breast cancer. Someone is going to sort out mechanisms of resistance to hormonal agents and ways to prevent that resistance. So, if you had somebody, for example, on an AI, who is responding, and you could figure out how to prevent that cancer cell from becoming resistant to treatment with an AI, they could be on that for a long period of time, maybe indefinitely, with just stable disease, relatively asymptomatic. That's going to be a major breakthrough coming up.

DR. LOVE: That's funny. Sometimes I think that people underestimate the potential impact of hormonal therapy because it's been around so long. It doesn't seem so high-techish, but it's pretty targeted therapy.

DR. JONES: It's very targeted therapy. It's much more targeted than Herceptin and HER2/neu. It's much more likely to respond. Everyone kind of forgets the data that McGuire published years ago. If patients were ER-PR positive, for example, there was a 70 percent chance they would benefit from hormonal therapy. Everyone seems to have forgotten that fact. But, you really can predict exactly who's going to respond, and you have a very high likelihood of that patient benefiting from hormonal therapy.

I grew up in an era in which the only treatment for metastatic breast cancer was hormonal therapy. We had no chemotherapy. We did have radiation therapy for bone metastases, but it was hormone therapy, some radiation therapy, and that was the only treatment. So, I was very accustomed to using hormonal therapy. And what's happened in the last decade is, we have all these great new agents that work really well with virtually no side effects, and these can replace some of the agents that used to have more side effects, like androgens and Megace. I still use those, but much less. And I moved them down the list of hormonal agents.

DR. LOVE: The other thing about hormonal therapy - and now you've been involved with clinical trials your entire career and you've seen this evolve, is the way that we do trials is different. I think we can become much more attuned to the issue of stable disease/clinical benefit. Patients who clinically are getting better, but yet you are only going to call them stable disease. If you look in some of the textbooks, the numbers that end up getting quoted a lot for the older hormonal trials were objective responses.

DR. JONES: Yeah that's true. A third of the patients have bone-only disease, maybe 60-70 percent of patients have bone involvement when they have metastatic disease. We all know that bone is very hard to measure. And basically, I think, you can't. But as a clinician, you put somebody on a hormonal agent, bone pain goes away. They get up out of their wheelchair. They're walking around. They stop taking pain pills. They've clearly benefited. X-rays and scans may show stable disease. So, clinically, every one of us is aware that patient's better, and the patient's aware they're better. It's just very hard to prove it for a clinical trial.

So, you're right. I think that even the FDA has accepted this, and a couple of the last hormonal agents to get approved have accepted stable disease more than six months as part of "clinical benefit", which includes objective responses as well as long-term stable disease.

DR. LOVE: I know you give lectures a lot to physicians in practice. What do you see in terms of the use of hormonal therapy in clinical practice, and do you think there's any sort of education gaps? Or how do you see people using hormonal therapy in clinical practice?

DR. JONES: I see that hormonal therapy is under-utilized in clinical practice, for a variety of different reasons. I've encountered oncologists who never use hormonal therapy. They just use adjuvant tamoxifen. As soon as that patient progresses, they go right on to chemotherapy. That, in my view, is a mistake. If you select your patients, 60 to 70 percent of patients can benefit from hormonal therapy. And that's as good as anything we do in current medical oncology. If the difference were that you give chemotherapy and the patient's cured, versus hormonal therapy and they're not cured, that would be the obvious answer, why you'd go to chemotherapy. But the name of this is palliation and trying to keep the patients as comfortable and as functional as long as possible.

DR. LOVE: What do you think the reasons are that people don't use hormonal therapy as much as you do?

DR. JONES: Well, I think that the prior hormonal therapies were fairly noxious. In my training days we did adrenalectomies, we did hypophysectomies. Those were major, fairly brutal surgical procedures with a lot of morbidity. And then the first AI that we had, for example, was aminoglutethimide, and that drug had a lot of side effects. Patients needed to take cortisone along with it. Then we went on to Megace with fluid retention. We went on to androgens, and women certainly don't like to take androgens, although these agents worked.

Now I think we have a group of agents that really are much better, with many fewer side effects, and yet I think a lot of oncologists remember hormonal therapy as something that they did before they really had the access to chemotherapy. I think it is a mistake to skip over hormonal therapy and go to chemotherapy, because you may never get a chance to come back and do hormonal therapy. But that is another area that I use hormonal therapy. Some patients have come in with fairly symptomatic, rapidly progressive breast cancer; they need chemotherapy. You put them into some degree of remission, you may well be able to stop their chemotherapy, give them a chemo holiday, at the same time put them on one of the new hormonal agents, and keep them in remission for a fairly long period of time.

