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Web Guide 2: Program
Supplement: Christopher Twelves, MD
DR CHRISTOPHER TWELVES SUPPLEMENT
DR NEIL LOVE: Dr
Goldberg referred to another encouraging ASCO report on a Phase
II trial of oxaliplatin and capecitabine. I met with the principal
investigator of this study Dr Christopher Twelves to learn more
about what might be an efficacious alternative to FOLFOX, which
is much easier to administer. Dr Twelves began our conversation
by summarizing the key findings from his presentation.
DR TWELVES: We treated 96 patients
altogether across a whole range of countries in Europe. So, it was
a very broad-based study. And one thing I emphasize is that, although
it was a Phase II study, this wasn’t a single-center study
in highly selected patients. This was conducted across a range of
different centers. So, the results are, I think, all the more impressive
for that in that the key criteria and the key end point that we
set ahead of time was the objective response rate. What we saw with
the combination of Xeloda and oxaliplatin was an overall response
rate of 55 percent. This is very much in line with what we would
expect with intravenous 5-FU/oxaliplatin, and I think we feel that
these are really very robust data, because they’re from multiple
sites in a large study population.
DR. LOVE: What did you see
in terms of toxicity?
DR TWELVES: The treatment’s well tolerated.
In Europe, in particular, we’ve been familiar with using 5-FU/oxaliplatin
for many years now. The combination of the fluoropyrimidine and
oxaliplatin typically causes neuropathy as its main side effect,
and that’s a slightly unusual toxicity for many people who
are used to treating colorectal cancer. But once you become used
to this sensory neuropathy, how to identify it, and when to reduce
or to stop the oxaliplatin, it’s easily recognized and easily
treated.
The side effects that we saw with substituting Xeloda for 5-FU
in the combination with oxaliplatin were principally this neuropathy.
We also saw some diarrhea. If we look for a difference between our
regimen and the IV 5-FU/oxaliplatin, I think a key difference is
that we saw very much less myelosuppression. So, the newer combination
is much less myelosuppressive than conventional 5-FU/oxaliplatin.
DR. LOVE: What do you think
the reason was that there was such a huge difference in the incidence
myelosuppression?
DR TWELVES: Well, you’re right, these differences
in myelosuppression are really very striking and, I think, potentially
important for patients, because we’re always concerned about
the risk of infection in patients receiving palliative chemotherapy.
I think the key difference is that 5-FU is much more myelosuppressive
than Xeloda. We saw this in the single-agent trial, and it’s
been followed through very clearly in the combination here. It really
is very striking. We saw no grade IV toxicity with the Xeloda/oxaliplatin
combination. In addition to the myelosuppression, which, as I say,
we saw virtually no serious myelosuppression with the Xeloda/oxaliplatin
combination, we only saw five patients receiving that combination
who had any grade IV toxicity. So, this really is a very well tolerated
regimen.
DR. LOVE: What about hand-foot
syndrome? What did you see there?
DR TWELVES: Hand-foot syndrome, we were certainly
very alert to, and we were concerned to manage this and to identify
this carefully, because it is a toxicity that’s characteristic
of and associated with Xeloda. But here, we were using a slightly
lower dose of Xeloda than is recommended for the single-agent use.
We saw only, I think, three percent of patients who got significant
hand-foot syndrome.
DR. LOVE: What was the dose?
DR TWELVES: The dose of the Xeloda was 2,000
rather than 2,500 milligrams per meter squared. What is important
when assessing the hand-foot syndrome is that only really a very
small proportion of patients had any symptomatic, any functional
impairment from that hand-foot syndrome.
DR. LOVE: Can you talk a little
bit more about the neuropathy? You mentioned that you have a lot
of clinical experience with oxaliplatin, of course, in Europe, in
terms of the typical clinical course and how do you manage the patient
in that situation?
DR TWELVES: I think it’s very interesting.
When we’ve been used to using both 5-FU and irinotecan and
5-FU and oxaliplatin, we have developed a feel for the different
toxicities. The striking thing with the combination involving irinotecan
is that there is an incidence of diarrhea and an incidence of myelosuppression.
We do see, not frequently, but occasionally, quite alarming toxicities
with that combination.
By contrast, when we use oxaliplatin even with 5-FU, we see very
much less myelosuppression, and we would see much less myelosuppression
with Xeloda. But the main toxicity we do see is this sensory neuropathy.
