Paclitaxel (Taxol) is a natural product
originally extracted from the bark of the Pacific yew tree, Taxus brevifolia,
which is now semisynthetically produced from reproductive material
of the European yew tree, Taxus baccata. It is an
antineoplastic drug that acts at the cellular level as a promoter of
microtubule assembly from tubulin dimers, stabilizing microtubules by
preventing depolymerization. After intravenous administration,
paclitaxel is metabolized in the liver and high concentrations are
excreted in the bile. Its dose-limiting toxicities include
myelosuppression (mostly neutropenia of a short duration), peripheral
neuropathy, hypersensitivity reactions, and mucositis.
Paclitaxel was initially investigated in phase I/II trials as a
treatment for ovarian cancers that were refractory to platinum
therapy and for advanced breast cancer. In metastatic breast cancer,
response rates of up to 56% have been reported following
paclitaxel monotherapy, with results mainly dependent on the
pretreatment history of patients. In multicenter trials, response
rates were lower, but relatively good survival results have been
achieved. Clinical trials in nongynecologic malignancies are
ongoing. So far, promising results have been observed in small-cell
and nonsmall-cell lung cancer, bladder cancer, esophageal
cancer, head and neck cancer, and others.
Initially, paclitaxel was administered as a 24-hour infusion to avoid
the hypersensitivity reactions observed in an early phase I trial of
paclitaxel in a 3-hour infusion. Since premedication with
corticosteroids (most often, dexamethasone), diphenhydramine, and
cimetidine was introduced into clinical practice, however, the risk
of hypersensitivity reactions has been largely eliminated.
Recently, published reports have shown that a short course of
intravenous prophylaxis is sufficient for the prevention of
hypersensitivity reactions, thereby enabling reinstitution of
shorter paclitaxel infusions. Thus, a 1-hour infusion of paclitaxel,
which permits the convenience of outpatient treatment, was
investigated in phase I trials. Hainsworth et al and Mross et al
showed that paclitaxel administered as a 1-hour infusion is safe and
produces substantial activity in a variety of tumors.[11,12] These
studies reinforced the observation that the myelotoxicity of
paclitaxel is schedule-dependent, with longer infusions producing
greater hematologic adverse effects.
Several clinical trials have also examined weekly administration of
paclitaxel.[1,13-17] An overview is provided in Table
1. In general, these trials showed that weekly administration of
paclitaxel yields a high dose intensity with limited hematologic
toxicities. Long-term use of weekly paclitaxel with doses of more
than 100 mg/m²/week may result in treatment-limiting
neurotoxicity. However, objective responses in phase II trials in
heavily pretreated patients have been rather high so far.
5-fluorouracil (5-FU) is a fluorinated pyrimidine that works as an
antimetabolite. The compound was developed in 1957 based on the
observation that tumor cells use the base uracil for deoxyribonucleic
acid (DNA) synthesis more efficiently than normal cells of the
intestinal mucosa. The drug is then rapidly metabolized by the human
liver, resulting in a short half-life of 10 to 20 minutes. In human
tumors, 5-FU is metabolized to 5-fluorouridine-5¢-monophosphate
(FUMP) and subsequently converted to the active nucleotides,
(FUTP) and 5-fluoro-2¢-deoxyuridine 5¢-monophosphate
(FdUMP). The primary mechanism of 5-FU cytotoxicity in experimental
tumors appears to be FdUMP inhibition of thymidylate synthase, and
consequently, inhibition of DNA synthesis.
The cytotoxic effects of 5-FU can be markedly enhanced if sufficient
amounts of reduced folate cofactor are present.[19,20] The
biochemical modulation of 5-FU by calcium folinate has been
extensively studied in patients with metastatic colon carcinoma.
Clinical trials examining 5-FU plus calcium folinate have
demonstrated increased response rates, prolonged time to disease
progression, and prolonged overall survival as compared to
UFT is composed of uracil and tegafur (1-[2¢-tetrahydrofuryl]-5-fluorouracil)
in a molar ratio of 4:1. Tegafur is converted to 5-FU in vivo.
Tanimura et al reported that the coadministration of uracil enhanced
the concentration of 5-FU in tumors and the resulting antitumor
activity of UFT.[22,23] Following oral administration of UFT, uracil
and tegafur are rapidly and completely absorbed from the gut into the
systemic circulation. Tegafur is subsequently metabolized to 5-FU by
one of two different pathways and enzyme systems, thereby behaving as
a prodrug of 5-FU.