DR. LOVE: So, you're saying in that situation that you would actually stop the chemotherapy even without the patient progressing?

DR. JONES: Correct. And switching them over to a hormonal agent, trying to give them a break off chemo. And I've been successful doing that, sometimes for a year, two years.
And the other thing is, if they have bone disease, I keep giving them an IV bisphosphonate on a monthly basis. That, plus hormonal therapy, is certainly great treatment for bone disease.

DR. LOVE: It's interesting. I know that that strategy, from having done keypad polling at meetings with oncologists, is commonly used by oncologists in practice, and yet you don't really see it talked about very much in textbooks and even review articles.

DR. JONES: No, you don't, because when you put up the kind of algorithm for treating breast cancer, it's hormonal therapy, going through all the agents first, then on to chemo. But in a practical setting - I mean, patients always want to know, "How many of these treatments do I have to have," when you're giving them some type of chemotherapy. A lot of patients are looking for a way to stop this, at least for a period of time.

DR. LOVE: The issue I see in terms of chemotherapy versus hormonal therapy is in visceral disease. It seems like even seeing a couple of lesions in the liver on CAT scan, almost any kind of visceral lesion, seems to trigger a visceral reaction in the oncologist to go to chemotherapy.

DR. JONES: That's right, and I think that's another potential error. If you've got the right clinical setting, ER-PR positive breast cancer, visceral disease or non-visceral disease, I really don't think it makes a difference. I can show you lots of examples in my practice of patients who have multi-site disease, bulky disease, who are relatively asymptomatic. They have a slow tempo of disease, who are ER-PR positive, who have gone to a hormonal agent and have long-term disease control with a hormonal agent, despite having 6- centimeter, 7-centimeter lesions in their liver. Now, there are other patients who are sick and need chemotherapy and you couldn't get away with this. So, you really have to pick your patients very carefully. But, it does work well for visceral disease.

DR. LOVE: I'm curious about your thoughts about another hormonal strategy, that we're going to probably see some results on fairly soon, which is the issue of combination hormonal therapy. It really got written off a long time ago although I think the trials that looked at that were the older, smaller kinds of trials. Of course, now we've got the ATAC Trial that's going to be coming out pretty soon, looking at a combination of Arimidex and tamoxifen. Any thoughts about that concept?

DR. JONES: I think it's going to have to be explored again. We've learned a lot over the years. We've gone from these really small trials to these huge trials, which can really detect fairly small differences. I think that with these new hormonal agents, the combination's going to have to be looked at again.
The other thing that's going to have to be looked at is, the idea of potentially - since we don't right now know how to overcome or prevent resistance to hormonal agents -alternating hormonal agents and seeing if we can prolong remission.

Estrogen is still a very useful agent, it's just not available or used in the United States. It is used in other countries. And potentially doing an anti-estrogen, doing an AI, doing estrogen, doing an estrogen receptor down-regulator, in six month blocks compared to just one agent until it fails, may end up being a better strategy. I think we're going to have to design some trials to look at alternating these agents to try to avoid resistance.

DR. LOVE: You're talking about high-dose estrogen?

DR. JONES: Generally high-dose estrogen, yes.

DR. LOVE: Actually, one of the things that I've heard from some of the investigators I've talked to recently is the idea that once a patient's progressed through an AI, that maybe their tumor cells have been able to adapt to the real, real, real low levels of estrogens. And once you stop the AI the estrogen levels come back up naturally. Maybe there's a similar kind of pharmacologic effect.

DR. JONES: That's possible.

Another area of hormonal therapy we need to look at are the AI's in premenopausal women. There is basically no data on these agents. If you remember way back when, we didn't think tamoxifen would work in premenopausal women, but it does. But it doesn't work as well as it does in an estrogen-deficient environment. So, we learned over the years that, if you give tamoxifen, for example, in a premenopausal patient with metastatic breast cancer, you have to suppress ovarian function to get maximum utilization. But we need some studies with the AI's plus or minus ovarian suppression, to see if they work. You might be able to actually get some benefit if you increase the dose of the AI in the premenopausal woman.

DR. LOVE: I think there have been some pilot studies or single institutions, small studies looking at ovarian suppression, making the woman essentially postmenopausal, where Ais have shown pretty good response rates. Is that a strategy that you've used clinically?

DR. JONES: It is. In fact, if I see a patient I'm going to start on an AI who is still premenopausal, I do suppress ovarian function. Right now, you have to do that, because we only have data of AI's in postmenopausal women. On the other hand, I think it's an area that really needs to be studied. Could you potentially treat a premenopausal woman by increasing the dose of one of the AI's to get estrogen suppression? I don't think anyone really knows the answer to that.

