| You are here: Home: BCU 4|2002: Interviews: Dr. Aman Buzdar
DR BUZDAR SUPPLEMENT:
DR NEIL LOVE: Both Dr Osborne
and Dr Winer mentioned one of the most discussed current topics
in breast cancer medicine, the early results of the ATAC adjuvant
trial. The Miami meeting "patterns of care" study demonstrated
that within a month of the presentation of these data in San Antonio,
30-50 percent of oncologists and surgeons had already incorporated
anastrozole into adjuvant treatment decisions for postmenopausal
patients. I met with Dr Aman Budzar, a steering committee member
of the ATAC trial, to learn more about what these data mean to patient
care and clinical research, and he began by summarizing the key
ATAC findings.
DR AMAN BUZDAR: The data as we all have seen now, with about
three years or two-and-a-half years of follow-up, clearly demonstrates
that anastrozole or Arimidex is effective in reducing the risk of
recurrence further compared to tamoxifen. And in the total patient
population, where we have about 83 percent of the patients in which
we know the receptor information; in that subgroup there is about
a 22-percent reduction in the risk of recurrence. This is substantial
because this is compared to tamoxifen. If you look at it, there
are about nine percent of the patients who are ER- and PR-negative.
If you take the whole group with the intent to treat analysis, there
is a 17-percent reduction in the risk of recurrence.
The other major striking finding of this study, even at this early
phase, is that it reduced the risk of contralateral and ipsilateral
breast cancer by almost 60 percent. The exact number would be 58
percent. This is, again, compared to tamoxifen, which is, again,
a major step in the right direction.
The second most important thing, which, from the safety point of
view, is that the study demonstrated there is a reduction in the
number of complications that are associated with tamoxifen. Essentially
because of the agonistic effect of tamoxifen there are increases
in the risk of thromboembolic complication, increases in the risk
of vaginal bleeding, increases in the risk of vaginal spotting,
vaginal discharge, and a small increased risk in endometrial cancer.
All those side effects are substantially lower in the anastrozole
arm of the study, compared to the tamoxifen. From the patient point
of view, the risk of endometrial cancer, even at this early follow-up,
is substantially lower, and it is identical to what you would expect
in the control patient population.
From the patient's point of view and from the physician's point
of view, it is extremely important that we all understand that tamoxifen,
which has been the standard of care; we now have a newer treatment
even though the follow-up is modest. But there is further reduction
in the risk of recurrence and fewer side effects are associated
with the newer therapy compared to tamoxifen.
The only thing that is on the slight increase is an increased risk
of bone-related complications. Because you are decreasing the estrogen
level in these patients there is increased risk of fractures, and
most of these fractures were actually either compression fractures
of the spine or wrist fractures or rib fractures. The risk of hip
fractures at this early stage of the study is identical between
the two arms of the study.
The third thing, which I think we need to very briefly address,
is that the combined arm, where we looked at anastrozole and tamoxifen
combined, compared to tamoxifen, there is no benefit. Essentially,
the data looks identical to what you would see with tamoxifen alone.
So, combining the two hormonal agents did not reduce the risk of
recurrence, and also did not modify the safety profile of these
agents. Some of the side effects that you would see with the presence
of tamoxifen were to a similar degree as they were in the tamoxifen
arm; i.e., risk of thromboembolic complications and things like
that.
DR LOVE: Was there any significant
difference in the side effects in the tamoxifen arm versus the combined
arm?
DR BUZDAR: I think at this point, the side-effect
profile looks very similar.
DR LOVE: So, there wasn't an
increase in fractures in the combined arm?
DR BUZDAR: In the combined arm there was a somewhat lower
risk of bone-related morbidity, yes.
DR LOVE: Another side effect
that was reported to be increased with Arimidex was arthralgias.
Any comment on that?
