Treatment of patients with advanced cancer--local or systemic--remains
largely a matter of palliation, with increases in survival measured in
months, rather than years. The term "salvage chemotherapy" reflects
the limitation of current treatments for these individuals. For patients
with previously untreated metastatic breast cancer, first-line treatment
with anthracyclines as a component has so far produced the greatest improvement
in response rate. In patients with anthracycline-resistant disease,
results of the most common second- or third-line therapy (mitomycin [Mutamycin]
and vinblastine, alone or in combination) have been disappointing, with
response rates ranging from 7% to 40%.
Although a breakthrough with significant impact on advanced cancer survival
is still in the future, current work has focused on improving the therapeutic
index of the agents administered, especially to patients who have received
prior anthracycline-based chemotherapy. One of the most important recent
additions to the armamentarium is docetaxel (Taxotere).
Phase I clinical trials of docetaxel began in 1990. The agent received
FDA approval in May 1996 for the treatment of patients with locally advanced
or metastatic breast cancer that has progressed during anthracycline therapy
or has relapsed during anthracycline-based adjuvant therapy. There have
been vigorous, ongoing clinical investigations of docetaxel, used alone
and in combination, as first- or second-line treatment, in many cancer
types. These studies have yielded impressive data for the drug as a single
agent; use of docetaxel in combination with various other agents is still
This report presents the design and preliminary results of a phase I
clinical trial testing the feasibility of docetaxel in combination with
One important goal of the development of combination regimens is to
improve response rates, palliation, and survival of patients with locally
advanced or disseminated cancer. The many patients in whom response to
anthracycline regimens is incomplete or temporary have a tremendous need
for better options. Mitomycin and vinblastine, alone or in combination,
have been commonly used as second- or third-line therapy for anthracycline-resistant
metastatic breast cancer and, as mentioned, demonstrate a range of activity
with response rates of 7% to 40%.
Docetaxel, when used alone, has demonstrated significant antineoplastic
activity against tumor cells of advanced breast, ovarian, and lung cancer.[6-8]
Phase II trials have shown that the agent produces the highest reported
antitumor response rate in anthracycline-resistant metastatic breast cancer,
generally showing a range of 29% to 50%,[9,10] with one study reporting
an objective response rate of 53%.
Preclinical investigations of docetaxel used in combination with 5-FU
have been encouraging. Taxoids and 5-FU have demonstrated true synergy,[6,11]
and the combination has reached approximately 70% of the maximum tolerated
single-agent dose for each agent. Docetaxel and 5-FU have different
mechanisms of action, and their toxicity profiles do not significantly
overlap. These positive indicators provide a rationale for this combination
in clinical trials, particularly in patients with recurrent and anthracycline-resistant
metastatic breast cancer and other neoplasms (eg, esophageal, stomach)
in which both agents are active.
This investigation, which focused on clinical feasibility, was designed
to determine the maximum tolerated dose and principal toxicities of the
docetaxel/5-FU combination regimen.
This phase I, nonrandomized trial involved the Cancer Therapy and Research
Center, Brooke Army Hospital and their affiliated institutions in San Antonio.
Patients with all types of locally advanced solid tumors and those with
metastatic neoplasms, exclusive of brain or leptomeninges, were selected.
Any patient with prior taxoid treatment, more than minimal pretreatment,
or antitumor therapy of any kind (eg, chemotherapy, radiation, hormonal,
or investigational therapy) during the previous 4 weeks was excluded.
Minimal pretreatment was defined as no more than six cycles of chemotherapy
with an alkylating agent (except platinum), no more than two cycles of
chemotherapy with mitomycin or a nitrosurea, or radiation to 30% or less
of body mass. All patients were required to have adequate bone marrow and
hepatic and renal function, as well as a Karnofsky performance status of
60% or greater.
A dose-escalation protocol with the following dosing schedule was implemented:
- Pretreatment with an abbreviated regimen of corticosteroid (oral dexamethasone,
8 mg twice daily), beginning 1 day before chemotherapy and continuing for
a total of 3 days, every 28 days
- Docetaxel administered over 1 hour by intravenous infusion on day 1
and given every 28 days
- 5-FU given as a simple intravenous bolus beginning immediately after
docetaxel, repeated daily for 5 consecutive days, every 28 days
The regimen consisted of five levels (I through V), with increasing
doses of docetaxel, 5-FU, or both, at each subsequent level (Table
1). The first two increases, to level II and then to level III, were
increases of both agents. At level IV, only the docetaxel dose increased,
with the dose of 5-FU remaining constant. At level V, the docetaxel dose
was constant, whereas the dose of 5-FU increased.
Dose-limiting toxicity was defined as the following:
- Grade 4 neutropenia for more than 7 days
- Febrile neutropenia
- Grade 4 thrombocytopenia
- Grade 3 or 4 nonhematologic toxicity (except nausea and vomiting)
- Grade 4 emesis, despite antiemetic regimen
The maximum tolerated dose was defined as the highest dose at which
three patients, of a maximum of six, experienced a dose-limiting toxicity.
The recommended dose is the dose level just below the maximum tolerated
Initially, 27 patients were enrolled in the study. There were no patients
with breast cancer in the initial cohort (four patients, three of whom
had breast cancer, were subsequently added at the time of this report).
Patients generally presented with refractory cancer. The majority of patients
had prior chemotherapy; 33% had more than one prior regimen of the type
our inclusion criteria permitted. These patients had a fairly wide burden
of tumor, with generally two or three organs involved, and significant
Patient characteristics by dose level are shown in Table
1. Tolerability of the combination did not seem to depend on the Karnofsky
scale, number of organs involved, or presence or absence of visceral disease.
The major toxicity, to date, has been neutropenia. Of the initial 27
patients enrolled in the study, 5 have been treated at the highest dose
level, and 4 of these 5 patients experienced grade 4 neutropenia at some
point during their successive courses of chemotherapy.
To date, none of the first 27 patients experienced grade 4 neutropenia
lasting more than 7 days. Two of the first five patients experienced febrile
neutropenia at the highest dose level. No patients developed an infection.
At this juncture, the level V dose of docetaxel/5-FU (60/300 mg/m²)
is projected as the maximum tolerated dose level, as well as the dose level
recommended for phase II studies. The projection is based on the low incidence
of febrile neutropenia and the general toleribility of this dose in this
patient population, but this will be determined definitely following accrual
of additional patients.
One patient, during one course, experienced grade 4 diarrhea, and another
patient experienced a sporadic and isolated course of stomatitis at the
highest dose level, which was also associated with febrile neutropenia.
Of the chronic nonhematologic events, neither fluid retention nor neurosensory
toxicity was clinically significant in the dose range studied.
Based on the preliminary experience with all patients enrolled to date,
the maximum tolerated dose is projected as 60 mg/m² of docetaxel for
1 day and 300 mg/m² of 5-FU for 5 days. Additional patients are being
treated to determine whether this dose can be recommended as an initial
dose in clinical practice based on the brevity and reversibility of toxicities
at this dose level. No unexpected toxicities have been observed. The principal
toxicity was granulocytopenia, and the major dose-limiting toxicity was
Following clear definition of the maximum tolerated dose and recommended
dose on the present schedule, the protocol will be amended to use 5-FU
on a 3-day dosing regimen as a potentially more feasible alternative in
general clinical practice.
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