| You are here: Home: BCU 4|2002: Interviews: Dr. Nicholas Robert
DR ROBERT SUPPLEMENT:
DR NEIL LOVE: One of the most
interesting aspects of the Miami meeting "patterns of care"
study was the variability in management of the HER2-positive patient.
For example, in women with HER2-positive metastatic disease, only
65 to 80 percent of oncologists appear to routinely incorporate
trastuzumab as first-line therapy, a practice that is widely considered
standard of care. A key related issue is the use of and selection
of chemotherapy to be added to trastuzumab in these women. I met
with Dr Nicholas Robert to discuss an initial report presented at
the San Antonio Symposium of a U.S. Oncology, Phase III trial comparing
trastuzumab and paclitaxel to trastuzumab, carboplatin, and paclitaxel,
a regimen that is now moving into Phase III trials in the adjuvant
setting. Dr Robert began our discussion by reviewing the background
for the study.
DR NICHOLAS ROBERT: The study really developed after the
pivotal trial, which demonstrated the utility of using chemotherapy
with Herceptin. Given that one of the arms used Adriamycin-Cytoxan
and there was cardiotoxicity associated with that, it did not seem
to be a regimen that we could go further with. So we were interested
in looking at Taxol and Herceptin and what we could do to improve
those results. Given the description of synergy with the platinums,
it seems like a natural combination to give Taxol and Carbo together
with Herceptin.
Furthermore, there is clinical data both, from Edith Perez from
the North Central Group, showing that Taxol and Carbo given every
three weeks produce about a 60-percent response rate. And then David
Loesch with U.S. Oncology did a similar study, but changing the
schedule giving treatment three out of four weeks, giving Taxol
at 100mg per square and Carbo with an AUC of 2. With that schedule,
we saw the same response rate of about 60%. So we felt that there
was clinical data in metastatic breast cancer using Taxol-Carbo
with very acceptable response rates comparable to other regimens
with combination chemotherapy. And adding that to Herceptin given
the laboratory evidence that there was synergism with this regimen,
that it was a very reasonable question to compare Taxol-Herceptin
versus Taxol-Carbo-Herceptin
DR LOVE: You talked about the
Carbo-Herceptin synergy, and at the time that you started this trial,
I guess that was just in the laboratory, but there has been some
clinical data, right?
DR ROBERT: Yes, there is clinical data. There are
actually two groups that have looked at this. John Marc Nabholtz
has looked at it in two pilots using either cisplatin or carboplatin,
and seen, especially in the Carbo arm improved results when you
combine it with Herceptin in FISH-positive patients. Interestingly
that has not been seen in cisplatin. Then there is another study
that Skip Burris did with the Sarah Cannon group where he gave Herceptin
upfront, and after eight weeks evaluated. And then some of the patients
got Carbo-Taxol and that was given in a weekly regimen, six out
of eight weeks with a dose of 70 per square of Taxol and Carbo with
an AUC of 2, and showed improved response rates. None of those trials
are randomized, so we are particularly excited about the trial that
we're soon to be completing, in terms of accrual which really does
randomize and compare does Carbo add to response rate in time to
progression? So that's the study that recruiting about 205 patients
and we are nearly completely done with that.
One of the concerns, you can imagine, of adding Taxol to Carbo
would be the perceived and increased neuropathy. We learned from
the Carbo-Taxol trial from Dave Loesch and Edith Perez as well,
that the peripheral neuropathy was acceptable and it was not a major
determinant in terms of a problem to the patients. What we did find
is an increase in myelosuppression, which is not a surprise adding
Carbo. We did not see any increase, in terms of problems with cardiotoxicity,
although some of these patients have had anthracyclines. It is a
first-line trial, but some of the patients had adjuvant anthracyclines.
DR LOVE: What kinds of cardiac
monitoring are you doing?
DR ROBERT: We follow left ventricular ejection fraction
and we have a baseline and follow it while the patients are on treatment.
