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Web Guide 2: Program
Supplement: Edward Lin, MD
DR EDWARD LIN SUPPLEMENT
DR NEIL LOVE: Capecitabine
has proven to be a valuable addition to the treatment armamentarium
in both breast and colorectal cancer. Many investigators have commented
to me that since the key dose-limiting toxicity of this agent is
hand-foot syndrome, an intervention that could prevent or treat
this complication, would have enormous clinical implications. Another
ASCO paper that attracted considerable attention was an interesting
study reported by Dr Edward Lin on a retrospective analysis of patients
receiving capecitabine for metastatic colorectal cancer, who are
also being treating for other reasons with a COX-2 inhibitor, celecoxib.
This provocative study suggested that these patients experience
significantly less hand-foot syndrome and I met with Dr Lin to learn
more about this data set. He began by discussing the background
to the study.
DR EDWARD LIN: We thought that this event might
be driven by the COX-2, which has been proven as the “central
regulatory mediator” of inflammation. We also, undoubtedly,
observe that patients, who are taking celecoxib with capecitabine,
have not experienced any hand-foot syndrome. So we have then taken
more of a systemic approach. For patients who are having tumor-related
pain – they were given celecoxib as well as capecitabine and
their hand-foot syndrome was observed and then compared to our historical
control group, where patients were just primarily treated with the
capecitabine alone and all the other NSAIDs were eliminated as confounding
factors.
DR. LOVE: So, initially you
had the thought that perhaps Celebrex, or patients who were already
on Celebrex for some other reason might have less hand-foot?
DR LIN: Right.
DR. LOVE: So that caused you
to do a retrospective analysis?
DR LIN: Right. Right.
DR. LOVE: Had that been done
before?
DR LIN: No.
DR. LOVE: When did you start
doing this?
DR LIN: We started to compile the data about
a year ago. In fact, I have been systemically treating patients
when they have tumor-related pain, and start the celecoxib with
the intention to really look at the cohorts of patients in terms
of what their hand-foot syndrome incidence was while they’re
receiving celecoxib.
DR. LOVE: So, were you also
treating patients who had hand-foot syndrome at that time?
DR LIN: More recently, no.
DR. LOVE: You actually started
treating them?
DR LIN: Right now, more recently, given our finding
was fairly consistent, we have five or six patients that were treated
when they had the hand-foot syndrome, and we given them celecoxib.
And, universally, their hand-foot syndrome has improved.
DR. LOVE: What dose do you
use?
DR LIN: The start at 200 twice a day. And I haven’t
gone beyond that. Only on a few occasions, have I gone beyond that.
DR. LOVE: Now, I assume that,
at the same time that you were treating them, you also stopped the
capecitabine?
DR LIN: No. Actually, just recently, we had a
case of a patient who was on the capecitabine/CPT-11 trial, and
she had grade III hand-foot syndrome. Despite dose reduction from
1,000 mg per meter squared down to 750, she still got hand-foot
syndrome. Now she’s down to 500 per meter squared and she
does not have hand-foot syndrome anymore, but her tumor actually,
unfortunately, progressed. So, for her, I have talked about various
other options. One of the options is to go back up on the capecitabine
to 900 and place the celecoxib, and she actually did well.
DR. LOVE: So you did that?
DR LIN: Yeah.
DR. LOVE: So you went back
up with the capecitabine to what dose?
DR LIN: To 900. She was last seen just about
three weeks ago, and there was no return of hand-foot syndrome.
We have quite a score of patients with hand-foot syndrome, and then
you place them on celecoxib, and we have about four or five of the
patients, and she’s one of them that have not experienced
return of hand-foot syndrome while maintaining the capecitabine
dose intensity.
DR. LOVE: Let’s talk
about the results first, of the retrospective study that you did.
How did you identify the patients, and then how did you identify
the patients to compare them to?
DR LIN: We have a pharmacy database, and we also
have kept a computer-generated database of when the celecoxib was
prescribed. So, I have continued tracking the patients who are getting
the celecoxib for pain or arthritis. Then, there is a prospective
trial that MD Anderson has performed in the past when the patient
was just specifically given capecitabine alone or given by the treating
physicians. And so that can be easily identified through the pharmacy
database.
DR. LOVE: So, you basically
were able to pull out patients?
DR LIN: Right. And eliminate the patients who
are taking aspirin or other NSAIDs. So, you eliminate those patients
and try to match the dose of the capecitabine between the two groups.
DR. LOVE: So, it was basically
a case-control study?
DR LIN: That’s right.
DR. LOVE: And then how many
patients did you actually find, who were receiving both capecitabine
and Celebrex?
DR LIN: We reported in our series about 30, 35.
In fact, we have more than that, about 45 patients. The reason that
was not included in the study, at the time there was no survival
data. And I also would want to match sort of the historical control.
