DR. LOVE: For the remainder of this program, we utilize a case based approach to explore the art and science of oncology and specifically, management of the woman with metastatic breast cancer. On our last program, we introduced this concept by having Dr Debu Tripathy present a case from his practice. For this issue, not only do we focus on a patient managed by a breast cancer research leader but we also bring in a number of other points of view. Interestingly , when I asked Dr Kevin Fox to select a challenging case of metastatic breast cancer from his practice, he chose a woman who presented at first diagnosis with a primary breast cancer and pulmonary metastases - similar, other than age, to Dr Tripathy's case. In our discussion, Dr Fox discussed the rationale for many of the major decisions made with this woman, and he began by reviewing her initial presentation.

DR. FOX: This patient came to me in 1995. She was 44 years old at the time. She was a premenopausal patient at the time who presented with a left lower inner quadrant breast mass that measured about 4 cm in diameter, but who, on routine preoperative workup, was found to have multiple lung nodules consistent with metastatic carcinoma. So, this was a patient who presented initially to me with metastatic disease. A biopsy of the breast mass disclosed an infiltrating ductal carcinoma that was strongly positive for estrogen receptor and negative for progesterone receptor.
Given the patient's minimal symptomatic state and the fact that she had disease confined to the pulmonary bed after extensive metastatic workup, I treated her with Zoladex as a means of ovarian suppression. And the patient had an objective response - both in the breast and in the lungs - that lasted approximately 26 months on Zoladex alone.

When she eventually progressed after over two years of Zoladex therapy, the patient was now 46 years old, had been amenorrheic for approximately 24 months; it took two months for her to achieve complete amenorrhea. At that point her progression was asymptomatic. Her progression consisted of moderate growth in her pulmonary nodules and a modest increase in the size of the breast mass. And at that point, the decision was made to continue her Zoladex and to add an aromatase inhibitor, which in this case was Arimidex. And the patient actually remained on a Zoladex-Arimidex combination for what was, if I remember correctly, approximately 28 months, during which time she had another objective response to treatment with the reduction in the size of her breast mass and a reduction in the size of her pulmonary nodules.

So, this is an example of a patient who was premenopausal, rendered menopausal by virtue of the administration of GnRH analogs, which was in and of itself an effective therapy for her metastatic breast cancer, and who, at the time of progression was actually continued on q GnRH analog and was given an aromatase inhibitor as a means of extending her response to hormonal therapy. One could argue that two years ago, after she failed Zoladex, that I should have prescribed tamoxifen as first-line therapy, but that's just another point of discussion. I chose Arimidex therapy in this particular case because this patient has a family history - not a personal history - of pulmonary emboli in two of her siblings. Now, I could not confirm this by medical record, but I took the patient at her word that two of her siblings had had pulmonary emboli, worked the patient up for a hypercoaguluable state, or thrombophilia, and found none of the common causes of thrombophilia. But, in this patient with an undefinable propensity towards thrombosis - based on a family history - I thought it most prudent to prescribe that hormonal therapy which was the least thrombogenic; in this case, Arimidex. I should say least thrombogenic when compared to tamoxifen.

DR. LOVE: So she's currently on Zoladex and Arimidex?

DR. FOX: On Zoladex and Arimidex for 28 months. That was discontinued in 2000 when the patient again had progression in her breast and her pulmonary bed. I actually tried to give her Zoladex and Aromasin, but she progressed. In this case, the second aromatase inhibitor was unsuccessful, and the patient was enrolled in an experimental trial of Taxol and liposome-encapsulated doxorubicin, to which she responded. The patient is currently alive and well, receiving chemotherapy with single-agent Taxol.

DR. LOVE: Let me just pick up on that a little bit. You know, it's really interesting the case that I just did with Debu Tripathy was a woman who presented with metastatic disease to the lung, except she was postmenopausal. When I think about women presenting first diagnosis with metastatic breast cancer, the first thing that pops into my mind is someone who's neglected their tumor. And yet, both Debu's case and yours, it doesn't sound like there's any big delay in diagnosis.

