Paclitaxel (Taxol) is a natural anti-cancer drug originally extracted
from the bark of the Pacific yew tree Taxus brevifolia, and
now semisynthetically produced from reproductive material of the
European yew tree Taxus baccata. It acts at the cellular level
as a promoter of microtubule assembly from tubulin dimers and
stabilizes microtubules by preventing depolymerization.
Paclitaxel was initially investigated in ovarian cancer patients
refractory to cisplatin (Platinol) or carboplatin (Paraplatin) and in
patients with advanced breast cancer.[1,2] The drug is now approved
for the treatment of ovarian, breast, and nonsmall-cell lung
cancer. Additionally, promising results have been observed in
small-cell lung cancer, bladder, esophageal, head and
neck, and gastric cancers.
When paclitaxel is given as a 24-hour infusion, the dose-limiting
toxicities have been identified as myelosuppression (mostly
neutropenia of short duration), peripheral neuropathy,
hypersensitivity reactions, and mucositis. Paclitaxel was
administered as a 24-hour infusion because hypersensitivity reactions
constituted a treatment-limiting toxicity in an early phase I
trial. The clinical use of premedication with corticosteroids
(most often dexamethasone), diphenhydramine, and cimetidine has
reduced the frequency of these hypersensitivity reactions. A short
course of intravenous prophylaxis has been shown to be sufficient for
the prevention of hypersensitivity reactions. A 1-hour paclitaxel
infusion was introduced mainly for the convenience of outpatient
treatment. Hainsworth et al and Mross et al showed that paclitaxel
given as a 1-hour infusion is safe and has substantial activity
against a variety of tumors.[10,11] These studies also confirmed that
myelotoxicity with paclitaxel was schedule-dependent.
Several clinical trials have examined weekly administration of
paclitaxel. These trials indicate that a high dose intensity is
reached with very limited hematologic toxicities. The long-term use
of weekly paclitaxel with doses > 80 mg/m²/wk may result in
treatment-limiting neurotoxicity appearing 8 to 12 weeks into
therapy. However, objective responses in heavily pretreated patients
with breast and ovarian cancer have been reported.[12-15]
Fluorouracil (5-FU), an antineoplastic antimetabolite, is a
fluorinated pyrimidine. This drug is very rapidly metabolized by the
human liver, resulting in a very short half-life of 10 to 20 minutes.
In human tumors, 5-FU is metabolized to fluorouridine monophosphate
and is subsequently converted to the active nucleotide forms
fluorouridine triphosphate and fluorodeoxyuridine monophosphate. The
primary mechanism of cytotoxicity in experimental tumors appears to
be fluorodeoxyuridine monophosphate inhibition of thymidylate
synthase and, consequently, inhibition of DNA synthesis.
The cytotoxic effects of 5-FU can be enhanced if sufficient amounts
of reduced folate cofactor are present.[17,18] The biochemical
modulation of 5-FU by leucovorin has been extensively studied in
patients with metastatic colon carcinoma. Clinical trials utilizing
5-FU with leucovorin have demonstrated increased response rates,
prolonged time to disease progression, and possibly prolonged overall
survival as compared to single-agent 5-FU.
UFT is composed of tegafur
(1-[2´-tetrahydrofuryl]-5-fluorouracil) and uracil in a molar
ratio of 1:4. Tegafur is converted to 5-FU in vivo. Tanimura reported
that the coadministration of uracil enhanced the concentration of
5-FU in tumors and the resulting antitumor activity of UFT.[20,21]
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 to 5-FU.
Pazdur et al has shown that UFT given at a daily dose of 370
mg/m²/d for 28 days without leucovorin generates a higher peak
plasma level of 5-FU than can be achieved with continuous infusion of
5-FU given at a dose of 250 mg/m²/d for 5 days. This
suggests that the same principle of biomodulation with leucovorin can
be applied to UFT. In phase I studies of UFT and oral leucovorin, the
dose-limiting adverse event was diarrhea.[24-26] Nausea, vomiting,
abdominal cramping, epigastralgia, and stomatitis/mucositis were also
observed. These events increased in severity with increasing doses of
UFT and oral leucovorin. Other minor events included mild fatigue,
transient hyperbilirubinemia, anorexia, and granulocytopenia.
The efficacy of oral UFT in combination with oral leucovorin when
administered on an outpatient basis has been demonstrated in phase II
studies of patients with metastatic colorectal carcinoma.
Responses were reported in a variety of metastatic sites including
liver, lungs, and bone, yielding rates from 25% to 42%. Recently, two
randomized phase III studies demonstrated a comparable efficacy but
less toxicity with UFT plus leucovorin compared with a 5-day bolus
5-FU plus leucovorin schedule in patients with metastatic colorectal
cancer.[28,29] UFT has shown clinical efficacy corresponding to the
clinical activity of 5-FU in a number of other tumors, including
carcinomas of the stomach, head and neck, nonsmall-cell
lung cancer, and breast cancer.