So, we limited our cohorts to about 33, 34 for the capecitabine/celecoxib
arm at the time of the reporting, which is about six months ago.
Since then, we have treated a few more patients, more sort of prospectively,
although not on the clinical trials.
We continue to make the same observation in terms of hand-foot
syndrome, also diarrhea as well. Basically what we have seen is,
in patients receiving both drugs, the observation that grade III
hand-foot syndrome is almost eliminated. In only one patient who
had hand-foot syndrome, we saw that he had bilateral DVTs, congestive
heart failure, and he actually had more of a foot syndrome, but
no hand syndrome, when he was taking celecoxib.
DR. LOVE: That’s intereting.
DR LIN: Because he had a lot of edema, and he
had grade III edema to begin with. But he went on capecitabine and
celecoxib, and he did well for seven months. He actually subsequently
has received a little bit of CPT-11 because his performance status
has improved. But later on, he did develop what we call foot syndrome,
but there’s just significant edema due to his heart failure.
And there’s relatively very little hand syndrome. There was
just mild erythema to begin with.
DR. LOVE: But other than that
patient, out of these 33 or 34 patients?
DR LIN: We really see very mild hand-foot syndrome.
And generally, just minor erythema, minor pain that really have
not interfered with patients’ daily work. Because, in general,
if you have patients who are taking capecitabine alone, when they
do develop hand-foot syndrome, particularly if you are continuing
the drug, their hand-foot syndrome generally universally gets worse.
DR. LOVE: Now, when you compare
that to the case controls, I assume the case controls are matched
for dose and the age of the patient?
DR LIN: Age was not. This wasn’t a perfect
world where we could match the age. It’s not a perfect study.
DR. LOVE: So, what did you
try to match up, exactly?
DR LIN: We tried to match up the dose.
DR. LOVE: Okay. So, you matched
the dose up, and then in the control group, what fraction of patients
had hand-foot syndrome?
DR LIN: What we have seen is about 34 percent
of patients had more than grade I, and approximately about 17 percent
of the patients had grade III hand-foot syndrome. Diarrhea was also
another interesting observation. Approximately 28 percent of the
patients, who were taking capecitabine alone, in fact, had to be
admitted for hydrations. We rarely encounter any need for hydration
in patients who are taking both drugs, although there are a couple
of patients that had developed dehydration, but generally they’ve
been getting away with just outpatient hydrations.
DR. LOVE: Now, out of the patients
who were on both drugs, what fraction of them were receiving full-dose
capecitabine, 2500 milligrams in divided doses?
DR LIN: There are only about two to three patients.
DR. LOVE: So, most of these
patients?
DR LIN: They are on one gram per meter squared
twice a day.
DR. LOVE: One gram per meter
squared twice a day. Any other comparisons that you made besides
the diarrhea and the hand-foot syndrome in these two groups?
DR LIN: Actually, this is not published yet,
but we have noted there are about six hospitalizations in patients
who have previously only received capecitabine. They were admitted
for reasons that I just alluded to earlier – diarrhea, pain
control, tumor pain control. We’re still compiling the data
but I think that seems to be a recurrent theme. The patients who
actually were given celecoxib seem to have much better pain control.
The performance status in our cohort of patients – about 30
percent of the patients are PS-2 patients. They have high LDH with
a relatively borderline performance status, but they all universally
have improved when you give the celecoxib along with the capecitabine.
DR. LOVE: So, are you saying
that the celecoxib is contributing to pain control as a separate
entity or, in some way is it related to the capecitabine, also?
DR LIN: I think it’s the same entity as
the inflammation-driven. So, at the time when you have high tumor
burden, they all generally release inflammatory cytokines, and that
actually may, in part, contribute to cachexia, weight loss, and
generally a poor quality of life. And there has been very definitive
data proving that if you give NSAIDs along with narcotics, you almost
always end up having better pain control. I think that’s in
part contributable to why the patients have fared better when they
have received the Celebrex.
DR. LOVE: Now, I assume that
these patients in the Celebrex arm are a little bit older than the
average patients?
DR LIN: Yeah. Median age is about 65 years old,
and the others are 55 years old.
DR. LOVE: So, the control group
is a little bit younger.
DR LIN: Yeah.
DR. LOVE: So, this was a little
bit of an older group of patients, as you might guess.
DR LIN: Right.
DR. LOVE: And any hints in
terms of antitumor effect?
