Carcinoma of the colon and rectum remains one of the most common
malignant diseases afflicting people living in industrialized
countries. The estimated number of new cases of colorectal cancer in
the United States in 1998 will exceed 131,000. During the same
year, colorectal carcinoma will result in an estimated 55,000 deaths,
remaining the second most common cause of cancer-related deaths in
the United States. The US populations lifetime risk of ever
developing invasive colorectal cancer is approximately 1 in 17.
Five-year relative survival rates for colorectal cancer have improved
modestly over the last 2 decades, and death rates for men with this
disease have decreased about 1.9% per year from 1990 to 1994.
Despite these results, 19% to 25% of patients will be diagnosed with
advanced colorectal cancer, for which systemic chemotherapy is the
mainstay of treatment.
Fluorouracil (5-FU) has been used in the treatment of cancer for
nearly 40 years. The rates of regression in advanced colorectal
cancer patients treated with the same dose and schedule of 5-FU have
ranged from 8% to 85%. A recent meta-analysis reported an 11%
overall response rate to single-agent 5-FU among patients with
previously untreated metastatic disease.
Modulation of 5-FU has been pursued using several agents, including
leucovorin, methotrexate, interferon-alfa (Intron A, Roferon-A), and
N-(phosphonacetyl)-L-aspartate (PALA), as a means to increase
antitumor activity. In the meta-analysis, the combination of 5-FU and
leucovorin showed an increase in response rate (23%) but not an
improvement in overall survival. Randomized trials of 5-FU vs 5-FU
and leucovorin have demonstrated prolongation of median survival with
the biochemically modulated regimens.[5,6]
A phase II study by the Southwest Oncology Group (SWOG) assessed the
efficacy and toxicity of seven different regimens of 5-FU in patients
with untreated advanced colorectal carcinoma. The median survival
for the entire patient cohort was 14 months, and no regimen was
superior relative to single-agent 5-FU (bolus or continuous infusion)
therapy in terms of response or survival. For patients treated with
bolus 5-FU or continuous-infusion 5-FU, the overall objective
response rate (confirmed and unconfirmed) was 29%, although the
continuous infusion produced a more favorable toxicity profile.
A recent meta-analysis demonstrated a higher tumor response rate in
patients treated with continuous-infusion 5-FU than in those given
bolus 5-FU (23% vs 14%), as well as a slight increase in overall
survival. With the limited advantages of prolonged infusion of
5-FU or modulation of 5-FU, development of alternative agents for
treatment of patients with metastatic colorectal carcinoma remains of
Camptothecin is a natural alkaloid product first extracted from the
stem wood of the Chinese tree Camptotheca acuminata.
Preclinical studies of the purified drug demonstrated activity in
mouse L1210 leukemia and rat Walker carcinosarcoma.[9,10] The
original preparation (camptothecin sodium) was evaluated in
clinical trials in the late 1960s and early 1970s. A preliminary
trial by Gottlieb and colleagues was encouraging, with 11 of 18
patients showing evidence of response or improvement (> 50%
decrease in tumor mass in 5 patients).
Subsequent phase II trials in advanced gastrointestinal cancer and
malignant melanoma failed to demonstrate significant clinical
activity of camptothecin sodium.[12,13] The toxic effects encountered
in both studies included gastrointestinal and hematologic effects and
hemorrhagic cystitis. Based on these data, Moertel et al concluded in
1972 that "camptothecin is a drug of protean and unpredictable
toxicity that has no clinical value in the management of
Clinical drug development from 1970 to 1985 yielded few agents of
merit for patients with advanced colorectal cancer. Marsoni et al
reviewed 42 investigational agents evaluated during this period and
determined 41 to be inactive against colon cancer. The only drug
with potential activity, tegafur, did not demonstrate significant
activity in a confirmatory trial when compared to 5-FU.
Investigators began to search for analogs of camptothecin with an
improved toxicity profile, better water solubility, and enhanced
therapeutic efficacy. Work by Kunimoto and colleagues led to the
synthesis of a more water-soluble, semisynthetic derivative of
camptothecin. Irinotecan hydrochloride (CPT-11 [Camptosar]) was
found to have greater in vitro and in vivo activity than its parent
compound while demonstrating less severe, more predictable toxicity.
Interest in the camptothecins increased with the discovery of the
novel mechanism of action of this class of chemotherapeutic agents in
Many anticancer agents are known to act as topoisomerase inhibitors.
