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You are here: Home: BCU 6|2002: Supplement: John Robertson,
MD, FRCS
DR JOHN ROBERTSON
DR ROBERTSON: No.
I think that it mainly was about patient acceptability particularly,
in the U.S. Initially, when Study 20 and 21 were being run –
those being the North American and the European, South African,
Austral-Asian studies – it was acceptable to give a 5 ml injection
in Europe. In North America, it was thought that you couldn’t
give 5 ml. If you remember, they had two 2.5 ml injections, one
in each buttock. So, at that point, it would have meant giving four
injections.
When it came to the global first-line study, Study 25, comparing
Faslodex versus tamoxifen, that was a single protocol. In fact,
it was a 5-ml injection that was used, and patients entered from
America did get a 5-ml injection. So now that we’ve got over
that hurdle, there would be no reason to think that we couldn’t
consider giving a higher dose, 5-ml in both buttocks. I think that
is something to be looked at. Clearly, 250 milligrams is an effective
agent, no question about it. We can see that. I think the point
you're raising is a scope for higher dose, and that’s certainly
something that one would want to consider and investigate.
DR LOVE: Any reason to think that there would
be a toxicity problem if you went up on the dose?
DR ROBERTSON: Apart
from the fact that you’re giving two injections and, therefore,
you may get double the number of injection site reactions. Although
we know from Study 20-21 that those are a pretty small, few in percentage
and not serious injection site reactions at all. In fact, what we
know from the fact that these were placebo-controlled, is that the
injection site reactions are the same in the placebo arm, as they
are in the active treatment arm. So, these are clearly injection
site problems and not drug problems, as such. It may be the base
carrier that takes it, but they’re not Faslodex problems,
because it was exactly the same in both arms, placebo and active
treatment injections. So, that would be one. But in terms of other
side effects, I don’t envisage any real side effects,
DR LOVE: How about hot flashes? What are you thoughts
on that, globally, after having treated a lot of patients?
DR ROBERTSON: I think
that it’s not a drug that causes hot flashes, both in terms
of its proposed mechanism of action and the fact it’s doesn’t
cross the blood-brain barrier, as far as we can see. I think the
problem is – and this would be an issue even for the first-line
study when we see the data – is that when you see postmenopausal
women, a lot of women get hot flashes for many years after they
enter their menopause. The problem with some of these studies is
that they measure hot flashes, but they don’t tell you, first
of all, what there was at the beginning of the study, and how many
people had hot flashes on no study treatment. I think it would be
important to know how many people had hot flashes before they started
and how many people get either new symptoms or get an increased
severity of the symptoms.
DR LOVE: The reason I’ve heard described
that it doesn’t cause hot flashes is it doesn’t penetrate
the blood-brain barrier. Is that correct?
DR ROBERTSON: Yes.
It doesn’t, so that’s why we think it won’t cause
them. But the point I’m making is, in the first-line study,
you may actually see some hot flashes in the Faslodex-treated arm,
but it may not be the drug that’s causing them. Because of
the way in which you report these things, which is you report a
symptom if a patient gets it at any time on the drug, but it may
be that they had those symptoms before they even started the treatment.
DR LOVE: Any thoughts on combining Faslodex with
any other agent, whether endocrine, biologic, chemotherapy, any
sort of natural combinations there?
DR ROBERTSON: There
are one or two natural combinations. The first natural combination
is with Faslodex and anastrozole – and we can come back to
that in a second. The second would be Faslodex and perhaps Iressa.
First of all, there’s some good cell culture work, in vitro
work, to suggest that Faslodex and Iressa would be a good combination,
and that you can prevent resistance and get longer control of the
cells in vitro by the combination.
In terms of Faslodex and Arimidex, or anastrozole, I think that
the rationale for that is that, if you reduce the level of estradiol
to a very low level, then Faslodex is maybe even more potent at
inhibiting the receptor. And I think that’s a natural combination,
and I suspect that some of those studies are going to start pretty
soon.
