PHILADELPHIAMost people would agree that standard-of-care
for frontline treatment of advanced colorectal cancer (CRCA) should
now be irinotecan (Camptosar) plus 5-fluorouracil/leucovorin
(5-FU/LV), stated Daniel G. Haller, MD, at an
investigators workshop sponsored by the University of Texas M.
D. Anderson Cancer Center and Pharmacia Oncology. As the basis for
this assessment, Dr. Haller of the University of Pennsylvania Cancer
Center in Philadelphia, cited presentations made earlier this year.
Dr. Haller raised the issue of what the proper endpoints for clinical
trials in advanced colorectal cancer should be. Overall
survival is still the one and only gold standard for new drug
approval for CRCA. Many of us believe that there should be other
markers for metastatic disease which might lead to drug
approval, he said. Other criteria, he suggested, such as progression-free
survival, response rate, or quality of life might be more
appropriate for judging efficacy of some new drugs such as the
cyclooxygenase-2 (COX-2) inhibitors.
As more drugs for colorectal cancer have become available,
researchers have had to face the problem of crossover therapy
complicating interpretation of the efficacy of initial regimens.
One, two, or three new drugs, each adding 1 or 2 months of
median survivorship, mean that the effect of first-line therapy can
be impacted upon, Dr. Haller said.
Determining Optimal Use
Even after a drug has been approved, achieving optimal clinical use
of the agent may take years of actual clinical experience. It
took us a long time to determine how to best give 5-FU, Dr.
Haller said. There is less overall toxicity from infusional
protocols such as the de Gramont regimen, and these have been
associated with significant improvements in response rate and in
progression-free survival, he said. As Dr. Haller noted,
however, data from meta-analyses have also shown that increased
response rates do not necessarily translate into increased survival.
phase III studies of irinotecan combination regimens found response
rates of 39% with irinotecan plus 5-FU/LV vs 21% with 5-FU/LV alone (P
< .0001)in patients without prior chemotherapy. Both studies
showed a significant survival advantage for the irinotecan
combination vs standard 5-FU/LV, despite the high number of
crossovers between the two regimens (see Figure).
Many patients in these trials eventually crossed over to receive
irinotecan or other drugs. This suggests that even if you give
drugs in sequence, you still maintain the overall survival advantage
of the first regimen to which the patient was randomized, Dr.
Haller noted. Although many trials of new agents start first with
heavily pretreated or advanced-stage patients, a growing body of data
in colorectal cancer shows that people who still look and feel
well actually benefit the most from combination therapy, he added.
Potential New Agents
Turning to potential new agents for advanced colorectal cancer, Dr.
Haller said that oxaliplatin has been on the horizon in the United
States for quite a long time, but has produced attractive response
rates in platinum-resistant cell lines. The pivotal de Gramont trial
showed an increase in response rate and progression-free survival,
but overall survival was not statistically significant.
With newer drugs such as oxaliplatin or irinotecan that may
produce myelosuppression, adding a fluoropyrimidine regimen that has
no significant myelosuppression has significant promise for the
future, because there may be less overall toxicity, he continued.
Dr. Haller said that some of the data from oxaliplatin trials may
have been confounded by the fact that there were patients who went on
to potentially curative surgery. More patients who were
previously thought to be unresectable are now going for surgical
intervention when they are getting combination therapy, he said.
A related problem plaguing clinical trials is that patients
randomized to the oxaliplatin arm in US trials, such as North Central
Cancer Treatment Group (NCCTG) N9741, can still get irinotecan off
trial as second-line therapy. This creates an unplanned
crossover arm for some trials, Dr. Haller said, and complicates
Dr. Haller acknowledged that current thinking is that most patients
with advanced colorectal cancer should get combination chemotherapy.
We need drug selection factors, he concluded, to
guide rational prospective selection of drugs for these