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Irinotecan Plus 5-FU and Leucovorin in Advanced Colorectal Cancer: North American Trials

Irinotecan Plus 5-FU and Leucovorin in Advanced Colorectal Cancer: North American Trials

ABSTRACT: Both fluorouracil (5-FU) and irinotecan (CPT-11 [Camptosar]) have shown activity in metastatic colorectal cancer and are approved for its treatment in the United States. Preclinical experiments in cell cultures and human tumor xenografts have indicated potential synergy when irinotecan is combined with 5-FU and leucovorin. The synergy appears to be sequence-dependent and is optimal when irinotecan exposure precedes 5-FU exposure by at least 24 hours. Four North American trials have been reported in which the three drugs were used together in either simultaneous, sequential, or alternating schedules. All three schedules showed activity in patients with metastatic colorectal cancer. The concern that diarrhea, which can be a dose-limiting toxicity with both irinotecan and 5-FU, would prevent the two drugs from being combined in reasonable doses has not proven to be a clinical issue. Phase III trials comparing the combination of the three drugs in a variety of schedules against 5-FU plus leucovorin alone are currently under way or in the planning stages.[ONCOLOGY 12(Suppl 6):59-63, 1998]

Introduction

An estimated 131,000 new cases of colorectal cancer were diagnosed in
the United States in 1997.[1] The current standard of practice among
most North American oncologists is to administer a potentially
curative course of chemotherapy in most patients with stage III
colorectal cancer and a palliative course of chemotherapy in many
patients with stage IV disease. The two drugs that are currently
approved by the FDA for the treatment of colon cancer are
fluorouracil (5-FU) and irinotecan (CPT-11 [Camptosar]).

Fluorouracil is known to be active in the setting of advanced
colorectal cancer. Pooled results from 10 trials in which colorectal
cancer patients with advanced disease were treated with intermittent-bolus
5-FU combined with leucovorin led to an overall response rate of 23%
and a median survival of 12 months.[2] Fluorouracil plus leucovorin
is also an effective adjuvant therapy. In patients with resected
stage III colon cancer, 6 months of treatment with 5-FU/leucovorin
for 5 consecutive days each month decreased the odds of recurrence by
approximately 33%.[3,4]

Irinotecan also is active in advanced colorectal cancer. A recently
completed North Central Cancer Treatment Group (NCCTG) trial reported
a 26% response rate (95% confidence interval [CI], 11.9% to 44.6%) to
irinotecan in patients who had not previously received chemotherapy
for advanced colorectal cancer.[5] In the cohort of patients with
advanced colorectal cancer that was refractory to 5-FU and
leucovorin, this NCCTG trial reported a response rate of 13% with
irinotecan (95% CI, 7.1% to 22.1%).[5] Both of these outcomes are
typical of published reports cited elsewhere in this monograph.

Based on the NCCTG data and results from other reported studies, in
1996 the FDA approved irinotecan for the treatment of patients with
advanced colorectal cancer that is refractory to 5-FU. To date, the
activity of irinotecan, either as a single agent or in combination
with other chemotherapeutic agents, has not been tested as adjuvant
therapy for stage II or III patients; therefore, its potential value
in such patients remains unknown. Future trials integrating
irinotecan into postsurgical treatment regimens for stage III
patients are in the planning stages under the aegis of the National
Cancer Institute’s cooperative research group clinical trial program.

The NCCTG and other trials have clearly shown that some tumors that
grow during treatment with 5-FU and leucovorin will shrink when
exposed to irinotecan. This observation implies a lack of tumor
cross-resistance to the two agents, at least in a proportion of
metastatic human colon cancers, and led to a number of experiments in
which irinotecan and 5-FU were combined in vitro and in human tumor
xenograft models.

Promising findings of these experiments led to treatment trials
employing a number of different dose and schedule strategies in
patients with advanced colorectal cancer. These trials were designed
to determine the maximum tolerated doses (MTDs) and response rates of
the combination of irinotecan and 5-FU in patients with advanced
colorectal cancer, as well as to provide survival data.

Because diarrhea is a major dose-limiting side effect of both
irinotecan and 5-FU/leucovorin, the possibility of life- threatening,
additive, or even synergistic toxicity exists. Investigators using
the combination of the three drugs have taken this into account in
their phase I trial designs.

