Metastatic cancer is incurable. Thus, quality of life is a critical
treatment issue. High efficacy, few side effects, and an outpatient
setting are important criteria for patients receiving second- or
third-line therapy. Currently, paclitaxel (Taxol) is the most active
drug in the treatment of metastatic breast and ovarian cancer.
Single-agent response rates of up to 56%, or as high as 80% when
used in combination with an anthracycline, have been reported.[2,3]
In recent trials, paclitaxel was administered via 24- or 3-hour
intravenous (IV) infusions. Since premedication with diphenhydramine,
cimetidine (Tagamet), and corticosteroids (most often dexamethasone)
has been introduced into clinical practice, the frequency of
hypersensitivity reactions with 3-hour paclitaxel infusions has been
greatly reduced. One-hour paclitaxel infusions have been investigated
primarily for the convenience of outpatient treatment. Hainsworth et
al showed that 1-hour paclitaxel is safe and has substantial activity
in different tumor types.
Several clinical trials have examined weekly administration of
paclitaxel, [5-9] which is predominantly cytotoxic for dividing
cells. Based on the results of these trials, we can conclude that
a high-dose intensity is possible with weekly paclitaxel
administration. Hematologic and nonhematologic toxicities are mild
and objective response rates are relatively high (30% to 48%).
However, paclitaxel administered at doses above 100 mg/m²/wk may
result in treatment-limiting neurotoxicity.
The development of new combination drug regimens has become an
important area of clinical research in the care of patients who fail
to respond during or after first-line treatment. Regimens that are
based on anthracycline and alkylating agents are routinely used as
first-line chemotherapy in metastatic breast cancer. Klaassen et al
demonstrated high activity with combination paclitaxel/high-dose 5-FU
in anthracycline-pretreated breast cancer patients. Additionally,
recent studies have reported response rates of 54% to 69% for the
combination of leucovorin/5-FU/paclitaxel.[11,12]
UFT (uracil and tegafur) plus oral leucovorin (a combination being
developed under the trade name Orzel) is an orally available agent
that provides activity comparable to 5-FU and has a favorable
This trial is an open-label, single-center, phase I study to
investigate the combination of paclitaxel (administered in a weekly 1-hour
infusion) with UFT plus leucovorin in patients with
anthracycline-resistant metastatic breast cancer. The dose-limiting
toxicity, the maximum tolerated dose, and the recommended dose for
phase II testing will be determined.
Patients with metastatic breast cancer who have recurrent or
progressive disease following therapy with anthracyclines, or
patients who are unable to be treated with anthracyclines due to
decreased left-ventricular cardiac function, are eligible. Patients
must have histologically or cytologically proven breast cancer, and
may have received hormonal, immuno-, or localized radiation, therapy.
Additionally, patients must be aged ³
18 and £ 70 years; have Eastern
Cooperative Oncology Group performance status greater than 2; have a
life expectancy ³ 12 weeks; and have
adequate hematologic, renal, and hepatic functions.
Exclusion criteria include prior treatment with paclitaxel,
significant history of cardiac disease, evidence of peripheral
neuropathy greater than Common Toxicity Criteria grade 2, and
symptomatic brain metastases.
Paclitaxel 80 mg/m²/wk is administered intravenously over 1 hour
for 6 weeks. Premedication consists of dexamethasone 4 mg IV,
clemastine (Tavist) 2 mg IV, and ranitidine (Zantac) 50 mg IV 30
minutes prior to paclitaxel.
UFT plus leucovorin is administered at a starting dose of 200 mg UFT
(absolute dose, escalated stepwise to 700-mg absolute dose in
subsequent dose levels), together with 90 mg leucovorin on days 1 to
42, followed by a 2-week period without treatment (Table
1 and Figure 1). The total
dose for this combination is divided into three doses, administered
orally every 8 hours. Depending on tumor response following cycle 1,
treatment continues for a maximum of two cycles.
The following hematologic parameters will be considered dose-limiting
toxicities (DLT): absolute neutrophil count [ANC]) < 0.5 ´ 109/L
for > 7 days; ANC < 0.1 ´ 109/L
for > 3 days; any episode of febrile neutropenia (temperature
>38.2°C, granulocytes < 0.5 ´ 109/L,
requiring IV antibiotics; platelets < 25 ´ 109/L;
and bleeding requiring platelet transfusion. Additional parameters
for dose-limiting toxicities are any nonhematologic toxicity Common
Toxicity Criteria grade ³ 3
(excluding alopecia, inadequately treated grade 3 vomiting, and grade
3 severe asthenia).
A minimum of three patients will be treated at any given dose level.
