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Web Guide 2: Christopher Twelves, MD
Edited comments by Dr Twelves
Phase II capecitabine/oxaliplatin trial (XELOX)
Objective response rate
Although this was a phase II study, it was not conducted at a
single center but rather at a number of different centers. Ninety-six
patients were treated, and the key end point was the objective response
rate. The combination of capecitabine/oxaliplatin had a 55% overall
response rate, similar to what is expected with intravenous 5-FU/oxaliplatin.
These are very robust data, because they are from multiple sites
in a large study population.
Tolerability
Capecitabine/oxaliplatin was well tolerated. Oxaliplatin in combination
with a fluoropyrimidine typically causes neuropathy as the predominant
side effect, which is a slightly unusual toxicity for many physicians
treating colorectal cancer patients. Nurses and patients must be
educated about this neurotoxicity. Once physicians become familiar
with the sensory neuropathy — how to identify it and when
to reduce or to stop the oxaliplatin — it is easily recognized
and treated.
For most patients, the neuropathy manifests as some numbness or
tingling in their fingers. Patients may also notice that they must
concentrate a little more to carry out fine motor tasks. Patients
should also be warned about some other unusual manifestations, which
are often precipitated by exposure to cold. There are patients who,
if they have a cold drink, get some spasm in their throat. Similarly,
some patients experience weakness or a temporary loss in the use
of their hands.
The neuropathy is cumulative, and it rarely occurs during the
initial cycles. Some patients can continue treatment for six months
without significant neuropathy, but quite commonly over that period
of time they develop some neuropathy.
Patients often say they have some numbness or tingling in their
fingers. When asked if it is troubling them and they say no, then
we do not do anything. If they say that they are starting to have
some difficulty and that their fingers are not as agile as before,
it is determined that they have a functional impairment. At that
point, the oxaliplatin dose is reduced or the drug is discontinued.
There is a gradual resolution of the neuropathy, which is highly
reversible over a period of time.
Neuropathy was also the principal side effect observed when capecitabine
was substituted for 5-FU in combination with oxaliplatin, and there
was also some diarrhea. About one-third of the patients stopped
the oxaliplatin because of the neuropathy. Even when the patients
who did not receive the full planned course of oxaliplatin were
included in the analysis, there was still a high response rate,
encouraging time-to-progression data and survival figures.
Capecitabine/oxaliplatin was much less myelosuppressive than conventional
5-FU/oxaliplatin. The difference in myelosuppression is very striking.
It is potentially important for patients, because there is always
concern about the risk of infection in patients receiving palliative
chemotherapy. As seen in the single-agent trials, 5-FU is much more
myelosuppressive than capecitabine. There was virtually no serious
myelosuppression with capecitabine/oxaliplatin.
There were only five patients receiving capecitabine/oxaliplatin
who had any grade IV toxicity. Aslightly lower dose of capecitabine
was used, and there was only a 3% incidence of significant hand-foot
syndrome. The capecitabine dose was 2,000 mg/m2/day, rather than
2,500 mg/m2/day. Only a very small proportion of patients had any
symptomatic or functional impairment from the hand-foot syndrome.
Research on capecitabine/oxaliplatin compared
to 5-FU/oxaliplatin
The two regimens look highly comparable. Although we are comparing
two different studies, the data for capecitabine/oxaliplatin match
closely the 5-FU/oxaliplatin data from the Intergroup (N9741) trial.
Also, the earlier 5-FU/leucovorin/oxaliplatin (FOLFOX-4) study results,
by de Gramont, look very similar to our data with capecitabine/oxaliplatin.
The big advantage with capecitabine/oxaliplatin for the patients
is convenience. There is also an advantage in terms of reduced myelotoxicity.
For the individual patient, the key advantage is that they will
only need to come to the hospital for their intravenous infusion
of oxaliplatin, while the rest of their treatment can be taken at
home.
Patients receiving an infusional 5-FU regimen may require a central
venous catheter. In terms of quality of life, substituting infusional
5-FU with oral capecitabine is something the patients will prefer.
My feeling is that, in a few years, capecitabine will replace
5-FU across the board. Clearly, there would be reluctance to substitute
on a purely ad hoc basis. Therefore, it is important to explore
these combinations accurately and carefully. At the same time, it
is impossible to imagine that every single 5-FU regimen, schedule
and combination will be the subject of a major randomized trial.