DR LIN: The hint was actually, when we really
look into that, and it’s not exactly a perfect world, matching
the prior chemotherapy regimens but nevertheless, we have seen that
quite a few patients have failed CPT-11 or oxaliplatin and the prior
5-FU therapies. And nevertheless, in patients who have received
these one or two lines of first-line chemotherapy, when they have
gone on, receiving capecitabine, the observation was that there
seems to be a reduction of their CEA, as well as increased disease
stabilization. Furthermore, we’ve also seen two PRs in patients
who have received prior irinotecan, in the patients who are receiving
capecitabine and celecoxib. That’s not seen in patients who
are receiving capecitabine. In fact, I have to look through all
our historical database to try to get a couple of patients who really
got PRs while receiving the capecitabine in order to try to make
the data less biased in terms of picking out the best performers.
So, the 3 PRs in our control arm were all chemo-naïve patients
who have no prior 5-FU exposures.
And their time to response is one of the other interesting observations.
Their PR lasted about nine months, and so far, we have about seven
patients who have received and continue to receive celecoxib and
capecitabine, lasted for about 12 months. In one patient, it’s
about 18 months, and still receiving therapy.
DR. LOVE: Is there some reason
to think that there might be some type of synergy between these
two drugs in terms of antitumor effect?
DR LIN: I believe the COX-2 is one of the central
regulators of inflammation, which is also known as the central playmaker
of tumor angiogenesis. As the various reports have shown that the
COX-2 is overexpressed in colorectal cancer, it’s one of the
major predictive prognostic factors for colorectal cancer in about
70 or 80 percent of the colorectal cancer the patients’ cases
are upregulating in terms of their COX-2. And furthermore, that
the COX-2 is upstream of the VEGF, FGF and PDGF and is a very potent
angiogenic factor.
The exact role COX-2 plays in terms of colorectal cancer progression
is still being teased out. But I think it is one of the very important
targets, considered an “oncogene target”, in colorectal
cancer treatment. And one of the studies that was suggested by Dr
Blanke, although they have given triple therapy plus COX-2, there
are data that did suggest potentially there is an improvement of
their chemotherapy side effects in terms of irinotecan-related diarrhea,
although they’ve seen increased vascular syndrome. My interpretation
of their data is that potentially the COX-2 is very much worked
through the antiangiogenic pathway. That’s probably why they
end up having the increased vascular syndrome such as myocardial
infarctions or strokes. And potentially, that’s why you’re
perturbing the tumor angiogenesis pathways. Also, there is indirect
evidence from the animal models, as well as other studies combining
with other chemotherapies, suggesting COX-2 is very important.
From our studies, while capecitabine is a very unique molecule,
it is activated through TP, which is also known as a platelet-derived
endothelial growth factor and is also a very potent angiogenic enzyme
that is acting, probably, upstream of the tumor angiogenesis. Furthermore,
capecitabine inhibits TS. There are some cell data, and also animal
data, linking TS through this thrombospondin pathway, and ultimately
it feeds back to the tumor angiogenesis. So, there is really an
important rationale for combining the 5-FU-based — particularly
to capecitabine-based — chemotherapy given that he delivery
of the capecitabine may be high in TP-high tumors, which is upregulated
in a lot of the colorectal cancers, as well as many other cancers.
DR. LOVE: But if you look at
the mechanism of action of capecitabine, the TP is only activating
the capecitabine.
DR LIN: Right.
DR. LOVE: It is not really
directly involved in the mechanism of action, other than that. Are
you saying that tumor cells that might tend to be more affected
by capecitabine, also would tend to be more affected by a COX-2
inhibitor?
DR LIN: Because I think the TP is an angiogenic
enzyme. And tumors have upregulation turning on the angiogenic phenotype.
So, potentially, you would deliver more cytotoxic drugs to the tumor
tissues whereas, if you’re giving systemic chemotherapy, you
could potentially poison the rest of the vascular system and may
end up having increased systemic vascular toxicities.
I think in this case, the combination clearly has to be proven
in the prospective clinical trials, but the idea is that you have
two drugs, potentially antagonizing their side effects, but also
focusing on potential enhancement of their antitumor activity and
improving the drug delivery to the tumor vasculature, as well as
to the tumor. I think that would make a lot of theoretical sense,
supported by preclinical as well as some of the preliminary clinical
data.
DR. LOVE: Getting back to hand-foot
syndrome, do you have any rationale for why, frankly, it occurs
in the hands and feet, as opposed to other locations?
DR LIN: That’s a very interesting question.
In fact, I just had a meeting this morning, trying to figure out
what we can do to figure out why hand-foot syndrome occurs with
capecitabine as well as why just a simple change in infusion will
give you hand-foot syndrome. With bolus 5-FU, you rarely encounter
hand-foot syndrome unless it’s with patients who may particularly
have DPD deficiency or through some type of mechanism that are still
not described.