Every patient treated at a given dose level must complete course 1.
Full evaluation of toxicity at that dose level must correspond to
dose-limiting toxicity and maximum tolerated dose criteria before the
next dose level is implemented. If one of the first three patients at
a given dose level experiences dose-limiting toxicity, up to three
more patients will be treated at this level.
This phase I trial opened in September 1998. As of June 1999, 15
patients have entered the study; 11 are evaluable for toxicity. The
median age is 55 years. Baseline patient characteristics are noted in Table
Toxicity by Dose Increments
Of the 11 evaluable patients, four were treated at dose level 1
(paclitaxel 80 mg/m², UFT 200-mg absolute dose) and seven were
treated at dose level 2 (paclitaxel 80 mg/m2, UFT 300-mg absolute
dose) without any problems. Two patients at dose level 2 received
only one treatment cycle due to disease progression. Four patients
are still in the study at dose level 3 (paclitaxel 80 mg/m², UFT
400-mg absolute dose). It is too early to provide results from this
Hematologic and Nonhematologic Toxicities
No severe hematologic or nonhematologic toxicities were observed in
dose levels 1 and 2. No cases of febrile neutropenia were observed (Table
The first patients in dose levels 1 and 2 tolerated the treatment
without any adverse effects. No severe hematologic and nonhematologic
toxicities were observed. At dose level 3 (paclitaxel 80 mg/m2, UFT
400-mg absolute dose), four patients are still in study. Although it
is too early to provide results from this dose level, results from
recent studies of monotherapy with weekly paclitaxel or UFT plus
leucovorin in metastatic breast cancer suggest that the combination
may produce higher activity with a low incidence of side effects in
The final results from this study may offer a second- or third-line
therapy for metastatic disease that has high efficacy, few side
effects, and takes place in an outpatient setting.
1. Holmes FA, Walters RS, Theriault RL, et al: Phase II trial of
Taxol, an active drug in the treatment of metastatic breast cancer. J
Natl Cancer Inst 83:1791-1805, 1991.
2. Gehl J, Boesgaard M, Paaske T, et al: Combined doxorubicin and
paclitaxel in advanced breast cancer: Effective and cardiotoxic. Ann
Oncol 7:687-693, 1996.
3. Rowinsky EK, Cazenave LA, Donehower RC, et al: Taxol: A novel
investigational antimicrotubule agent. J Natl Cancer Inst
4. Hainsworth JD, Hopkins L, Thomas M, et al: Taxol administered by
1-hour-infusion: Preliminary results of phase I/II study comparing
two dose schedules (abstract 413). Proc Am Soc Clin Oncol 13:156, 1994.
5. Klaassen U, Wilke H, Strumberg D, et al: Phase I study with a
weekly 1-hour infusion in heavily pretreated patients with metastatic
breast and ovarian cancer. Eur J Cancer 32A:547-549, 1996.
6. Fennelly D, Aghajanian F, Shapiro F: Phase I and pharmacologic
study of paclitaxel administered weekly in patients with relapsed
ovarian cancer. J Clin Oncol 15:187-192, 1997.
7. Breier S, Lebedinsky C, Pelayes L, et al: Phase I/II weekly
paclitaxel 80 mg/m2 in pretreated patients with breast and ovarian
cancer (abstract 568). Proc Am Soc Clin Oncol 16:163a, 1997.
8. Seidman AD, Murphy B, Hudis C, et al: Activity of Taxol by weekly
1-hour infusion in patients with metastatic breast cancer: A phase II
study (abstract 517). Proc Am Soc Clin Oncol 16:148a, 1997.
9. Lück H-L, Marhenke D, Petry KU, et al: Weekly paclitaxel
monotherapy as salvage treatment in pretreated patients with
metastatic breast cancer: Experience with a 1-hour schedule (abstract
233). Breast Cancer Res Treat 46:59, 1997.
10. Lopes NM, Adams EG, Pitts TW, et al: Cell kill kinetics and cell
cycle effects of Taxol on human and hamster ovarian cell lines.
Cancer Chemother Pharmacol 32:235-242, 1993.
11. Klaassen U, Wilke H, Philippou Pari C, et al: Phase I/II study
with paclitaxel in combination with weekly high-dose 5-FU/folinic
acid in the treatment of metastatic breast cancer (abstract 186).
Proc Am Soc Clin Oncol 14:122, 1995.
12. Klaassen U, Ehricke S, Hilger R, et al: Phase I/II and
pharmacologic study of paclitaxel plus oral UFT and leucovorin in the
second-line treatment of patients with metastatic breast cancer
(abstract 2187). Proc Am Soc Clin Oncol 17:39, 1998.