DR. LOVE: So, if you see a woman who you want to use hormonal therapy, ER-positive - the kinds of criteria that you were talking about before - who's had, for example, adjuvant tamoxifen, what's the strategy you'd use?

DR. JONES: Well, there are a couple of aspects of this. One, if a patient is higher risk - and to me, that's women with positive nodes - I keep patients on tamoxifen much longer than five years. I hear some of my colleagues discussing all the theoretical reasons why that's not a good idea, but, in fact, in my practice in the last 20 years of doing exactly that, I've had great success keeping high-risk women on tamoxifen much longer than five years. Do I know if that's right? I don't know. But I also don't think the issue is settled. So, I'm far more likely to see a patient seven or eight years later, who recurs, who is recurring on tamoxifen, where I have to then treat them with an AI.

DR. LOVE: So, in that situation, if the woman's still menstruating?

DR. JONES: Well, the patients that are on long-term tamoxifen, longer than five years, generally are not going to be menstruating, because somewhere in that time they've likely gone into menopause. The younger women who I give tamoxifen to are usually node-negative, they might still be menstruating for five years. I stop the tamoxifen at five years in that group of women.

DR. LOVE: What's a typical clinical scenario in a premenopausal woman where you'd use an AI plus ovarian suppression?

DR. JONES: I'll give you an example. There's a young woman in my practice. She had a small node-negative cancer, ER-PR positive, low S-phase. I think that kind of patient actually does not need chemotherapy. We've recently reported our data on this. This is a cancer about 1.5 centimeters, low S-phase, that patient has less than a five-percent chance of recurrence. Unfortunately, this was one of those young women who did recur about three years out with liver metastases. At that point she was still menstruating. My strategy there was a little bit different, because I think she developed metastatic disease on tamoxifen, still menstruating. At that point, I suppressed ovarian function and continued the tamoxifen for a period of time.

She actually benefited for about two years. Now, alternatively, based on the data with AI's versus tamoxifen first-line metastatic breast cancer, my strategy today would be to suppress ovarian function and put her on an AI, rather than keeping her on the tamoxifen, just because I think these agents work better for metastatic disease.

I think ovarian suppression can be with one of the LH-RH agonists or can be oophorectomy. That's highly negotiable with each individual patient. These younger women often don't want to go for immediate oophorectomy. That's still very good treatment. But there are a lot of issues to deal with, with some of these young women. So, I think that an LH-RH agonist is a good way to kind of bridge the gap. This particular patient was on an LH-RH agonist for about a year, plus she stayed on tamoxifen, but now it would be an AI. And I think at the end of a year, she negotiated a time when she could take some time off from work and have an oophorectomy and then she could stop taking the LH-RH agonist.

DR. LOVE: What about AI's in the adjuvant setting? Have you had any patients where you wanted to give adjuvant tamoxifen, but there was a contraindication or a situation where the patient couldn't tolerate it, where you substituted an AI?

DR. JONES: Yeah. I think we're moving very quickly to probably using the AI's in the adjuvant setting. As you know, there are lots of big clinical trials. The ATAC Trial has 9200 women enrolled. The first results of that are going to be presented this year at San Antonio. No one knows what those results are yet at this point in time. And there are other trials that are under way, and these are all large trials, 4000+ patient trials. I'd be very surprised if the AI's don't show superiority to tamoxifen in these studies, but that remains to be seen.

As we are moving closer, I certainly see oncologists who, for the reasons you describe, either patient tolerance or they've had a fairly recent DVT or something like that, will use an AI rather than tamoxifen. I haven't quite made that leap of faith myself in my practice, but I'm a lot closer now than I was a year ago. And certainly, if someone had a history of a DVT four years ago, I might think about the use of an AI. In the studies with AI's, they're not totally devoid of having thromboembolic events. They are about half the rate they are with tamoxifen. I think some of those patients are sicker patients or have other risk factors for DVT. So, you can't switch to one of these and expect that you're not going to have another possible DVT.

DR. LOVE: Do you have a gut feeling that the risk of DVT in a woman on an AI would be the same as a placebo, or do you think it's actually increased?

DR. JONES: I think it's probably about the same as placebo, but - I don't think it's increased, and certainly, with all AI's, it's about half what it is with tamoxifen.

DR. LOVE: It's interesting, because I can't remember a person that I've interviewed for this series who hasn't speculated that the Arimidex arm was going to be better than the tamoxifen arm in the ATAC Trial and maybe the other adjuvant trials as they evolve for the AI's. But where you really see a lot of controversy and questioning and head scratching is about the combination arm in the adjuvant setting. There you have the issues of both the efficacy, as well as some of the side effect profiles. Any speculations or guesses about the combination arm?