Pazdur has shown that UFT administered at a daily dose of 370
mg/m²/day for 28 days without calcium folinate generates a
higher peak plasma level of 5-FU than that achieved with continuous
infusion 5-FU at 250 mg/m²/day for 5 days. Several phase I
studies of UFT plus oral calcium folinate have been performed.[26-28]
The maximum tolerated dose of UFT was 350 to 400 mg/m²/day ×
28 days, in combination with calcium folinate 150 mg/day × 28
days. One cycle consisted of 35 days. The major dose-limiting adverse
event was diarrhea. Nausea, vomiting, abdominal cramping,
epigastralgia, and stomatitis/mucositis were also observed. These
events increased in severity with increasing doses of UFT plus oral
calcium folinate. Other minor events in these phase I studies
included mild fatigue, transient hyperbilirubinemia, anorexia, and
granulocytopenia. The efficacy of oral UFT in combination with oral
calcium folinate in the home setting has been demonstrated in phase
II studies that evaluated a total of 140 patients with metastatic
colorectal carcinoma.[29,30] Responses were reported in a variety of
metastatic sites, including the liver, lung, and bone, yielding
response rates from 25% to 42%. UFT also exhibited clinical efficacy
in a number of other tumors, including carcinomas of the stomach,
head and neck, nonsmall-cell lung cancer, and breast
cancer. This corresponds to the clinical activity of 5-FU.
Because many cases of cancer are incurable, palliation of symptoms
and improved quality of life are critical aspects of therapy. A high
level of efficacy, especially in second- and third-line treatments,
few side effects, and patient conveniencepreferably by means of
outpatient administrationare equally important. This open-label
phase I study was designed to evaluate the combination of UFT plus
oral calcium folinate plus a 1-hour infusion of paclitaxel for the
treatment of patients with solid tumors, for whom no other
established therapy exists.
UFT plus calcium folinate is an oral agent with activity comparable
to intravenously administered 5-FU plus calcium folinate. Paclitaxel,
administered on a weekly schedule, leads to high dose intensity and
high response rates with limited hematologic toxicities. Thus, this
outpatient regimen offers the advantages of oral delivery of 5-FU and
a weekly paclitaxel infusion, which requires minimal monitoring.
Myelosuppression is infrequent with UFT plus calcium folinate therapy
and its side effects should compare favorably with commonly used regimens.
It is the primary objective of this study to determine the
dose-limiting toxicity(ies), maximum-tolerated dose, and recommended
phase II dose of weekly paclitaxel administered in combination with a
stable dose of UFT plus calcium folinate in adult patients with solid
tumors. The secondary objectives are to further evaluate the safety
of this combination and to obtain preliminary efficacy data. In the
event that a positive risk-benefit ratio is observed, the combination
of UFT plus calcium folinate and weekly infusional paclitaxel could
be useful in a number of tumor types.
The study has been approved by the Ethics Committee of Tübingen
University. It will be conducted as a multicenter trial with the
German Phase I/II study group of the Working Party for Medical
Oncology (Deutsche Phase I Studiengruppe der AG Internistische Onkologie).
A number of criteria must be met for patients to be eligible for
admission to the study. Patients must have a histologically confirmed
diagnosis of a solid tumor for which no other established therapy
exists, such as extensive-stage small-cell or nonsmall-cell
lung cancer, inoperable head and neck or bladder cancer, or
previously treated ovarian or breast cancer. Patients may or may not
have received prior chemotherapy, hormonal therapy, or localized
radiation therapy. Patients must be between 18 and 70 years, they
must have an Eastern Cooperative Oncology Group performance status of
0 to 2, and a life expectancy of ³ 12
weeks. Adequate hematologic, renal, and hepatic functions are also
required for investigational protocols. Patients will be excluded if
they have a significant history of cardiac disease (ie, uncontrolled
high blood pressure, unstable angina, congestive heart failure,
myocardial infarction within the previous year, or cardiac
ventricular arrhythmias requiring medication); severe, active
infections; or serious underlying medical conditions. Brain
metastases or evidence of grade ³ 2
peripheral neuropathy (National Cancer Institute [NCI] Common
Toxicity Criteria) are also exclusion criteria.
UFT will be administered at a fixed dose of 300 mg/m²/day plus
calcium folinate 90 mg/day for 28 days (days 128) followed by 1
week without treatment. This 35-day period defines the length of a
treatment cycle. Both UFT and calcium folinate will be orally
administered in three daily doses, with 8-hour intervals between doses.
Following adequate premedication, a single 1-hour intravenous
infusion of paclitaxel will be administered in 1-week intervals (days
1, 8, 15, 22), followed by a 1-week period without treatment; ie,
re-treatment will start at day 36. The starting dose of paclitaxel
will be 50 mg/m², escalated stepwise in subsequent cohorts
of patients to 60 mg/m2, 70 mg/m², 80 mg/m², 90 mg/m²,
and then 100 mg/m² (Figure 1).
Higher doses will not be administered in order to avoid peripheral neurotoxicity.