We are careful to speak to our nurses, speak to our colleagues about
this, so that they recognize it, and also to speak to the patients
and explain it to them.
For most of the patients, it simply reflects some numbness or tingling
in their fingers. They may notice that they have to concentrate
a little more to carry out fine tasks. But we also warn patients
that there may be some more other unusual manifestations, often
precipitated by exposure to cold. There is a portion of patients
who, if they take a cold drink, get some spasm of their throat.
Alarming, if they haven’t been warned about it, but we know
it’s a characteristic, an uncommon but characteristic pattern
of toxicity. Similarly, we hear of patients who, when they go to
get something out of the refrigerator, get weakness or loss of use
of their hand temporarily. Again, something which is alarming unless
you’ve warned the patient that it may occur.
Because we were alert to these toxicities, to the neurotoxicity,
one of the things that we saw in the combination study with Xeloda
and oxaliplatin is that about a third of the patients did have to
stop their oxaliplatin, and mostly as a consequence of their neuropathy.
But what we were encouraged by was that even when we included these
patients, and I should emphasize we included all the patients in
these analyses we’re discussing, who didn’t receive
the full planned course of oxaliplatin, we still saw this high response
rate, encouraging time-to-progression data, and survival figures.
DR. LOVE: What’s the
usual time course in terms of the neuropathy? When does it occur?
DR TWELVES: It’s a cumulative neuropathy,
and it’s something that we question patients about. It occurs
very rarely during the initial cycles. As you continue over a period
of several months it becomes increasingly a feature. There are some
patients who can continue treatment for six months without a significant
neuropathy, but quite commonly over that period of time they do
develop some neuropathy and, at that point, we’d withdraw
or reduce the dose of oxaliplatin, and expect to see a gradual resolution
of the neuropathy.
DR. LOVE: To what extent is
it reversible?
DR TWELVES: It is highly reversible over a period
of time.
DR. LOVE: One of the natural
questions here is whether or not this combination or the 5-FU/leucovorin
infusion and oxaliplatin combination could go into the adjuvant
setting? Do you think that this neuropathy is going to be a significant
deterrent?
DR TWELVES: I don’t. I think that this
combination is really quite attractive in the adjuvant setting,
partly because of the efficacy data. It really is quite striking
now that the recent Intergroup study has shown in the comparison
between 5-FU/irinotecan, 5-FU/oxaliplatin, and oxaliplatin/irinotecan,
that there really are very good data showing that oxaliplatin is
at least as effective as irinotecan, and arguably more effective
as a partner for 5-FU. So, I think the efficacy data clearly points
to the need to explore 5-FU or Xeloda in combination with oxaliplatin
in the adjuvant setting. And the overall safety profile, I think,
makes it attractive for patients receiving adjuvant treatment, and
the neuropathy isn’t something that should be a substantial
obstacle there.
DR. LOVE: When do you decide
to stop oxaliplatin because of the neuropathy? What’s the
usual? Is there just a quality-of-life issue or are there certain
symptoms that you see and say, “Hey, we need to stop”?
DR TWELVES: I think we question the patients.
We discuss it with them on a regular basis with each treatment cycle,
and we get a sense of the pace at which they’re noticing some
changes. But when patients are starting to get something functional
– we’ll often hear patients say that they’re getting
some numbness or tingling in their fingers, and then we’ll
say to them, “Is it troubling you? Do you have difficulty
doing your buttons? Do you have difficulty using a knife and fork
or a pen,” and many of them will say, “Oh, no. No. No
problems at all.” In which case, we’d be relaxed about
it.
If they come back a few weeks later and they say that they’re
starting to have some difficulty, that they’re aware their
fingers are not as agile as they usually were, that’s the
point at which we’d tease out whether they’re getting
a functional impairment and then back off.
DR. LOVE: Now, you mentioned
the Intergroup study, and I guess there’s always a certain
hazard in trying to make indirect comparisons. But as you look at
that, the arm in the study with oxaliplatin, and compare it to what
you saw in your study with capecitabine and oxaliplatin, what did
you see there? Did they look comparable to you?