DR LOVE: What specifically
are you reporting? What kind of data right now?
DR ROBERT: Well, right now, we are showing that the two
arms are very comparable, the only major difference really is in
myelosuppression, which was predictable. We are not seeing any fall-off
in left ventricular ejection fraction. We've had some cardiac problems,
but some of these patients had prior cardiac history, so really
nothing to suggest that we are seeing a negative interaction.
DR LOVE: This regimen, also,
I think it's being taken to the adjuvant setting, isn't it?
DR ROBERT: Yes, the rationale for doing the pilots that
Nabholtz's group did is really to fuel the data that was necessary
to do this large adjuvant trial for the Breast Cancer International
Research Group. A very well designed trial looking at Adriamycin-doxorubicin-Cytoxan
followed by Taxotere versus that same regimen given with Herceptin
being given with Taxotere. And then really a departure from using
anthracyclines in the adjuvant setting, these are patients that
include node-positive patients, high-risk node-negative, and using
Carbo or cisplatin, Taxotere and Herceptin.
DR LOVE: But you are looking
at Taxol?
DR ROBERT: Yes, we are using Taxol in our particular trial.
But regardless, I think if we can show proof of principal that adding
Carbo to a Taxane, improves results in patients that are HER2-positive.
What's nice about our trial, we started when people were still doing
immunohistochemistry as a way to identify patients, but we've collected
blocks with Dr Slamon, who is a co-investigator in this trial. His
laboratory will be looking at the blocks in terms of FISH positivity.
So we'll have data to report, not only on IHC but also on FISH from
our trial.
DR LOVE: For your trial the
criteria is purely IHC?
DR ROBERT: With IHC 2+ and 3+.
DR LOVE: Mmm.
DR ROBERT: Then, we subsequently changed the criteria to
IHC 3+ or FISH-positive, because as many as 60% of patients that
are 2+ may be FISH-negative.
DR LOVE: What are you doing
yourself in a non-protocol setting for the HER2-positive patient
with metastatic disease? Let's talk about the patient who has not
had a prior taxane. How do you sort through the options when they
present for first metastasis?
DR ROBERT: Well, I still very much use the Taxol-Herceptin
regimen, at this point that's the regimen that has the most experience.
But I am eagerly awaiting the results of this trial to see if Carbo
does add. From the trials looking at metastatic breast cancer Phase
II and from the laboratory evidence, you would think that that combination
would be superior, but we don't have that kind of evidence. We are
getting, from the pilots done by Nabholtz and Slamon that there
is time to progression prolongation, which is very enticing. One
trial was 12 months and the other was 17 months, which compares
very favorably to the 7 months from the Genentech pivotal trial.
So we are really getting a signal here that the three-drug combination
may be the preferred way to give treatment. It's kind of exciting
because at this point there may be some other agents that can be
combined with Herceptin, but this may be a really unique strategy
in terms of treating patients that are HER2-positive.
DR LOVE: What about Herceptin
monotherapy without chemotherapy in the metastatic setting, do you
do that at all?
DR ROBERT: Yes I do, and I think that's a very attractive
approach. I think if you remember how we give endocrine treatment
- single agent, one after another - there's a lot of experience
treating patients with metastatic breast cancer with indolent disease,
identifying them as hormone-receptor-positive, and using endocrine
treatment. Fortunately, we have a number of newer agents, even today,
that are available for our patients, and there's no reason not to
use that same approach in someone who is HER2-positive. And some
may think that a HER2-positive patient has an aggressive course,
but that is not necessarily true. If you have evidence that the
tumor is indolent, slow growing and there isn't significant tumor
burden, I think it is eminently reasonable to use Herceptin. We
have the Chuck Vogel experience that shows that there is a very
acceptable response rate clinical benefit. We have a very nicely
done trial by Skip Burris. His group gave Herceptin up-front and
then took those patients who didn't respond or progressed and used
chemotherapy. So, I think that is a real strategy. It's interesting,
I've polled other people and, I think with a couple of exceptions,
everyone else agreed that this is an approach that should be considered
in the appropriately chosen patient.