DR. FOX: I don't think so. This is not someone who admitted to neglecting her breast mass. I have to say that the mass at presentation was a little bigger than we see on average around here, but since I've now known her for a while, she has been extremely compliant and I, in retrospect, have no suspicions that she was negligent. Having said that, one of the reasons I presented this case is because of the rarity of this presentation. We don't see, as you know, the opportunity to see patients presenting de novo with metastatic disease. It's quite uncommon. If we see 500 new breast cancer patients in this place a year, we might see two or three that present de novo with metastatic cancer. The number seems far lower than the textbooks suggest we should see under normal circumstances.

DR. LOVE: The number that you see in the national statistics is five percent, although that might be even high. I don't know if there are any good demographic studies of these, their ages, clinical presentation. Are you aware of that or any clinical experiences in terms of the kinds of situations where you see this?

DR. FOX: I think the short answer is no. I haven't seen them - I haven't seen population studies that
tried to define the likelihood of presenting with metastatic disease, at least not in this country. The observation that I've made here over 17 years is that patients who present with metastatic disease, where there is a clear history of negligence, incredibly across all socioeconomic groups. This bias I think we have that negligence of breast lesions and the resulting development, untimely development, of metastatic breast cancer is a socioeconomic phenomenon, I think, is a misguided notion.

DR. LOVE: I agree with you. Sometimes I've seen women who take care of themselves. They take care of their family. They work, very responsible. And it's almost like they have one isolated area of denial.

DR. FOX: Yes. Exactly. And I remember a medical school professor who was, above all other things, blunt, when asked - by a well-meaning student - how on earth a patient could ignore something as heinous as a 6-cm fungating breast mass sort of looked at us all and said "Think about it. There's one thing about your own physical appearance, at least one thing that you ignore every day." And I don't think any of us had fungating breast masses, but the point was, we were not in a position to be judgmental and, you know, this is the way people are going to be. We don't see them that often, though, as you know. That is also a rare presentation anymore. We don't see a lot of breast masses that have grown because of patient neglect.

DR. LOVE: The other thing that's kind of curious about this case - and, again, the same thing with Debu's case - is even though it appeared to be a timely diagnosis - although you say it was a little bit larger than normal - it's not really behaving like a virulent ER-negative type tumor. It's almost behaving as if it is an ER-positive tumor, but now she's had over four years of response to hormonal therapy.

DR. FOX: Right. And in that four-year period, she's never had a symptomatic day until I started giving her chemotherapy. Then she had, I'd say, fairly substantial toxicity from her Taxol and liposome-encapsulated doxorubicin combination. Now, granted, it was a dose-finding study. It was a dose-escalation study where you're going to run into toxicity sooner or later, but she happened to have the misfortune of entering the study when we were at one of our higher dose levels. So, she got mylosuppression and she got a bit of neuropathy and she got fatigue and she got some nausea. But up to that point, this breast cancer had behaved quite nicely and had never caused her a day of symptoms, illness, loss of work, anything.

DR. LOVE: What about symptoms from the endocrine treatment? What kinds of symptoms did she get from the Zoladex and did that change at all when she added the Arimidex in?

DR. FOX: When she started on the Zoladex, she got menopausal symptoms. In this patient they were restricted to hot flashes. Were they debilitating hot flashes? Surprisingly, no. She was in her mid 40s at the time, and she had some vasomotor instability, but it wasn't such that it required a lifestyle change on her part. And I have to say that with the addition of the aromatase inhibitor in this patient, that level of symptoms didn't seem to change.

DR. LOVE: Do you think that you've seen, clinically, an association of vasomotor symptoms and aromatase inhibitors in general in post-menopausal women?

DR. FOX: You read the clinical data, and your interpretation of the data may bias your observations. But I have to say that the postmenopausal symptoms - the vasomotor instability for patients who are starting this drug and have had no prior cancer treatment - is in keeping with what you would expect from tamoxifen. That is, most patients seem to get hot flashes. If patients are already taking tamoxifen and are switched to an aromatase inhibitor, which is a much more common scenario for me these days, I can say categorically that the hot-flash patterns don't seem to change one iota. Those that are debilitated by hot flashes tend to remain so. Those who are having modest hot flashes, which is the majority, tend to continue to have them. I really haven't seen aromatase inhibitors dramatically increase or decrease that toxicity of tamoxifen.

