Edited excerpts from the discussion:

DR DRAGON: This 55-year-old woman presented with a locally advanced, ER-positive, PR-positive, left breast tumor and bone metastases approximately three years ago. She underwent a subtotal mastectomy, axillary dissection and reconstruction. She was given tamoxifen, to which she responded, and then letrozole, which also resulted in significant disease control.

DR LOVE: Did this patient know she had breast cancer and neglect it or was she just one of those cases that presents with metastatic disease?

DR DRAGON: She was very frightened. She had been treated for DCIS a number of years earlier with a right mastectomy and then had reconstruction. She knew there was something wrong in her left breast and she did not want to deal with having another episode of breast cancer.

DR LOVE: Was the left breast tumor an obvious lesion?

DR DRAGON: At the time I saw her, she had a four-centimeter mass that was fixed to the skin and clearly obvious as a breast cancer, and she knew that.

DR LOVE: Did she have bone pain from the metastases?

DR DRAGON: No.

DR LOVE: What was her life situation at that time?

DR DRAGON: She is a fashion model in her second marriage with two kids. Her son is a medical resident at a university center. She travels internationally on a regular basis. Her husband is a businessman in the community. They are independent financially and very secure.

DR LOVE: When she presented with locally advanced disease, how would you describe her mental state?

DR DRAGON: That’s an interesting question. When she first presented to the breast surgeon and he sat down with her to explain that this looked like breast cancer, she became very unstable emotionally and actually had to be hospitalized for a couple of days.

She went directly from the surgeon’s office to an inpatient psychiatric unit. She improved very rapidly, then came to see me and was ready to hear about how to get better.

DR LOVE: What was her psychological and medical history?

DR DRAGON: She had never had any medical or psychiatric illnesses before, except for the DCIS.

DR LOVE: How did she react to the idea of hormonal therapy?

DR DRAGON: Hormonal therapy fit in very well with her lifestyle. She was able to maintain an active travel schedule, seeing me between her travels to Europe, the Far East and Hawaii. This is a woman who was used to traveling a great deal and continued to do so while on therapy.

DR LOVE: How did she do emotionally after her initial reaction?

DR DRAGON: During periods when her disease was clearly beginning to progress, she would become tearful, but with a little bit of support and emphasis about the potential control of her disease with other therapies, she readily compensated within the span of an office visit and was able to go back to normal functioning.

DR LOVE: What hormonal therapy did she receive?

DR DRAGON: We started with tamoxifen and she achieved excellent disease control. When we reached an optimal level of control in the breast, the surgeon did a wide excision and cleaned out her axilla for local control, because initially this was an ulcerated lesion. We did not radiate the local area. She had excellent control of her bone metastases as well.

DR LOVE: What prompted the decision to use tamoxifen initially as opposed to an aromatase inhibitor?

DR DRAGON: It’s a good question. We began therapy five years ago. If I saw this patient today, I would probably start with an aromatase inhibitor.

DR LOVE: After tamoxifen she received letrozole. How did she tolerate endocrine therapy?

DR DRAGON: She did not experience any toxicity with either agent. When she progressed, it was primarily in the breast. She never developed more bone metastases or pain.

We then started fulvestrant, which was approximately 18 months ago. She received fulvestrant for four months, and we did not give her a loading dose. She clearly progressed on the chest wall and in the axilla and at that point, we began discussing systemic chemotherapy.

DR LOVE: Eric, what options would you have presented to this patient at this point?

DR WINER: I wouldn’t have totally ruled out using another hormone, but it’s certainly reasonable to move on to chemotherapy at this point.

I would like to comment on fulvestrant. It’s perplexing to a lot of people that it doesn’t perform better given that in the randomized trials it was at least as good as, if not a little bit better than anastrozole (6.1). Some of that may relate to the setting. There’s some concern that using it after an aromatase inhibitor may not be the optimal setting for this agent, although it’s the way we all give it. Ongoing studies are evaluating estrogen priming for brief periods of time after an aromatase inhibitor followed by fulvestrant. Then there’s the issue of a loading dose. It may turn out that one of the problems is that it just takes a long time to get to an optimal therapeutic level.

DR LOVE: Do you use a loading dose?