DR BUZDAR: I think that is a very subtle thing. The majority
of patients in the metastatic setting who were offered this drug,
it is a very occasional patient that will have discomfort that may
need some NSAIDs or something like that. But the majority of patients,
at least in my own personal practice, who are on the study, I have
not seen any patient where it has been an issue that resulted in
changing or stopping therapy.
DR LOVE: Now, getting back
to the fractures. We're comparing anastrozole to tamoxifen. We know
tamoxifen has an agonist effect on bone. We don't have a placebo
or control arm. Is there any way to make any estimate about how
much of the increase in fractures is just the absence of the tamoxifen
effect?
DR BUZDAR: Yes. Actually, there is a sub-protocol where
we are looking at this. There we are looking systematically at the
turnover of the bone markers, the bone density change, and while
there is not a concurrent control, but an age-match control, small
sub-cohort of women, in which we are doing similar studies. That
data is a separate, independent protocol, which is a complimentary
protocol to ATAC. That data will become available in the next few
months and that will shed some more light on this problem with the
bones.
DR LOVE: Do you have any gut
feeling in terms of whether or not anastrozole increases bone loss
beyond a normal postmenopausal woman?
DR BUZDAR: I personally think yes, because I think the thing
is that you are taking a postmenopausal woman and decreasing the
estrogen. And even though a postmenopausal woman has a lower estrogen
level, you are further decreasing it by 95 to 98 percent. So, I
think it is real. But the thing is, here is a side effect in which
you could follow the patient closely. You can see if there is a
change in bone density. You could then appropriately provide interventions
that are highly effective and do not cause any substantial morbidity.
And a number of women, at least in the clinic when I see them, family
physicians have them already on either bisphosphonates or they are
getting calcitonin and taking tons of other medication to decrease
their risk of osteoporosis.
DR LOVE: So, do you think that
in a non-protocol setting that's the strategy that you should follow
a patient and monitor bone density? Or what about using anything
preventably?
DR BUZDAR: It would be good, if you're going to start a
lady on anastrozole as an adjuvant therapy, it would be good to
get a baseline bone density. And then usually, when we see these
patients, we just look at the mammogram, do a physical examination.
But I think that periodically these ladies should have now a bone
density study. And if you see that there is decrease in bone density,
then it would be appropriate to start an intervention type of therapy
in these patients.
DR LOVE: Another interesting
part of the toxicity profile was the decrease in stroke.
DR BUZDAR: Oh, there is no question that all the agonistic
effects of tamoxifen, which are associated with pulmonary emboli,
stroke, deep vein thrombosis, they are substantially reduced in
the anastrozole arm compared to the tamoxifen arm.
DR LOVE: Another interesting
finding, there was less weight gain in the anastrozole arm. Any
thoughts on that?
DR BUZDAR: Yeah. I think the thing that is from P-1, where
they had a placebo versus tamoxifen, it did not show that there
was any weight change. But in this large study, there is evidence
to suggest that there was some weight gain in women who were on
the tamoxifen arm and there was no substantial change in the weight
on the anastrozole arm. The question is whether there was a decrease
in the weight, but I don't think that is, because most of the patients
don't have any significant GI side effects to decrease their appetite
or things like that. I think it may be real.
DR LOVE: Any idea why we didn't
see it in P-1 and some of the other studies?
DR BUZDAR: I think in P-1, they did look at it fairly closely.
Again, you're looking at a global patient population and different
cultures, different diet patterns, different things, and I don't
know whether this is due to that or whether this is a real phenomenon.
But as far as I see the patients in the clinic, the majority of
patients with a history of breast cancer, even if they're on chemotherapy,
just after diagnosis, I think maybe it is the stress or something
that women do gain some weight. I think all of us gain weight.
DR LOVE: Unfortunately. (Laughter)
One of the things that's been pointed out about the data that's
been presented so far is that only about 20 percent of these patients
also got chemotherapy. It was a relatively low-risk population.
About two-thirds of them were node-negative. The question is are
you going to see these same benefits in a patient who gets adjuvant
chemotherapy?