DR. LOVE: Let's dissect a little bit some of the decisions that you made along the way. And the first one was to use a LH-RH agonist. Do you think that if this same woman had presented to 100 oncologists in the community, that that is generally what the treatment would have been? I guess
I'm specifically wondering about the choice of chemotherapy versus hormonal therapy in a pre-menopausal woman with lung mets.

DR. FOX: Well, I think that there's a definite - I don't want to speak inappropriately for practitioners, but I think there's definitely a bias away from hormonal therapy in young women with visceral metastases. And I have a bit of a problem with that. I think that in a patient who presents with pulmonary metastases, is asymptomatic and has, by definition, an incurable problem, in that context I think our first obligation is to treat her condition without producing untoward toxicity. Under circumstances like those, I think we owe the patient an eight- to 12-week trial of the hormonal therapy to establish her ability to respond. The counter argument that hormonal therapies require too long to work and that a patient like this doesn't have eight to 12 weeks to await the success or failure of a hormonal therapy, I think, is misguided. This patient was not symptomatic - and I didn't believe was likely to become symptomatic, if she received an ineffective hormonal treatment. So, my own feeling is that any patient with a hormone receptor-positive metastatic breast cancer, who is untreated, deserves a trial of hormonal therapy, unless she has symptomatic hepatic metastases or unless she has symptomatic pulmonary pharynchamal metastases. Under those two conditions, no, I think maybe it's a disservice to give people hormonal therapy for an 8- to 12-week trial. I wish I knew that percentage of community oncologists would give such a patient chemotherapy. This patient clearly was able to benefit for what turned out to be a four-plus-year period from therapies that did her essentially no harm and gave her an excellent quality of life for a long stretch.

DR. LOVE: Did you biopsy any of the pulmonary nodules?

DR. FOX: Well, I actually elected not to. The radiologic appearance of them was typical of pulmonary metastases, so I decided to do an in vivo test of diagnosis by observing their increase or decrease relative to the breast mass, assuming that if the breast mass decreased in response to therapy, the pulmonary lesions would follow suit. And they did actually, over the course of this patient's treatment, correlate very well. But it was the pathognomonic radiologic appearance for metastases of these nodules that led me away from putting the patient through an invasive procedure. None of them was particularly amenable to CT-guided needle biopsy, because of the relatively proximal location, as I recall, and it would have required a thoracotomy and biopsy or a video-assisted thoracoscopy and biopsy. I just elected not to put the patient through that, but assessed her response to treatment instead.

DR. LOVE: Now, her response to the Zoladex, would that have classified as a partial response?

DR. FOX: Yes. She has only ever had PRs. Her breast mass has never, ever resolved absolutely completely. Her pulmonary nodules never resolved absolutely completely, either. They met the clinical trial criteria for partial response by virtue of their reduction in size.

DR. LOVE: I'm curious about how you approached it in terms of therapeutic trial with hormonal therapy. If she had been ER-negative would you have still not biopsied the pulmonary nodules?

DR. FOX: I guess I would not have. I probably would have used the same philosophy. I would have initiated some form of systemic therapy, whatever first-line chemotherapy was appropriate in 1997 and I probably would not have biopsied them. But I see where you're going with that. I absolutely see where you're going with that.

DR. LOVE: Maybe if she did have some other kind of primary that might have responded to whatever chemotherapy; whereas, you know, hormonal therapy, if you see a response, you pretty well know you're dealing with breast cancer.

DR. FOX: Right. No, you make a good point. I guess it's my inherent reluctance to do invasive procedures that drives that decision.

DR. LOVE: Now, in this situation, you were swayed against using tamoxifen, which I guess you could have either combined with the Zoladex or stopped the Zoladex and started the tamoxifen, but you were swayed against it because of her thrombotic history. If she didn't have the thrombotic history today and a patient were presenting like that, what would you have done?

