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are here: Home: CCU 1 | 2003:
Mace L Rothenberg, MD
Edited comments by Dr Rothenberg
Development of oxaliplatin in the treatment of colorectal
cancer One of the primary reasons for the development of oxaliplatin
in colorectal cancer is very provocative data from the laboratory
looking at the NCI 60- human tumor cell line screen, where
they looked at patterns of activity against different tumor
types. They evaluated whether the concentration to inhibit
50 percent growth of those cell lines is average, above or
below average for those 60 cell lines. Cisplatin and carboplatin
have very little activity against the eight colorectal cancer
cell lines and require higher-thanaverage concentrations to
achieve that 50 percent inhibition. Oxaliplatin has a very
different profile. In six of those eight colorectal cancer
cell lines, it required lower-than-average concentrations
to inhibit growth by 50 percent. These findings distinguish
oxaliplatin as being not only structurally but also functionally
different from the other platinum salts.
Potential role for oxaliplatin in overcoming
5-FU resistance
Oxaliplatin’s interactions with other drugs, specifically
5-FU, may be one of the reasons we’re seeing its activity
in colorectal cancer. It may prevent one type of resistance
mechanism seen in the laboratory and in patients. When cells
upregulate thymidylate synthase (TS), they become less sensitive
to 5-FU. Oxaliplatin reduces TS and may be resensitizing cells
to inhibition by 5-FU. This may explain why patients respond
to oxaliplatin/5-FU after progressing on frontline 5-FU alone.
Key recent and ongoing clinical trials
with oxaliplatin
The natural evolution of oxaliplatin is already playing
out. We’ve seen preliminary data from the NCCTG trial
N9741 that showed a survival advantage for FOLFOX-4 over IFL
in the frontline setting. Oxaliplatin has also been moved
to the adjuvant setting in the MOSAIC and NSABP trials. It's
also being studied in conjunction with capecitabine to see
whether or not there are advantages of not requiring a central
venous catheter and whether oral therapy can give you the
same kind of efficacy that we see with intravenous 5-FU therapy.
There's going to be a lot of interest in that, and there are
actually now several Phase II trials under development that
will be looking at the capecitabine/oxaliplatin combination
in various settings — first-line, second-line and the
adjuvant setting.
Comparison of capecitabine/oxaliplatin
(XELOX) versus FOLFOX
These Phase I/II trials are likely to be designed around
equivalence. However, capecitabine is a more complicated drug
than just an oral version of 5-FU. It actually has potential
tumor selectivity, with thymidine phosphorylase (TP) being
expressed at higher levels in tumor cells than normal cells.
The more mature follow-up in trials using a capecitabine/oxaliplatin
combination has shown very encouraging median survivals that
are certainly in the ballpark, and maybe even higher than
those that have been seen with infusional 5-FU and oxaliplatin
combinations.
Improved survival due to newer chemotherapy
agents
We will be debating the merits and shortcomings of the newer
regimens for the foreseeable future, but we shouldn’t
lose sight of the fact that the median survival on these trials
is now in the order of 18 to 20 months. When I was in medical
school 20 years ago, the median survival for people with metastatic
colorectal cancer was six months. It's hard to think of another
common solid tumor where we’ve seen a tripling of the
median survival in patients with metastatic disease, so all
those drugs are important. Which one you use first versus
which one you use second may not be as important as making
sure that you integrate all those drugs into a treatment regimen.
Nonprotocol management of the patient with
metastatic colorectal cancer
It's not a short visit with patients anymore. I can no longer
say, "I'll give you 5-FU and see you in one week."
How do we rationally combine the available agents in the individual
patient's specific situation? I talk to them about the body
of evidence that exists for infusional 5-FU given with irinotecan
— a Douillard or FOLFIRI-type of regimen — showing
a survival advantage over 5-FU. I would also talk about the
FOLFOX regimen, showing an advantage over IFL. I tell them
that those two regimens have been compared head-tohead in
only one trial that showed it didn’t matter which one
you gave first; you got excellent overall survival with either
one.
Next, I would tell them that we need an infusion catheter
for each of those regimens. We’d talk about the side
effects and that would help focus me on one regimen versus
another. If a patient was more likely to be harmed because
of a particular side effect, then that might make me lean
in one direction with that patient and another direction for
another patient.
Substituting capecitabine for infusional
5-FU
Oncologists often ask: Must we give 5-FU by infusion? Is
capecitabine/ oxaliplatin equivalent to 5-FU/oxaliplatin?
My response is that capecitabine/ oxaliplatin appears promising.
I would not be able to say that capecitabine/ oxaliplatin
has definitively proven itself to be equivalent or superior
to any other therapy. If there are some compelling reasons
why some patients do not want a central venous catheter, and
they understand that the data is Phase II — not Phase
III data — and are comfortable with that level of uncertainty,
then I treat those patients with capecitabine/oxaliplatin.
I like to adhere to the gold standard, which is giving the
drugs the way they were given in the clinical trial. If we
are going to deviate from that, then patients need to be aware
that there's a greater degree of uncertainty.
Select publications regarding
oxaliplatin in metastatic colorectal cancer
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