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You are here: Home: BCU 6|2002: Supplement: Joyce O'Shaughnessy,
MD
DR JOYCE O’SHAUGHNESSY
DR NEIL LOVE: Welcome to Breast Cancer Update.
This is medical oncologist Dr Neil Love. The June 15th issue of
the Journal of Clinical Oncology contains the formal report of a
data set that has been widely discussed since its first presentation
at the December 2000 San Antonio Breast Cancer Symposium. The paper,
in the metastatic setting, by Joyce O’Shaughnessy et al, reports
a survival advantage to the combination of capecitabine and docetaxel
compared to docetaxel alone. Major randomized trials in metastatic
disease reporting a survival advantage to a chemotherapeutic regimen
have been rare to non-existent. On the last issue of Breast Cancer
Update, Dr Terry Mamounas noted that based on these encouraging
data, the NSABP is considering a new neoadjuvant trial incorporating
the so called XT or Xeloda-Taxotere regimen, and also, a new adjuvant
study of XT in breast cancer patients with local tumor recurrence.
Last year, when I interviewed Dr O’Shaughnessy about the XT
study, she noted that her group, US Oncology was planning a new
trial looking at capecitabine-docetaxel as adjuvant therapy and
I met with her to obtain an update on reactions to these findings
by oncologists. She began by reviewing the current data set.
DR JOYCE O’SHAUGHNESSY:
The event rate now is very, very mature. The median survival on
Taxotere alone is 11.5 months, and for the XT it is 14.5 months,
so a median difference of three months. At the 12-month mark, 57%
of women were alive with XT compared to 47% with Taxotere alone.
So, basically, the results are mature, and it is a real deal. There
are low treatment-related deaths, very similar serious adverse events,
very similar hospitalization rates, and etcetera. So, XT is no worse
in terms of major toxicities than Taxotere alone, and it is definitely
superior in terms of overall survival.
If you look at the women who got Taxotere versus XT and the number
of people who got chemotherapy at some point after their study therapy
after their disease had progressed, it was pretty high. About two-thirds
on both arms of the study, got chemotherapy, so these women were
still aggressively treated, and there was no major imbalance. Patients
were treated appropriately; some got Herceptin, a lot got Navelbine
and some got additional taxanes, a third got more hormonal therapy.
So, it was good aggressive therapy and really no imbalances.
But of the patients, of the total number of patients who got Taxotere,
everybody – 256 patients – 18 percent went on to get
Xeloda at some other point in their therapy. But if you look at
the denominator as those who got any chemotherapy, which was about
60-65%, 27% of those got Xeloda. So, one point to be made is that
not everybody is able to get additional therapy. 35-40% of people
did not get any more therapy afterwards, likely because their disease
was quite advanced and they just really couldn’t tolerate
any more and it wasn’t appropriate to give them any more.
So, one of the controversial areas is should you give sequential
single agents, or could you give XT? One point is that if you’ve
got 35 percent or 40 percent of people not getting any additional
therapy, that means there isn’t going to be the opportunity
to give everybody sequential. So, for 60-65 percent, there was the
opportunity to give them additional therapy. I think the number
was around 50 patients, who got the Taxotere and later went on to
get Xeloda. If you look at the hazard ratio for mortality in the
patients who got Xeloda after the Taxotere, compared to any other
chemotherapy agent – so, the othe comparative group is any
other chemotherapy – the hazard ratio for mortality was 0.5.
So, there was a 50-percent reduced risk of dying after your Taxotere,
if you got Xeloda, compared to any other chemotherapy agent. The
actual survival figures, as I recall in terms of median survival,
were something like 14.5 months with the Xeloda versus 11 months
or something like that. Now, this was just a subset analysis, but
it still reached statistical significance because it was a 50-percent
reduction.
If you do a similar analysis on the group who got Taxotere alone
in the study, who later went on to get Navelbine, if you look at
that group compared to any other chemotherapy, excluding Xeloda,
the hazard ratio was 1.0. It didn’t make any difference whether
you got Navelbine or whether you got any other chemotherapy drug.
There was no difference in your mortality. So, that’s very
interesting.
DR LOVE: What do you think it means?
DR O’SHAUGHNESSY: It
give us some data to say after Taxotere fails the patient and you’re
going on to your next agent, if you are using, in fact, sequential
single agents, it would be very reasonable to choose Xeloda. You
get a 50-percent reduction in the risk of dying, at least based
on these data, compared to other chemotherapy agents, suggesting
that Xeloda is one heck of an active agent in these patients and
is associated with improved survival, compared to any other chemotherapy
agent such as Navelbine. Now, these are small subset analyses, but
it’s very, very interesting. I can’t think of any other
reason that should be, because it makes no difference. If you lump
all other chemos together, if you take Navelbine out and look at
that separately, the hazard ratio for mortality is all the same.
Actually, it gives some credence to the folks who have been saying
all along that it’s okay to give Taxotere single-agent followed
by Xeloda single-agent, that your survival is going to be no different,
if you compared the sequence to the XT combination. So, it gives,
certainly, some credence to that argument. The way I interpret the
data from a conservative standpoint, which I certainly think is
very fair, is that, if you have a patient with indolent disease
– not particularly symptomatic – I think it’s
very reasonable to give Taxotere sequentially with Xeloda. And the
Miles data would suggest that they do quite well with that.