DR WINER: I haven’t outside of a study (6.2). I don’t think we know yet the optimal way to administer fulvestrant, and there’s a lot of interest in learning the most effective way to use it. One reason why there have been delays in initiating any type of large adjuvant trial with fulvestrant is that until we define the optimal way to use this drug, we’re just shooting ourselves in the foot if we try to start a trial sooner.

DR LOVE: If you were to begin chemotherapy at this time, what regimen would you choose?

DR WINER: As a general rule, I’m a singleagent guy and I’m not convinced that combination therapy is superior to giving single agents sequentially. The two trials that have shown that combination therapy may be superior — that is, the docetaxel with or without capecitabine study and the paclitaxel with or without gemcitabine trial — are both flawed in that there was not an appropriate crossover (O’Shaughnessy 2002; Albain 2004). In the studies that have evaluated crossover, there is absolutely no difference in survival between single agents and combination therapy (Sledge 2003).

So, in this woman who is not terribly symptomatic and for whom you want to do your best to minimize the impact of therapy on her quality of life, be as specific as you can with the therapy and eliminate drugs that aren’t working, I would definitely use single-agent chemotherapy. In my view, it almost doesn’t matter whether you use capecitabine or a taxane or an anthracycline. For that matter, you could probably use gemcitabine or vinorelbine, although they’re less commonly used in this situation. I believe that response rates and time to progression are more dependent on when you administer the drug than on which drug it is.

DR LOVE: Would you consider incorporating bevacizumab?

DR WINER: This patient would have been eligible for the ECOG trial with bevacizumab. The results presented at ASCO showed approximately a five-month improvement in time to progression and a doubling of the response rate (Miller 2005a). Unfortunately, bevacizumab is a very expensive drug, for which we don’t have an identified target. We just don’t know who benefits and who doesn’t, or perhaps everybody benefits a little bit.

If I were going to use bevacizumab, I would give bevacizumab in combination with paclitaxel, the way it was done in the ECOG trial.

DR LOVE: Dr Dragon, what happened with this patient?

DR DRAGON: This predated the bevacizumab data, which I still don’t know what to do with. We talked about the options and had a similar conversation about the many different choices of sequential single agents and agreed that ultimately she would probably see a lot of different drugs. We offered capecitabine as a reasonable option that would allow her to maintain her lifestyle, and she found an oral agent to be very appealing.

DR LOVE: How important was the issue of alopecia for her?

DR DRAGON: At this point, very important. She understands that, at some point, that’s going to be an issue, but the availability of drugs — including vinorelbine, gemcitabine and capecitabine — that don’t cause significant alopecia basically allowed her to compensate for the loss of control in her life.

DR LOVE: Eric, if you had seen this woman before the bevacizumab data were presented, what therapy would you have used?

DR WINER: Capecitabine.

DR LOVE: Would that change now that we have the bevacizumab data?

DR WINER: Since those data became available, I tend to somewhat cautiously use bevacizumab in this setting, and when I do, I’m a little uncomfortable combining it with capecitabine, given the negative data from Kathy Miller’s previous study (Miller 2005b).

Now, I don’t know if that trial was negative because bevacizumab isn’t as effective in combination with capecitabine as it is with paclitaxel or whether it’s because of the setting — that is, first line versus not first line. I tend to think it’s probably not agent specific but rather more related to the fact that the ECOG paclitaxel trial was conducted with patients who had not received prior treatment in the metastatic setting.

I think that even today, I probably would pick capecitabine alone and hold off on doing anything else in this particular patient.

DR LOVE: Kevin, how would you think through this decision?

DR FOX: The same way. The decision would rest entirely upon which drug fits the patient’s lifestyle, desires and limitations. This patient seems like a logical and almost perfect candidate for capecitabine.

DR LOVE: Eric, I think a lot of physicians share Dr Dragon’s concern about not knowing how to apply the bevacizumab data (6.3). How would you respond to this concern?

DR WINER: I think part of the reason that people are uncertain is that we don’t have a huge amount of data on bevacizumab. We have these two studies and we don’t know much about bevacizumab with other agents. We’ll probably learn more in the next few years.