DR. JONES: No. It was actually a bold move to incorporate it, because theoretically, in my mind, the combination might be one of those situations where you could prevent the emergence of resistance to a single hormonal agent. It'll just remain to be seen. I've gotten asked a few times - and I don't quite know what the answer is - "What is it going to take from the ATAC Trial to convince oncologists to use this drug. To switch from tamoxifen to this drug?" What kind of results would really convince us? Obviously, if there's a survival difference, I think then the use of the AI's in the adjuvant setting would become the standard of care.

If there's a modest difference in disease-free survival but no difference in survival, I don't know. If there's a difference in side effect profile - if anastrozole was much better tolerated than tamoxifen - that would be a reason to switch over. I see oncologists doing that. A woman that, let's say, complaining bitterly of hot flashes is going to go off.

DR. JONES: There are a lot of other second- and third-generation questions with the AIs in the adjuvant setting. One question is - Can you avoid the emergence of resistance by switching to another hormonal agent midstream? There's a tamoxifen-letrozole trial that has four arms, of which patients get either tamoxifen or letrozole for two years, switching to the other agent versus either agent just for five years.

And then there's an exemestane trial that we've participated in, where patients get tamoxifen for two to three years and are randomized to exemestane or tamoxifen for the remainder of the five-year period. Both of those are really kind of asking questions about sequence and preventing the emergence of hormonal resistance. So, that's a very interesting question. And then the third question that's being asked - and these studies are even farther behind. The NSABP just initiated the B-33 Trial. This is the first study looking at a hormonal agent longer than five years, other than the B-14, which looked at tamoxifen for five versus ten years. In this trial, they're looking at two years of exemestane versus placebo. There's a similar trial with letrozole that's five years of letrozole versus placebo. The MA-17 trial that a lot of the U.S. cooperative groups are participating in looks at what's the effect of one of the AI's after five years of tamoxifen?

DR. LOVE: Kathy Pritchard brought up an interesting point . What if the ATAC Trial's positive and Arimidex then becomes or AI's then become first adjuvant therapy, are these other trials going to become antiquated?

DR. JONES: That's a concern for those of us who are in the middle of all of these. The tamoxifen followed by exemestane versus continued tamoxifen trial, the accrual on that one is just about complete. So, that study will get done. Some of these others that are halfway through in their accrual or just starting out on their accrual, it's going to be a big issue. Like with NSABP, that study is just starting. So, again, it depends what the results from the ATAC Trial are. If they're so overwhelmingly convincing, then I think these other studies will have trouble being completed. But, there are a lot of worldwide differences. We have been talking about hormonal therapy in the United States. In Europe, Australia, elsewhere, they use lots of hormonal therapy, they're not in a rush to go to chemotherapy. They really don't know why we use all the chemotherapy we do. A lot of patients don't even get adjuvant chemotherapy. But they're very, very keen on giving hormonal therapy. So, I think that's where we see a lot of the developments coming from hormonal therapy. And they don't really understand why we don't use as much hormonal therapy. So, I think some of these studies, even though they might have a slowdown on accrual in the United States, I think they will probably be completed in other countries.

DR. LOVE: You were talking before about the idea of combination endocrine therapy as a way to potentially prevent resistance. Biologically or intuitively, does it make more sense to give both types of therapy up front together or the sequencing?

DR. JONES: I don't know. That's a good question. I don't think anyone knows an answer to that. I think that ultimately what we're going to find is someone who is doing studies on the molecular mechanism of resistance figuring out why that occurs and how you can block it. And we'll be adding another pill of some sort or injection or something to block the emergence of hormonal resistance. Because, really hormone therapy is the first biologic therapy. Herceptin usually gets that designation, but if you think about it, you've got a predictive test that tells you who's going to benefit. And you've got treatment that stops the growth of cancer and produces long-term stable disease as we've talked about. It really is biologic therapy. If you could figure out how to avoid the emergence of resistance to that therapy, then patients could live a very long period of time on these agents.

DR. LOVE: As you pointed out earlier, the response is actually higher than with Herceptin in
HER2-positive patients.

DR. JONES: Yeah. Even under the best conditions, the best data, FISH-positive, you get maybe a 40-45 percent response rate. But if you really look at the data on Herceptin, there is a group of patients who have stable disease there. They're not counted, but probably ought to be counted, because those patients have clinical benefit.

DR. LOVE: The other thing about this issue of sequencing is, if you do wait two years or five years to switch to another therapy, there are going to be recurrences within those two years or five years.