DR. FOX: Well, I think that the argument of whether tamoxifen constitutes an equivalent treatment relative to GnRH agonists or superior or inferior treatment, I think it's sort of an unanswerable argument. Thrombosis history aside, my inclination in general is to use GnRH analogs in situations like this for the simple reason that it assures compliance. I think that toxicities from GnRH analogs are really restricted to menopausal symptoms, whereas tamoxifen, I have gotten the sense, can produce some other undesirable toxicities, such as weight gain, changes in mood, and sometimes more genitourinary symptoms than I think are acceptable, and sometimes more genitourinary symptoms than I see with a GnRH analog. Those are observations, and there's no data to support those biases.
I also would prefer to use Zoladex or Lupron first at the time of progression on the GnRH analog. Giving the tamoxifen to the patient at that point is a simple and generally harmless maneuver. So, using these hormonal therapies in sequence is always the best way to treat hormone-sensitive breast cancer. And if you're going to use that sequence, Lupron or Zoladex followed by tamoxifen, to me, always made more sense than the opposite.

DR. LOVE: There was a meya-analysis published suggesting greater benefit from combining ovarian suppression/ablation plus tamoxifen. Any thoughts on that?

DR. FOX: Well, there were a couple of clinical trials that compared Zoladex plus tamoxifen, I believe just to tamoxifen. And there was a pooled analysis of two studies. I had the opportunity to review that for the New England Journal of Medicine. They did not accept the manuscript. But the flaw in those studies is always that you never get a pure comparison of the combination to the individuals drugs given in sequence. And therein lies the problem, I think, with interpreting such a meta-analysis. Of course, if you compare the combination to the single agents the rates of response will generally be higher. The toxicities will generally be higher. The survival rates might be ever so slightly longer, but the disadvantage is we don't really know what sequence of hormonal therapies the so-called control groups tend to get. And I would submit that if someone did a pure endocrine study of Drug A plus Drug B versus Drug A followed by Drug B, and follow that kind of a process to the letter, you probably wouldn't see a significant difference in outcome. And the second arm of that study, the A followed by B, is virtually guaranteed to have less toxicity. So, I still haven't jumped into the combined hormonal therapy camp, based on the available information. So, I would still recommend them as single agents.

DR. LOVE: I guess you see the same phenomena in metastatic disease in terms of chemotherapy.

DR. FOX: Yes. And the problem now - and this is getting off the subject of hormonal therapy - I think that there are two studies now, which give reasonable evidence that combinations of agents are better than single agents. And the one example, I guess, would be Taxol plus Herceptin versus Taxol alone. And now the other example that we have to deal with is the Taxotere plus Xeloda versus Taxotere alone. If you really believe that the effects of chemotherapeutic agents, when given together, are purely additive, then you'll see what most trials have shown, which is response rates go up, toxicities go up, and survival doesn't get better. The Taxotere-Xeloda study, there was enough of a survival difference in that study to reach statistical significance and for the FDA, after review of the data, to approve the combination as legitimate in treating metastatic breast cancer. Having said all that, have I started treating patients with Taxotere and Xeloda? Not at all. Because I think that until those of us who do this every day have an opportunity to review the toxicity data in more detail, my enthusiasm is going to be somewhat limited.

DR. LOVE: Are there situations where you do use that combination right now?

DR. FOX: Let me give you just one example, because I've only done it one time. I first saw this data at San Antonio last December, and perhaps being naturally a little bit skeptical about it, I made a decision to do it in a patient whose situation was the development of a large soft-tissue sternal metastasis, multiple lung nodules and a unilateral symptomatic pleural effusion within two months of the completion of adjuvant chemotherapy with AC-Taxol. And construing that patient's carcinoma as being unusually resistant and virulent, and because that patient had become symptomatic relatively quickly, she was given the Taxotere-Xeloda combination. But I have to say it was given at doses, which represented a reduction over those done in that clinical trial. The Taxotere dose was given as prescribed in that trial. The Xeloda dose was given at a dose of 2 grams per square meter per day, which I believe represents a 20 percent reduction in the dose from that study. So, I did not treat the patient exactly in accordance with that study.

