Irinotecan in the First-Line Treatment of Colorectal Cancer
Irinotecan in the First-Line Treatment of Colorectal Cancer
Irinotecan (CPT-11 [Camptosar]) is a semisynthetic, water-soluble
derivative of the plant alkaloid camptothecin. Based on the results
of extensive clinical evaluations, irinotecan received FDA
approval for use in fluorouracil-refractory stage IV colorectal
cancer. Other potential uses of irinotecan, both in colorectal cancer
and in other types of malignancies, are currently under active investigation.
This review will focus on the potential use of irinotecan, either
alone or in combination, in the first-line treatment of colorectal
cancer. It should be emphasized that these first-line strategies are,
at the time of this writing, being actively investigated and are not
presently recommended for routine clinical use.
Irinotecan (CPT-11) is one of several derivatives of camptothecin
entering the clinical arena. (The "CPT" in CPT-11 is an
abbreviation for camptothecin.) Camptothecin is the active isolate
from the stem wood of Camptotheca acuminata, a tree that grows
throughout most parts of Asia.
Initial clinical trials of irinotecan in the 1970s reported
encouraging evidence of antitumor activity; however, substantial and
unpredictable toxicities were also encountered.[3-5] This unfavorable
toxicity profile caused a loss of clinical interest in the
camptothecins until more than a decade later, when the mechanism of
action of camptothecin was demonstrated to be the inhibition of the
nuclear enzyme topoisomerase I.[6-10]
Knowledge of the target of camptothecin rekindled activity in the
development of soluble analogs that could be more practically applied clinically.
One such series of investigations led to the identification of 7-ethyl-10[4-(1-piperidino)-1-piperidino]-1-carbonyloxy-camptothecin
as an agent with good aqueous solubility and a favorable preclinical
activity profile.[11-13] Phase I testing of this agent, called CPT-11
at that time, was initiated in Japan[14,15] and subsequently in the
United States[16,17] and France. These early phase I trials
demonstrated evidence of antitumor activity of irinotecan in
advanced, treatment-refractory colorectal cancer patients, leading to
an extensive worldwide development program of the drug in this disease.
Shimada et al published the first phase II study of irinotecan in
patients with metastatic colorectal cancer, 81% of whom had
fluorouracil-refractory disease. A major objective response rate
of 27% was reported in the 63 evaluable patients treated, with a 22%
response rate in those who had been treated previously with fluorouracil.
In a subsequent trial conducted in the United States, 43 patients
with fluorouracil-refractory colorectal cancer were treated with
irinotecan by 90-minute infusion weekly for 4 weeks followed by a
2-week rest period. This trial reported similar results, with a major
objective response rate of 23%. Furthermore, an additional 31% of
patients who did not achieve a major response demonstrated either
stable disease or a minor clinical regression, increasing the
percentage of patients who derived some demonstrable antitumor
activity to 54%.
These data were later analyzed in combination with data from two
other trials of irinotecan in fluorouracil-refractory colorectal
cancer involving a total of 304 patients. The major objective
response rate was 13%, with an additional 49% of patients achieving
clinical benefit in the form of either a minor response or disease stabilization.
Antitumor activity of irinotecan in patients with previously
untreated colorectal cancer had been noted in a small population of
such patients treated in the initial phase II study by Shimada et
al. To more thoroughly investigate this issue, our group at
Memorial Sloan-Kettering Cancer Center in New York performed a formal
phase II trial of irinotecan in chemotherapy-naïve patients with
measurable metastatic colorectal cancer. In this trial, 41
patients received a starting dose of 125 mg/m2 of irinotecan weekly
for 4 weeks, followed by a 2-week break. We observed a major
objective response in 13 patients (32%; 95% confidence interval [CI],
18% to 46%). In addition, 44% of patients demonstrated a lesser
degree of antitumor activity, in the form of either a minor response
or stable disease. Treatment was reasonably well tolerated, with
diarrhea and neutropenia being the major dose-limiting toxicities encountered.
At the time of initiation of the trial, our group was unaware of the
work of Abigerges et al demonstrating the utility of an intensive
loperamide-based antidiarrheal regimen for the management of
irinotecan-induced late-onset diarrhea. Of the first 18 patients
treated in our study, 10 (56%) required a dose reduction during
therapy. After we became aware of the above-referenced antidiarrheal
regimen, we began applying it assiduously. In the remaining 23
patients subsequently started on the trial, this decreased the
proportion of those requiring a dose reduction to 9%.