I think with oxaliplatin, if the regulatory authorities do not require
a randomized trial, capecitabine could be substituted straightaway.
However, a randomized trial will probably be expected by the regulatory
authorities, given the incidence of colorectal cancer and the impact
this will have in the population.
Trials evaluating adjuvant oxaliplatin in combination
with capecitabine or 5-FU
These combinations are quite attractive for the adjuvant setting,
partly because of the efficacy data. The recent Intergroup (N9741)
trial demonstrated that oxaliplatin was at least as effective as
irinotecan and arguably more effective as a partner for 5-FU. The
efficacy data clearly indicate the need to explore 5-FU or capecitabine
in combination with oxaliplatin in the adjuvant setting. The overall
safety profile makes it attractive for patients receiving adjuvant
treatment. Neuropathy should not be a substantial obstacle.
Managing advanced colorectal cancer in patients
with a poor performance status
Patients enrolled in clinical trials do not accurately reflect
the patients seen on a daily basis. It is now clear that combination
chemotherapy, arguably with capecitabine/oxaliplatin as a strong
contender, represents the gold standard. However, the gold standard
may not be appropriate, desirable or chosen by every individual
patient with advanced colorectal cancer. There is a proportion of
patients who are less fit, do not want intravenous treatments and
prefer oral treatments with a fluoropyrimidine, such as capecitabine.
In the coming years, patients will have two or more choices —
a more intensive treatment in the form of combination chemotherapy
that will impact on response rates and survival or a viable and
attractive alternative of single-agent capecitabine. There is a
nice distinction between these different approaches. I do not think
a one-size-fits-all approach will be the best.
CASE 2:
64-year-old man with extensive metastatic liver disease |
History
This man had surgery and adjuvant 5-FU several years previously.
He had been well, until he developed some discomfort in his
abdomen. He was a slim and relatively fit gentleman. He had
not lost a substantial amount of weight and was still eating,
but he was a bit less energetic. However, he was still up
and about and active. On physical exam, his liver was enlarged
and he had right upper quadrant tenderness. His family doctor
sent him for a scan, which confirmed the presence of extensive
liver metastases. His disease was confined to the liver.
Follow-up
The patient enrolled in the capecitabine/oxaliplatin phase
II clinical trial, which he tolerated very well.
Case discussion
This patient had come in with his son, who was very well
informed with documents from the Internet. Patients are coming
to us with information, and we need to talk to them in a different
way to discuss these options. This gentleman really wanted
combination chemotherapy, because he wanted the best possible
treatment. He was a fit man, so this was appropriate.
There is now a range of different treatment options for
metastatic colorectal cancer, a luxury that was unheard of
just a few years ago. There is oxaliplatin, irinotecan, capecitabine
or intravenous 5-FU.
Since he was concerned about hair loss, diarrhea and other
significant toxicities, they preferred oxaliplatin to irinotecan.
Fortunately, he was invited to participate in the phase II
capecitabine/oxaliplatin trial. Without that clinical trial,
he would otherwise have been treated with 5-FU/irinotecan.
As he received capecitabine/oxaliplatin, his performance
status was maintained and even improved — partly because
of the discomfort in his abdomen resolving. He tolerated the
treatment well. He developed some neuropathy, although not
severe enough to discontinue the oxaliplatin. He was relieved
and pleased to see that he was able to maintain his lifestyle
during the trial. He was an active man and an active walker.
As with other patients, there was a sense of being involved,
because of the oral chemotherapy.
With capecitabine/oxaliplatin, at least half of the patients
have a major reduction in their tumor mass and about one-third
have either disease stabilization or a minor reduction in
their tumor. This patient had a good response. His originally
palpable liver was no longer palpable, and his discomfort
went away. Additionally, his CEA came down very impressively.
He completed over six months of capecitabine/oxaliplatin
and remained off treatment for four months, but eventually
his disease progressed. Perhaps reflecting his favorable experience
with his initial treatment, he was interested in receiving
more chemotherapy, and we treated him with irinotecan. He
gained some benefit, albeit less than with oxaliplatin. After
the irinotecan, he was still reasonably fit, and he participated
in an experimental-drug protocol. He died a few months ago.
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