NEW ORLEANSA meta-analysis of two independent phase III
randomized multicenter studies further strengthens the
conclusion that the combination of irinotecan (CPT-11,
Camptosar)/fluorouracil (5-FU)/leucovorin represents a new reference
standard in the first-line treatment of patients with metastatic
colorectal cancer, said Leonard Saltz, MD, associate attending
physician, Division of Solid Tumor Oncology, Memorial Sloan-Kettering
The combination significantly improved response rate, lengthened time
to tumor progression, and prolonged survival, compared with
5-FU/leucovorin alone, Dr. Saltz said at the 36th Annual Meeting of
the American Society of Clinical Oncology (ASCO).
In the first trial, conducted primarily in North America, as well as
Australia and New Zealand, patients were randomized to receive the
combinationbolus 5-FU 500 mg/m² plus leucovorin 20
mg/m² plus irinotecan 125 mg/m² weekly for 4 weeks followed
by a 2-week restor the Mayo Clinic bolus 5-FU/leucovorin
Eligible patients had histologically proven colorectal cancer;
unresectable measurable metastases; performance status of 0, 1, or 2;
and no prior chemotherapy for metastatic disease.
In the second trial, conducted primarily in Europe, patients received
infusional 5-FU weekly or biweekly. Centers selected which 5-FU
schedule they would use, and patients were randomized to that
schedule with or without irinotecan.
The entry criteria for this study were essentially the same as for
the North American trial.
Post-accrual follow-up is mature in both studies, Dr.
Saltz said, 20 months and 19 months, respectively.
Confirmed response rates for the North American trial were 39% for
the irinotecan combination vs 21% for 5-FU/leucovorin alone (P
<.0001), and for the European trial, 35% vs 22%, respectively (P
= .005), Dr. Saltz reported. In the meta-analysis, response rates
were 37% for 5-FU/leucovorin/irinotecan, compared with 21% for
5-FU/leucovorin alone (P <.0001).
Time to tumor progression in the North American trial was 7 months
for the combination vs 4.3 months for 5-FU/leucovorin alone (P
= .004), and in the European trial, 6.7 months vs 4.4 months,
respectively (P < .001). The meta-analysis showed a time to
tumor progression of 6.9 months vs 4.3 months, respectively (P
I call your attention to the more significant P values
and the narrowing of the confidence intervals, Dr. Saltz said,
indicating the increased confidence that we gain from larger numbers.
He added that in a Cox regression analysis performed to compensate
for potentially important prognostic variables, the superiority of
the irinotecan combination therapy remained at the same significance (P
Overall survival in the North American trial was 14.8 months for the
combination vs 12.6 months for 5-FU/leucovorin alone (P =
.042), and in the European trial, 17.4 months vs 14.1 months,
respectively (P = .032).
Results from the meta-analysis for overall survival15.9 months
vs 13.3 months, respectivelywere now highly statistically
significant (P = .003), again with narrowing of the confidence
intervals. In the Cox regression model, the superiority of the
irinotecan combination remained highly statistically significant (P
A Question About Crossovers
In the question-and-answer session following his presentation, Dr.
Saltz was asked how many control patients in the trials had crossed
over to receive irinotecan and whether this could have affected the
He responded that in the North American trial, 55% of control
patients received irinotecan as second-line therapy. National
databases show that approximately 70% of patients go on to get
second-line therapy, and 80% of those are irinotecan based, which
works out to about 56%, he said, so this trial accurately
reflects the incidence of patients who are able to go on to
second-line therapy with irinotecan.
He reminded the audience that not everyone who progresses
through a first-line regimen is well enough for a second-line
regimen. Patients failing 5-FU who have poor performance
status, bowel obstruction, or elevated bilirubin, for example, would
not be candidates for second-line irinotecan. It is possible
that one of the reasons were seeing an advantage for first-line
combination therapy is the increased number of patients who are
exposed to both drugs, he said.
When an audience member suggested that the combination therapy with
irinotecan should not be the new standard because second-line
treatment in the control arm has never been tested
prospectively, Dr. Saltz strongly disagreed.
For the reasons I just outlined, I think that we have
prospectively tested that question, he said. I would
point out that you simply cant mandate second-line therapy in
trials, because patients are frequently not well enough to receive
it. I think this trial fairly accurately reflects sequential vs
concurrent administration of irinotecan.
New Standard of Practice
The discussant, Daniel G. Haller, MD, professor of medicine,
University of Pennsylvania Cancer Center, said that although
the planned primary endpoints of these trials were progression-free
survival and response rates, respectively, both trials reached the
regulatory measure of success, a statistically significant 2- to
3-month improvement in median survivorship.
In the United States, Dr. Haller said, the combination of
5-FU/leucovorin and irinotecan represents a new standard of practice
and a new control arm for clinical trials. He added that the
combination has been approved by the FDA with either bolus or
Referring to a subgroup analysis also presented at the ASCO meeting
(abstract #991), Dr. Haller said, It appears that the
combination is the standard for all patients. He added that the
abstract suggests that the survival benefits appear greatest in
the good-risk patients, but that all patients entering these trials
Dr. Haller also pointed out (referring to abstract #2443 presented at
the ASCO meeting) that the benefit was achieved without a
marked recorded increase in toxicity or a negative impact on quality