DR BUZDAR: That's an important question, because 20 percent
of the patients did get chemotherapy. And in those patients, participation
in the trial was delayed until they finished their systemic chemotherapy.
So, they did not start the study drugs until they had finished the
chemotherapy. In that sub-population, we are looking at it a lot
more detailed. The key thing in that sub-population would be to
look at the patient population, who are known ER-positive and why
these patients got chemotherapy. I am sure there is some physician
selection bias that these patients' physicians thought that they
were at an increased risk of relapse. Because if you look at the
overall patient population, more than 30 percent of the patients
are actually node-positive. But out of that, only 20 percent of
the patients got chemotherapy.
DR LOVE: Hmm.
DR BUZDAR: We have to look at it in a little more detail
about why, and what the impact was. Right now, the number of events
when you subdivide it, I think it's too early to tell. But these
are important questions that we really have to answer eventually.
And there are an adequate number of women, even though they are
only 20 percent. But 20 percent of 9,000 patients is a lot of patients.
DR LOVE: There were a lot of
older women in this study. I mean, I could envision maybe some of
these node-positive patients were older and the doc didn't want
to give them chemotherapy.
DR BUZDAR: There was actually no age cutoff. The oldest
patient, I think, in the study was over 90 years of age.
DR LOVE: Right. You mentioned
the lack of benefit that was seen in the combination arm. Any speculation
about what was going on there biologically?
DR BUZDAR: My simplistic take on this is that I don't think
that we have ever seen that combined hormonal therapy has any synergistic
or additive effect with the earlier agents and the newer agents.
And I think this was an elegant study and, if there was going to
be any synergistic or additive benefit by using combined hormonal
therapy in breast cancer, this was an ideal setting. I can sit and
speculate, but I really don't know.
DR LOVE: I'm curious about
your thoughts in terms of the application of these data to patient
care and, also, how you see it affecting clinical research right
now. First of all, in terms of patient care, clearly there are going
to be a lot of patients who are on adjuvant tamoxifen, where the
question is going to come up: Should they be switched to anastrozole?
What are your thoughts on that?
DR BUZDAR: This study was designed to evaluate patients
who are de novo, starting adjuvant therapy. In that subgroup of
patients, I think the data is quite clear that we have to share
with our patients that we have a drug which has a modest follow-up,
but it has a better safety and better efficacy profile. And the
women have to be active participants in making the decision.
The question is that: How about the woman who is already a year,
two or three, on tamoxifen and is free of disease? This study did
not address that question. Maybe, if the patient is having substantial
morbidity from taking tamoxifen or having excessive side effects,
in those individual patients, I think you may be able to switch
them to an aromatase inhibitor. But I would not just because of
this data, across the board, switch a patient who is taking tamoxifen,
tolerating the drug well, and has been under therapy for a while.
There are studies that are specifically evaluating that question
of after two or three years on tamoxifen if you go to an aromatase
inhibitor will that further reduce the risk of recurrence. Those
studies are either accruing patients or they have finished accrual.
In the next few years, you will see the data, and then we may be
able to answer these questions with actually appropriately controlled
data. We have to wait. I personally would not advise anybody to
switch except those few patients in which there may be substantial
morbidity being caused by the tamoxifen.
DR LOVE: You said that you
would present this information as an option to patients. What are
you expecting is going to happen? Let's say the next 100 postmenopausal
women that you see on who you want to use adjuvant hormonal therapy.
DR BUZDAR: I personally think that it is my responsibility
as a physician, to share all my new knowledge, or all of my knowledge,
with the patient and let them be active participants. I think if
I was the patient, if somebody told me that here, I have a treatment
which may cause fewer side effects and may increase your odds of
remaining free of disease, at least in the next two to three years.
If I were the patient, I would go with the newer therapy, even though
there may be shorter follow-up. Of course, we like to see all drugs
be followed for 20-30 years, but we can't decide the fate of patients
and wait for 20 years until these data become mature. We have to
provide the information which we have and let the patient make up
their mind. Also, we have to guide them as to what the shortcomings
of the data are and what the strengths of the data are.