DR. LOVE: And what happened?

DR. FOX: She has had a transient response to therapy. And her level of toxicity with respect to mucositis has necessitated about a 20 percent reduction in her dose of Taxotere. But she has had a sustained four-month response to treatment.

DR. LOVE: One of the things about combination therapy in metastatic disease - whether it's chemotherapy or hormonal therapy - is the implication for the adjuvant setting. Where you're really only going to get one shot. And actually Debu was pointing this out when we were talking about the very same data, and it kind of gets back to hormonal therapy, also. Of course, the big example that we have right now, that we're waiting for, is the ATAC Trial. Arimidex versus tamoxifen versus the combination. I guess we really don't have evidence in metastatic disease right now of Arimidex and tamoxifen together. Although we do have these date from the meta-analysis you were talking about, of tamoxifen and ovarian ablation, which in a way, it's kind of endocrinologically, a little bit similar.

DR. FOX: Right. To me, it just gets down to whether your treatment goals are in keeping with increased toxicities. Adjuvant therapy requires that we first buy into the concept that if we're treating a patient with curative intent, we're going to accept a level of toxicity that we find to be acceptable. And that requires that the chemotherapy be given for a fixed period of time and that the chemotherapy's toxicity be within reason by virtue of its production of lethal side effects and hospitalization. So, I think when you're looking at treating with curative intent, you give toxicity a much wider berth. I think the hormonal therapy is not entirely different, if we show that patients with curable breast cancer can have their period of freedom from recurrence or their rate of cure increased by giving a couple of hormonal therapies together, then by all means we should do it. Providing that that hormonal therapy combination doesn't produce untoward toxicities, such as an unacceptable rate of thrombosis, unacceptable weight gain or unacceptable vasomotor symptoms. And I think that the ATAC Trial will spell that all out very clearly.

If you're treating someone with metastatic carcinoma that's not curable, and your goals are basically to produce the longest period of freedom from symptoms and freedom from treatment-induced toxicity that you can, I think that using drugs in sequence rather than in combination, just somehow better fits that role. Because with metastatic disease therapy, there are no defined end points, and we're obligated to treat people without interruption.

DR. LOVE: Any hunches or guesses about what we're going to see in the ATAC Trial?

DR. FOX: Well, I'm going to guess that we're going to see that any combination of tamoxifen and aromatase inhibitors may produce a very, very small benefit. I think it's going to make clinical decision-making harder, rather than easier. Because if we see small benefits, those small benefits are going to have to be taken in the context of what will probably be small increases in toxicity. And I think all of us are going to wrestle whether or not giving combined agents is worth doing. I would say that, if we see a statistically significant reduction in the risk of recurrence and a statistically significant reduction in the risk of dying from metastatic breast cancer by giving tamoxifen and Arimidex in combination, and if there is a minimal increase in the rate of thrombosis - let's call it one to two percent - and there is no real augmentation in toxicities in any other way, sure I'll do it. And I'll prescribe them both. But I think it's going to be more of a toxicity question than it is an efficacy question, to be honest with you.

DR. LOVE: What about the single agent comparison, in tamoxifen versus Arimidex in terms of just monotherapy for adjuvant disease?

DR. FOX: Well, if you extrapolate the story from the metastatic disease trial, if you can extrapolate that to the comparisons of the single-agent tamoxifen versus Arimidex, I suspect what we're going to see is a very modest difference between the two. The clinical trials that look at first-line therapy are going to be inherently biased a little bit when 10 to 20 percent of your study population has already taken tamoxifen as an adjuvant therapy, which was the case in the Arimidex study. I believe it was 10 percent of the population had had prior tamoxifen exposure. And if you look at that study and you accept that Arimidex was a tad better than tamoxifen, then it'll probably be a tad better in the adjuvant setting. And I think that if we extrapolate what we know about the drug's toxicities into the adjuvant setting, the aromatase inhibitors will turn out to be the winners, because I think they're probably, on balance, ever so slightly easier to take. So, if I'm allowed to predict outcomes of trials in which I'm not participating, I guess my prediction will be that we will stop using tamoxifen and we will start using aromatase inhibitors in that select population of patients.