My other comment is that this is a woman who has never received any chemotherapy before, so even if she receives capecitabine initially and you plan to use bevacizumab in the second-line setting, she’s still more like the ECOG patients, and so I don’t think you’re burning any bridges by giving her single-agent capecitabine.

DR LOVE: Kevin, what do you think about using bevacizumab in the second-line setting in a patient who has received no prior adjuvant therapy?

DR FOX: I think it makes perfectly logical sense. I don’t think we ought to make blanket rules about the use of bevacizumab exclusively as first-line therapy, because not every patient will be like the patients who were actually in the clinical trial.

DR LOVE: Dr Dragon, can you follow up on what happened with this woman?

DR DRAGON: She was started on capecitabine 10 months ago and had a very rapid and gratifying response. The node went away and the skin disease disappeared. Her bone disease was already asymptomatic. The response continued for more than nine months, and just this last month, her node became palpable. Her skin disease has still not recurred, but I think she’s starting to progress.

DR LOVE: Eric, what are your thoughts about the dosing of capecitabine?

DR WINER: I usually don’t bother calculating a precise dose per meter squared. I never use the 150-milligram pills. I’d start a normal-sized woman at 1,500 milligrams twice a day, and then adjust as necessary. Clearly, responses are seen at those doses.

I know that Larry Norton has been talking about some interesting scheduling ideas on capecitabine dosing. It may be a drug that will be more effective with different dosing, but at the moment, I think we’re left dosing it with a modification of the package insert, meaning two weeks on, one week off, but with lower doses.

DR LOVE: What about other taxanes, docetaxel and nab paclitaxel, in combination with bevacizumab?

DR WINER: I tend to be somebody who likes to see a little data. I don’t see a reason for giving nab paclitaxel with bevacizumab at the moment. Once there are some safety data with the combination, and I don’t have any reason to think that it won’t be safe, then I think that’s fine.

DR FOX: Eric, do you foresee using single agent bevacizumab under any circumstances?

DR WINER: Well, in the study that Melody Cobleigh, George Sledge and Kathy Miller did evaluating bevacizumab as a single agent, it showed a bit of single-agent activity, mostly in heavily pretreated patients (Cobleigh 2003). I probably wouldn’t be in a rush to do that at the moment, but I think it’s a question to be asked in clinical trials.

One other thing I want to mention about the ECOG trial is that unlike most of the previous studies we have evaluating paclitaxel or any agent, the ECOG trial is one of the first that actually systematically excluded patients with HER2-positive disease. As we winnow down the patient populations, there may be somewhat unexpected findings in terms of response rate and time to progression. So in that ECOG trial, two-thirds of the patients had ER-positive disease, like this patient, and a third of the patients had ER-negative disease, which in that study, by definition, was triple-negative disease.

DR DESAI: Eric, do you feel the ECOG study data should change the way we practice?

DR WINER: I think that we’re not quite sure what to do with the data. In my talk at ASCO, I carefully chose my words and said that it was reasonable to use bevacizumab in settings similar to the ECOG trial. However, it’s not mandatory, and different people will approach this question in different ways. Hopefully we’ll have some more data in the not-distant future.

DR LOVE: It’s been interesting to see how in breast cancer the reaction to the bevacizumab data has been completely different from what we saw in colon and lung cancer. In colon cancer, people jumped on the data and actually started using it with FOLFOX, even though the trial was with IFL. In lung cancer, reimbursement issues exist, but the researchers feel that once it is reimbursable, they’ll begin using it.

DR FOX: I think this stems from the fact that in the treatment of metastatic breast cancer we have lots of choices, whereas up until recently there were few choices, and even fewer good choices, in treating lung and colon cancer. As a result, we tend to be a little bit more circumspect with respect to what we’re going to use and what kinds of toxicities we’re willing to accept.

DR LOVE: Eric, when do you think we’ll begin to see adjuvant bevacizumab breast trials?

DR WINER: In the not-too-distant future. ECOG will be sponsoring a pilot study similar to the pilot feasibility study we saw with trastuzumab many years ago. A Phase III concept has already been submitted to the NCI from ECOG, so I suspect that study will open in 12 to 24 months, and I think it’s a reasonable study (6.4).

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