Despite many advances in diagnosis and
treatment of early lesions, colorectal cancer continues to be a
significant problem in the United States. Approximately 40% to 50%
of patients diagnosed with colorectal cancer will develop metastatic
disease. Currently available therapy is far from satisfactory.
Combination therapy with 5-fluorouracil (5-FU) and oral calcium
folinate produces a response in about 25% to 30% of patients with
metastatic colorectal cancer and can provide palliation and modest
impact on overall survival.[3-6] The current second-line agent for
treatment of patients with 5-FUresistant colorectal cancer is
irinotecan (CPT-11) (Camptosar), which provides a small, albeit
statistically significant survival advantage over supportive care
and infusional 5-FU.
Tegafur is a prodrug that is hydroxylated and converted to 5-FU by
hepatic microsomal enzymes. Uracil is a competitive inhibitor of
dihydropyrimidine dehydrogenase (DPD), which forces drug out of the
catabolic pathway, leading to increased and sustained serum levels of
5-FU. The addition of uracil to tegafur in a 4:1 molar
concentration resulted in the clinical development of UFT. Based
on experience using oral calcium folinate to modulate 5-FU, research
was initiated to evaluate UFT plus oral calcium folinate (Orzel). The
maximum tolerated dose of this combination was found to be 300
mg/m²/day of UFT plus 150 mg/day of oral calcium folinate given
in three divided doses daily for 28 days with 7 days of rest.[12,13]
Phase II studies showed the regimen of UFT plus oral calcium folinate
to be well tolerated, the main side effect being diarrhea.
Response rates varying from 25% to 42% were observed.[14,15]
Hand-foot syndrome is a side effect with protracted intravenous
infusions of 5-FU or capecitabine (Xeloda), but it has not been
observed with UFT plus oral calcium folinate. In addition, when UFT
plus oral calcium folinate is administered in a 28-day schedule,
grades 3 and 4 neutropenia and stomatitis are markedly less than with
5-FU plus oral calcium folinate, which is associated with these
toxicities in over 40% of treated patients.
Single-agent oxaliplatin has shown a response rate of approximately
10% in patients whose disease progressed on a 5-FUbased
regimen. Adding oxaliplatin to 5-FU regimens in previously
treated patients produces responses in 25% to 30% of patients. In
previously untreated patients, response rates as high as 40% to 60%
with median survival in excess of 15 months have been
reported.[18,19] The above results of the oxaliplatin/5-FUbased
regimens provide the rationale for combining oxaliplatin and UFT plus
oral calcium folinate. This regimen may produce similarly good
results with an improved toxicity profile. This phase I study has
been designed to determine the dose of oxaliplatin combined with UFT
plus oral calcium folinate suitable for future phase II studies of
this combination in metastatic colorectal cancer patients.
An estimated 30 patients with advanced colorectal adenocarcinoma will
be entered onto this single-site, open-label, phase I study of
oxaliplatin administered intravenously once every 2 weeks in
combination with UFT plus oral calcium folinate given for 3 weeks (21
days, as 5 days of drug administration followed by 2 days of rest;
cycles are repeated every 28 days). Antitumor response will be
documented but the determination of response rate is not a study objective.
The regimen of drug administration will be based on a 4-week schedule
to maintain the established schedule and starting dose of oxaliplatin
(85 mg/m2 every 2 weeks). The schedule of UFT plus oral calcium
folinate therefore will be adapted from a 35-day cycle (drugs given
on days 1 through 28) to a 28-day cycle (drugs given for 5 days
followed by 2 days of rest from days 1 through 21, for a total of
three courses in each cycle). The 2-day rest period was added in an
attempt to decrease gastrointestinal toxicity.
To participate in this study patients must have histologically proven
advanced/metastatic colorectal cancer; have received prior
chemotherapy with both 5-FU and irinotecan; have measurable or
evaluable disease; and give informed consent acknowledging that they
have been informed of the experimental nature of the trial. Patients
must be ³ 18 years of age; have an
Eastern Cooperative Oncology Group performance status of 0 or 1; have
adequate bone marrow, liver, and renal functions; have not received
prior chemotherapy or radiotherapy within the last 4 weeks (³
6 weeks if mitomycin or a nitrosourea); and have completely recovered
from treatment-related toxicities. Patients who are fertile must
agree to use medically effective contraception throughout the treatment.