DR. LOVE: So, I hear you saying you think probably the Arimidex arm is going to be a little bit better than tamoxifen and maybe the combination arm might be a little better than the Arimidex?

DR. FOX: Right. And the issues are going to come down to, here again, the issue of what constitutes acceptable toxicity.

DR. LOVE: Interesting.

DR. FOX: Yeah.

DR. LOVE: You mentioned that it was your speculation that perhaps the Arimidex arm is going to be better in the ATAC Trial, maybe the combination arm will be even better. If that turns out to be the case, would you be substituting either of the other aromatase inhibitors for Arimidex in the adjuvant setting or using Arimidex?

DR. FOX: In the adjuvant setting, I think we need to dance with the data that we see. If the clinical trial shows that Arimidex is superior to tamoxifen and/or less toxic, then I think our obligation is to use Arimidex until we have equally convincing data from the other clinical trials, which compare the other aromatase inhibitors to tamoxifen. So, I personally would just stick with the one upon which the data is based and not extrapolate.

DR. LOVE: Did you by any chance see the paper that came out - I think it was the British Journal of Cancer - looking at pharmacokinetic and serum estradiol levels out of the ATAC Trial?
The bottom line that I thought was very interesting was that the anastrozole levels were a little bit lower in the combined arm, but it really didn't affect estradiol suppression. The estradiol suppression in the Arimidex arm was pretty much the same as it was in the combination arm, so that mild pharmacologic interaction really didn't have any effect in terms of the estrogen-lowering effect of Arimidex. The bottom line's going to be what the trial shows in terms of efficacy. But it's a little bit reassuring to see the biology of what would explain what we hope would be the clinical results.

DR. FOX: Right. I agree.

DR. LOVE: Getting back to your case again, in this situation you substituted an aromatase inhibitor in this patient because of the thrombotic history. In this case it was metastatic disease. Have you done that same thing in the adjuvant setting?

DR. FOX: I've only had two situations. In each case, because the patient was heterozygotic for factor-V Leiden, in one case it was also a patient who gave a compelling family history of thrombosis in siblings, all occurring at a young age. Her workup revealed that she had a factor-V Leiden mutation. Another patient actually developed breast cancer in the setting of having a known mutation and a thrombosis history. In each case, these patients had intermediate-risk cancers, which were hormone receptor-positive and were very definitely candidates for adjuvant hormonal therapy. One of the patients was chronically anticoagulated, and will be for life. This is a patient who had probably had at least, in her lifetime, 12 thrombotic events, several of which were pulmonary emboli. In the other case, the patient who was found to have a factor-V Leiden mutation, who did not herself have a thrombosis history - here again, the same logic applied. But those are the two cases in which I've shied away from tamoxifen for reasons of thrombosis or fear of thrombosis.

DR. LOVE: Any patients would you consider it on, who might have intolerable hot flashes or, for whatever reason, just don't want to take tamoxifen?

DR. FOX: There are three cases in which I've made the changeover to an aromatase inhibitor. One was for intractable vasomotor symptoms and two were because of depression. Not that tamoxifen is known to produce depression with a predictable likelihood. But in these particular cases, the depressive symptoms were severe enough to warrant withdrawal of any potential offending medication. In both cases, upon the withdrawal of tamoxifen, the depression did lift, and the ultimate substitution of tamoxifen with aromatase inhibitors did not result in a reappearance of the depressive symptoms. Those are three times when I have willingly changed from tamoxifen to an aromatase inhibitor because of some significant degree of intolerability.

DR. LOVE: In this case, again, you were using a combination of an LH-RH agonist and an aromatase inhibitor. And there actually has been some pilot data reported on that. I think John Robertson reported at ASCO a couple of years ago, showing that it looks like a woman who has ovarian suppression responds the same way any postmenopausal woman would. Have you seen those data?

DR. FOX: Yes, I have. And those data did appear after I had elected to do this on my own empirically in this particular woman. I don't think I took my hint from that particular presentation but was reassured by it when it came out after I'd made that maneuver. It comes to me as no surprise. The logic of the benefit of an aromatase inhibitor should be such that one would not anticipate a decrease in effectiveness in a premenopausal woman, as long as we create a menopausal state.
So, it was no surprise, but reassuring at the same time.