DR LOVE: When you do use Herceptin,
how long do you use it for in the metastatic setting?
DR ROBERT: I use it still as long as the patient has no
evidence of any cardiac problems. The strategy, which needs to be
proven as correct and there is a trial that is going to address
that by MD Anderson. But when I have a patient fail on a Herceptin-Taxane
combination, I will then use another drug like Navelbine and continue
the Herceptin. The idea is, especially with the evidence that Navelbine
is synergistic, that you are getting more benefit by combining.
Now do we know if that's really true? We don't. There is a trial
that MD Anderson is going to do where they are going to randomize
patients for second-line and they will either get Navelbine or Navelbine-
Herceptin. So they will be able to address the issue of: do you
get more of a response or more time to progression benefit by using
the combination after someone's failed first-line Herceptin.
DR LOVE: So you continue, at
least, until a second chemotherapy.
DR ROBERT: That's right, I'll continue it. Often what I'll
do is, I'll use a taxane- Herceptin combination, treat for 6 months
to maximum response, and then stop the treatment and just give the
patient single-agent Herceptin. If you look at the Genentech pivotal
trial, that was the study design. People did not stay on chemotherapy
forever and most of the patients had the chemotherapy stopped.
DR LOVE: What about beyond
the second chemotherapy?
DR ROBERT: Well, there are other synergistic agents, or
agents that could be additive when using Herceptin. I'll often continue
Herceptin with another agent.
DR LOVE: What about the ER-positive,
HER2-positive patient with metastatic disease? What is your thought
process there?
DR ROBERT: When I see that phenotype, we have some conflicting
data, in terms of the aromatase inhibitors. Lipton has shown that
there doesn't seem to be any enhanced effect compared to tamoxifen.
On the other hand, Matt Ellis, in his studies, suggests that there
is a benefit of aromatase inhibitors in someone that's HER2-positive.
He also looked at HER1. In general, I'm concerned in someone who
is HER2-positive, if I'm only giving an endocrine intervention.
It depends on the setting, if you have a 1 centimeter tumor, postmenopausal
patient, negative nodes, ER-positive and HER2-positive, and it's
a low grade tumor, I would consider not sending tamoxifen. We have
not identified the role of Herceptin in the adjuvant setting.
On the other hand, if I had someone with metastatic disease that
was FISH-positive, I would certainly use Herceptin. And I would,
depending on the tumor load and if the tumor was ER-positive, consider
another endocrine intervention if she failed tamoxifen for example,
and not necessarily go right to chemotherapy.
DR LOVE: You are saying that
you would use endocrine therapy and Herceptin at the same time?
DR ROBERT: I would give that some consideration if the patient's
disease was indolent. I'm not aware of any experience that would
suggest that that is of greater benefit than using Herceptin or
an endocrine agent by itself. Those are questions that are going
to be asked and hopefully the answers will give us better guidance.
DR LOVE: What's your usual
approach to the HER2-positive patient on first metastatic disease
who has had ACT adjuvant therapy?
DR ROBERT: That's a problem patient. It depends on when
they failed. If they failed within a year, and it depends on how
they got their Taxane. If they got q 3-week Taxol, we know that
weekly Taxol can salvage some of those patients. I would be comfortable
using the taxane and Herceptin in that setting. Certainly, using
Navelbine-Herceptin is another combination that's becoming more
popular. Joyce O'Shaughnessy at the San Antonio meeting had a poster
to looking at Gemzar-Herceptin in showing response rate in 20-plus
percent range. Interestingly Gemzar, at least in one of the assays
appears to be antagonistic, but another assay suggests that it's
additive. I have to share some, skepticism may not be the best word,
but whatever we see in the laboratory or in preclinical models,
it is important to confirm them at the bedside and do clinical trials
because it doesn't always translate.