I think the main shortcoming is the relatively short follow-up.
But the strengths of the data are that there is a significant reduction
in the risk of recurrence, there are fewer side effects and side
effects that have potentially lethal complications are substantially
modified with the newer therapy.
DR LOVE: Any thoughts on what
you think we're going to see in the future in terms of survival?
DR BUZDAR: If anything, what we learned from the development
of this agent, in the second-line setting it was better than the
old standard. The first-line data still is not mature, but we saw
some of the data of the other aromatase inhibitors that do suggest
that there is survival advantage. My personal bias without the data
is that eventually, especially in the adjuvant setting, there will
be gains in survival with the newer aromatase inhibitor, compared
to the tamoxifen, because these drugs have better anti-tumor activity.
DR LOVE: You talk about these
drugs. What are your thoughts in terms of substituting one of the
other aromatase inhibitors that are available - letrozole or exemestane
- in the adjuvant setting at this point?
DR BUZDAR: I think that is a very important question and
we need to address that right now the data is available with anastrozole.
The other two agents which are available for the physicians to use,
but we don't have the safety data or their efficacy data in this
type of setting. I would have reservations to just, with a broad
brush, label this is a class action effect, and switch a patient
to another agent, which we don't have any data available.
DR LOVE: You mentioned the
dramatic reduction in second breast cancers. It seemed like it started
pretty quickly in terms of when the curves started to diverge. What
are the implications of that, particularly in terms of prevention?
DR BUZDAR: I feel it has tremendous implications. Already
in Europe, they are going to evaluate this drug in a prevention-type
setting, and also in DCIS, to see that if compared to tamoxifen
it further reduces the risk of recurrence and the risk of developing
ipsilateral and contralateral breast cancer.
DR LOVE: Is that something
you would like to see studied in the United States also?
DR BUZDAR: I hope that some of our cooperative groups, who
have been carrying out these studies, take this as an important
lead. And I think we need to explore this further by doing definitive
studies in high-risk women, especially in postmenopausal women.
Because in postmenopausal women, even though tamoxifen does reduce
the risk of developing breast cancer, in that subgroup of women
the toxicity of tamoxifen is substantial.
DR LOVE: Thrombosis, endometrial
cancer particularly?
DR BUZDAR: Endometrial cancer, yes. So, I think if here,
the safety of this compound is better and it shows higher potential
to reduce the development of the cancer, I think it is an important
issue and it should be evaluated.
I think these data, from the safety point of view, clearly show
that the safety profile of this is much better than tamoxifen. And
the main safety concerns with tamoxifen have been agonistic effects;
i.e., risk of thromboembolic complications and the effect on the
endometrium, which causes either vaginal bleeding, vaginal discharge,
and small risk of endometrial cancer. But even a woman, who has
just vaginal bleeding and doesn't have endometrial cancer, she still
has to go through a number of tests and invasive and non-invasive
procedures before we know that she doesn't have the problem. Here,
we have an agent in which that side effect is essentially not existent,
at least in the preliminary analysis of the data. So, it makes it
a very attractive agent to be evaluated in a preventative type of
setting.
DR LOVE: What about the implications
of these data on clinical research? One area would be in terms of
current trials that are out there. There are many trials, even trials
that are looking at different chemotherapeutic regimens that include
as part of that a specification to receive adjuvant tamoxifen if
they're ER-positive. What do you see the clinical trial groups doing
now?
DR BUZDAR: We have to take a hard look at it, especially
with the new studies. The studies that are ongoing, I think we should
not change the design of those studies. But the new studies, we
have to take into consideration that here you have a drug which
has better anti-tumor activity. And my feeling is that this issue
has to be considered in the planning of the next generation of adjuvant
studies.
