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You are here: Home: BCU 6|2002: Supplement: John Robertson,
MD, FRCS
DR JOHN ROBERTSON
So, my take on whether we prescribe it is, I think there are two
types of people to think about. People who are very cautious and
say, “I’m going to stick with tamoxifen until we get
more data, longer-term data.” For those clinicians or patients,
I think what it does tell us is that, if you had a patient who had
some reason that you were uncomfortable putting them on tamoxifen;
i.e., that they had a history of thromboembolic disease or cerebrovascular
accident, this data suggests that we could put them onto anastrozole
with a very low threshold. I know a number of clinicians that have
already been doing that off label. But I think this data gives us
even more confidence, maybe to lower that threshold. So, if you
say, “Well, I’m sticking with tamoxifen as my standard
treatment,” you may be prepared to, as I say, give anastrozole
with a low threshold to patients who have some reason to think that
they may have a side-effect profile that you would not wish to start
them on tamoxifen.
Then I think there’ll be people who will look at the data
and say, “The efficacy data here is sufficient for us to start
somebody on anastrozole.” By the time patients are one, two,
three, five years on anastrozole, we’ll have far more data
to make decisions.
Secondly, we look at the side-effect profile of the two drugs and
there are things that you can weigh up in favor of either of the
drugs. In fact, in many cases, anastrozole has got a better side-effect
profile than tamoxifen. Okay, there are more fractures, but there
are fewer DVTs, there are fewer cerebrovascular accidents, there
are fewer hot flashes, there’s less endometrial cancer. And
the other argument that you could put is that, in fact, the tamoxifen
side-effect profile, where it may be treatable, is usually not preventable.
You know, how do you prevent DVTs? How do you prevent the cerebrovascular
accidents? How do you prevent endometrial cancer? So, as the main
side effect of anastrozole, the bone fractures, is something that
potentially one could treat with bisphosphonates, calcium supplements,
exercise. And so some clinicians and patients may look and say,
“Well, there is better efficacy here, and we are prepared
to take the risk,” if you put it that way, of the lack of
long-term follow-up data, and in fact we would be prepared to start
them on a bisphosphonate, knowing that this should hopefully deal
with some of the bone-mineral density loss.”
So, I think for clinicians across the country there’ll be
a spectrum of response is to this data. Some clinicians will be
more conservative, use it in selected patients whom they see side-effect
profiles from tamoxifen that they feel would have risk factors for
them. And I think there’ll be other clinicians and patients
who will embrace the efficacy data and take the possibility of unknown
long-term side effects in terms of bone mineral density or treat
them prospectively by giving them bisphosphonates.
DR LOVE: Do you think that it’s an issue
that should be raised with any postmenopausal woman starting on
tamoxifen, as an option?
DR ROBERTSON: Yeah,
I think the data should be discussed with them. If the issues are
explained clearly, I think most women are able to voice their opinion
about these matters, and I would certainly think that it’s
something that should be raised. Remember that this is a large study.
It’s one of the largest adjuvant studies ever done. And I
think that to ignore that data is doing a disservice to women, I
think.
DR LOVE: I’ve heard people say that they
may be more willing to think about using anastrozole in a high-risk
woman, in a multiple node-positive woman, as opposed to a woman
who maybe has a lower risk for recurrence, node-negative, small
tumor. Does that kind of approach make sense to you or not really?
DR ROBERTSON: I don’t
think it really makes sense to me. I suspect what they’re
saying is that the up-sort benefit is greater. And that’s
true. But the side-effect profile is the same. I don’t think
there’s really any real rationale for that. I think if you’re
going to use it as your standard adjuvant therapy for node-positive
patients then there’s no reason not to use it for node-negative
patients.
DR LOVE: What about using one of the other aromatase
inhibitors – letrozole, exemestane – as adjuvant therapy?
Do you think that that also should be something that’s considered
in a non-protocol setting at this point?
DR ROBERTSON: I don’t
think that. One has to look and see what the studies that come out
show. I don’t necessarily think that you can extrapolate to
say that because drugs are efficaciously the same in the advanced-disease
setting that they will be exactly the same in the adjuvant setting,
either in terms of efficacy or in terms of side-effect profile.
For example, we know that the degree of inhibition of aromatization
is slightly different. There have been some claims with regard to
letrozole that they may reduce, not estradiol, which is the main
estrogen, E-2, but E-1, fractionally more than the other aromatase
inhibitors. Now, does that translate into an efficacy difference?
I’m not sure if it does. Let’s wait and see.
But the other side of that is that there are always two sides to
a sword, and it may translate into an efficacy benefit, or may not.
Particularly, it may translate into a higher side-effect profile,
or may not. For example, if you have a little bit of estrogen left
in the woman’s system that may give her some protection in
terms of bone mineral density loss and bone fractures. Whereas,
if you completely take estrogen out of her system, even a small
amount of estrogen remaining may make a big difference in terms
of the bone mineral density loss and the fracture rate. So I don’t
think that we can assume that the efficacy and the side-effect profiles
are exactly the same. In fact, I’ve been on record to say
before that if you were to ask me, I think that the difference between
the aromatase inhibitors in the adjuvant setting will not be in
terms of efficacy, but it’s most likely to be in terms of
the side-effect profile. That’s what will distinguish between
the aromatase inhibitors in the adjuvant setting. But, that’s
a personal view.
DR LOVE: What about the ER-positive, premenopausal
woman? First, let’s talk about the women that’s, let’s
say, very high risk, although I hear what you’re saying about
that, 10 positive nodes. She’s going to get some kind of chemotherapy.
Normally, she would receive tamoxifen. Maybe some people would give
her tamoxifen plus an LHRH agonist, if she hasn’t stopped
menstruating after the chemotherapy. What about the issue of the
non-protocol use of an LHRH agonist plus anastrozole in that kind
of a woman?
DR ROBERTSON: There
is some data, as you say, to add in an LHRH analog after chemotherapy
if they’re still menstruating, you’re referring obviously
to the INT 0101 study. And that did show a benefit of the combination.
Should you substitute anastrozole for tamoxifen? I’ve got
to say that being evidence based in terms of the medicine that we
carry out in our own center, I would not do that at this point in
time. Unless there was, again, an issue about the tolerability of
tamoxifen; a history of DVT or some other reason, cerebrovascular
accidents in the past, where you would, I think wouldn’t do
it without some rationale for substituting anastrozole for tamoxifen.
But, as a general statement, I would go with the known and proven
treatment, standard treatment, I think.
I think the thing to see here with the ATAC data is that it doesn’t
answer all the questions. It tells us that a drug, which appears
to be efficacious than tamoxifen – but it doesn’t answer
all the questions. It doesn’t answer the question of combination
with chemotherapy. It doesn’t necessarily answer the question
of sequencing of tamoxifen or an aromatase inhibitor. Should you
give one, sequence them, two years-three years/ three years-two
years? It doesn’t answer those questions. It simply tells
us that we’ve got a very active drug that, on its own, appears
to be more active than tamoxifen. Clinicians are going to have to
with patients weight out the unknowns in terms of some of the longer
term bone mineral density questions, sequencing, and interactions
with chemotherapy, and make decisions based on those as to whether
they’re going to use the drug or not.
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