DR. JONES: Correct. I think that might generate new kinds of questions - alternating hormonal therapy
every year for a five-year period or a ten-year period. Those studies are just being dreamed about at this time.

DR. LOVE: I've got to get back to something you said earlier. I was fascinated by it. That's the issue of duration of tamoxifen. Because I've seen over the last ten years, there's been an interesting shift in practice. I do keypad questions when I do meetings or I ask people what they do, so I've been able to see that back before the B-14 data came out, people were using it indefinitely. Then since that data came out, there's been an amazing shift towards people stopping therapy at five years. The consensus conference pretty well endorsed stopping therapy at five years. It's always been kind of a curious phenomenon to me, particularly in patients who have multiple positive nodes and are doing completely fine. Maybe you've had a hysterectomy, I mean, the ideal patient. To just automatically stop patients - I rarely hear patients say what you said before, it seems like you have a different viewpoint on that.

DR. JONES: I do. I don't think it's established at all. It was established in the B-14. I think there's no added value for tamoxifen longer than five years in women with negative nodes. That was the B-14 trial. Bernie Fisher and the NSABP in the past have always said, "This is the data. This is the study. Don't extrapolate," but yet everyone has extrapolated to women with positive nodes who are at much higher risk of a recurrence. In my own practice, I haven't extrapolated. I've just continued the tamoxifen. When I tell patients that there are no studies showing it's safe to stop that is a true fact.
I think we have a little of the data from Scotland, where they had some women with positive nodes, but not enough to be definitive, knowing whether longer tamoxifen is better.

Of course, that's the whole basis of the ATLAS Trial that's being run, and I think the British are well aware that this issue isn't settled. Even Sir Richard Peto is aware that it hasn't been settled. Pushing hard in the ATLAS Trial, five versus ten years of tamoxifen in 20,000 women, we all may not live long enough to see those results. But I think that shows that there certainly are people in the world that don't feel this is a settled issue.

DR. LOVE: You talked about some of the things that have evolved in hormonal therapy over the last five or ten years. What do you see in terms of new changes that are going to occur in the next two or three years in hormonal therapy, that affect clinical practice?

DR. JONES: I think there are two or three drugs coming along that really are very interesting drugs and will probably make it to the marketplace. One is Faslodex. It's been considered different things, but it really seems to be a new class of hormonal agent. It's an ER receptor down-regulator. The receptors are destroyed in the breast cancer cell. I think, at least in the North American trial, patients have much longer duration of response with Faslodex than with Arimidex. We know Arimidex is better than tamoxifen, at least, again, in the North American trial, not necessarily in the European trial. So I think that drug is an extremely interesting drug that's going to fit nicely into hormonal therapy.

DR. LOVE: I think you were participating in some of the Faslodex studies. It's an injectable agent? Also, what was your experience in those trials?

DR. JONES: Faslodex is a very well-tolerated injectable agent. It's given as an intramuscular injection once a month. Patients had very high acceptance of that and very few if any kind of local reactions and things. So, it's a virtually non-toxic drug. I had quite a few patients on that trial. I still have several patients that remain on the trial. The code's blinded, but we know from the preliminary results that duration of response was prolonged in the Faslodex compared to Arimidex. So my guess is that my patients who are still on the study are probably on Faslodex, just because they've had, based on what I've seen from the data.

DR. LOVE: Where do you see Faslodex fitting in through the whole algorithm of hormonal therapy?

DR. JONES: Well, we don't know. The AI's first for metastatic breast cancer. But, if Faslodex has longer duration of disease control, that's the name of the game. I think you really would be compelled to consider using that first and using an AI after that drug.

DR. LOVE: What about some of the other new agents that are coming out that you're excited about?

DR. JONES: I think the other hormonal agent that seems to be very promising is SERM3. It's an Eli Lilly drug. It's really a very potent anti-estrogen. We participated in some studies with that, which were recently presented by Aman Buzdar at ASCO. I think that drug may have a little harder time being positioned with the other ones and finding its approval in the United States just because of the availability of other really good agents. But that drug was very well tolerated. Virtually every patient I had on that trial - it was a Phase II trial - seemed to benefit for long periods of time with good control of bone disease. So, I think that's a very intriguing drug.

A lot of these drugs are at least being considered for prevention of breast cancer. That's going to become increasingly a more difficult area, unless we find some way to get some very solid scientific evidence in a small group of women that one of these agents looks like a blockbuster for prevention. We're right in the middle of the STAR Trial with huge numbers of patients. These are such massive efforts, that you're going to have to have fantastic scientific insight to know which agent to pick for the next STAR type trial if you're going to do another 20,000-women trial. So, a lot of people are looking at surrogate markers of prevention. But I think the AI's and SERM 3 and some of these others are really candidate agents for prevention studies.

