Based on in vitro and laboratory animal data, leucovorin
(also known as folinic acid or citrovorum factor)
was brought to clinical trials. This biochemical modulator
has the ability to enhance the cytotoxic effect of 5-
FU against colorectal cancer cells by increasing inhibition
of thymidylate synthase, a key enzyme involved in
DNA synthesis that is a primary pharmacologic target of
5-FU. Multiple clinical trials indicated roughly a doubling
of objective tumor response rates, and a recent
meta-analysis confirmed a small but statistically significant
improvement in patient survival compared to single
agent 5-FU.
The improved tumor response rates with 5-FU and
leucovorin in advanced colorectal cancer have translated
into an improvement in survival for patients with stage
II and III colon cancer following curative surgical resection.
1,2 There is a national consensus that patients with
stage III (node-positive) colon cancer should receive six
months of postoperative chemotherapy. Since the
absolute benefit for patients with stage II (node-negative)
colon cancer is smaller, the use of postoperative
chemotherapy in this setting is individualized.
Until recently, no more effective agent than 5-FU
was identified for the palliative treatment of colorectal
cancer in spite of dozens of phase II studies of various
chemotherapeutic drugs spanning more than three
decades. In the past decade, several new active cytotoxic
chemotherapeutic agents have been identified, and molecularly-
engineered monoclonal antibodies have also been
developed that have entirely different mechanisms of
action. These new agents have resulted in major
improvements in the systemic therapy of colorectal cancer.
Irinotecan (CPT-11, Camptosar)
This camptothecin derivative has been shown to yield
single agent response rates in the range of 10 to 20 per-cent in patients with colorectal cancer, and to improve
survival compared to supportive care as second-line
treatment. In advanced disease, when combined with
5-FU and leucovorin in the “IFL” or “FOLFIRI”
regimens, randomized clinical trials have demonstrated
that irinotecan significantly improves objective tumor
response rates and extends median survival by 2-3
months.3 However, this drug can cause life-threatening
diarrhea and leucopenia, which have limited its
clinical utility.
Capecitabine (Xeloda)
This orally administered fluorinated pyrimidine has
been shown in controlled clinical trials to be equally as
effective as intravenous 5-FU and leucovorin but less
toxic.4 It can cause mucocutaneous toxicity, however,
including the “hand-foot syndrome” and diarrhea, which
require careful monitoring.
Oxaliplatin (Eloxatin)
This platinum derivative is much more active than
cisplatinum or carboplatin against human colon cancer
cells in vitro. Its single agent activity in colorectal cancer
is similar to irinotecan. When combined with 5-FU and
leucovorin, it can yield tumor responses in about 30
percent of patients as second-line therapy for metastatic
disease. Response rates of 40 to 50 percent have been
reported in several studies when oxaliplatin is combined
with infusional 5-FU and leucovorin (i.e. the “FOLFOX”
regimen)5. A large intergroup, randomized clinical
trial6 has indicated that the FOLFOX regimen is
significantly more active than the IFL regimen for the
treatment of advanced colorectal cancer, with improved
response rates and patient survival. The primary side
effects of oxaliplatin are peripheral neuropathy and
myelosuppression, but the incidence of life-threatening
side effects associated with FOLFOX is significantly
reduced compared to IFL.
A randomized clinical trial (known as the MOSAIC
trial) of the FOLFOX regimen versus 5-FU and leucovorin
demonstrated a significant improvement in threeyear,
disease-free survival when presented at the 2003
meeting of the American Society of Clinical Oncology
(ASCO)7. This provides a reasonable basis for the use of
this regimen as postoperative surgical adjuvant therapy
for patients with high risk colon cancer. |
