LOS ANGELES--Irinotecan (Camptosar), also known as CPT-11, should be
standard therapy for patients whose metastatic colorectal cancer has
become resistant to fluorouracil (5-FU), David Cunningham, MD, said
at the plenary session of the American Society of Clinical Oncology
(ASCO) annual meeting. Dr. Cunningham is head of the Gastrointestinal
Cancer Unit, Royal Marsden Hospital, London, UK.
In a multicenter phase III trial, patients randomized to irinotecan
were 2.6 times more likely to be alive at 1 year following treatment
and lived significantly longer than those who received only best
"We found that the quality of life of patients on the CPT-11 arm
of the trial was significantly better and also that they had fewer
symptoms related to the underlying cancer," Dr. Cunningham said.
"The findings are so impressive that we would no longer consider
best supportive care to be an acceptable treatment option for this population."
Irinotecan, a topoisomerase I inhibitor, is licensed by the FDA for
use as second-line therapy in metastatic colorectal cancer, based on
a 15% objective response rate seen in pretreated metastatic
colorectal cancer patients in a phase II trial.
There has been concern that this improvement might not be sufficient
to make the agent a worthwhile option in these patients, in view of
the agents significant problems with diarrhea.
Thus, Dr. Cunningham and his colleagues initiated this randomized
phase III trial to confirm the clinical benefit of irinotecan vs no
active anticancer therapy in terms of overall survival in resistant
metastatic colorectal cancer.
Inclusion criteria included tumor progression within 6 months of
prior 5-FU, no more than two prior 5-FU palliative regimens, and no
bulky disease. Patients with poor performance status (PS of 2 or
less) were also excluded because studies had shown that irinotecan is
not effective in that population.
The trial randomized 279 patients in a 2:1 ratio to either
irinotecan, 350 mg/m² every 3 weeks (300 mg/m² if age 70 or
more, or PS = 2) plus optimal supportive care, or optimal supportive
Overall survival rates were significantly better in the patients
treated with irino-tecan (see Figure),
and the curves began to separate within 2 months of beginning
treatment (P =.0001). At 12 months, the odds of death were 2.6 times
higher with best supportive care than with irinotecan (36.2% survival
for irinotecan vs 13.8% for supportive care).
Multivariate analysis found that the five most important prognostic
variables were performance status, weight loss, hemoglobin level,
alkaline phosphatase level, and number of involved organs.
"After correcting for all of the major prognostic factors,
treatment with CPT-11 continues to have a major, significant impact
on the risk of death for this patient population," Dr.
More patients in the treatment arm survived without deterioration in
performance status, and more had pain-free survival.
"CPT-11 prolongs survival, improves quality of life, and
improves control of tumor-related symptoms," Dr. Cun-ningham
said. "The results are sufficiently important for us to believe
that this represents a new standard of care for second-line treatment
of patients with colorectal cancer. When the disease has become
resistant to treatment with 5-fluorouracil, patients should be
Nearly All Become Resistant
Virtually all patients with metastatic disease eventually become
resistant to 5-FU. The effect of irinotecan occurred regardless of
prior response to 5-FU.
"Median survival of patients with metastatic colorectal disease
is about 12 months. CPT-11 adds an additional 3 months to that,"
Dr. Cunningham said. "Patients were able to carry on a normal
life for much longer."
Irinotecan has a well-known tendency to cause sometimes serious
diarrhea and did cause severe diarrhea in about 22% of patients, but
Dr. Cunningham said that the diarrhea was readily managed by
conventional antidiarrheal agents in this study.
In discussing the study, Michael OConnell, MD, of the Mayo
Clinic, agreed that irinotecan had a highly significant short-term
survival effect but pointed out that median survival was prolonged by
only 2.7 months and that there was no long-term survival benefit
associated with treatment.
However, Dr. OConnell also noted that the cost of irinotecan is
similar to that for other agents used to treat advanced cancer and
that the drug is widely available and can be given as outpatient treatment.
He suggested that the dose should perhaps be reduced to 300 mg/m²
for patients over age 70 and that the drug might not be appropriate
for patients with bulky disease, especially hepatic tumors, or for
those who have had prior pelvic radiation and are therefore more
susceptible to severe diarrhea.