DR TWELVES: They look highly comparable. And
although comparing two different studies and this isn’t a
randomized comparison, the fact that it’s a large study, that
we have nearly 100 patients in the Xeloda/oxaliplatin Phase II,
means that we have really quite tight confidence intervals. We have
robust data. And I think that, insofar as one can make comparisons
across trials, this is a valid setting in which to do so. So, the
data that we see match really very closely the 5-FU/oxaliplatin
data in the Intergroup study. But, also, if we look at the earlier
5-FU/oxaliplatin studies, the FOLFOX-4 study from Aimery de Gramont
again, our data, if you stuck them side by side, look very similar.
The big advantage for the patients is in terms of convenience.
We’ve spoken about the advantage in terms of reduced myelotoxicity,
but I guess for the individual patient the key advantage is that
they will need to come up to the hospital for their intravenous
infusion of oxaliplatin, but the rest of their treatment will be
taken at home. However, if the patients are having an infusional
5-FU regimen, many of them will require a central venous catheter.
They’ll have to come to the hospital, in most cases, either
to start or to finish the infusion, and some places even, the patient
may need to stay in hospital for the duration of the 48-hour infusion.
So, I think in terms of quality of life, substituting an infusional
5-FU with oral Xeloda is something that the patients are going to
prefer.
DR. LOVE: Do you think that,
at this point, it is rational to substitute Xeloda in these combinations
as opposed to infusional 5-FU? Or do you think we need to see the
comparative clinical trials before we take that action, clinically?
DR TWELVES: I think that’s a very interesting
question, and one that I have slightly mixed feelings about. I think
all the data that we’re seeing with Xeloda over recent years
show that it is able to substitute for 5-FU, certainly given as
a bolus, and almost certainly when given as an infusion, especially
in combination with other agents. My personal feeling is that, in
a few years’ time, there’s no reason why Xeloda shouldn’t
have replaced 5-FU across the board.
How we get there is quite challenging. Clearly, we would be reluctant
to see substitution on a purely ad hoc basis. It is important to
explore these combinations accurately and carefully. But at the
same time, it’s impossible to imagine that every single 5-FU
regimen and every single 5-FU schedule and combination is going
to be subject to a major randomized trial. So, common sense tells
us that there has to be some kind of limit. With oxaliplatin, I
think we would feel very confident that, if the regulatory authorities
didn’t require a randomized trial, we would feel very happy
making that substitution straightaway. I’m pretty confident,
though, that a randomized trial will be expected by the regulatory
authorities and, given the incidence of colorectal cancer, given
the importance and the impact this will have in the population,
that’s maybe not surprising. So, I think the answer is yes
and no. Do I think we need the randomized trial to make the substitution
or the decision? Probably not. Do I think it will be done? Yes,
I do.
DR. LOVE: You talked about
the approach to the patient who generally has a good performance
status. What about the patient who has a poor performance status
or the elderly patient? How do you think through that decision?
DR TWELVES: Although we’ve been talking
about clinical trial patients, we’ve always got to bear in
mind that clinical trial patients don’t accurately reflect
the patients who come through our door on a day-by-day basis. I
think it is now clear that combination chemotherapy, arguably with
Xeloda and oxaliplatin a very strong contender, does represent the
gold standard. That isn’t to say that the gold standard is
appropriate, desirable or, indeed, would be chosen by every individual
patient who has advanced colorectal cancer. And I think there will
be a proportion of patients who are less fit, who don’t wish
intravenous treatment, who will prefer oral treatments with a fluoropyrimidine,
with Xeloda as an alternative.
And I think what’s maybe going to emerge in the coming years
is that we will have two or more choices to give the patient. One
will be a more intensive treatment with an impact on response rates,
but also on survival in the form of the combination chemotherapy,
but the other will also be a viable, attractive alternative, the
single-agent Xeloda, which we know is effective. We know it’s
well tolerated. We know that it can be taken at home. So, I think
there’s a nice distinction and clear blue water, if you like,
between these different approaches. And I don’t think a one-size-suits-all
approach is going to be the best.
DR. LOVE: It’s interesting,
you can look at clinical research data being presented at meetings
or on paper, but also, I think, another perspective is how it plays
out in clinical care. Can you pick out a patient, maybe, who you
treated with this combination, either as part of this trial or elsewhere,
that you could discuss with us as part of this program, to give
us an example of how it plays out in clinical care?
