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Select Excerpts from the Interview
Track 2
DR LOVE: Would you discuss the data you presented at San Antonio
evaluating the feasibility of core needle breast biopsies for gene assays in
community practice?
DR HOLMES: We just completed a neoadjuvant study of FEC followed by
docetaxel and capecitabine (Holmes 2006). The key to this effort was that
we were able to obtain tissue from core biopsies, which was a big step for us
because we have community-based practices.
We submitted the core biopsy tissue for in vitro chemosensitivity testing to Dr Lajos Pusztai at MD Anderson to perform microarray assays and look for signatures denoting responsiveness. The primary objective was to correlate the patient’s pathologic complete response with these molecular signatures.
We shipped 195 tissue samples to MD Anderson, but because tumors are comprised of tumor cells and stroma, we had approximately a 65 percent recovery of good tissue that could be evaluated. We had our learning curves, but we were able to prove that we could do this in the community.
Our next trial will be a neoadjuvant study conducted in patients with HER2-positive disease, and again, the key will be to continue to develop this approach toward personalized medicine.
The first two weeks of this study will be a run-in period during which we will administer trastuzumab, lapatinib or trastuzumab with lapatinib. We’ll obtain a biopsy as a baseline, and at the end of two weeks we will rebiopsy to evaluate what changes have occurred.
Then, the patients will be treated with FEC-75 followed by weekly paclitaxel. During the entire time, they will receive the anti-HER2 agent(s) to which they were randomly assigned up front. Then they’ll undergo surgery.
The endpoint will be pathologic complete response, and we hope to integrate that with tissue biomarkers. For the patients who do not achieve a pathologic complete remission, we would like to obtain a third, optional biopsy to see what’s different about the tumor and to perhaps use that as a springboard for other therapy.
Tracks 9-11
DR LOVE: What’s your take on the new data set presented at San Antonio
on the BCIRG 006 trial (Slamon 2006)?
DR HOLMES: The idea behind the BCIRG 006 trial was to evaluate patients
with centrally determined FISH-positive disease to establish whether up-front
treatment with trastuzumab reduced relapse rate.
The second strategy was based on the understanding of the mechanisms of synergy and whether a nonanthracycline-containing regimen could be evaluated, particularly because of the known cardiotoxicity of trastuzumab. Would it be possible to incorporate trastuzumab earlier without having to wait until the completion of the anthracycline?
The three arms in the study were AC followed by docetaxel (AC
T), which
was a standard in the community, AC followed by docetaxel/trastuzumab (ACTH) and trastuzumab/carboplatin/ docetaxel (TCH).
The great thing about this trial is that it continues to provide new answers
and new questions, and now we find that the TCH and ACTH arms are
equally effective (1.1).
DR LOVE: What about the evaluation of TOPO II status? Is that helpful in
selecting therapy for patients with HER2-positive disease (1.2)?
DR HOLMES: It is still an unanswered question. Some would say that if the
disease is TOPO II-amplified, then perhaps the patient should receive an
anthracycline. Others would argue that you can avoid the cardiotoxicity,
because you do not have to administer the anthracycline, and you can choose
a much more user-friendly trastuzumab regimen.
I believe that many more of us will probably use the TCH regimen if we’re worried about cardiac toxicity.
Tracks 12-14
DR LOVE: Can you discuss the AC versus TC study reported by Steve
Jones and your group, US Oncology ( Jones 2005, 2006)?
DR HOLMES: This was a straightforward, simple idea embraced by the
community, many of whom have concerns about the anthracyclines. We have now seen not only a better outcome in the total population with TC but also
benefits in every subset (1.3), although these were not preplanned analyses.
Of course, right now one question that comes immediately to mind is, what is the HER2 status of those patients? That analysis is ongoing. However, at the time that this trial was being conducted, HER2 status was not a routine parameter that we evaluated.
DR LOVE: Some people have said, “This is only one study.” How do you
evaluate the efficacy data?
DR HOLMES: It is one study, and it was a small study by modern adjuvant
standards. However, it’s not inconsistent with the data in the literature, which
suggest that docetaxel is superior to the anthracyclines in head-to-head studies
conducted in the metastatic setting. I don’t have any problems with this study
because it is reasonably sized, and the dose intensity was maintained.
I’ve started to incorporate the TC regimen much more frequently in my
practice, especially in situations in which I have concerns about chemotherapy
tolerance. However, at this time, I have not given up on the standard AC/taxane regimen for my patients with node-positive disease.
DR LOVE: What’s your personal experience with the tolerability of TC
versus AC?
DR HOLMES: AC is now recognized as a highly emetogenic regimen, and
patients experience delayed nausea and vomiting. I was once on a panel that
was discussing emesis, and somebody said, “Oh, that’s just AC.” Well, AC is
associated with a lot of delayed nausea and vomiting.
You find a lot of hidden toxicity if you step into the shoes of a patient. It can be incapacitating. With TC, you don’t have that burden of emesis and nausea.
Tracks 17-18
DR LOVE: Let’s talk about the US Oncology trials evaluating nab paclitaxel.
It has been stated that neurotoxicity resolves more quickly with nab paclitaxel than with paclitaxel. Is that the case?
DR HOLMES: Yes. In our dose-dense trial, in which we were administering
nab paclitaxel at 260 mg/m2 every two weeks, I had two patients who experienced
neurotoxicity, but we saw the deep tendon reflexes return quickly.
The other aspect of nab paclitaxel that’s so terrific is the mechanism of action (1.4). Many tumor cells have a substance on them that you might think of like flypaper — SPARC, which stands for Secreted Protein Acidic and Rich in Cysteine.
SPARC has an affinity for albumin, which has the “payload” of drug inside. When this albumin-bound drug attaches to the tumor, the payload is delivered. There you have a particularly targeted therapy.
So number one, you have a targeted therapy, and number two, you don’t have the Cremophor®, which is the source of the reactions with paclitaxel, for which we use dexamethasone, and which resulted in the use of long infusion times. Number three, although the Cremophor allowed us to basically dissolve pine bark and deliver it as a soluble substance, this would also accumulate in the bone marrow and in the nerves, causing prolonged retention of the drug in a place where it’s not wanted. With nab paclitaxel, the drug is preferentially diverted to the target.
Tracks 18-19
DR LOVE: How are you approaching the use of nab paclitaxel in your
practice for patients with metastatic disease?
DR HOLMES: I administer nab paclitaxel in preference to paclitaxel, period.
DR LOVE: How much of an advantage is it to be able to avoid premedication
and to have shorter infusion times?
DR HOLMES: It’s a huge advantage. Patients have a life. They have kids.
They have day care. At its best, getting through the clinic is difficult. I have
emergencies, so I’m backed up. There are all kinds of built-in delays.
We all think we know what it is to go through therapy from the patient’s standpoint, but it’s hard to remember all the delays, all the problems: “Oh gosh, counts aren’t up today. You have to come back later.”
To begin with, these people have a life, and their time is valuable. In addition, not having to take the dexamethasone is a huge benefit. How many people are hyperactive? They can’t sleep that first night. They have to take the steroids and then take lorazepam or something else to relax them.
Finally, we all know that patients gain weight on adjuvant chemotherapy. Apparently, they do not eat more, and their energy intake isn’t increased, but their energy expenditure is decreased. Add this anabolic agent on top of that, and we know that some women are sensitized to this.
Then there’s that minority of patients who develop acne from the dexamethasone. Really, less is more, and avoiding premedication is a tremendous advantage.
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