This article describes a phase I study investigating the combination
of oral UFT plus leucovorin in combination with a 1-hour infusion of
paclitaxel in patients with solid tumors for whom no other
established therapy exists. Compared with other cancer treatment
regimens, this combination has the advantages of an oral regimen in
combination with a weekly infusion of paclitaxel, which requires
minimal monitoring. Previous studies suggest that myelosuppression
following UFT plus leucovorin is observed infrequently and that the
side effects of treatment should compare favorably with commonly used regimens.[26-28]
The primary objective of this study is to determine the dose-limiting
toxicity, the maximum tolerated dose, and the recommended phase II
dose of weekly paclitaxel given in combination with a fixed dose of
UFT and leucovorin in adult patients with solid tumors.
This study is an open-label, phase I trial with UFT given at a dose
of 300 mg/m² in combination with 90 mg absolute leucovorin for
28 days (days 1 to 28) followed by a 1-week period without treatment.
This 35-day period defines the length of a treatment cycle. UFT and
leucovorin are given orally, with the total daily dose divided into
three doses with 8-hour intervals.
Following adequate premedication, a single 1-hour infusion of
paclitaxel is administered intravenously in 1-week intervals (days 1,
8, 15, and 22) followed by a 1-week period without treatment. The
starting dose of paclitaxel was 50 mg/m². Paclitaxel is stepwise
escalated in 10 mg/m² increments up to 100 mg/m² (Table
1). The dose of UFT plus leucovorin will not be escalated during
A minimum of three patients are treated at a given dose level, and
there is no intrapatient dose escalation. All patients to be treated
at a given dose level must complete course 1, with a full evaluation
of toxicity at that dose level, before escalation to the next dose
level in a subsequent cohort of patients.
If one of the first three patients at a given dose level experiences
a dose-limiting toxicity, three more patients are treated at this
dose level. If a total of three or more of six patients experience a
dose-limiting toxicity at a given dose level, that dose level will be
regarded as the maximum tolerated dose. Definitions of dose-limiting
toxicity are shown in Table 2.
After the maximum tolerated dose has been reached, 10 additional
patients will be treated at one dose level below the maximum
tolerated dose for evaluation of the cumulative toxicity and to
determine the recommended dose for phase II. Patients are treated for
a maximum of four cycles, or until progression of disease or
unacceptable toxicity occurs.
Toxicity will be evaluated using the Common Toxicity Criteria scale.
Patients are evaluable for response if they have received at least
one full course of therapy. World Health Organization criteria will
be used for assessment of tumor response. The study has been approved
by the Ethics Committee of Tuebingen University and is conducted as a
multicenter trial within the German phase I/II study group for the
Working Party For Medical Oncology.
For study eligibility, 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. Requirements include age > 18 years and < 70
years, Eastern Cooperative Oncology Group performance status 0 to 2,
and life expectancy ³ 12 weeks.
Adequate hematologic, renal, and hepatic functions are required.
Patients with a significant history of cardiac disease, ie,
uncontrolled high blood pressure, unstable angina pectoris,
congestive heart failure, myocardial infarction within the previous
year, or cardiac ventricular arrhythmia requiring medication, or
patients with severe active infections or other serious underlying
medical conditions are excluded.
Currently, 26 patients with a median age of 57 years have been
entered into protocol. Tumor types included are nonsmall-cell
lung cancer (18 patients), small-cell lung cancer (3 patients),
bladder cancer (3 patients), and ovarian and head and neck cancer (1
patient each) (Table 3).
Currently, six patients have been entered at dose level 4 with
paclitaxel 80 mg/m² weekly. Fourteen patients are fully
evaluable at this time, with a median 2.2 cycles applied per patient
(range: 15 cycles). The dose-limiting toxicities observed have
been diarrhea in four patients and fatigue syndrome in two patients.
The preliminary assessment of toxicities is summarized in Table
4. There was a surprisingly low incidence of peripheral
neuropathy, with five patients developing grade 1/2 toxicity. The
hematologic side effects were also mild and did not exceed grade 2.
Interestingly, seven patients experienced fatigue syndrome rated
grade 1 or 2 and two patients experienced dose-limiting grade 3
fatigue syndrome. One of these patients, with nonsmall-cell
lung cancer, was not able to carry on her daily household activities
during treatment, and fully recovered from fatigue within 4 weeks
after discontinuation of protocol therapy.
Preliminary responses have been observed in 14 evaluable patients,
with three patients achieving a partial remission and four patients
with disease stabilization. Recruitment into the protocol is
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