Paclitaxel (Taxol) is a very active agent in
the treatment of metastatic breast cancer, yielding single-agent
response rates up to 56%, or, in combination with an
anthracycline, as high as 80%.[2,3] In these trials, paclitaxel was
administered intravenously over 24 or 3 hoursthe 24-hour
infusion being more common in the United States, and the 3-hour
infusion more common in Europe. The shorter infusion schedule is
associated with a lower rate of severe myelosuppression; on the other
hand, it may produce more peripheral neuropathies. A 1-hour infusion
of paclitaxel, offering the added convenience of outpatient
treatment, has been investigated in phase I studies. On this
schedule, paclitaxel was shown to be safe, with substantial activity
in several different tumor types.
Paclitaxel works at the cellular level,[3,5] predominantly impairing
dividing cells at the G2/M phase of growth. For this
reason, repeated doses are theoretically beneficial, reaching more
cells at the susceptible point in the cell cycle. Based on this
concept, several clinical trials have examined weekly administration
of paclitaxel (Table 1),[6-10]
leading to the following conclusions regarding weekly paclitaxel dosing:
High-dose intensity is possible with weekly administration.
Hematologic toxicity is mild.
Long-term treatment with paclitaxel at doses > 100 mg/m2
may result in treatment-limiting neurotoxicity.
Objective response rates are relatively high (30% to 48%).
Anthracycline and alkylating agent-based regimens are used routinely
as first-line therapy for metastatic breast cancer. Failure to
respond is generally accepted to be a poor prognostic factor for
response to available salvage therapy. The development of new
combination drug regimens, therefore, has become important to the
care of this patient population. In a recent phase I/II study, for
instance, combination-therapy with calcium folinate/5-fluorouracil
(5-FU)/paclitaxel yielded response rates of 54% to 69% as salvage
therapy for anthracycline-resistant breast cancer.[12,13] In this
study, 500 mg/m2 of calcium folinate was administered as a
2-hour infusion prior to 5-FU at a dose of 2.0 g/m2
intravenously over 24 hours; 175 mg/m2 of paclitaxel was
administered intravenously over 3 hours. All drugs were given on day
1; calcium folinate and 5-FU administrations were repeated weekly on
days 8 and 15. The cycle was repeated every 3 weeks. The duration of
response was 8 months.
Klaassen et al are currently performing a phase II trial of uracil
and tegafur (UFT)/oral calcium folinate (Orzel) plus paclitaxel as
second-line treatment of metastatic breast cancer. Patients will
receive a single paclitaxel infusion (175 mg/m2 over 3
hours) on day 1; UFT plus calcium folinate will be administered three
times a day for 14 days, followed by 1 week without treatment. UFT
will be escalated in 100-mg increments from a total starting oral
dose of 30 mg/day, whereas oral calcium folinate will be administered
as a fixed dose at 300 mg three times a day.
This phase I trial was designed to determine the dose-limiting
toxicity, maximum tolerated dose, and recommended dose for phase II
testing of weekly paclitaxel administered by 1-hour infusion in
combination with UFT/oral calcium folinate for the treatment of
patients with anthracycline-resistant metastatic breast cancer. We
also wanted to assess early efficacy and safety information on this
The study has an open-label, single-center, phase I design. The
patient population includes patients with anthracycline-resistant
metastatic breast cancer. Premedication consists of dexamethasone 4
mg intravenously, clemastine 2 mg intravenously, and ranitidine 50 mg
intravenously administered 30 minutes before paclitaxel. Paclitaxel
80 mg/m2 as a 1-hour infusion is administered at 1-week
intervals for 6 weeks. Oral UFT/calcium folinate is administered at a
starting dose of 200 mg UFT (absolute dose, escalated stepwise to 700
mg total absolute dose in subsequent groups), together with 90 mg
calcium folinate on days 1 to 42, followed by a 2-week period without
treatment (Figure 1).
UFT/calcium folinate is administered orally in three divided doses, 8
hours apart. Depending on tumor response following cycle 1, treatment
continues to a maximum of two cycles.