DR. LOVE: Yeah, actually the AI's are going to be looked at in the prevention setting in Europe, the IBIS-II study. Initially, they're not going to have a combination arm. It's just going to be Arimidex or tamoxifen. Actually, they're going to have a placebo arm, which is kind of interesting, too.

DR. JONES: Yeah. There's always the big debate about why these studies didn't show the same thing as the P-1 trial in the United States, but they didn't have the power of the P-1 trial, and necessarily the same risk groups as the P-1 trial.

DR. LOVE: What are some of the other changes that you've seen in terms of clinical research impacting patient care today over the last 10 years, that have affected your practice?

DR. JONES: Well, we've talked about hormonal therapy. We've talked about IV bisphosphonates. I think the other area really is the development of all the new effective chemotherapy drugs. You and I are around for a long time, when Adriamycin was the only new drug we had for a 20-year period. And now we've got the taxanes. We have capecitabine. We have Navelbine. We have a lot of drugs that you can use. And we get very good palliation out of these drugs.

There's also some emerging data that some of these combinations - like Taxotere/capecitabine - might have a survival advantage compared to just giving Taxotere alone. We haven't seen that up to this point in time, but again, that's a matter of trying to control metastatic cancer, and we have a much bigger armamentarium than we had in the past. And that's a big advance.

We also now have at least the opening era of pure biologic therapy with drugs like Herceptin and others that will be coming along. I do think that we're going to have a lot of these new agents that are probably more static than cytocidal - kind of like hormonal therapy. I think we're going to have to accept that stable disease and a relatively asymptomatic patient is a good thing, particularly if they're stable for a long period of time. If you have somebody that has stable disease for two or three years on a pill or a simple injection and has basically no symptoms that are cancer, that's a really worthwhile kind of achievement.

DR. LOVE: You were talking about the capecitabine/Taxotere study, and I actually interviewed your partner, Joyce O'Shaughnessy about that. What's your take on that trial? I guess the issue there is there wasn't a crossover. But what are your thoughts?

DR. JONES: Well, there was some crossover, because I updated this at ASCO, and Joyce presented this last year at San Antonio. She's really the lead person. About 17 percent of the patients on Taxotere did get capecitabine. From marketing surveys, that's not too different than the frequency of use of capecitabine in this country. So, people say that no one got it, but that's not completely accurate. In fact, close to one-fifth of the patients did receive capecitabine and crossed over.
The study has a very convincing survival difference. Honestly, I was surprised by that, but it's very real. We haven't seen that with the other combinations of taxanes with Adriamycin or Taxotere/Adriamycin and so on. It really hasn't yet been a big survival difference.

DR. LOVE: So, are you taking that into your practice?

DR. JONES: I use it for some patients. I think I give patients a choice. If a younger patient who wants to be very aggressive, I certainly have to present that as an option. An older patient who doesn't want to be so aggressive, doesn't want to have quite so many side effects, you could consider something like a weekly Taxol treatment. That might be a little kinder, gentler kind of treatment. But I think it's definitely got to be one of the therapeutic options.

DR. LOVE: I know one of the points that Joyce brings up, too, is that maybe one of the real impacts of that study point towards the adjuvant situation where we're already using a lot of taxanes. Maybe, with the right dose, to add in capecitabine is not going to add very much toxicity and give you a little bit more of an anti-tumor effect.

DR. JONES: Sure. I think the metastatic setting has always been the testing ground for adjuvant regimens. At least now, you have a solid scientific lead to potentially plug into adjuvant treatment.

DR. LOVE: What's your usual algorithm in terms of using chemotherapy, or do you generally use single agents?

DR. JONES: Up to this point, I've generally used single agents.

DR. LOVE: Of course, I'm talking about the metastatic setting.

DR. JONES: Right. And most patients I've treated, I've treated with Adriamycin combinations, AC. Everyone sort of forgets that Sid Salmon and I developed the AC regimen and published that 26 years ago. It was a different regimen then, than the NSABP uses, but in fact, was still basically the combination of those two drugs. So, in the adjuvant setting, my patients who have gotten AC, I think, have gotten different regimens. So when they recur, I would usually use a taxane as a single agent, unless they go onto a clinical trial. I try to get patients on clinical trials, but sometimes they don't fit for various reasons. Then I would usually use capecitabine and then usually Navelbine. If I've used Taxol every three or four weeks, I might come back and use weekly Taxol then as one of the salvage regimens, or again, put patients into various clinical trials that we might have available.