DR LOVE: What are your thoughts
about what you saw yesterday with the ATAC trial?
DR ROBERT: Very interesting. The fact that it was reported
and the results are significant, I think they will have a huge impact
on clinical care. There are a few issues. One is the trial itself
since there are people still on unblinded treatment arms. What's
going to happen to that population of patients? I suspect that those
patients will need to be informed of the outcome and the results,
that's a for sure. And some patients may choose to go to the aromatase
inhibitor.
The question is outside of a clinical trial what do we do with
our next patient? In a postmenopausal patient, given the benefit
that was perceived in terms of disease-free survival and the toxicity
profile, which looks more favorable. One of the things that caught
my eye was the weight difference although in randomized trials tamoxifen
versus placebo there's not supposed to be any weight difference,
it hasn't been demonstrated. There was a weight difference between
the aromatase inhibitor and tamoxifen. Certainly there are patients
who are on tamoxifen, who are very convinced that they have gained
weight because of the tamoxifen. So given that, and given the reduced
thromboembolic effects, given the reduced hot flashes, there is
more arthralgias, there's right now no benefit to bones and maybe
there is increase fracture rate. But I think overall considering
aromatase inhibitors, given the data we heard, is an option that
will need to be addressed when you see patients.
The other big question is what do you do with patients who are
on tamoxifen? What do you do with someone who is on tamoxifen for
two years? Is it reasonable to switch? I think, at this point, it
certainly is an option. You don't have to do that and continuing
with tamoxifen is reasonable, especially for someone who's already
been on tamoxifen. But certainly the data needs to be shared with
patients. Some patients may choose to switch to an aromatase inhibitor.
DR LOVE: It sounds like you
would be comfortable with that?
DR ROBERT: Yes, I would be because you have to look at the
ATAC trial not just in isolation. There are multiple trials in advanced
disease showing that the aromatase inhibitors are superior to tamoxifen.
Given that data, as well as now the data from the ATAC trial, I
think it's certainly appropriate to discuss and consider using the
AIs in the adjuvant setting.
DR LOVE: I guess some of the
concerns I've heard expressed is about the question of switching
someone whose been on adjuvant tamoxifen for two to three years
to an aromatase inhibitor. We don't really have data on what the
effects of that specific strategy will do.
DR ROBERT: Right. But I think it's maybe begging the issue
a bit, that if we know that tamoxifen has a benefit, we know at
this point - you have to remember this is a reported trial - that
AIs appear superior. And we know that the first lead in the adjuvant
setting is disease-free survival advantage. You don't see immediate
survival advantage. I think it is reasonable to consider this. It
is somewhat analogous to the change in thinking in the use of chemotherapy
in node-negative breast cancer. There was enough evidence when there
was a disease-free survival advantage to make the switch and start
offering high-risk, node-negative women adjuvant chemotherapy. Some
people argued, at the time, when this data was unfolding that you
needed to see survival data. That would have deprived patients of
a successful intervention. In the same situation, I mean we are
all looking at a drug that is effective and does have a track record
- tamoxifen, but this is really the art of medicine meeting science.
DR LOVE: Let's talk about what
you're going to do when you go back to your practice and see patients.
You see a patient who is presenting, a postmenopausal woman who
has just been diagnosed with an ER-positive breast cancer. Is that
an option you are going to discuss or suggest?
DR ROBERT: I would certainly discuss the ATAC trial and
the evidence that anastrozole looks superior to tamoxifen in terms
of disease-free survival. It has a toxicity profile that may be
perceived as more favorable. I suspect we'll go over that information
and when asked for a recommendation we'll recommend anastrozole.
DR LOVE: In that situation
would you use letrozole or exemestane?