DR TWELVES: I remember one gentleman in particular
who came along to see me. He came along with his son, who was very
well informed, was involved indirectly in medicine himself, and
they’d clearly read around the literature. They’d come
well informed with their documents off the Internet. And they decided
that they preferred the idea of oxaliplatin to irinotecan, because
they were concerned about hair loss, diarrhea and other significant
toxicities. And this gentleman and his son were really very keen
on combination treatment, because they wanted the best possible
treatment for him — and he was a fit man, so this was appropriate.
But they did prefer the sound of oxaliplatin rather than irinotecan.
He was a man in his sixties. He’d had his surgery some two
or three years earlier and had adjuvant 5-FU treatment. And he’d
then been well then, until he’d developed some discomfort
in his abdomen, went and saw his general practitioner, his family
doctor, and was then scanned and confirmed as having liver metastases.
And his son was understandably very concerned about this. His son
lived some way away from his father, came back to stay with his
father and was obviously very keen to be there and part of that
decision-making process.
DR. LOVE: Can you talk about
how extensive the liver disease was and if there was disease anywhere
else?
DR TWELVES: His only disease that we were aware
of was in the liver, but it was extensive disease. He wasn’t
suitable for resection of his hepatic metastases, which would have
been the optimal treatment for the minority of patients where that
is possible.
DR. LOVE: And what were his
performance status and his specific symptomatology?
DR TWELVES: Well, he was reasonably well. He
was a slim looking gentleman, but he’d always been fit and
apparently had not lost a substantial amount of weight. He was a
bit less energetic than he’d been previously, but he was still
eating. He was still up and about, and he was still active. And
when we did treat him – and we were fortunate in that at that
time we didn’t have access ourselves to oxaliplatin, out with
clinical trials, and we would otherwise have treated him with 5-FU/irinotecan.
We were fortunate that we had the trial with Xeloda and oxaliplatin
on our books and ongoing at that time, and that we were able to
offer him participation in that trial.
DR. LOVE: You mentioned that
he had some discomfort. Could you feel his liver?
DR TWELVES: Yes. His liver was enlarged. He was
tender in the right upper quadrant when we examined him. But he
was generally a fit and active man. And as he went through the Xeloda/oxaliplatin
treatment, what was encouraging is that his performance status,
which was good to begin with, was maintained and even improved.
I think part of that was undoubtedly the discomfort in his abdomen
was settling.
He found the treatment was well tolerated. He didn’t get
the side effects that all patients receiving chemotherapy are concerned
about. They are concerned, I think, that their quality of life is
going to be affected and that they’ll be debilitated. But
he was really very relieved and very pleased to see that he was
able to maintain his lifestyle within the trial. We’d see
him on a fairly regular basis. But he was having his treatment just
once every three weeks with his infusion of oxaliplatin, and then
was taking two weeks’ worth of his Xeloda tablets at home,
which he was able to take himself, organize himself. I think, like
a good many other patients, there was maybe a sense, with oral chemotherapy,
that it’s something we do with the patients, rather than something
that we do to the patient. I think many of them enjoy that sense
of being involved.
DR. LOVE: That’s interesting.
How did he compare his quality of life and the toxicity of therapy
on that combination compared to the adjuvant therapy he had?
DR TWELVES: Well, the striking difference that
he noted and that, I think, everyone who has had the standard that
we were using at the time as adjuvant treatment — the so-called
Mayo regimen, where patients are coming up on a Monday-to-Friday
basis over five successive days — is the time at the hospital.
And with the best will in the world, even if the infusion of chemotherapy
takes only a very few minutes, there’s time spent waiting
to receive the infusion, there’s time spent finding somewhere
to park the car. Certainly, in our hospital, simply getting to the
hospital through the traffic, finding somewhere to park the car,
these can have a major impact on the patient’s quality of
life. And if you’re spending five days out of every four or
five weeks, to some extent with your day wrapped up or tied up around
the hospital, then clearly there’s an impact on quality of
life. And that’s obviously much preferable, if the patient
is able to take their treatment at home.
DR. LOVE: Was he working at
the time he was treating?
DR TWELVES: He wasn’t working, no. He was
an active man who used to enjoy going out, getting out and about.
He was an active walker. And as soon as his son had seen him started
on the treatment, his son was able to go back down to his family
and resume his normal lifestyle. So, as I think is often the case
with patients with cancer, the diagnosis and its treatment affects
more than just the individual. It was clear that the family was
relieved and content when he was on treatment, when he was tolerating
treatment, and that they were able to relax and back off a little
bit.
