The American Cancer Society estimates that 130,200 cases of
colorectal cancer are diagnosed in the United States each year. Of these, 32,000
are stage IV (ie, metastatic disease) at the time of original diagnosis. In
addition, each year, another 39,000 patients previously diagnosed with stage I
to stage III disease develop metastatic disease. As a result, approximately
71,000 people annually present with metastatic colorectal cancer. Approximately
10% of these patients will have isolated hepatic metastases that can be
surgically resected, while the remainder will be candidates for systemic
For nearly 40 years, the mainstay of chemotherapy for patients
with metastatic colorectal cancer has been fluorouracil (5-FU). Three
meta-analyses assessed the efficacy of single-agent
5-FU vs biochemical modulation of
5-FU with leucovorin, sequential treatment with methotrexate followed by
5-FU, and bolus administration vs IV infusion of 5-FU.[1-3] Regimens that
included either leucovorin or methotrexate or 5-FU administered as an infusion
improved the response rate significantly (by 50% to 100%), but the improvement
in overall survival was modest, from 0.5 to 2 months (Table
1). Notably, overall
survival with 5-FU-based regimens consistently averaged 12 months or less.
A European trial demonstrated that the schedule of
administration regimen of 5-FU influences both efficacy and safety. This trial
randomized patients with metastatic colorectal cancer and no prior treatment for
metastatic disease to treatment with the de Gramont regimen (combining
leucovorin and an IV bolus dose and infusion of 5-FU plus leucovorin
administered over 2 hours for 2 consecutive days every 2 weeks) or the Mayo
Clinic regimen (consisting of leucovorin and a daily bolus injection of 5-FU for
5 consecutive days every 4 to 5 weeks).
The response rate with the de Gramont regimen was more than
twice that of the Mayo Clinic regimen (32.6% vs 14.5%; P = .0004), and
progression-free survival was significantly higher (6.4 mo vs 5.1 mo; P = .001).
There was a trend toward improved median survival with the de Gramont regimen
that did not reach statistical significance (14.3 months vs 13.1 months; P =
.067). However, the de Gramont regimen was associated with lower rates of grade
3/4 neutropenia, mucositis, and diarrhea, but higher rates of grade 1 and 2
epistaxis and conjunctivitis.
The emergence of two novel cytotoxic agents, irinotecan (CPT-11,
Camptosar) and oxaliplatin (Eloxatin), over the past 5 years caused a marked
change in the direction of clinical trials in patients with metastatic
colorectal cancer. Rather than focus on biochemical modulation of 5-FU, recent
clinical trials have evaluated the impact of adding each of these agents to
standard therapy. This review will concentrate on data from two randomized
trials that evaluated 5-FU/leucovorin, with or without oxaliplatin, in this
Like other platinum compounds, oxaliplatin inhibits DNA
replication and transcription through the formation of intra- and interstrand
DNA adducts. However, unlike cisplatin (Platinol) or carboplatin (Paraplatin),
oxaliplatin is a diaminocyclohexane (DACH) platinum (Figure
1). The DNA adducts
of oxaliplatin are bulkier and more hydrophobic than those of cisplatin or
carboplatin, and these properties contribute to its enhanced activity in
inhibiting DNA synthesis and its lack of cross-resistance with cisplatin and
Oxaliplatin platinates DNA much faster than does cisplatin15
minutes for oxaliplatin vs an average of 48 hours for cisplatin. However, unlike
cisplatin and carboplatin, oxaliplatin adducts are less susceptible to DNA
excision repair enzymes, and have equivalent activity in DNA mismatch
repair-proficient and -deficient cells in vitro.
Activity Spans Several Cell Lines
In preclinical studies, oxaliplatin demonstrated activity
against six of eight colorectal cancer cell lines in the National Cancer
Institute automated screening panel, whereas cisplatin and carboplatin had no
activity against these cell lines (Figure 2). In in vitro studies,
oxaliplatin was synergistic with
5-FU and leucovorin.[9-11] In one series, oxaliplatin and 5-FU demonstrated
synergy in 78% of the situations tested, including four human colorectal cancer
cell lines, three different drug administration sequences, and three different
durations of exposure to 5-FU.
In phase I studies, oxaliplatin was administered over 2 to 6
hours on an every 3-week schedule. The dose-limiting toxicity in phase I studies
was cumulative, reversible paresthesia, and occurred at a dose of 180 to 200
mg/m2.[12,13] Therefore, the dose of oxaliplatin chosen for phase II studies was
130 mg/m2 administered on an every 3-week schedule. In order to accommodate the
every 2-week scheduling of the de Gramont regimen, a dose of 85 mg/m2 was
selected in order to maintain a stable dose intensity of
The clinical activity of oxaliplatin monotherapy has recently
been reviewed. In two phase II trials conducted in patients with previously
untreated colorectal cancer, 12% and 24% of those who received 130 mg/m2 of
single-agent oxaliplatin achieved objective responses. The median durations of
response were 6 and 7 months, the median times to tumor progression were 4
months in both studies, and the median survivals were 13 and 14.5 months.
Two phase II trials evaluated the combination of 5-FU/leucovorin
and oxaliplatin as initial therapy for patients with metastatic colorectal
cancer.[15,16] Both were performed using chronomodulated drug administration
schedules, and both reported impressive objective response rates of 59% and 67%.
The median progression-free survivals were 8.4 and 11 months, and median
survivals were 15 and 18.5 months.
These results prompted the initiation of two randomized trials
of 5-FU/leucovorin, with or without oxaliplatin, as first-line chemotherapy in
patients with metastatic colorectal cancer. In one trial, the drugs were
administered in a chronomodulated fashion, and in the other, they were given
using a nonchronomodulated, biweekly schedule.
This European multinational, multicenter phase III trial (also
known as EFC 2962) evaluated the contribution of oxaliplatin as first-line
treatment in patients with metastatic colorectal cancer. Between August 1995
and July 1997, 420 patients were enrolled in the trial. Eligibility criteria
included histologically confirmed adenocarcinoma of the colon or rectum,
inoperable metastatic disease at enrollment, no prior immunotherapy or
chemotherapy for metastatic disease (but adjuvant chemotherapy that had been
completed at least 6 months prior to enrollment was allowed), at least one
bidimensionally measurable lesion on magnetic resonance imaging (MRI) or
computed tomography (CT) scan, a World Health Organization (WHO) performance
status (PS) ≤ 2, and adequate serum chemistry values and bone marrow reserve.
Patients randomized to the control arm were treated with
leucovorin 200 mg/m2 IV over 2 hours, followed by
5-FU 400 mg/m2 administered as an IV bolus followed by a 22-hour infusion at 600
mg/m2 on days 1 and 2 every 2 weeks. Patients randomized to the experimental arm
received the same schedule of 5-FU plus leucovorin, with oxaliplatin 85 mg/m2 IV
over 2 hours on day 1 only.
The primary end point of the trial was progression-free
survival. Secondary end points included response rate as determined by an
independent review panel based on a confirmatory scan obtained at 4 weeks,
overall survival, quality of life (QOL), and safety of the regimens. The null
hypothesis was that there was no difference in progression-free survival, and
the alternative hypothesis was that there would be a 43% difference in median
progression-free survival (from 7 to 10 months), which was considered a
clinically significant improvement. The study was designed to have ³ 80% power
to detect a significant difference at the 0.05 level.
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