DR. LOVE: With that sort of 10-year perspective, I guess the introduction of capecitabine as an oral agent is another big difference in terms of what's happened in terms of patient care.

DR. JONES: That's true. And I think we're going to see a lot more oral agents as opposed to IV agents. I'm sure, along the line, there's an oral bisphosphonate that will be studied in breast cancer, as opposed to an IV bisphosphonate.

DR. LOVE: Clodronate?

DR. JONES: Clodronate, but, in this country - and I've done that on occasion with patients - the standard is still an IV bisphosphonate. I think we are going to see a lot more oral agents and oral combinations.

DR. LOVE: You mentioned that usually you go to a taxane before proceeding to other therapies, capecitabine, et cetera. Any situations where you go to capecitabine first?

DR. JONES: I've done that on occasion for a particular patient who might not want to lose her hair again. I think that's probably one of the big advantages. And we actually did a study. Joyce, I think, is the lead person on this, again, of CMF versus capecitabine, as first-line therapy for metastatic breast cancer. They clearly were equivalent. So, I don't think you lose anything by doing that. Again, it's patient selection and what patients' wishes are. I can remember well a patient that had beautiful white hair. It had come back after treatment. She had been in a clinical trial. She had a four-year complete remission with Taxotere. But when she recurred, she really didn't want to lose her hair again. She still had her wig, but did not want to lose her hair. We treated her with capecitabine for about a year. Then we had to do something else.

DR. LOVE: What dose do you use the capecitabine at?

DR. JONES: Well, again, we participated in the studies. I think the dose that got approved is a little too high for most patients. Some patients can tolerate that dose, but I think about 2000 milligrams per meter squared for 14 days is more like it. You have to be very careful with the hand-foot syndrome. During the clinical trials of capecitabine, I saw more hand-foot syndrome in about a two-year period than I had seen in the other 25 years of my career. I thought it was kind of an obscure side effect of the old 5-FU treatments. But once we started using capecitabine, we saw it was a very common side effect. You have to be pretty proactive with that. You really have to stop patients when they start getting fairly significant symptoms.

DR. LOVE: When you do that and you are proactive and educate the patients to look for symptoms, do you see much hand-foot?

DR. JONES: You see much less, and it's very tolerable when you do that. Another thing I do with some patients - certainly, if they're responding I don't keep pushing treatment on an every-three-week basis - I go to every four weeks. That extra time off really helps. I've had patients that I've treated every four weeks with Taxol for four years and had good control of their cancer. And I've had patients for two years on capecitabine. Again, it's kind of a matter of spreading the treatments out to try to minimize, to be proactive and to try to prevent the hand-foot syndrome.

DR. LOVE: Let me get back to the main track of our discussion. There were a couple of other points I wanted to just pick up on, that I was thinking about as you were talking. You mentioned AC and the fact that you developed it or were involved in developing it. I think you referred to using it in the adjuvant situation. Yet there are people like Gabe Hortobagyi who are kind of uncomfortable about AC, as opposed to other Adriamycin-containing regimens, such as his FAC regimen. Any thoughts on that?

DR. JONES: It goes back a long way in history and actually Gabe and the M.D. Anderson group developed FAC at the same time we developed AC. We were kind of doing these in parallel. We published a series of papers on metastatic disease. These were all Phase II studies, kind of uncontrolled at the time. I think M.D. Anderson group's been wedded to having 5-FU in theirs, but wedded to using Adriamycin by continuous infusion for three days. That's their regimen and, by God, they're going to stick to it. I think finally the NSABP discovered AC and kind of modernized it, although the dose of we originally used was even a little bit higher than the current 600 per meter squared. I think the Adriamycin dose has been really well established at the 60 per meter squared. I've heard different people say this. I think the fact is, at least in the randomized trials that AC x 4 is as good as anything that's available. If you look at the CALGB trial using the same doses of 60 and 600 per meter squared for FAC - four courses of FAC at that dose were as good as lower doses given for six treatments, at least that was in the adjuvant setting. So, I think routinely I'll give four treatments. I think there's a big issue of Taxol, and that's a whole other issue. But M.D. Anderson basically never gives less than six or eight treatments. So, that's one of the reasons they feel uncomfortable recommending four treatments, while the rest of us, including the NSABP, is very comfortable using four treatments with AC in the right setting for the right group of patients.

DR. LOVE: I think his argument is that, in general, the trials have shown an advantage in the adjuvant setting to Adriamycin, an advantage over CMF, and that most of those were six cycles. And these four cycles of CA was only equivalent, sort of an indirect argument. Do you buy that?