DR LOVE: Well, you're saying
that we shouldn't change the current studies, but, for example,
if we have a woman who comes in, is on a trial randomizing between
two different schedules of adjuvant taxanes, the trial specifies
that all the patients, regardless of what arm, are going to get
tamoxifen if they're ER-positive. Are you saying that that should
continue, or should there be an option to receive (Interrupted)
DR BUZDAR: Well, I think that area, since we have right
now close to 20 percent of the patients - and I think that is one
of our high priorities, to look at that subgroup to see whether
we see a similar trend. My personal feeling is that it would be
a similar trend in ER-positive patients. I don't think the chemotherapy
would negate the effect of any of these agents. But right now we
just haven't had a chance to look at that issue. And I have the
feeling that in the next few months, we will have that, because
we are looking at this.
DR LOVE: Are there any trials
that you were involved in developing right now, or new trials that
are about to be launched, which are going to include adjuvant anastrozole?
DR BUZDAR: We are actually in the process of, at MD Anderson,
developing our new adjuvant and neoadjuvant study. And obviously,
we have to give very good thought to see whether we should stick
with tamoxifen after chemotherapy or whether we should substitute
it with anastrozole. I'm hoping that the steering committee and
the data monitoring committee will come up, relatively quickly,
with this answer. But if we see a similar type of trend in patients
who have been exposed to chemotherapy, I think that will reassure
us that it is not any drug-drug interaction.
DR LOVE: Actually, what are
you considering right now in terms of this new neoadjuvant/adjuvant
study? What are you going to be looking at?
DR BUZDAR: The main thing we are looking at in our study
at MD Anderson - the standard arm is essentially taxane being given
for 12 weeks, weekly and then four cycles of FAC. The control arm,
the research arm in that study is evaluating the role of Taxotere
plus capecitabine because in the metastatic setting that drug combination
shows a survival advantage and a higher response rate. So, we want
to see whether, in the adjuvant or neoadjuvant setting, if instead
of using just the taxane alone, combining these two agents will
further reduce the risk of recurrence.
DR LOVE: So, what is the actual
randomization that you're thinking about?
DR BUZDAR: The randomization is either a patient gets weekly
Taxol for 12 weeks or they will get three cycles of Taxotere plus
capecitabine. The FAC part will be identical. Everything else will
be identical in the study.
DR LOVE: Why not use Taxol-capecitabine
or Taxotere alone? Why are you having different taxanes there?
DR BUZDAR: The reason why we stuck with our control arm
as a weekly Taxol, was because we just finished a prospective study
in which we evaluated q three-week Taxol versus a weekly fractionated-dose
of Taxol. The weekly fractionated-dose of Taxol, in the neoadjuvant
setting, resulted in twice as many pathological CRs, both in the
breast and in the lymph node, compared to the patient receiving
the same chemotherapy only on a different schedule. So, we wanted
to maintain that. We did not want to switch it to Taxotere, because
with Taxotere, there is a little less data that it has schedule-dependent
anti-tumor activity.
DR LOVE: I see. So, that's
your control arm.
DR BUZDAR: Mm-hmm.
DR LOVE: What kind of dose
are you thinking about for the Taxotere-Xeloda?
DR BUZDAR: We are going with a somewhat lower dose of both
capecitabine and Taxotere in this study because of the substantial
morbidity of dose modification in that metastatic protocol which
was required. After one or two cycles, in the majority of patients,
the dose had to be modified to avoid the morbidity of infectious
complication.
DR LOVE: So, the initial starting
dose in that study was 75 milligrams for Taxotere and 2.5 grams
of capecitabine. What are you going to use in your study?
DR BUZDAR: In our study, we are going with 75 of Taxotere
and 2000 of capecitabine per meter squared.
DR LOVE: Is that a combination
that you've used yourself in treating patients?
DR BUZDAR: In some of the patients, we do, in the metastatic
setting. But now this will be the ultimate test. Again, we are using
our same type of approach. Patients, who come with an intact primary,
they will get the taxane part of their therapy up front. So, if
you have an intact primary, you can tell what the clinical reduction
in the volume of the tumor is in the breast, and what the reduction
is in the nodes. And then, essentially, all the systemic therapy
is delivered up front. And then the local therapy is done.
