Select Excerpts from the Interview*

 Track 2

DR LOVE: How do you approach deciding between combination versus single-agent chemotherapy for metastatic disease?

DR VALERO: There are two combination regimens that have been proven to be superior to single-agent taxane therapy. One is gemcitabine plus paclitaxel, which was compared to paclitaxel alone. The data were presented at ASCO last year, showing an improvement in time to progression and preliminary evidence of an increase in overall survival (Albain 2004; [5.2]).

The other study compared docetaxel plus capecitabine to docetaxel alone and also showed a time to progression and overall survival advantage (O’Shaughnessy 2002; [5.1]).

Based on the evidence, both of these combinations are reasonable for firstline chemotherapy of metastatic disease. However, in some patients, sequential chemotherapy is our preference. I tend to use more sequential single-agent chemotherapy, but I believe the role of combination chemotherapy in some instances is well documented by the two studies I just mentioned.

DR LOVE: Which situations, specifically?

DR VALERO: For women who have symptomatic breast cancer with visceral involvement, it is essential to have a response to alleviate the symptoms and improve their quality of life. In those patients, in spite of the enhancement of the adverse events, I strongly consider combination chemotherapy.

 Track 3

DR LOVE: When you utilize capecitabine, what dose do you use?

DR VALERO: In patients with a good performance status who are not heavily pretreated, I use 2,000 mg/m² daily in two divided doses for 14 of 21 days. After two cycles of therapy, I will consider escalating the dose if the patient has no toxicity. For patients with a poor performance status, in whom you’re going to consider capecitabine as a second- or third-line therapy — patients who are fragile — I may use 1,750 mg/m² daily.

We recently published in the Annals of Oncology about our experience at MD Anderson with different doses of capecitabine (Hennessy 2005; [5.3]). We believe that a lower dose is preferable, even though the FDA-approved dose is 2,500 mg/m².

I believe this publication really confirms what we do in the clinic. When you have a Phase II study in several locations, but you select people out and monitor them very closely, capecitabine can be administered at a higher dose. I could deliver capecitabine at 2,500 mg/m² daily, but it needs close monitoring with a patient who is able to follow very closely with her oncologist. In the clinical trials, as soon as the patients start to develop early signs of mucositis, diarrhea or hand-foot syndrome, capecitabine is stopped immediately (5.4).

Then the patient reports to the oncologist or the research nurse for instructions. Then you restart the capecitabine, and you may restart it at a lower dose. So it needs some very close monitoring. In general, most patients at the end of the day receive an average dose of around 2,000 mg/m² daily as a single agent. In some patients, I also use even lower doses — 1,500 mg/m² daily.

The bottom line is — the evidence that a lower dose is efficacious is just not there. Our study is one of the first that provides information (Hennessy 2005; [5.3]), but it was not a prospective study to assess response and time to progression in a well-designed Phase II fashion.

DR LOVE: Even though we don’t have definitive evidence right now, do you feel that you’re compromising efficacy by reducing the dose?

DR VALERO: I personally don’t. We have to remember that we are giving palliative chemotherapy. I believe some of our traditional ways to develop drugs in the metastatic setting haven’t been, in my opinion, optimal because we escalate the dose until we make patients as sick as possible and then we determine that’s the maximum tolerated dose (MTD).

Remember that MTD is based on administration of one cycle. Ideally, you would like to develop a therapy in which you’re going to determine an MTD for patients who receive at least four cycles, which is what you’re using in the adjuvant setting. Most patients will receive a median of four cycles in the metastatic setting.

 Track 4 - 5

DR LOVE: Can you overview what we know about fulvestrant, how you utilize it in your practice, and how you dose it?

DR VALERO: I believe fulvestrant has been a major step in hormonal therapy for women with estrogen or progesterone receptor-positive breast cancer. It provides patients with an agent with a different mechanism of action. I have been using it in many of my patients with hormone-sensitive breast cancer.

DR LOVE: What is your approach in the postmenopausal patient who’s had prior adjuvant tamoxifen?