DR. JONES: Well, it's an indirect argument. I'm concerned that using the older doses of 50 and 500 per meter squared is really under-dosing patients based upon all the other trials that have been done. The CALGB, which came the closest, did the four courses of FAC using 60 and 600, and that was the best treatment out of the three. So, in my mind, those are the right doses of AC to use. I think one of the big issues is how many treatments with AC is needed. Is six better than four? The old Sydney Farber trial of five versus 10 courses of AC was grossly underpowered to show any difference. So, that's really not an adequate study. Studies that had 400 patients in the '70s, now you have studies that have 3000 patients. You can detect much smaller differences. So, I know ECOG is planning to do a trial of six versus four courses of AC, and I think that's one of the unanswered questions. Would longer treatment with AC be of value?

DR. LOVE: I guess the bottom line that I'm hearing is that right now you're using four cycles of AC.

DR. JONES: For a lot of patients. The business of adding Taxol to this is very controversial at the moment. Ourselves, as well as a lot of other people, are in the midst of trials where AC-Taxol is the standard treatment arm, and we're looking at some variation on this. I think accrual, kind of across the country, has been probably hurt. But at the same time, at least - and no one says this - in my own practice, for example, if I saw a patient with positive nodes, ER-PR negative, I would clearly give AC-Taxol. I think that treatment's effective in that group. On the other hand, if I had a patient with one or two positive nodes, ER-PR positive, I can't in my own good conscience at this point in time give them AC-Taxol. I'm going to give them just four courses of AC. A lot of people argue maybe that's not enough treatment. Well, that needs to be settled by a clinical trial. If you don't think that four is adequate treatment, then do a trial of six versus four, or eight versus four. The problem with doing a lot more Adriamycin is you have really increase the risk of cardiac toxicity. With four courses of AC, the risk of cardiac toxicity is quite low.

DR. LOVE: What about the issue of Taxotere versus Taxol? Do you use Taxotere in the adjuvant setting at all?

DR. JONES: We have done some studies where we've used Taxotere in the adjuvant setting. We've actually done a clinical trial that has not gotten a lot of attention yet, but we actually have some data with Taxotere in the adjuvant setting. We presented that at ASCO this year. We've done a clinical trial where we studied Taxotere in the adjuvant setting. At the time we planned this trial, we actually didn't have enough data on Adriamycin plus a taxane to incorporate that combination. So, what we did was a clinical trial of AC x four versus Taxotere- x four. So, there's no Adriamycin in the regimen. We presented the preliminary results at ASCO this year. There's actually significantly less major toxicity with the Taxotere and at least so far, equal efficacy. So, I think that's an adjuvant regimen. The rest of the world is kind of moving to Adriamycin or to Epirubicin-taxane combinations, and that may be where this goes. But we've done this. We have looked at an adjuvant regimen that removed the anthracycline.

DR. LOVE: What about in the metastatic setting, Taxotere versus Taxol?

DR. JONES: I'm still running a trial for our group, U.S. Oncology, that Aventis, the former RPR, sponsored, and that was Taxotere versus Taxol first line. That's kind of the oldest living clinical trial that we have in our repertoire. The trial was opened in 1995, and we have just recently closed it. But it's still open, I think, internationally. It still is one of those questions. I personally think there's probably a difference between the agents, with maybe Taxotere being slightly more active, but at a higher price with some more toxicity. So, I think that study is probably going to close pretty soon, and we will eventually have some data from that trial.

DR. LOVE: Outside the protocol setting right now, what are you doing in terms of choosing one of those two in the metastatic setting?

DR. JONES: I give patients the choice. It depends what the setting is, the age of the patient, their general condition, what they want to achieve. A young patient who wants to be more aggressive, I would treat with Taxotere-capecitabine. A little older patient, I might use Taxol every three to four weeks with a pretty good side-effect profile.

DR. LOVE: On the last issue of Breast Cancer Update we introduced the breast cancer clinical trials supplement that was introduced at the recent Lynn Sage Breast Cancer Symposium, and can be accessed on breastcancerupdate.com. The very first presentation at the Lynn Sage meeting was given by one of the great figures in breast cancer epidemiology and prevention, Dr Malcolm Pike. One very fascinating aspect of this lecture was a review of the effect of postmenopausal hormone replacement therapy on breast cancer risk, and while this information was delivered mainly in terms of the implications for the general menopausal population, as I listened to this fascinating review, it occurred to me that another very important potential group was the breast cancer survivor, where the question of estrogen replacement is a key and daily issue for the practicing oncologist.

Home · Search