Conversely, given the early separation of those survival curves
and the early death rate with Taxotere alone, there’s certainly
going to be a subgroup of patients who are not going to have the
opportunity to cross over. Those patients, it seems very fair to
me, to say, “Give those the combination of XT,” you
know, the more aggressive, more symptomatic, the folks who you’ve
got to have a response on.
There is, however, still a hypothesis on the table, which we really
cannot confirm or refute at this time. It still is possible that,
if you did a randomized trial of XT versus single-agent Taxotere
followed by single-agent Xeloda, there would be a survival advantage.
That is based on the fact that the XT has very clear biochemical
and preclinical synergy, which is very different than most of the
doublets we have. So, the hypothesis on the table is that XT is
not just any doublet.
DR LOVE: You’re talking about thymidine
phosphorylase.
DR O’SHAUGHNESSY:
Right. Upregulation of thymidine phosphorylase by Taxotere, leading
to greater conversion of the capecitabine prodrug to 5FU at the
tumor site. This combination has very, very clear preclinical synergy,
which very few of our doublets, empirically chosen, do. So, it still
may be, at the end of the day that giving the doublet is best for
all patients, but we certainly can’t say that based on the
data.
DR LOVE: The other thing that I’ve been
thinking about for a while – and I actually talked to David
Miles and interviewed him in San Antonio – was I don’t
think there’s any head-to-head, randomized comparison to Taxotere
and Xeloda. Correct?
DR O’SHAUGHNESSY:
Correct.
DR LOVE: So the question is if there had been
a third arm, XT versus Taxotere versus Xeloda alone, with crossovers
what would you have seen in terms of response rate and maybe even
more interestingly in terms of survival.
DR O’SHAUGHNESSY:Well,
I think, it’s an interesting point because I think people
are really taking a second look at Xeloda. I know I am. It’s
quite an active compound. There was a small randomized Phase II
trial comparing Xeloda to Taxol, 175 per meter every three weeks.
It was a very tiny study, 20-24 patients on each arm. It was stopped
prematurely, because at that time – started several years
ago – it was very difficult to randomize people to a pill
versus an IV. That’s why the numbers are so small. But the
response rate with the Xeloda was 36 percent compared to 26 percent
with Taxol, widely overlapping confidence intervals. So, you could
say, basic equivalence is that you would probably say from those
data.
So, the small amount of data we have using Xeloda earlier in metastatic
breast cancer, when we compared it to IV CMF in larger numbers,
67 patients receiving front-line Xeloda, elderly patients, median
age 70, the response rate was 30 percent. And about half of those
had some adjuvant therapy so, not all anthracycline pre-treated.
We know Taxotere has a solid 30-percent response rate in the anthracycline
pre-treated patients, so it’s possible Xeloda could be close
to equivalent to Taxotere.
DR LOVE: It’s kind of interesting, when
you think about the psychology of giving an oral drug versus intravenous,
both on the prescribing physician and the patient. I’ve heard
all different viewpoints on that. There’s the strong medicine
for a serious situation thing that maybe made you lean towards intravenous
therapy. But the other issue is that if you have a patient who is
relapsing for the first time after having intravenous adjuvant therapy,
it’s a tremendous disappointment for a patient. Just emotionally
having to go back to intravenous therapy versus a pill, I’ve
heard that point brought up, also.
DR O’SHAUGHNESSY:
Yes. I think that’s right. I think that women want effective
therapy. What I find, Neil, is that for women who relapse, they’re
scared to death. Most of them are still in fight mode at that point.
When you go through the laundry list of options in metastatic breast
cancer, I’ve had several look me in the eye and say, “I
want the most effective one.” And so, I’ll lean them
towards combination chemotherapy.
On the other hand, there are many women who have very, very indolent
disease. They’re older. They know they’ve been at this
a long time. They know they’ve got time, and they want quality
of life. So the idea of a pill, and an effective pill, is very,
very good for them.
DR LOVE: Although it’s interesting you mentioned
quality of life, because I saw at the Chemotherapy Foundation Meeting
some quality-of-life data on the XT study.
DR O’SHAUGHNESSY:Yes.
That’s a good point because a careful quality-of-life analysis
was done in the big Phase III trial, and the curves are absolutely
overlapping for the first four-five months of the study. Then they
start to split, with XT being superior, for the clear reason that
there was better tumor control. The deterioration in the Taxotere
arm is undoubtedly due to tumor progression. The Phase III trial
was pretty much heavily tumor burdened, heavily pre-treated patients.
Two-thirds were getting the study therapy as second- or third-line
therapy. So, these were sicker patients.
So, you’re right. XT was, if anything, somewhat superior
– although not statistically significant, but still somewhat
superior quality of life, particularly towards the latter part of
treatment. But, still, from an acute toxicity standpoint, there
is no question that the XT has more toxicity than Taxotere alone.
Taxotere has a little bit more febrile neutropenia associated with
it because it’s more myelosuppressive. But you don’t
get the diarrhea and the hand-foot syndrome that you can get from
the XT combination.
DR LOVE: I think it really gets back to what you
were saying about looking at the patient in terms of how long you
have to wait for a response, what kind of condition they’re
in. But, when I first saw those quality-of-life data, Dan Budman
was talking about the fact that in the long run, tumor control and
tumor itself is really the issue in terms of metastatic breast cancer
and quality of life.
DR O’SHAUGHNESSY:
That’s right. I would agree with that. And not only from a
physiologic standpoint, but also from a psychological standpoint.
Tumor control is king for us.
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