DR VALERO: Our approach in the institution is to use an aromatase inhibitor up front and then fulvestrant as second-line therapy. Fulvestrant is approved for patients who have failed tamoxifen, so you can use one agent or the other. In the palliative setting, I believe you can use it either way. Fulvestrant has been shown to be as effective as anastrozole (Howell 2005, Robertson 2003) and tamoxifen (Howell 2004; [5.5]). I use them in sequence. I don’t believe there is any information that one sequence is better than the other. I use an aromatase inhibitor, and then I use fulvestrant as a second-line therapy.

DR LOVE: How do you dose and schedule fulvestrant?

DR VALERO: At MD Anderson, we use a loading dose. We administer 500 mg on day one and 250 mg on day 15 and day 29, and then monthly. Many of the key investigators in the early development of the drug believe it is important to attain steady state. As you know, there is no randomized data for the loading approach.

Currently, it is FDA approved at 250 mg monthly and is reimbursed by Medicare at that dose. With all of those caveats, I believe — and I don’t know if this is my bias — the loading approach is reasonable.

While we think that may be the best dosing schedule, we won’t know unless we do a pharmacokinetic study and also, importantly, a very large study to show that the doses are equally effective. I’m not sure if we’re going to be seeing a dosing study large enough to determine efficacy. You can look at the pharmacokinetics in a smaller study, but I don’t know if we’re going to see efficacy differences.

DR LOVE: Another potential strategy, which is being tested in the SoFEA study (5.6), is combining an aromatase inhibitor with fulvestrant. Many oncologists ask me about the patient who relapses on an aromatase inhibitor. Why not keep her on the aromatase inhibitor and then add in fulvestrant? Is that something you ever do or you think makes sense?

DR VALERO: You’re right on target. That is a huge controversy right now about whether or not to maintain lower estrogen levels in a postmenopausal patient and try a different hormonal manipulation. But we have to be cautious. We learned from the ATAC study that lowering the estrogen levels and bringing in something that competes for the ligand — in that case tamoxifen — didn’t result in a benefit. If you look at most of the data with combined hormonal therapy throughout a couple of decades, there really hasn’t been clear evidence that two hormonal therapies are superior to one.

On the other hand, there is preclinical data generated by different laboratories — including Kent Osborne’s lab — where lowering the ligand (in this case estrogen) and using fulvestrant had a synergistic effect. This is the basis of the randomized study of anastrozole plus or minus fulvestrant (SWOG-S0226; [4.8]).

DR LOVE: How do you approach hormonal therapy in a premenopausal patient with metastatic disease? If the patient is on ovarian suppression, would you consider fulvestrant or an aromatase inhibitor in that woman?

DR VALERO: We participated in the multicenter trial headed by Robert Carlson from Stanford. In fact, we enrolled the majority of the patients on that trial, which currently has 27 patients. It’s a Phase II study looking at hormonal levels and the efficacy of goserelin and anastrozole (Carlson 2004; [5.7]). I’m the principal investigator from MD Anderson.

With this minimal number of patients, we have been very impressed with the combination, and the clinical benefit rate currently is 72 percent. I believe that hormonal therapy in these women, which is the first biological therapy, makes a lot of sense. Believe it or not, this is the only study that is currently available to obtain preliminary efficacy data. The trial is still ongoing.

What is the standard of care in patients who have failed tamoxifen and are coming in for hormonal therapy? The standard of care is to use ovarian ablation — medical or surgical. If the patient has had surgical ovarian ablation, an aromatase inhibitor makes sense. Right now, I know that a lot of people are using goserelin and an aromatase inhibitor.

Fulvestrant has not been studied a lot in patients who are premenopausal, because there are not many premenopausal patients with ER-positive disease who are coming in for a second hormonal therapy. But I believe that is changing.

We’re using less cyclophosphamide, so fewer women are becoming menopausal after receiving chemotherapy. More women who relapse may have ER-positive disease and be premenopausal, and the pool may increase.

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