DR ROBERT: I think at this point, given that it was anastrozole
that showed an advantage, it would be consistent to use anastrozole
and not one of the other AIs. Do I think that other AIs are going
to have the same benefit? The answer is yes. But we don't have an
adjuvant trial showing that the other AIs have that advantage at
this point. So unless there are other issues like cost or toxicity,
then I think the appropriate thing, from my vantagepoint, would
be to use anastrozole.
DR LOVE: What about the ER-positive
woman, who is premenopausal, gets adjuvant chemotherapy and at the
completion of that chemotherapy, when you are ready to start hormone
therapy has stopped menstruating.
DR ROBERT: That's an interesting situation. It depends a
little bit on her age and what kind of chemotherapy. There are some
patients, certainly younger patients in their early forties, if
you give them only 4 cycles of AC, there is a chance that if their
period stopped, it will restart. And we know that tamoxifen does
have a role and menopausal status is not an issue for tamoxifen.
In an older patient one may feel more comfortable, and one can imagine
the strategy though, if you are not sure what's going to happen,
you start off with tamoxifen and depending how they do, switch over
to an AI. But that's a strategy that's not been demonstrated in
terms of its utility.
The other thing I would say is that the monitoring of patients
is going to be a little different. With tamoxifen we've been worried
about endometrial cancer, we haven't worried about bones, it's going
to be opposite. You have someone who is 65 years old getting her
bone mineral density is going to be important. Starting her on anastrozole
you are going to have to make sure you follow her bone mineral density
and be ready to intervene with a bisphosphonate. That may not be
a bad idea anyway, in terms of the breast cancer, all of that literature
is still unfolding.
DR LOVE: We did see an interesting
presentation here, with some more data suggesting that maybe bisphosphonates
will decrease bone mets.
DR ROBERT: That's right and Trevor Powles presented, in
the adjuvant setting, the use of clodronate. Interestingly the benefit
was only when you were on clodronate and that's not a drug that's
available in this country. Fosamax, another bisphosphonate is, but
I am not aware of any data where you see a benefit in terms of breast
cancer protection.
DR LOVE: I want to pin you
down a little bit more though. You have a 43-year-old woman strongly
ER-positive, 5 positive nodes, you gave her whatever chemotherapy
you would give her in that situation and at the completion of the
chemotherapy she's not having her menstrual periods.
DR ROBERT: At this point, I'd probably give her tamoxifen.
The ATAC trial was restricted to postmenopausal women. If you asked
me if I was sure that she would not begin menstruating again, would
an AI be something that would work, the answer would be yes. You
can make it a little bit more interesting by having her continue
to menstruate and what should I do then.
DR LOVE: That was my next question.
DR ROBERT: Nancy Davidson updated the ECOG trial and someone
asked the question about chemotherapy in premenopausal women that
were node-positive or hormone receptor-positive in seeing chemotherapy
versus chemotherapy followed by Zoladex, ovarian ablation for five
years, versus chemotherapy, Zoladex and tamoxifen. Unfortunately
what's missing in that trial is the fourth arm which is pretty much
a standard of care, which is to follow chemotherapy with tamoxifen
for five years in someone who has an ER-positive tumor. What to
do if she's still menstruating? And it's interesting, in that study
there was demonstration that amenorrhea led to a better outcome
than patients who continued to menstruate did. And in younger women,
looking at estradiols, using that as a surrogate of women, who continued
to menstruate, there was a benefit by giving ovarian ablation and
tamoxifen.
In a high-risk woman who continues to menstruate after chemotherapy,
I think it is reasonable, even though there is only disease-free
survival advantage to date, to ablate ovaries. Now, the question
is how long to ablate ovaries and should we ablate them surgically,
permanently, irreversibly or is there a rationale to use an LHRH
analog. But we have this conflict here because we are, at one moment
saying it's reasonable to use an aromatase inhibitor which gets
rid of estrogen, and another moment we are talking about maybe the
potential, at a later date to reintroduce estrogen. So we have these
two different approaches that appear to be in conflict.