Patients are ineligible for the study if they have received prior
treatment with oxaliplatin; have any active or uncontrolled
infection, including known infection with the human immunodeficiency
virus; have a history of myocardial in-farction within the previous 6
months or current clinical evidence of congestive heart failure; have
history of any other cancer (except nonmelanoma skin cancer or
carcinoma in situ of the cervix) in the last 5 years; or have central
nervous system metastases or carcinomatous meningitis. Documentation
of a negative serum human chorionic gonadotropin pregnancy test must
be available for premenopausal women of reproductive capacity and for
women less than 12 months after menopause. Patients with medical or
psychiatric disorders that would interfere with informed consent or
make them a poor risk for participation in this trial, and who are
currently using or planning to use other investigational therapy or
any other anticancer therapy, are also ineligible.
Oxaliplatin will be administered as a 2-hour intravenous infusion on
days 1 and 15 (Table 1). UFT
plus oral calcium folinate will be given daily in two divided doses
on days 1 through 5, 8 through 12, and 15 through 19: The UFT daily
dose will be rounded up or down to the nearest 100 mg, and given in
divided doses twice a day. If the total number of capsules a patient
is to receive in one day cannot be divided equally, the highest dose
will be given in the morning. A 30-mg dose of oral calcium folinate
will be administered concurrently with each dose of UFT. Patients
should not consume any food for 1 hour prior to and 1 hour following
the ingestion of UFT plus oral calcium folinate. Courses will be
repeated every 28 days in the absence of disease progression or
At least three patients will be studied at each dose level and each
will complete one course (28 days) before proceeding to the next dose
level (Table 1). At each dose
level, the first patient entered will be observed for at least 4
weeks (28 days) prior to the entry of subsequent patients. Dose
escalations are not permitted in individual patients.
If none of the initial three patients treated at a given dose level
develop dose-limiting toxicity, dose escalation will continue (Table
2). If one of the initial three patients treated develops
dose-limiting toxicity, then three additional patients will be
entered on the same dose level. If none of the three additional
patients treated at the same dose level develop dose-limiting
toxicity, dose escalation will continue. If two or more of the
initial three patients treated on a dose level or one or more of the
additional three patients treated on a dose level develop
dose-limiting toxicity, dose escalation will cease. Up to nine
patients may be treated at a given dose level to ensure that the
maximum tolerated dose criteria are met before declaring that dose
level the maximum tolerated dose (the highest dose level that does
not cause dose-limiting toxicity in more than one patient).
Dose-limiting toxicity is unacceptable toxicity within the first
course of therapy, defined as grade ³
3 nausea, vomiting, or diarrhea, uncontrolled by aggressive
antiemetic or antidiarrheal support; grade 4 neutropenia or
leukopenia that persists for > 3 days or febrile neutropenia
defined as a temperature ³ 38.5°C
and an absolute neutrophil count < 1,000/µL; grade ³
3 hematologic toxicity with the exception of neutropenia and
leukopenia; grade ³ 3 other toxicity
including gastrointestinal, renal, cardiac, pulmonary, hepatic, and
neurologic toxicity; or inability of the patient to take ³
75% of the planned UFT plus oral calcium folinate dose.
Responses will be graded according to the World Health Organization
guidelines. Tumor status will be evaluated after two courses of
therapy (8 weeks). Patients with progressive disease will discontinue
protocol treatment. Responding or stable patients may continue to
receive this therapy until disease progression as long as the
toxicity profile is acceptable.
Patients with evaluable but nonmeasurable disease, defined as disease
that cannot be measured in conventional fashion but can be evaluated
for tumor response, are eligible for this study.
The combination of oxaliplatin with UFT and oral calcium folinate is
based on the impressive results obtained with the combination of
oxaliplatin and 5-FU in advanced colorectal cancer. Phase III trials
comparing 5-FU plus oral calcium folinate regimens with or without
oxaliplatin demonstrated near doubling of response rates and
significant impact on time to disease progression with the addition
of oxaliplatin. In addition to patient convenience, UFT plus oral
calcium folinate also offers advantages over intravenous
5-FUbased regimens. UFT plus oral calcium folinate has been
shown to produce therapeutic efficacy similar to 5-FU plus oral
calcium folinate with a marked reduction in toxicities, such as
grades 3 and 4 neutropenia and mucositis. It can provide sustained
levels of 5-FU, similar to those achieved with protracted intravenous
5-FU infusions, without technical complications such as line sepsis
UFT plus oral calcium folinate has been examined in the adjuvant
setting of colon cancer in a large, randomized National Surgical
Adjuvant Breast and Bowel Project (NSABP) trial, which completed
accrual in March 1999. The subsequent adjuvant trial (NSABP CO-7)
will compare a weekly 5-FU plus oral calcium folinate regimen against
the same regimen plus oxaliplatin. The trial described herein, which
combines oxaliplatin and UFT and oral calcium folinate, will
hopefully provide the basis for evaluation of this regimen in the
metastatic setting, as well as in potential future adjuvant trials.
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