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DR SMITH: This is a 91-year-old lady
with Stage II breast cancer, diagnosed
in 1990. At the time, her tumor was 2.4
centimeters, estrogen receptor-positive,
but lymph node-negative. She underwent
mastectomy and took adjuvant
tamoxifen for seven years.
Since that time she’s developed mild to
moderate dementia and, according to
her family, she may forget to take her
pills from time to time. The patient
herself is not aware of this.
She did quite well until September
2004, when she presented with right
hip pain. A bone scan showed diffuse
bone metastases, mostly involving the
hips and femurs, bilaterally, with a right
superior pubic ramus fracture.
A CT scan showed multiple liver metastases,
five in number, with the largest
one being three centimeters in size, and
no other sites of disease.
The pubic ramus fracture was irradiated,
which resolved her pain, and she
was started on pamidronate and fulvestrant,
with stabilization of her disease
for eight months.
DR LOVE: You mentioned that the
patient has dementia. Were you able to
discuss treatment with her in a way that
she understood?
DR SMITH: She did understand that her
cancer had returned and that she needed
some treatment.
DR LOVE: Did her symptomatology
improve on the fulvestrant?
DR SMITH: Yes, her pain resolved and
that was the only symptom she was
having.
DR LOVE: Dr Osborne, what are your
thoughts on the use of fulvestrant?
DR OSBORNE: Two clinical trials were
conducted comparing fulvestrant versus
anastrozole for second-line therapy in
patients who had received tamoxifen
in the adjuvant or metastatic setting
(Pippen 2003; Robertson 2003; [4.1]).
One study was conducted in North
America and the other in Europe and
the rest of the world. The data from
both trials were very similar. The
complete response rate was slightly
higher with fulvestrant, whereas the
partial and objective response rates were
very similar. In terms of stable disease
and clinical benefit, fulvestrant was
a tiny bit better than anastrozole. In
one of the trials, duration of response
favored fulvestrant, but by and large,
the drugs were very similar.
How does fulvestrant compare with
tamoxifen in the front-line setting?
All the preclinical data suggested that
fulvestrant would be significantly better
than tamoxifen, so a trial was conducted
comparing these two endocrine agents.
In the receptor-positive group, fulvestrant
and tamoxifen were similar in
response and time to treatment failure, but overall, tamoxifen looked slightly
better in some of the parameters.
DR LOVE: Would you have used fulvestrant
in this patient?
DR OSBORNE: Because of the data
showing superiority of aromatase
inhibitors relative to tamoxifen, in a
previously untreated patient I would
tend to go with an aromatase inhibitor
first. However, in this patient, who has
received tamoxifen and suffers from
dementia and may not be taking her
pills correctly, I think she’s a perfect
candidate for fulvestrant, and I totally
agree with its use in this situation.
DR GRADISHAR: One of the issues is
whether there’s a particular sequence
of endocrine therapy that’s optimal,
in terms of prolonging time to disease
progression or overall survival. The
EFECT trial is one effort to look at
patients who have progressed through
a nonsteroidal aromatase inhibitor, be
it anastrozole or letrozole, and are then
randomly assigned to receive either
fulvestrant or the steroidal aromatase
inhibitor exemestane. There are no data
from that trial yet; it’s probably three
quarters of the way to its accrual goal at
this point.
DR LOVE: Kent, the SoFEA trial in
Europe is evaluating another strategy
in patients who are progressing on
aromatase inhibitors. Those patients
are randomly assigned to fulvestrant,
exemestane or fulvestrant plus anastrozole.
I know there are oncologists in
practice who have continued an aromatase
inhibitor and added fulvestrant.
What do you think of that strategy in
the clinical setting?
DR OSBORNE: I think it’s a good
idea, but as you know, there are no
data. I have to say I have done it in a
few patients based on two preclinical
studies that have evaluated this: my
own and Angela Brody’s. Fulvestrant
seems to work much better when there’s
no estrogen around. Even though
postmenopausal women have lower
estrogen levels in the blood, their
tumors don’t necessarily have lower
estrogen levels, and fulvestrant seems to
be more effective when estrogen is low.
It would be interesting to see the results
of a clinical trial evaluating that.
DR LOVE: A lot of people have talked
about the issue of how to dose fulvestrant.
My simplified understanding of it
is that since it’s a competitive inhibitor
for estrogen, you could increase dose or
get rid of the estrogen.
DR OSBORNE: Yes, you could do it
either way, but I am concerned that
in premenopausal women, it doesn’t
work very well. Obviously, they have
a lot of estrogen in their blood, and we
know it doesn’t work well for conditions
like benign endometriosis. I think
the estrogen in the premenopausal
woman is too much to be competitively
inhibited with the fulvestrant dose that
we’re now using. Plus it takes three to
six months to get the dose to steady
state when you start at 250 mg a month,
and that’s a problem. Some patients may
be taken off fulvestrant after only two
months of therapy, before the blood
levels are even high enough to make a
difference.
Ongoing trials are evaluating fulvestrant
at doses of 500 mg on day one, 250
mg on days 14 and 28, and then once
a month. That’s based on a computer
model of the pharmacokinetics of the
drug. Whether insurance companies
will pay for that loading dose outside of
that trial is another issue.
DR LOVE: Do you use that strategy in a
clinical setting?
DR OSBORNE: Yes. I do.
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