DR. LOVE: It kind of makes sense. You're making the woman postmenopausal. And I guess it's also worth saying, that I think an aromatase inhibitor without ovarian suppression in a premenopausal woman would not be advisable.

DR. FOX: Right. I think Matt Ellis has made the point in public forum that it's contraindicated because it doesn't work, but it's also contraindicated because it has the potential to be virulizing. Now, if you increase dihydroepy endosterone levels by giving a premenopausal woman an aromatase inhibitor, she may have virulizing effects, and I think that is yet another poorly appreciated contraindication to aromatase inhibitors in young women. I have not committed the sin, but I have seen it committed several times in patients who have been referred for opinions about hormonal therapy.

DR. LOVE: When you decided with this patient that you wanted to move on to chemotherapy - and you mentioned that you put her on a trial - what is your thought process of the patient who's completely chemotherapy-naïve? And how do you sort of make your decisions about which agent to use, and how did this trial sort of fit in that algorithm?

DR. FOX: Well, the clinical trial was a dose-finding study of Taxol and liposome-encapsulated doxorubicin. So, our institutional commitment was to that study in patients who were eligible and willing. Would I have given this patient a Taxol-anthracycline combination off clinical trial? Absolutely not. This was done on a research agenda. Outside of a research agenda or outside of a clinical trial, I sort through this simply by trying to establish which single chemotherapeutic agent is likely to produce benefit for this patient with the most acceptable toxicity profile. And had I had the decision to make over again in this patient and did not have a clinical trial available to me, I probably would have given this patient a single-agent anthracycline. You may recall, I said that she was on a Taxol D-99 study, and then when she went off that study she has been treated with Taxol alone as a single agent, but has - by virtue of probably seven months or so on Taxol - developed a neuropathy. This has been a devastating consequence in this patient, albeit mild, because she is an accomplished seamstress, and this has impaired her ability to do that thing which she likes best. Her passion for sewing, unfortunately, did not come to light for me until she'd already established a moderate degree of neuropathy. The patient is now off all chemotherapy. She is on a chemotherapy holiday at the moment. Now, having said all that, looking back, I probably would have selected for this patient a non-neuropathic chemotherapeutic agent, either single-agent Adriamycin or a single-agent gemcitabine or Xeloda. I think choosing among them requires experience with the drug toxicities and experience with dosing. So, having been around long enough to have more experience with anthracyclines, I probably would have chosen them.

DR. LOVE: Now, again, putting aside this issue about her occupation and your concern about neuropathy, what generally would be the regimen or agent of choice in this kind of clinical situation in terms of chemotherapy.

DR. FOX: I tend to use taxanes as single agents. The unresolvable decision is whether to use Taxol or Taxotere. I do like to give therapies on a weekly or every-other-weekly basis, because I think aggregate toxicities are more acceptable. Having said that, I think that giving Taxol on a weekly basis has proven, in my own limited experience, a little bit more palatable for patients than weekly Taxotere. Weekly Taxotere is a very effective therapy but has produced some undesirable skin and nail changes, which have made it a little bit more cumbersome for patients with respect to toxicity. But, in general, I favor single-agent taxanes.

DR. LOVE: I've always been very interested in the whole issue of clinical trials and randomization and the challenges of randomization and the ethics of randomization. You made an interesting comment, which was that if that trial you put her on with Taxol and encapsulated doxorubicin hadn't been available, you would have used the single agent.

DR. FOX: Yes.

DR. LOVE: Now, did you, when you presented the trial to her, tell her that?

DR. FOX: Absolutely. I made it very clear to this patient that my normal practice would not be to use drugs in combination, but we were using two agents in combination mostly for the purposes of seeing how safe it was to give them together. That's a pretty lukewarm way to present a clinical trial to a patient, but this particular patient embraced the idea very quickly. She enrolled on this clinical trial for what I believe were sincerely altruistic reasons, which was quite admirable. But it would have been unethical for me to not be clear about the fact that this was a departure from the normal recommendation under these circumstances.

