NEW ORLEANSNew data demonstrate that the recently approved
combination of irinotecan (Camptosar), 5-fluorouracil (5-FU), and
leucovorin (LV) in-creases overall survival when used as first-line
therapy in patients with metastatic colorectal cancer, without a
significant increase in side effects.
Scientists presented three new analyses of two studies that were the
basis of the Food and Drug Administrations approval this spring
of the topoisomerase inhibitor irinotecan with 5-FU/LV for first-line
therapy of metastatic colorectal cancer, a highly resistant
malignancy and the second leading cause of cancer deaths in North America.
Leonard Saltz, MD, one of the presenters and associate attending
physician, Division of Solid Tumor Oncology, Memorial Sloan-Kettering
Cancer Center, called the drug trio the new reference standard.
Langdon Miller, MD, vice president of clinical oncology, Pharmacia
Co., Peapack, NJ, reported that on average, patients receiving
irinotecan and 5-FU have a significantly improved tumor control and
longer survival than the patients receiving 5-FU/LV, the therapy that
has been standard for metastatic colorectal cancer for several
Mature Data Reanalyzed
Dr. Saltz and his colleagues conducted a meta-analysis of the two
studies, one based in North America and the other in Europe,
reanalyzing the data on each participant as if they were part of one
With the meta-analysis, we found that the P values
became more statistically significant, Dr. Saltz told ONI.
The smaller the P value, the more confidence we have in
the validity of the results.
Response rates, time to progression, and survival were superior to
those revealed when the original studies were reported individually.
Originally, the European data showed a survival advantage, while the
American study did not, Dr. Saltz said.
Now that the data have matured, both studies reveal a survival
advantage for the patients receiving irinotecan/5-FU/LV. Combined
survival for the irinotecan/5-FU/LV patients was 15.9 months,
compared to 13.3 months for the 5-FU/LV group.
In the meta-analysis of data from 842 patients in the two studies,
the combined response rate was 37% for irinotecan/5-FU/LV vs 21% for 5-FU/LV.
Combined time to tumor progression was 6.9 months in the
irinotecan/5-FU/LV group, compared with 4.3 months for those
Side effects were tolerable and treatable, and there were
no more treatment-associated deaths than with the previous treatment,
Dr. Saltz reported.
Its clear that this is a better way to treat patients
than what we were doing before, he said.
Robert D. Knight, MD, director of clinical research and oncology at
Pharmacia, presented a reanalysis by subgroup of the North American
study. The researchers investigated a variety of factors, including
age (up to age 65 and older than 65), gender, performance status,
organ sites affected by metastatic disease, the presence of liver
metastases (liver metastasis is associated with poor prognosis in any
cancer), and serum LDH level (higher lactate dehydrogenase levels are
associated with poor prognosis).
No matter which subgroup we looked at, the patients always did
better on the irinotecan/5-FU/LV arm than they did on the 5-FU/LV
arm. So everyone had the chance to benefit from the addition of
irinotecan to their treatment, Dr. Knight said.
Even the elderly and those who had poor performance status did well
on irinotecan/5-FU/LV, Dr. Knight said, despite the belief in
clinical oncology that older, frail people might be less likely to
tolerate a combination therapy or a new drug administered after
Those patients who showed the greatest improvement in survival had
normal LDH and normal performance status, regardless of all the other
factors. For this group, median overall survival on
irinotecan/5-FU/LV was 26 months vs 16 months with 5-FU/LV.
Age, gender, and other factors did not influence outcome based on the
type of therapy used. Other factors did, but to a lesser degree than
LDH and performance status, Dr. Knight said. These were serum
bilirubin, only one site of organ metastasis, and normal vs elevated
white blood cell count.
Response rates (greater than 50% shrinkage) analyzed by baseline
tumor area and organ site were also better in all patient subgroups
receiving irinotecan/5-FU/LV than in those given 5-FU/LV, Dr. Knight
Median time to progression also improved with irinotecan/5-FU/LV. The
greatest improvement occurred in those with normal serum LDH; these
patients had a median time to progression of just over 9 months,
compared with a little more than 4 months for those receiving
Dr. Knight said the next step in development of the therapy is to
study it as an adjuvant to surgery. At least two large trials
comparing irinotecan/5-FU/LV with 5-FU/LV in this setting are under
way now, one in the US and Canada and another in Europe.
A new treatment that adds a new drug to an older one may improve
survival, but it may also cause adverse effects that lower quality of
life, Dr. Miller said.
The question is: Are these toxicities offset by other
quality-of-life improvements related to improved disease
control? Dr. Miller asked. In the end, what is the
Dr. Miller reported quality-of-life data from the North American
study. We have shown that by adding irinotecan to 5-FU/LV, we
lengthened life without impairing the patients quality of
life, Dr. Miller said. This was achieved with a modest
increase in diarrhea, but neutropenia and mucositis were decreased.
Patients in the irinotecan arm had a higher rate of diarrhea than the
5-FU arm, but its average duration was only a couple of days, he
said, and patients reported that it wasnt a major issue.
New Standard of Care
The discussant for the ASCO session, Daniel G. Haller, MD, professor
of medicine, University of Pennsylvania Cancer Center, said that the
data presented by Dr. Saltz contains an unambiguous message.
In the United States, Dr. Haller said, the combination of 5-FU,
leucovorin, and irinotecan represents a new standard of practice and
the new control arm for clinical trials. And the combination has been
approved by the FDA, with either bolus or infusional
Dr. Haller suggested that it might be time for US oncologists to
hold the Mayo, in light of the toxicity and efficacy of
the Mayo regimen and the superiority of the irinotecan combination.
He told ONI that the new therapy showed superiority in the most
important endpoint, overall survival, without a marked increase in
toxicity of treatment. It met the FDA review criteria for new drug
approval, giving it one of the strongest imprimaturs.
Dr. Hallers comments echoed those of Dr. Saltz, who concluded
that his groups meta-analysis further strengthens the
conclusion that CPT-11 [irinotecan]/5-FU/LV represents a new
reference standard in the first-line treatment of patients with
metastatic colorectal cancer.
Dr. Haller commented that although the prolongation of life in the
overall meta-analysis was not long (2 to 3 months), it was
clinically and statistically significant.
Dr. Saltz commented that patients want to know the best a physician
can do and said of the new therapy, Even if its slightly
better, its better. As a doctor, I want to give the best
Dr. Haller said he looks forward to studies to assess the relative
benefits of combinations in different patient populations, based on
patient demographics and tumor biology.