Hsiang et al, while evaluating compounds for topoisomerase II
inhibitory activity, demonstrated that camptothecins blocked the
enzymatic action of topoisomerase I. Several authors have
reviewed the action of camptothecins on topoisomerase I
activity.[19,20] The topoisomerase I enzyme transiently cleaves and
reseals one DNA strand through a transesterification reaction. This
allows the other DNA strand to pass through the transient break and
changes the DNA topology. The resulting topoisomerase I/DNA complex,
also known as the cleavable complex, is the target for camptothecin
and its derivatives. Irinotecan binds to the cleavable complex and
inhibits resealing of the parent DNA, thereby halting nucleic acid
synthesis. Collision between the replication fork and the stable
cleavable complex results in double-strand DNA breaks and ultimately
cellular death through apoptosis.
Irinotecan is rapidly converted in vivo by cellular carboxylesterases
to its active metabolite, SN-38, which is 250 to 1,000 times more
potent an inhibitor of topoisomerase I than the parent compound. It
has also been shown that the antitumor effectiveness of irinotecan
can be accounted for by the intracellular concentrations of SN-38.
Topoisomerase I activity is present in all cells, but Giovanella and
colleagues have shown that levels of the enzyme in colon cancers are
30-fold higher than in normal colonic mucosa. Several colon
cancer xenografts that have been studied also expressed significantly
higher levels of topoisomerase I. In these experiments, the
xenografts were highly resistant to multiple chemotherapeutic agents;
however, several camptothecin analogs demonstrated significant
activity. Giovanella et al found 9-amino-camptothecin to be highly
effective in this xenograft model, inducing disease-free remissions
in several established tumors.
Houghton et al have also studied camptothecin analogs in
chemotherapy-resistant colon cancer xenografts. These analogs
demonstrated impressive in vivo activity, which was strongly schedule
dependent. The optimal schedule was equivalent to a low-dose
continuous administration of the camptothecin analog. As a result of
these preclinical findings and the development of more soluble
analogs, camptothecin derivatives once again moved into the clinical arena.
Multiple phase I studies of irinotecan have been performed using many
different schedules. Initial phase I studies of irinotecan began in
Japan in 1986. The common dose-limiting toxicities (DLTs) encountered
in these studies were hematologic (primarily leukopenia/neutropenia)
and gastrointestinal (primarily diarrhea). The schedules currently
used in Japan include 100 mg/m² of irinotecan weekly or 150
mg/m² every 2 weeks.[24,25]
European phase I studies have concentrated on three different
schedules; the most widely used of these involves a single irinotecan
infusion every 3 weeks. Abigerges and colleagues encountered a
DLT of delayed diarrhea with a dosage of 350 mg/m² every 3
weeks. Subsequent incorporation of high-dose loperamide allowed
for further dose escalation. At the highest dose of 750 mg/m²,
grade 4 granulocytopenia was the DLT.
Initial phase I trials in the United States used two different dose
schedules. Rowinsky and colleagues evaluated a single 90-minute
infusion of irinotecan every 3 weeks, with doses ranging from 100 to
345 mg/m². At the highest dose levels of 290 and 345
mg/m², the investigators encountered a spectrum of
gastrointestinal side effects, including diarrhea, nausea, vomiting,
abdominal cramps, and anorexia. They suggested a phase II starting
dose of 240 mg/m².
Rothenberg et al at the University of Texas Health Science Center in
San Antonio developed another schedule consisting of weekly
treatments for 4 weeks, followed by 2 weeks rest, with courses
repeated every 6 weeks. With this regimen, the DLT was diarrhea
at the 180 mg/m² dose level, and the recommended starting dose
for phase II trials was 150 mg/m². The definition of maximum
tolerated dose (MTD) differed between these two US phase I trials, as
did the supportive measures, which likely accounts for the
differences in recommended phase II starting doses.
Other investigators have used granulocyte colony-stimulating factor
(G-CSF [Neupogen]) support in an attempt to escalate the irinotecan
dose on the weekly × 4 schedule while minimally increasing the
MTD. The MTD for an every-other-week schedule also is under investigation.
Based on the phase I schedule developed in San Antonio and initial
encouraging results from Japan, further phase II trials were
developed to assess the efficacy and toxicity of CPT-11 in patients
with advanced colorectal carcinoma.
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