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Leonard B Saltz, MD
Edited comments by Dr Saltz
Clinical issues raised by Intergroup N9741
Intergroup N9741 raised a number of questions, including
the use of bolus versus infusional fluorouracil. In that trial,
the control arm was the IFL regimen (bolus irinotecan/fluorouracil/leucovorin).
The investigational arm was the FOLFOX-4 regimen, which is
two 22-hour fluorouracil infusions with leucovorin infusions
in the middle with oxaliplatin. So we’ve got two variables
— irinotecan versus oxaliplatin, and fluorouracil bolus
versus fluorouracil infusion. In that study, the overall survival,
time to tumor progression and response rate were superior
for the FOLFOX arm. However, there are some confounding issues
that make it difficult to know how to put those data into
context.
One study that helps us was reported at ASCO in 2001 by
Christopher Tournigand. This evaluated oxaliplatin versus
irinotecan without varying the fluorouracil. So, all patients
got the same biweekly fluorouracil/leucovorin, and the variable
was whether they got oxaliplatin or irinotecan. All patients
were planned for a crossover; as soon as they failed on one,
they went onto the other. In that study, the survival of the
two arms as well as the time to tumor progression of the first-line
and second-line regimen are virtually identical, and response
rates to first line are identical.
The study is underpowered, with only about 110 patients
in each arm, but when you look at the survival curve it is
very hard to be convinced that a larger study would have shown
a significant divergence. This suggests that when used with
infusional fluorouracil, the choice can be irinotecan or oxaliplatin.
The safety profiles with the infusional, biweekly regimen
appeared to be easier for patients to tolerate, and for doctors
to deal with, because fewer dose modifications were required.
Application of clinical trial results to
practice
Either regimen of irinotecan/fluorouracil/leucovorin or
oxaliplatin/fluorouracil/leucovorin would be an appropriate
first-line consideration, and those are my current default
positions when I see patients outside of a clinical trial.
I am routinely recommending that they have an indwelling catheter
inserted and that we treat them with a biweekly fluorouracil
infusion plus either irinotecan or oxaliplatin. We discuss
the relative merits and downsides to each drug. Since I'm
not convinced there are efficacy data to help us select one
over the other, I talk to patients about the different side-effect
profiles. For patients where GI toxicity or loss of hair is
going to be particularly problematic, oxaliplatin-based therapy
is better. For patients where neurotoxicity could be particularly
problematic, irinotecan is a better choice.
Use of tumor markers in postsurgical management
Oftentimes I'll be asked whether or not a tumor marker should
dictate a major change in therapy; I'm not a believer in doing
that. Tumor markers are overused in this country. They do
provide some information, but they are an indication to look
more carefully, not necessarily to act. For example, I do
not advocate the initiation of therapy due to a bump in CEA
where you can’t find any evidence of tumor any other
way. I do not advocate changing a therapy if the CEA starts
going up or abandoning a therapy if the CEA doesn’t
go down. I look at how the patient is doing, I look at the
CAT scan or MRI evidence, and that is what tends to help me
make my decisions. In very borderline situations a significant
movement of CEA may color my decision, but in general I don’t
advocate making major therapeutic decisions on the basis of
a marker. I haven’t found markers other than CEA to
be particularly helpful in colorectal cancer and I don’t
routinely obtain them.
Select publications regarding the
use of tumor markers in the postsurgical management of colorectal
cancer
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