DR. LOVE: That's interesting that you identified altruism as part of her motivation. Is that something that you see in a lot of breast cancer patients entering clinical trials?

DR. FOX: In patients entering clinical trials, I think it's very much an essential ingredient. However - and this may be construed as an inflammatory remark - I've seen in patients, collectively, I've seen too little altruism. It has to be present in all patients in order for there to be legitimate motivations in enrolling in clinical trials. You know, the patient's benefit is never as easily quantified in the long run as the benefit of all patients once the clinical trial is completed. But without at least a little sense of altruism, clinical trial participation is an uphill battle, getting some patients to participate.

DR. LOVE: Do you think that most breast cancer patients are giving truly informed consent? I was interested by the fact that you were so open with her, that this wouldn't have been normally the way you'd approach it, and it sounds like you were telling her that, really, she didn't stand to benefit that much. Do you think that breast cancer patients are getting that kind of openness?

DR. FOX: I hope so. We have our own way of trying to enroll patients on clinical trials. I like to think we do it in the most non-coercive manner possible. Whether we really do that or not, I don't know, but being - I think being heavy-handed about clinical trials, as though that is the patient's only choice, is not fair. This has to be presented to people in a circumspect way. They need to know what their choices are and they need to know that clinical trials are essential, extraordinarily important, and that the key to getting anywhere. But for a patient to respond favorably to that kind of a pitch, they have to be inherently altruistic.

DR. LOVE: What are your current areas of research interest?

DR. FOX: We have several clinical trials that are sort of in the developmental stages. We, like everybody else, are interested in biological therapies. We're interested in combining Herceptin with other chemotherapeutic agents. Since the Taxol-Herceptin combination may truly be an example of synergy between agents, then, I think we have an obligation to find out if there's tolerability with Taxol and other drugs and whether there's a correlation between in vitro data and clinical outcome. So, we're studying Herceptin with gemcitabine, or we're going to, because I think that the in vitro data would suggest that that shouldn't work. And I want to find out if the in vitro data is bunk. We're proposing doing a study of Herceptin and Celebrex, or Celecoxib, the idea being that HER2 non-over-expressers can be coaxed to express HER2 and to take advantage of Herceptin in that setting.
We're also interested in looking at fertility preservation in young women receiving adjuvant systemic chemotherapy. There is a simple clinical paradigm that says that if you suppress ovarian function with Leuprolide or with Zoladex before you give chemotherapy, then that patient, upon completion of that chemotherapy, will stand a better chance of retaining her menses, and thus stand a better chance of bearing children. So, we have been using, in this hospital, Leuprolide to prevent amenorrhea in women receiving adjuvant chemotherapy, who have a particular interest in childbearing. We're not offering this across the board for patients receiving chemotherapy to preserve menstrual function, because we don't know if that's a good or a bad idea. We're doing it purely to make patients capable of childbearing in the future. So, we've piloted this concept and have recorded data now in about 17 women, and we've found that ovarian function can be preserved. The obvious question of whether or not it would have been preserved anyway, without the Lupron, is unanswerable and will require a randomized trial. But that's the thing that has piqued my interest the most lately.

DR. LOVE: Do you see that going into a randomized study?

DR. FOX: Well, the Southwest Oncology group has expressed an interest in it. The person who was the moving force behind the project, while doing her fellowship here, was Dr. Hallie Moore. She's now at the Cleveland Clinic, and they're a SWOG institution. And Hallie's sort of picked it up and run with it, and there has been some interest at SWOG. I don't know. We're not a SWOG member. I don't know where it will go.

DR. LOVE: That's interesting. Is the LH-RH agonist used just during the chemotherapy?

DR. FOX: Yes. there's probably a right way to do it. I don't know if we're doing it the right way, but we start it a week prior to chemotherapy and then we give it with each chemotherapeutic cycle and, when chemotherapy ends, Lupron ends. And then we just wait for the return of cyclic menstrual function. And I've found that almost everybody gets their period in an average of five to six months.

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