Concurrent with our investigations, a cohort of
chemotherapy-naïve colorectal cancer patients received
irinotecan in a clinical trial conducted at the Mayo Clinic, using
the same starting dose and schedule. This trial reported major
objective responses in 8 of 31 patients (26%; 95% CI, 12% to 45%).
European development of irinotecan has focused primarily on the use
of a brief infusion given once every 3 weeks. Rougier et al conducted
a trial of this once every-3-week schedule in colorectal cancer
patients, utilizing a 350 mg/m² starting dose. Of the 213
patients in this trial, 48 had received no prior cytotoxic
chemotherapy and 165 patients had progressed after one
fluorouracil-based chemotherapy regimen. The response rate to
irinotecan in this trial was 18%, with activity rates essentially the
same in both chemotherapy-naïve and fluorouracil-refractory patients.
Thus, three independent phase II trials have confirmed the
substantial single-agent activity of irinotecan in the first-line
treatment of colorectal cancer patients.
A consideration of the pros and cons of the use of irinotecan in the
first-line treatment of colorectal cancer requires serious
consideration of the toxicity profile of irinotecan, and a comparison
of this toxicity with that of the fluorouracil-based chemotherapy
regimens that are now routinely used in first-line therapy. The two
major dose-limiting toxicities of irinotecan are diarrhea and neutropenia.
Diarrhea due to irinotecan can be divided into two distinct
syndromes: early-onset diarrhea, which occurs during or shortly after
irinotecan administration, and late-onset diarrhea, occurring more
than 24 hours after irinotecan administration.
Early-onset diarrhea is the most common manifestation of a
cholinergic syndrome that can occur with irinotecan administration.
This syndrome is characterized by rapid-onset diarrhea and may also
include abdominal cramping and diaphoresis. The syndrome is
relatively unusual, however, and, if encountered, is easily managed
with atropine. The incidence of previously treated patients reporting
grade 3 or 4 diarrhea within 24 hours of irinotecan administration in
the pivotal phase II US trials was 8%.
Late-onset diarrhea, while representing a much more serious
problem, has become far more manageable now than it was in the
earlier irinotecan trials. Late-onset diarrhea was the major
dose-limiting toxicity encountered in initial phase I and II trials.
This late-onset diarrhea most commonly occurred on approximately day
10 of the treatment cycle.
Two major changes have occurred that have greatly reduced the
incidence of late-onset diarrhea. First, investigators and clinicians
have become more familiar with irinotecan and its toxicity profile.
As doctors become more adept at discerning the early signs of
gastrointestinal toxicity and adjusting the irinotecan dose
accordingly, the incidence of severe diarrhea has declined.
Perhaps more importantly, based on work initially reported by
Abigerges et al, use of an intensive regimen of loperamide has
become standard practice in patients treated with irinotecan. The
loperamide must be started at the first sign of diarrhea, and taken
at a dose of 2 mg every 2 hours (or 4 mg every 4 hours during the
night) until the patient has been free of diarrhea for 12 hours.
Failure to adhere strictly to this schedule appears to be associated
with less successful treatment of the diarrhea.
The overall incidence of dose-limiting diarrhea in the 41
chemotherapy-naïve patients in the trial reported from Memorial Sloan-Kettering
was 29%. Of 193 fluorouracil-refractory patients who received
the 125 mg/m² starting dose of irinotecan, 65 (34%) developed
grade 3 or 4 diarrhea.
To properly assess the importance of late-onset diarrhea with
irinotecan, one needs to compare its incidence with that of severe
diarrhea in similar patient populations treated with
fluorouracil-based regimens. The North Central Cancer Treatment Group
(NCCTG) reported a large, multicenter, phase III trial of the two
most widely used schedules (in the United States) of fluorouracil
plus leucovorin in chemotherapy-naïve colorectal cancer
patients. In this trial, dose-limiting diarrhea occurred in 32%
of patients receiving weekly fluorouracil plus high-dose leucovorin
and in 20% of patients receiving daily × 5 low-dose leucovorin.