Other drugs can also cause hand-foot syndrome, which include Doxil
and Taxotere. My personal thought about hand-foot syndrome, number
one, I think we’ve made probably a first step of identifying
what hand-foot syndrome is, what the etiology of it is. I think
it’s due to the drug, period, because you don’t give
the drug, you don’t have the hand-foot syndrome. So, it’s
drug-driven. But is it the direct effect of the drug? My thought
is it’s probably due to its own metabolites because of the
way the drug is metabolized and where it’s accumulated. And
both hands and the feet seem to be in the periphery of the circulation
where these metabolites would accumulate in these areas causing
the inflammation, is our current working hypothesis. And, in fact,
we’re going to prove it in our prospective trials, and document
the COX-2 levels as well as trying to figure out what metabolites
accumulate in the hands and feet.
DR. LOVE: What would you expect
biochemically? What kind of metabolite would you expect to see more
in the hands and feet than other parts of the body?
DR LIN: That’s a very good question. I
think the metabolites are probably prostaglandin-like. As you know,
5-FU is a fluoropyrimidine and whether it’s actually upstream
of the inflammation or downstream of the inflammation, where it
may have acted upon some of the promoters of the prostaglandin production.
That’s totally speculative at this point.
DR. LOVE: But, again, what
about the anatomy about the hands and feet is different? Is there
something about the capillary system, or what’s different
anatomically?
DR LIN: I think the foot is easier to understand
because it seems to have a delay of blood circulation. There might
be a difference in terms of how these metabolites are cleared, because
enzymes may be expressed in various tissues. It may be potentially
one of those sites where you have more accumulation of the 5-FU,
in the hands and feet, which might be equivalent, by the way, in
the tumors, so to speak. But I’m not aware of any data for
patients who have developed hand-foot syndrome, who have had better
tumor response. We clearly don’t have data to suggest that.
I think it’s still one of the toxicities highly specific to
patients who are receiving continuous infusion 5-FU and, also, capecitabine,
as well as some of the other drugs.
DR. LOVE: Now, as you’ve
been presenting these data and discussing these data, what kinds
of questions are you getting? What kinds of objections are you getting?
What kind of reaction are you getting? Because whenever you present
mainly retrospective data, it’s always subject to people criticizing
it. What kind of response are you getting to this?
DR LIN: I, myself, am even criticizing the data
for the very fact that it’s retrospective. Retrospective data
are hypothesis generating. This is our basis for the large prospective
trials, where we’re going to be giving full-dose capecitabine
with a higher dose of celecoxib, with the primary objective to achieve
better tumor response. As well, we are looking for a fair comparison
to the historical data, looking at the dose intensity of the capecitabine,
quality of life, and the incidence of hand-foot syndrome. In the
historical control with data from thousands of patient, we should
be able to at least get some idea of when you use the combination
with the approved dose of capecitabine, and whether we could duplicate
similar findings.
DR. LOVE: What are you going
to do next in terms of clinical trial testing of this hypothesis?
DR LIN: Well, the first phase is really looking
at the combination for the feasibility, toxicity, tolerance and
quality of life. We hope to get some idea of how much adding celecoxib
to the capecitabine platform is going to add in terms of its clinical
benefit. This combination has the great advantage of being a pure
oral regimen and the fact that many patients who have been previously
treated, receiving both drugs have maintained very good quality
of life. If they have demonstrated a good response, they generally
have gone back to the community and gone back to their usual daily
routine activities. And so we’re trying to duplicate that
and, in the meantime, try to improve upon their tumor response.
I think the COX will play a role in colorectal cancer, so as the
EGFR antagonists, so as probably the VEGFR antagonists and so as
the oxaliplatin, CPT-11. I think how we’re going to utilize
the agents in the best smart way is really the key for our treatment
of colorectal cancer. And we’re actually developing —
this is one of the major themes of our development is — how
to develop surrogate markers to monitor the progress of the patients
such treated and validate those markers in a prospective fashion,
so that when the patients walk into the room you will be able to
tell patients, “You’re probably better off taking this,
versus this.” And you will have multiple choices of the different
regimens, hopefully, in the future for colorectal cancer and they
will be tailored in a fashion that’s proper for each individual
patient.
DR. LOVE: Do you see Celebrex
potentially being used in any of the intravenous combinations? DR LIN: It has been used. It has been proposed.
One of the studies that’s been discussed in Dr Blanke’s
presentation, was, previously, using a triple therapy with celecoxib.
I think, given oxaliplatin coming into the picture, that study may
be somewhat revised to integrate oxaliplatin and CPT-11 as well
as Xeloda, with the celecoxib. Our way of approaching that is taking
a slightly different twist, and we will focus with our Phase II
trial on the hand-foot syndrome and tumor efficacy proving the initial
observation and hypothesis. Then we will bring it beyond a step
of adding EGFR antagonists and really “pilot” more targeted-therapy
combinations, rather than the pure cytotoxic combination plus some
of the “targeted agents.”
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