DR. LOVE: What happened to
the tumor in his liver with treatment?
DR TWELVES: He had a good response. He was one
of the more than 50 percent who got a major response in terms of
a reduction in the tumor masses on scanning. And as I say, that’s
what we would expect to see with this combination in at least half
of the patients. But I think that does also bring up another point
that, of the patients who don’t get a major reduction, we’ve
noted that about a third of all patients get stabilization or a
minor reduction in their tumor. So, if we can expect at least 50
percent of patients, at least half the patients, to get a major
response, on top of that another third get stabilization of their
disease.
DR. LOVE: So, you’re
talking about 80 to 90 percent of the patients with clinical benefit.
DR TWELVES: Yes. The bottom line is that when
the patient comes back two or three months later, having had their
repeat scan, less than one in four, maybe one in five of those patients,
you’re going to have to tell them that the treatment has failed.
DR. LOVE: Now, again with this
man, did the discomfort he was having in his right upper quadrant
go away or get better?
DR TWELVES: Oh, yes. Yes. His liver that was
palpable originally was no longer palpable. The discomfort that
he’d experienced went away. He was very happy, and certainly,
I remember that ahead of having his scan, he was hoping and expecting
that he would indeed have benefited.
DR. LOVE: What about tumor
markers?
DR TWELVES: His tumor markers, his CEA tumor
marker came down, also. He had a strikingly high CEA tumor marker,
into four figures, which came down, not to normal, but came down
really very impressively. He subsequently did progress. He completed
something over six months of chemotherapy. He remained off treatment
for some months after that, but eventually his disease did progress.
He was still keen for further treatment, and maybe reflecting on
his favorable experience with the initial treatment, he was keen
to receive more chemotherapy, and we treated him with irinotecan
when he progressed. Again, he gained some benefit, rather less benefit
than he had with his Xeloda/oxaliplatin, but he again gained some
benefit from that.
DR. LOVE: How long was he off
the oxaliplatin/capecitabine combination when he then progressed?
DR TWELVES: He was off his chemotherapy for about
four months. So, he spent around six months on chemotherapy and
four months off chemotherapy. But I think what’s important
when looking at that balance of time, is that the six months that
he spent on chemotherapy, he was maintaining his normal lifestyle.
He wasn’t spending his time coming to the hospital, receiving
multiple injections. He was at home, enjoying a good quality of
life.
DR. LOVE: Did he have any neuropathy
from oxaliplatin?
DR TWELVES: He developed some neuropathy. It
wasn’t so severe as for us to have to stop the oxaliplatin.
As we always do, we discussed with him the neuropathy in advance,
and he would tell us how it had changed or hadn’t changed
over each visit. But it was something that certainly didn’t
cause him any distress.
It’s interesting when we look at the number of cycles that
the patients received on average in the study, it’s interesting
to see that the average number of treatment cycles was, in fact,
10. And this is something that we often look at when we’re
first looking at trial data, we look at how many cycles of chemotherapy
patients received. Clearly, if patients are benefiting from chemotherapy,
the majority of them will complete or nearly complete the planned
treatment course. If they’re not benefiting, either because
the disease is progressing or their quality of life is affected,
then they’re likely to fail to complete that number of treatments.
And the majority of patients received almost that full course of
treatment.
DR. LOVE: Interesting. Now,
in this case, when he relapsed four months later you switched him
to irinotecan. What happened after that?
DR TWELVES: He had some response. He’d
been fit at the start of that and, even after completing that treatment,
he was still reasonably fit and took part in one of the experimental
drug treatment programs. Again, he was always keen to be involved,
and a very well informed patient. And he died a few months ago.
DR. LOVE: So, he died a few
months ago.
DR TWELVES: Yes.
DR. LOVE: At the time that
he died, had you stopped therapy prior to that time, or was he getting
treated with antitumor therapy?
DR TWELVES: He’d stopped therapy. He received
the Phase I drug, but it was clear that his cancer had progressed
through the Phase I treatment, and at that point he was less fit
than he had been before. And we were quite keen to give him a period
off chemotherapy at the end of his illness. And at that point, he
was happy to concentrate more on the time at home with his family
rather than receiving chemotherapy.
After he died, this patient’s son very kindly sent us a donation
for our research funds as a token of both his father’s appreciation,
but also that of the whole family.
DR. LOVE: As you look back
on this case, what are the major teaching points that come out in
your viewpoint of it?