What we are going to look at it is, is there a higher fraction
of patients who will get pathological CR in the experimental arm
and are we able to preserve the breast in a higher fraction of patients
because these things are surrogate end points. They do predict from
our previous experience, that if you could render the patient pathologically
CR, these patients will do very well in the long run. And if you
have a study arm in which there is a higher fraction of patients
who have achieved pathological CR, that arm in the long run will
have fewer recurrences and fewer disease-related morbidity or deaths.
DR LOVE: The NSABP presented
their pre-op Taxotere studies. Any comment on that?
DR BUZDAR: Well, I think that's a very good study. That
study clearly demonstrates the same concept, that if you utilize
alternate non-cross-resistant therapies, you can reduce the volume
of the cancer. And the data clearly demonstrated that patients'
pathological CR rates - in the arm which received Taxotere almost
twice as many patients got pathological CR in the breast compared
to the arm which received just four cycles of AC. So, it clearly
demonstrates that by using alternate non-cross-resistant therapy,
you are able to get a higher fraction of patients pathological CR
and in a somewhat higher fraction of patients breast preservation
was feasible. My personal bias is that once the data becomes mature,
there will be a higher number of women who will be alive, free of
disease, in the arm that received the taxane and AC combination
compared to the AC control arm.
DR LOVE: Of course we don't
know that right now, but the other intriguing thing about that study
that we also still don't know about is the arm that got the Taxotere
post-op.
DR BUZDAR: I think the timing of the initiation of chemotherapy
does not make any difference. I think that is an important question
that, in the long run, will answer in which subgroup the treatment
had major impact. Because then, after AC, you have patients who
are, say N-zero. They are one to three positive nodes. Still they
might have 10 positive nodes, that which subgroup it had the major
impact. My feeling is that the proportional reduction and risk of
recurrence and death will be the same. But the design of the study
will answer what is the actual impact in different risk groups.
DR LOVE: How much toxicity
do you think you add to Taxotere by adding the capecitabine?
DR BUZDAR: We hope that it will be manageable by reducing
the dose of capecitabine. Of course, there will be some additional
toxicity because you are adding two drugs. But with modification
of the dose, we feel that it should be feasible because you are
giving only four cycles. And if there is, we have appropriate dose
modification criteria in the study, that we will modify it if there
is morbidity or if it is a neutropenic-type episode with the association
of fever we can add growth factors. But if it is non-hematological
toxicity then we might have to modify the dose of the agents.
DR LOVE: Are you also developing
an adjuvant study?
DR BUZDAR: Our philosophy is that patients will come with
an intact primary, we'll do the same protocol. In a neoadjuvant
setting, we'll deliver all the systemic therapy and in the patients
who have surgery already done, had local therapy and finished, we
have the same protocol. Essentially, the end point of the study
will be combined data. But the advantage of this is that you can
see in the neoadjuvant setting, the impact in down staging the tumor.
DR LOVE: That's interesting.
So, in other words the study is set up for two randomization arms.
Then if a patient, for example, is referred from another institution
and they've already had their surgery, they just get the same randomization
post-op?
DR BUZDAR: That's right. They get identical treatment. They
will be randomized between those two arms of the study. If they
had local therapy, if they did not have local therapy and they're
willing to participate, then they will get all systemic therapy
up front.
DR LOVE: Interesting. So, if
they've had their surgery, they'll still be randomized to FAC followed
by either Taxol or Taxotere-capecitabine?
DR BUZDAR: That's right.
DR LOVE: How long will it be
before you have answers to this?
DR BUZDAR: Because there are hard end points, that patients
in which the tumor is still intact, we have, almost, what we call
a continuous monitoring system.
DR LOVE: Right.
