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Capecitabine/Irinotecan Combination Regimens in Colorectal Cancer

Capecitabine/Irinotecan Combination Regimens in Colorectal Cancer

ABSTRACT: Capecitabine (Xeloda) and irinotecan (CPT-11, Camptosar) both have demonstrated single-agent activity in patients with colorectal cancer. In an analysis of pooled results of two phase III studies, capecitabine provided advantages over intravenous fluorouracil (5-FU) plus leucovorin in patients with metastatic colorectal cancer. In another analysis, metastatic colorectal cancer patients who received irinotecan along with 5-FU plus leucovorin had significantly improved overall survival as compared with those who received 5-FU plus leucovorin alone. Capecitabine and irinotecan have distinct mechanisms of action and only partially overlapping toxicities. Combinations of these agents therefore are being explored in patients with colorectal cancer. This report briefly reviews current and ongoing trials evaluating capecitabine/irinotecan combination regimens in treating this disease. [ONCOLOGY 16(Suppl 3):27-29, 2002]

Oral fluoropyrimidines have the
potential to simplify and supplant fluorouracil (5-FU)-based combination chemotherapy
for colorectal cancer. Capecitabine (Xeloda) is absorbed intact through the
gastrointestinal tract and is activated by a three-step enzymatic cascade.
Capecitabine was designed rationally to generate 5-FU preferentially in tumor
tissue through exploitation of the higher activity level of thymidine
phosphorylase (TP) in tumors rather than in normal tissue.

Pooled results of two identical, randomized phase III studies[1,2]
demonstrated that the use of single-agent oral capecitabine provided advantages
over administration of intravenous (IV) 5-FU plus leucovorin (Mayo Clinic
regimen). When used as first-line therapy for metastatic colorectal cancer (n =
1,207), capecitabine achieved a significantly superior tumor response rate (26%
vs 17%; P < .0002), equivalent time to disease progression (P = .9535; hazard
ratio = .997; median: 4.6 vs 4.7 months), and equivalent overall survival (P = .48; hazard ratio = .96;
median: 12.9 vs 12.8 months) when compared with results using 5-FU plus leucovorin (Mayo Clinic regimen). Furthermore, the trials demonstrated
an improved safety profile of capecitabine, with significantly (P < .001)
lower incidences of diarrhea, stomatitis, nausea, and grade 3/4 neutropenia than
seen with use of 5-FU plus leucovorin. The only side effect that occurred more
frequently with capecitabine was the cutaneous condition known as hand-foot
syndrome.

Irinotecan (CPT-11, Camptosar), a semisynthetic camptothecin derivative that
inhibits topoisomerase I, also has good single-agent activity in colorectal
cancer. Two independent phase III studies have shown that irinotecan plus 5-FU
plus leucovorin (bolus or infusional regimen) achieves significantly improved
overall survival when compared with use of 5-FU plus leucovorin alone in patients with metastatic colorectal cancer.[3,4]

Preclinical studies demonstrated that sequential administration of low-dose irinotecan plus capecitabine was highly curative in in vivo xenograft models of human colorectal
cancer.[5] These two drugs have distinct mechanisms of action, only partially
overlapping toxicities, and single-agent activities in colorectal cancer. It
therefore seems logical to identify a capecitabine/irinotecan combination regimen for the treatment of colorectal cancer. In this regard,
several phase I/II clinical trials have been initiated that are exploring
various treatment schedules (Table 1).

Trials Exploring First-Line
Irinotecan/Capecitabine in Colorectal Cancer

Results of three phase I/II clinical trials aimed at identifying the optimal
regimen of irinotecan plus capecitabine as first-line therapy for colorectal
cancer were presented at the European Conference on Clinical Oncology (ECCO 11)
held in October 2001.[6-8]

In the study conducted in the United Kingdom and the Netherlands, 27 patients
with previously untreated, measurable metastatic colorectal cancer received
capecitabine (750-1,250 mg/m² twice daily on days 1-14 of a 21-day cycle) in combination with irinotecan (200-350 mg/m² on
day 1 of a 21-day cycle) given every 3 weeks.[6] The maximum tolerated dose was
1,250 mg/m² of capecitabine twice daily plus 300 mg/m² of irinotecan. However, the most feasible regimen was identified
based on the predominant grade 3/4 side effects that occurred during the first
three treatment cycles, which were diarrhea and neutropenia. Thus, the
recommended regimen for further clinical development was 1,000 mg/m² of
capecitabine twice daily plus 250 mg/m² of irinotecan. The preliminary efficacy
data are very promising, with an overall response rate of 52%. Tumor responses
have been observed at all dose levels. An extended phase II and pharmacokinetic
study is underway.

Early data from another phase I pharmacokinetic study also demonstrated some
clinical activity with capecitabine plus irinotecan given every 3 weeks in
patients with a range of gastrointestinal tumors (colorectal, gastric, and
pancreatic).[7]

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