DR TWELVES: I think the first thing is that we
now have a range of different treatment options, and it really is
a luxury that was unheard of just a few years ago. We now have a
range of fluoropyrimidines – oral or intravenous 5-FU, so
Xeloda or IV 5-FU. We have oxaliplatin, irinotecan, combinations,
first or second-line. So, we now are faced with talking to our patients
in a different way. They’re coming to us with information,
and we need to talk to them in different ways to run through these
options. So, I think the first key message is that we have new choices
and new ways to treat these patients.
The second point is that patients receiving combination chemotherapy
for metastatic colorectal cancer can certainly have a very good
quality of life. There was a tendency, certainly, in the U.K. a
few years ago, to wait until patients were really highly symptomatic
from their disease before treating them. Increasingly, these days,
we also, as many other parts of the world have done for some time,
are treating patients who are less symptomatic at an earlier stage
of their disease because we know we have more effective treatments,
that they’re well tolerated, and that it’ll maintain
their quality of life. So, there are more choices for the patients
for us to discuss, and we can maintain their quality of life rather
than wait until the patient becomes less fit.
DR. LOVE: It sounds like, as
you look back on the almost two years that you worked with him,
certainly that 10 months when he was getting oxaliplatin/capecitabine
and then off therapy, it sounds like he had a very good quality
of life and maybe even beyond that for a while. It sounds like,
the way you described him at first diagnosis of metastatic disease,
that you would think he probably wasn’t going to stay well
very long.
DR TWELVES: Yeah. He was becoming symptomatic,
and I think he’s the sort of patient who we stand to gain
a lot with combination treatment. His disease wasn’t resectable,
but he was fit. He was keen for such treatment. I’m sure that
if we waited another six or eight weeks, he maybe would have been
less fit. Our options might have been lesser, and maybe at that
point oral Xeloda would have been an alternative, or intravenous
5-FU. But he was at the stage where he was becoming less well, but
still certainly sufficiently fit to want combination chemotherapy.
DR. LOVE: What are some of
the new developments in the treatment of rectal cancer that you
think are important, both in terms of things that have been demonstrated
in clinical trial and what you see coming down the road the next
couple of years?
DR TWELVES: Well, it is a useful distinction
to make between rectal cancer and colon cancer, especially in the
treatment of early disease, especially in the adjuvant setting,
where the benefits of adjuvant systemic treatment are rather less
clear in rectal cancer than they are in colon cancer. If I was to
take a guess at this, I think what we’re maybe most looking
towards is the use of chemotherapy with radiotherapy in rectal cancer.
And there’s clear potential to use fluoropyrimidines as radiosensitizers.
But that’s been a little clumsy, in that it’s required
either repeat bolus injections or intravenous infusions or continuous
infusions, which really are not an elegant of a patient-friendly
way of delivering 5-FU. I think one of the advantages of oral fluoropyrimidines
is that you can give Xeloda either according to the classic two
weeks of treatment-one week of rest, or you can explore different
schedules and work those schedules around the radiotherapy patterns
in treating patients with rectal cancer.
DR. LOVE: Of course, the other
thing that’s interesting – I’m curious whether
you think there’s a practical implication to this –
is the observation that radiation therapy seems to potentiate TP,
the enzyme that activates capecitabine. Do you think that’s
an academic, laboratory finding, or do you think that really has
some impact in terms of clinical care? DR TWELVES: The proof will come through the clinical
trials, but it is interesting, because this effect on thymidine
phosphorylase and its effect on the enzyme TP may actually be very
important. And it’s perhaps worth looking now to the breast
cancer situation, where we’ve recently had really striking,
very encouraging results in patients with metastatic breast cancer
who were randomized to receive either docetaxel, which we would
consider the gold standard for patients who have received a prior
anthracycline. So, patients were randomized either to receive that
alone or in combination with Xeloda. The striking improvement in
survival that was seen, — statistically significant improvement
in survival in the metastatic setting — was really more than
we might have expected from simply adding a fluoropyrimidine. And
the fact that we know docetaxel does have an effect on thymidine
phosphorylase; this may be a mechanism by which you can increase
the generation of active 5-FU within the tumor cell. Now, if this
synergy is a real effect and if it can be demonstrated with radiotherapy
to have a similar impact in rectal cancer, then I think that could
be very exciting.
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