A dose-limiting toxicity is determined by the following hematologic
parameters: granulocytes (absolute neutrophil count [ANC]) < 0.5
× 109/L for > 7 days; ANC of < 0.1 × 109/L
for > 3 days; any episode of febrile neutropenia, defined as
temperature > 38.2ºC; granulocytes < 0.5 × 109/L,
requiring antibiotics and hospitalization; platelets < 25 × 109/L;
bleeding requiring platelet transfusion; or failure of recovery of
granulocytes (1.5 × 109/L) and/or platelets (100
× 109/L) by day 57. In addition, any nonhematologic
toxicitycommon toxicity criteria (CTC) of ³
grade 3excluding alopecia and inadequately treated grade 3
vomiting, is considered dose-limiting.
At least three patients will be treated at each dose level. If none
of these patients develops a dose-limiting toxicity during the first
cycle, the next dose level may be opened. If one of the first three
patients develops a dose-limiting toxicity, a maximum of three
additional patients will be treated at this dose level.
The maximum tolerated dose will be reached if three of six patients
at a given dose level develop a dose-limiting toxicity during any
cycle of treatment. The recommended dose for phase II testing will be
one dose level below the maximum tolerated dose. Once it has been
determined, 10 additional patients will be treated at that dose level.
This phase I trial opened in September 1998. The first patients in
dose level 1 tolerated the treatment without problems. At this time,
we are not able to provide results from the trial. Results will be
available at the end of 1999. The results from recent studies with
monotherapy of weekly paclitaxel or UFT/calcium folinate in
metastatic breast cancer suggest that the combination may be expected
to produce high activity and a low incidence of side effects. This
would be an important advance for the population of patients with
anthracycline-resistant metastatic breast cancer, who currently have
little chance of cure.
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, Donehover RC, et al: 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 a phase I/II study comparing
two dose schedules (abstract 413). Proc Am Soc Clin Oncol 13:156, 1994.
5. 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.
6. Klaassen U, Wilke H, Strumberg D, et al: Phase I study with a
weekly 1 h infusion of paclitaxel in heavily pretreated patients with
metastatic breast and ovarian cancer. Eur J Cancer 32A:547-549, 1996.
7. Fennelly D, Aghajanian F, Shapiro F: Phase I and pharmacologic
study of paclitaxel administrated weekly in patients with relapsed
ovarian cancer. J Clin Oncol 15:187-192, 1997.
8. Breier S, Lebedinsky C, Pelayes L, et al: Phase I/II weekly
paclitaxel 80 g/m2 in pretreated patients (pts) with breast (BC) and
ovarian cancer (OC) (abstract 568). Proc Am Soc Clin Oncol 16:163a, 1997.
9. Seidman AD, Murphy B, Hudis C, et al: Activity of Taxol (T) by
weekly 1 hour infusion in patients (pts) with metastatic breast
cancer (MBC): A phase II and pharmacologic study (abstract 517). Proc
Am Soc Clin Oncol 16:148a, 1997.
10. Lück H-J, Marhenke D, Petry KU, et al: Weekly paclitaxel
monotherapy as salvage treatment in pretreated patients with
metastatic breast cancer: Experience with a one hour schedule
(abstract 233). Breast Cancer Res Treat 46:59, 1997.
11. Dees A, Verweij J, van Putten WL, et al: Mitomycin C is an
inactive drug in the third-line treatment of hormone and chemotherapy
refractory breast cancer. Eur J Cancer Clin Oncol 23:1343-1347, 1987.
12. Klaassen U: Phase I/II study with paclitaxel (T) in combination
with weekly high-dose 5-FU/folinic acid (HDFU/FA) in the treatment of
metastatic breast cancer (MBC) (abstract 186). Proc Am Soc Clin Oncol
13. Klaassen U, Ehricke S, Hilger R, et al: Phase I/II and
pharmacology study of paclitaxel (P) plus oral UFT [1-(2-tetrahydrofuryl)-5-FU
+ uracil) and leucovorin (LV) in the second-line treatment of
patients with metastatic breast cancer (abstract 2187). Proc Am Soc
Clin Oncol 17:39, 1998.
14. Paul DM, Garrett AM, Meshad M, et al: A phase II trial of
paclitaxel, 5-fluorouracil and leucovorin (TFL) in metastatic breast
cancer (abstract 259). Proc Am Soc Clin Oncol 14:140, 1995.