DR BUZDAR: Because you can't change the pathological outcome
once the systemic therapy is delivered. So, we will be watching
this study carefully to see how it goes from a safety point of view
and from an efficacy point of view.
DR LOVE: But, for example,
in these kinds of studies, about how many patients would you accrue
in a year?
DR BUZDAR: Actually, we are seeing more and more patients
who are candidates for these types of studies. The last study which
we did, in two-and- a-half years we accrued the number of patients
we needed for a study where we answered the question of weekly versus
q three weeks. In the previous studies, it took a little longer,
but I think still, one of the strengths of MD Anderson is that it's
one of the few institutions where you can still do a single- institution
adjuvant and neoadjuvant type of study.
DR LOVE: In that study, in
two-and-a-half years, about how many women did you accrue?
DR BUZDAR: I think we had more than 500.
DR LOVE: Wow! So, you would
think that you're going to start to get some hints, at least about
the pre-op efficacy, within maybe a year or two.
DR BUZDAR: Yes.
DR LOVE: Any guess what it's
going to show?
DR BUZDAR: Looking at what we have seen from the NSABP or
our own studies, in which we evaluated the addition of a taxane
to FAC, I am optimistic. I think there will be a higher fraction
of patients who will have a pathological CR in the experimental
arm, which is Taxotere plus capecitabine.
DR LOVE: Really? That's interesting.
Why do you think that?
DR BUZDAR: Because that combination has a higher likelihood
of causing objective regression, and the weekly Taxol, at least,
is as good as q three weeks Taxotere. But unless weekly Taxol is
as good as the combination of capecitabine and Taxotere, because
those are the only two modifications in the whole study.
DR LOVE: One of the things
that's been discussed has been the fact that the taxanes - and I
guess this was part of the rationale for the Taxotere-capecitabine
study - upregulate TP. When you've looked at that basic data, is
that impressive to you in terms of being a reason? Or do you think
it's just that there are two different agents on board?
DR BUZDAR: Well, I think there is some experimental data,
and we are going to do some correlated studies by measuring these
types of things in the tumor, baseline and subsequently after therapy,
and try to correlate with the outcome and the responses. There are
a number of secondary end points in the study because the patients,
who have an intact primary, you essentially have initial tumor and,
subsequently, want to see what is happening at the cellular or molecular
level in these tumors.
DR LOVE: You mentioned this
trial that you're looking at for neoadjuvant and adjuvant therapy.
Any studies that you're working on right now or thinking about in
terms of management of HER2-positive patients in the adjuvant or
metastatic setting?
DR BUZDAR: There are a number of studies. Actually, in the
neoadjuvant setting, we are doing a study in which we are essentially
using four cycles of Taxol, four cycles of FAC, plus-minus - It's
a randomized trial. The patients either receive Herceptin or don't
receive Herceptin. That is a study that actually just started at
our institution and has a small number of patients on it.
DR LOVE: Again, it is just
a single-institution study?
DR BUZDAR: It is a single-institution study.
DR LOVE: Is that your study?
DR BUZDAR: It's my study.
DR LOVE: So, it's neoadjuvant
Herceptin plus chemotherapy?
DR BUZDAR: It is either chemotherapy alone with Taxol and
FAC, four cycles and four cycles of each, or we give Herceptin with
it.
DR LOVE: Hmm.
DR BUZDAR: We are doing very close cardiac monitoring and,
also again, you don't have to wait for years to see what the benefit
will be. You could assess if there is truly some additional benefit,
as we saw in the metastatic setting, again, we should be able to
see as the study progresses, that there should be a higher fraction
of patients who get pathological CR in the group which is receiving
Herceptin.
DR LOVE: What are you defining
as HER2-positive in that trial?
DR BUZDAR: We are going with what is now considered as a
standard, either they have to be 3+ on HercepTest or they have to
be FISH-positive.
DR LOVE: How is the scheduling
being done, particularly in terms of when is the Herceptin given?
DR BUZDAR: The Herceptin is given weekly.