DR LOVE: Is there any more biologic basis for
either one of those combinations? I’m trying to think mechanistically
why, for example, Iressa and Faslodex would be more potent than,
say, either one alone.
DR ROBERTSON: I think
that there are mechanistically potentially differences. The reason
for using, as I say, Faslodex and anastrozole is that, by reducing
the estradiol level, you would then have a more potent, pure anti-estrogen,
which would in a sense block any remaining stimulation of the receptor.
DR LOVE: I guess that goes along with what you
were saying before in terms of the dose effect.
DR ROBERTSON: Mm-hmm.
DR LOVE: So, that one makes sense.
DR ROBERTSON: That
would make sense, and there’s some support for that, too,
from the premenopausal studies looking at Zoladex plus tamoxifen.
If you reduce estradiol levels, you can perhaps get a better initial
response and a better time to progression on the combination, than
a single agent. Although, when you put the second agent in, you
get a second response with the sequential tamoxifen, right? But
we’re talking first treatment. So, there’s some support
for that combination from premenopausal studies.
The Faslodex and Iressa has, I think, a separate rationale, which
is that we know that one of the blocks to endocrine sensitivity
in terms of interaction and cross-talk is the Type 1 growth factors,
HER2/neu and EGFR. We also know from the cell culture work that,
if you give cells tamoxifen and then they become resistant, and
you then come in with Iressa, you can reverse that resistance.
We also know from some of that cell culture work – this is
Professor Rob Nicholson’s work in Tenovus Institute in Cardiff
– that if you give tamoxifen and Iressa, you can actually
delay the outgrowth of resistance to tamoxifen. And so I think that
the combination of an anti-estrogen and Iressa is different from
the combination of an aromatase inhibitor and Iressa, and biologically
they’re different.
DR LOVE: I guess another combination might be
an LHRH agonist plus Faslodex if you find that it’s not as
effective in premenopausal women?
DR ROBERTSON: Absolutely.
I think that there’s an attraction of looking to see if we
can get a single monotherapy that’s effective. But I agree
that, if you didn’t, then that would be another way around,
which would be effectively making women postmenopausal and then
treating her as a postmenopausal patient.
DR LOVE: This kind of reminds me a little bit
of the report you had at ASCO a couple of years ago, looking at
I guess it was goserelin and anastrozole making the woman postmenopausal.
DR ROBERTSON: Yeah.
And, in fact, since then, we have actually done the endocrinology
in that.
DR LOVE: Oh, really?
DR ROBERTSON: What
you can see is that you do see a logarithmic fall in estradiol when
you give them Zoladex and tamoxifen. Then when you change from tamoxifen
to Arimidex in combination with Zoladex, you see a further logarithmic
fall that’s statistically significant in terms of the estradiol
levels.
DR LOVE: So, it’s pretty much what you’d
expect?
DR ROBERTSON: It
is. It is. So I think that the responses that we saw clinically
are supported by the endocrinological data there.
DR LOVE: That’s interesting. When we first
started talking about that trial of metastatic disease, of anastrozole
and goserelin, the question I had for you was – suppose the
ATAC trial shows an advantage for the anastrozole arm? Obviously,
there are trials now looking at anastrozole and goserelin in the
adjuvant setting. But then the other question comes in – what
about using that combination off study? That kind of leads into
the issue of the ATAC trial. So, let me start out first, before
we get into the issue of the premenopausal, let me get your take
on the early ATAC results.
DR ROBERTSON: I think,
first of all, they are interesting. If you were to ask me is it
what I would have expected, then the answer is no. I mean, just
for people in the audience to know, who have not seen the data,
the ATAC data shows that anastrozole gives you a significantly improved
recurrent-free survival over either tamoxifen alone, or the third
arm of the study, which was the combination of anastrozole plus
tamoxifen. And that’s statistically significant.