But one strategy we could consider in the future is should we be
giving ovarian ablation and tamoxifen or should we be doing ovarian
ablation and an aromatase inhibitor. Certainly in metastatic disease
there's a meta-analysis looking at ovarian ablation versus ovarian
ablation/tamoxifen, suggesting that the combination was superior.
In my own clinical practice, I've had in a few patients excellent
results where a woman was menstruating, didn't want to get chemotherapy,
gave her Zoladex and Arimidex, sort of a double-dex approach, and
had the resolution of pulmonary nodules with an excellent clinical
outcome.
DR LOVE: Generally speaking,
how do you approach a premenopausal woman in the metastatic setting
who's not had hormone therapy?
DR ROBERT: Who is still menstruating?
DR LOVE: Yes.
DR ROBERT: And has an ER-positive tumor. Actually, I've
done this in a stepwise fashion. The meta-analysis doesn't speak
to the issues of crossing over. Since the objective in metastatic
disease is palliation, depending on her symptoms, tumor burden,
and disease free interval, if endocrine treatment is an option,
one could consider using tamoxifen, then following with ovarian
ablation, and then following that with adding an aromatase inhibitor.
I recently saw such a patient who is menstruating but has extensive
metastatic disease and my plan is to treat her with chemotherapy,
specifically Carboplatin and Taxol. Then I will follow that with
endocrine treatment. She's also being evaluated to see if she has
a FISH-positive tumor.
It's kind of interesting, with the exception of ovarian ablation
and tamoxifen, combining endocrine treatments have been, unlike
chemotherapy, generally an unsuccessful strategy. But we'll see;
maybe ovarian ablation and an AI will work. Now we have Faslodex,
an estrogen-receptive downregulator, which has the potential of
being additive to another endocrine intervention.
DR LOVE: Do you have any experience
with Faslodex?
DR ROBERT: I have some very limited experience, but it is
certainly something that I think will be developing more and more
experience with. We have now available in our practice the compassionate
use of Faslodex and there is certainly going to be a greater interest.
It is really, I think fortunate for patients to have another potential
endocrine intervention. If you think about it, now we have tamoxifen,
we have AIs, in premenopausal patients we have LHRH analogs, we
have Megace, we have Faslodex, and we can even use androgens.
DR LOVE: One of the issues
about Faslodex is that it's a monthly intramuscular injection. How
have you found that in terms of patient's acceptance?
DR ROBERT: That has not been a problem. It was perceived
as a potential problem but when you compare it to what we do giving
chemotherapy, I think it's an alternative. It may turn out that
the dose of 250 mg may not be the ideal dose and we may find that
women may get two injections a month to get a better outcome to
truly downregulate the estrogen receptor. I don't see that as a
problem, given the option is chemotherapy for that patient or a
drug like megestrol acetate that leads to weight gain. I think that
this will be well received.
DR LOVE: What have you seen
in terms of side effects, both yourself, as well as what you've
seen in the reported clinical trials of Faslodex?
DR ROBERT: Unfortunately, what was initially touted by Professor
Howell about not seeing hot flashes, they are seen. But outside
of that, I think it's like the other endocrine interventions, generally
well tolerated.
DR LOVE: Have you had a chance
to see the data on the Faslodex-Arimidex trials?
DR ROBERT: Yes, I have seen it.
DR LOVE: What were your thoughts
on those data comparing Faslodex to Arimidex?
DR ROBERT: My impression is they're comparable. The American
Trial suggested there may be some superiority and that probably
will need to be better evaluated with further trials whether there
is another comparison. Part of the problem may be the dose of Faslodex
and there may be superiority if a higher dosage is used. That should
be evaluated and should be addressed. But I saw those studies as
very helpful because it certainly provided evidence that Faslodex
was another option for our patients who we can try to continue to
control their disease using non-chemotherapy interventions.
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