A minimum of three patients will be treated at each dose level, and
there will be no dose escalation for any given patient. All patients
to be treated at a given dose level will have had to complete course
1, with a full evaluation of toxicity corresponding to dose-limiting
toxicity and maximum tolerated dose criteria, before escalation to
the next dose level in a new cohort of patients. These criteria may
entail treatment of additional patients at the dose level in order to
more fully define the toxicity profile before dose escalation.
If one of the first three patients at a given dose level experiences
a dose-limiting toxicity, three more patients will be treated at this
dose level. If none of the three patients or two or less of six
patients experience a dose-limiting toxicity during their first
course of treatment, the next dose level will be opened. If serious
toxicities occur during later courses, dose escalation may have to be
reconsidered. If three or more of six patients experience a
dose-limiting toxicity at a dose level, that level will be regarded
as the maximum tolerated dose.
After the maximum tolerated dose has been reached, 10 additional
patients will be treated at one dose level below the maximum
tolerated dose to evaluate the cumulative toxicity and to establish
the recommended dose for phase II. If the maximum tolerated dose has
not been reached during dose escalation, 10 additional patients will
be treated at the highest dose level (100 mg/m²) (Table
Patients will be treated for a maximum of four cycles or until
progression of disease or unacceptable toxicity occurs. Patients will
not be re-treated unless they have recovered completely from toxicity
(hematologic and/or nonhematologic). Patients who require more than 2
weeks treatment delay will be removed from the study.
Evaluation of Response/Toxicity
All patients will be evaluable for toxicity from the time of their
first chemotherapy dose. Toxicity will be evaluated using the NCI
Common Toxicity Criteria scale. Patients will be evaluable for
response if they have received at least one full course of therapy.
The World Health Organization criteria will be used to assess tumor
response. Time to progression will be calculated for all patients
from the first day of treatment until the first evidence of disease
progression or death. Three to six patients will be tested at each
dose level. It is estimated that 30 to 40 patients must be enrolled
to determine the maximum tolerated dose and the recommended phase II
dose (Table 3). Descriptive
statistics will be employed in the analysis of all safety and
laboratory observations and efficacy data (response rate and time to progression).
The combination of paclitaxel and 5-FU constitutes a promising
regimen that has been investigated mainly in breast cancer patients.
Anthracycline and alkylating agentbased regimens are routinely
used as first-line chemotherapy in metastatic breast cancer; however,
disease progression often occurs during or after this treatment,
thereby requiring additional therapies.
In recent studies, response rates of 54% to 69% have been reported
for the combination of calcium folinate/5-FU/paclitaxel as salvage
chemotherapy after prior exposure to mostly anthracycline-containing
regimens.[35,36] A 55% overall response rate, with a median duration
of 8 months, was achieved in one of these studies involving 20
patients with anthracycline-refractory disease. In this study,
calcium folinate 500 mg/m² was administered as a 2-hour infusion
prior to administration of 5-FU and paclitaxel. 5-FU was administered
at a dose of 2.0 g/m² over 24 hours and paclitaxel 175 mg/m²
was infused over 3 hours. All drugs were administered on day 1, and
calcium folinate and 5-FU were repeated weekly on days 8 and 15.
Treatment was repeated every 3 weeks.
A phase II trial of first-line treatment of metastatic breast cancer
with infusional 5-FU, folinic acid, paclitaxel, and cisplatin
(Platinol) achieved an overall response rate of 82% with only
moderate side effects. The high response rates observed in these
studies support the use of prolonged fluoropyrimidine exposure.
The combination of paclitaxel and 5-FU has also been successfully
employed in the treatment of patients with gastrointestinal cancers.
Partial remissions were observed in 32% of patients in a phase II
trial using a 24-hour continuous infusion of high-dose 5-FU
administered weekly in combination with paclitaxel every second week
as a short infusion in patients with gastric cancer. The further
development of this regimen includes alternating the weekly doses of
paclitaxel and cisplatin combined with continuous 24-hour infusions
of 5-FU. Activity has also been reported with paclitaxel/5-FU
combinations in patients with esophageal cancer. This
regimenpossibly with the addition of cisplatinmay also be
used for neoadjuvant treatment in this disease.
A phase I trial of UFT plus calcium folinate with paclitaxel as
second-line treatment of metastatic breast cancer is currently
ongoing. In this study, a single infusion of paclitaxel at a fixed
dose of 175 mg/m² is administered over 3 hours intravenously on
day 1. Oral UFT plus calcium folinate is then administered for 14
days followed by a 1-week period without treatment. This therapy is
repeated every 21 days. UFT is escalated in 100-mg increments from a
total starting dose of 300 mg/day; calcium folinate dose is fixed at
30 mg three times a day.
The study described herein will take the use of protracted 5-FU
(administered orally as UFT plus calcium folinate) in combination
with paclitaxel one step further by applying paclitaxel in a
dose-dense, moderately toxic weekly schedule. It is hoped that an
active palliative regimen for the outpatient treatment of a variety
of patients and cancers will result.
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