It also shows, in terms of side-effect profile that anastrozole
was statistically better tolerated in terms of hot flashes, cerebrovascular
accidents, DVTs, and also in terms of vaginal dryness, discharge,
and endometrial cancer. It showed that tamoxifen was better tolerated
than anastrozole in terms of musculoskeletal symptoms, such as joint
pains, and also in terms of bone fractures. So, that’s the
summary of the data. And if I’d been asked to predict what
I thought the trial would have shown, I would have said that after
this time period, it would have shown no difference, that it was
perhaps a non-significant separation of the curves. But, in fact,
we do see a therapeutic efficacy in favor of anastrozole.
People ask the question – is that something that we can put
any security on? I think that there are some reasons to think that
this is a true result. First of all, this study had 9,366 patients.
It’s the largest adjuvant endocrine study that’s ever
been done. When this study started out, the largest two studies
previous to this were the CRC study, and the NSABP B-14 tamoxifen
study, which had around 2,200-2,600 patients. So, this was a huge
study. I think the possibility that this is a chance event from
the size of the study is unlikely.
A second thing, I think, that gives us some security is that there
appears to be some internal consistency within the data. By that,
I mean, if you look at the number of local recurrences, the number
of distance recurrences, number of contralaterals, each of those
three measures of breast cancer disease control are better on anastrozole
than on tamoxifen. So, it’s not that one area of control seems
to be better than another and it overrides the whole analysis. All
three show consistency that anastrozole gives you less recurrences,
distant metastatic, contralateral, than tamoxifen.
The third thing that is reassuring about the data is that it’s
consistent with what we know previously about aromatase inhibitors.
If you look at the anastrozole versus tamoxifen data in first-line
metastatic disease, we know that in hormone-receptor-positive patients,
you’ve got a benefit. The benefit was 10 months versus six
months in terms of time to progression. If you looked at the Spanish
study of first-line therapy, Milla-Santos, it was 10 months versus
six months. If you looked at the letrozole versus tamoxifen study,
the benefit in terms of time to progression, it was something like
9.8, I think, versus 5.3-5.5 something. It was roughly four months.
And if you looked at the exemestane study, with which I put less
store by, because it was a small Phase II, 30 patients per arm,
but also mostly because it was an open-label study. But, even that,
the TTP, the difference is around four months as well.
So we’re beginning to pick up in first-line metastatic disease
that the aromatase inhibitors as a class of agents are better than
tamoxifen. And you can define what that benefit was. It was around
four months, 10 versus six, for all of the studies, suggesting that,
in that setting, the aromatase inhibitors were roughly equivalent,
but that we knew that they were better than tamoxifen. Now we’re
seeing an additional benefit in the adjuvant setting. So it tends
to suggest, again, that if you look at this external data to the
ATAC study, it suggests that the aromatase inhibitors are a better
class of agent, and that this shows through in the adjuvant setting.
So, I think all of those things are supportive of the efficacy data.
Should patients be placed on anastrozole immediately? I’m
sure that’s your next question. I think that there are two
things to say. One is I think that the data is pretty secure in
terms of efficacy. I think the other thing to note about efficacy
is those curves are diverging. And if you look at the tamoxifen
data, there is quite a lot large carry-over effect, even after the
drug was stopped. If you were to ask me, I suspect those curves
will continue to diverge. The second thing is, I suspect, too, although
we need to wait for this data to show through, that that will eventually
transfer into a survival benefit.
However, I think that there is one point to raise, which is the
safety issue. With this large number of patients, I think what it
does do is it gives us confidence that there are not any really
serious but very uncommon side effects from anastrozole. Otherwise,
I think you may have picked those up in this number of patients.
But the second things is that, because it’s a large study
and it’s based on event numbers, you get the data quite soon
after starting the trial. This is now, 30-odd months after the trial.
So people may say, “Well, have we seen the full extent of
bone-mineral density loss or fracture rates?” And there’s
more data to come on that, no question. I mean, there’s a
bone-mineral density sub-protocol, which will start to show us what
the rate of loss is and how long that may be – takes before
we see recovery of bone mineral density. So, I think that while
we know that efficaciously anastrozole is better, there is still
some more data to get on the longer-term side effects in terms of
bone mineral density.
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