DR LOVE: But, I mean, at the
same time as the chemotherapy?
DR BUZDAR: They get chemotherapy on day one, and then they
start the next day with -
DR LOVE: So, they're basically
getting FAC, which includes Adriamycin at the same time that they're
getting Herceptin?
DR BUZDAR: In the first phase of the protocol, we have done
this in the reverse sequence because of the neoadjuvant setting
of our previous trials. There we start with the Taxol first for
12 weeks, and then we gave four cycles of FAC, which is an additional
12 weeks of therapy, and they get weekly Herceptin throughout the
study.
DR LOVE: Any concerns in terms
of giving simultaneous Adriamycin and Herceptin?
DR BUZDAR: The first thing is, we are using epirubicin in
this study. And, also, we have a cardiologist very closely monitoring
these patients to see if there is a change in the cardiac ejection
fraction. We will do thorough evaluation to see how big a problem
that, or if there is any.
DR LOVE: Epirubicin. The study
you mentioned before, was that - maybe I didn't hear you correctly.
Was that FEC or FAC?
DR BUZDAR: FEC. It is epirubicin. Only, instead of giving
doxorubicin, we're giving epirubicin.
DR LOVE: But in the other study,
it's actually doxorubicin?
DR BUZDAR: In the other study, it is doxorubicin.
DR LOVE: And you specifically
chose epirubicin because of your concerns about Herceptin and cardiomyopathy?
DR BUZDAR: We thought that it, at least, would potentially
offer a lower risk of cardiac dysfunction.
DR LOVE: Interesting. Now,
are you taking the same strategy with that study, that if the women
comes in and she's already had primary surgical therapy, she gets
randomized to those two arms?
DR BUZDAR: In this, Herceptin study?
DR LOVE: Right.
DR BUZDAR: No. There are other groups that are looking at
that. We want to see what the pathological down staging is, or,
i.e., get a quick end point. So, this study is only open to the
patients who are coming with an intact primary. We have another
study, which is actually a cooperative group study, for patients
who come after mastectomy.
DR LOVE: Sure.
DR BUZDAR: We are recruiting those patients into that study.
DR LOVE: That's the Intergroup
study or the NSABP study?
DR BUZDAR: No. It's actually BRCG's.
DR LOVE: Oh the BRCG. Interesting.
What other studies are you aware of that are looking at neoadjuvant
Herceptin?
DR BUZDAR: I think there are a number of other studies looking
at it. I don't have the list, but I think there are number of other
institutions and even some of the groups are looking at these type
of issues.
DR LOVE: Have you seen any
other trials that are using Herceptin at the same time as an anthracycline
because that seems a little unusual?
DR BUZDAR: I'm not aware of it.
DR LOVE: George Sledge did
the presentation yesterday.
DR BUZDAR: I saw that.
DR LOVE: A pilot study. He
was very careful to talk about how they set the design up, although
he brought up the fact that later on they found out that maybe the
pharmacokinetics were not what they were expected. But at least
they were trying to set the study up so they wouldn't have Herceptin
onboard at the same time as they had an anthracycline.
DR BUZDAR: The thing in these studies that we are doing,
the total cumulative dose of epirubicin is very small. So, the risk
of cardiac dysfunction should be very small. We are giving only
four cycles of therapy, and this is a dose-dependent phenomenon,
and we hope that it will not be an issue. But, of course, that's
why the study is being done. We want to see whether it has any issues
or whether it can be safely delivered.
DR LOVE: I know in the other
studies you've done, there hasn't been a specific tumor size cutoff.
Is that the case, or do they have to have a specific tumor size
to be eligible for either one of those studies?
DR BUZDAR: For the neoadjuvant Herceptin study the tumor
has to be more than two centimeters.
DR LOVE: How about the other
one?
DR BUZDAR: The other one, any patient, if we think the patient
will need systemic cytotoxic therapy, we will offer it to them.
Of course, if the patient is willing to participate in the research.
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