This review addresses three main topics. First, data on interactions
between 5-FU and irinotecan observed in a number of cell culture and
human tumor xenograft experiments will be summarized. Second, recent
or ongoing North American trials in which irinotecan and 5-FU plus
leucovorin have been administered concurrently, sequentially, and in
an alternating fashion will be reviewed. Finally, relevant toxicity
data, as well as current knowledge about the mechanisms and
treatments of irinotecan- and 5-FU-induced gastrointestinal toxicity,
will be presented and discussed.

Preclinical Data

Fluorouracil

Fluorouracil inhibits the enzyme thymidylate synthase (TS), thus
interfering with the formation of new strands of DNA during
replication. Fluorouracil is also incorporated into RNA and DNA,
where it inhibits DNA synthesis.[6] Leucovorin is a reduced folate,
which, when combined with 5-FU, augments 5-FU cytotoxicity by
increasing the inhibition of TS by the 5-FU metabolite 5-fluoro-2¢-deoxyuridine
monophosphate (FdUMP).[7]

The role of 5-FU in the treatment of colorectal cancer has been
explored for over 40 years. Modulation of 5-FU by leucovorin has been
demonstrated to improve response rate, but not median survival, over
bolus 5-FU alone.[2] Nevertheless, 5-FU, with or without leucovorin,
has become the standard therapy for patients with advanced colon
cancer in North America.

Irinotecan

Irinotecan binds and stabilizes topoisomerase I as it works to uncoil
DNA during cell division. This stabilized complex of
inhibitor-enzyme-DNA halts advancing DNA replication forks, resulting
in double-strand DNA breaks and consequent apoptosis.[8] Irinotecan
is converted by carboxylesterases to its more active metabolite,
7-ethyl-10 hydroxy-camptothecin, or SN-38.[9,10]

Irinotecan Plus 5-FU and Leucovorin

The clinical activity of both 5-FU/leucovorin and irinotecan in
patients with metastatic colorectal cancer makes the combination of
these therapies clinically attractive. There is reason to believe,
however, that this therapeutic combination may result in antagonism.
Fluorouracil is converted to FdUMP, leading to inhibition of TS,
depletion of deoxythymidine triphosphate (dTTP) pools, and inhibition
of DNA synthesis, resulting in G1/S cell-cycle arrest. The active
metabolite of irinotecan, SN-38, stabilizes the covalent complex
between topoisomerase I and nuclear DNA, leading to DNA double-strand
breaks and accumulation of cells in the G2 phase of the
cell cycle.

Hence, 5-FU may inhibit the DNA synthesis required for the
cytotoxicity of SN-38. Conversely, SN-38 may cause cells to
accumulate in the G2 rather than in the S phase, when they
would be most sensitive to 5-FU plus leucovorin.

Mullany et al addressed these issues in studies of SN-38 plus 5-FU
and leucovorin in HCT-8 cells in vitro. They observed a
sequence-dependent interaction of SN-38 and 5-FU plus leucovorin. The
combination was less than additive when cells were treated with
simultaneous administration of SN-38 and 5-FU plus leucovorin or when
5-FU plus leucovorin was followed by SN-38, but was synergistic when
SN-38 was followed by 5-FU plus leucovorin.[11] Other groups have
found similar results.[12-18]

Mullany et al further demonstrated that SN-38 resulted in
accumulation of cells in the S phase when therapeutically achievable
nanomolar concentrations of SN-38 were used for time periods
corresponding to three serum half-lives in vivo. Moreover, this
S-phase-slowing was accompanied by inhibition of TS activity in the
face of constant TS protein levels. Further studies revealed that
SN-38 increased dTTP pools.

Taken together, these results are consistent with a model in which
elevated dTTP pools account for the observed synergy of SN-38
followed by 5-FU plus leucovorin. The increased dTTP pools after
SN-38 therapy inhibit TS by depletion of the normal substrate,
deoxyuridine monophosphate (dUMP), and enhance 5-FU-associated
inhibition of TS. In addition, the dTTP-associated inhibition of
thymidine kinase decreases salvage thymidylate synthesis. Thus, the
preclinical studies define a rational schedule for clinical
evaluation of irinotecan plus 5-FU and leucovorin and explain, at
least in part, the mechanism of this interaction.

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