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Docetaxel in Combination With Flourouracil: Study Design and Preliminary Results

Docetaxel in Combination With Flourouracil: Study Design and Preliminary Results

ABSTRACT: The relatively recent introduction of a new class of chemotherapeutic agents--the taxoids--has raised hope of improved survival for patients with advanced or metastatic cancer. Following encouraging preclinical results of taxoid combinations, this phase I, nonrandomized trial was designed to evaluate a 1-hour intravenous infusion of docetaxel (Taxotere) on day 1 combined with fluorouracil (5-FU) as a daily intravenous bolus for 5 consecutive days. To date, 27 patients with advanced solid neoplasms have received 86 courses of docetaxel/5-FU at the following dose levels: 25/100, 35/150, 50/200, 60/200, and 60/300 mg/m². Preliminary results showed no unexpected toxicities, and the principal toxicity was neutropenia of short duration. A treatment regimen of 60 mg/m² docetaxel on day 1 and 300 mg/m² of 5-FU given for 5 days, with a single course length of 28 days, is projected as the maximum tolerated dose. [ONCOLOGY 11(Suppl 6):33-35, 1997]


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.[1] 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%.[2]

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.[3] 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.[4] 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 under investigation.[3,5,6]

This report presents the design and preliminary results of a phase I clinical trial testing the feasibility of docetaxel in combination with fluorouracil (5-FU).


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%.[2]

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%.[2]

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.[12] 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.

Patients and Study Procedures

Study Design

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 dose.


Patient Characteristics

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 visceral involvement.

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.

Hematologic Toxicity

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.

Nonhematologic Toxicity

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 febrile neutropenia.

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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2. Valero V, Holmes FA, Walters RS, et al: Phase II trial of docetaxel: A new, highly effective antineoplastic agent in the management of patients with anthracycline-resistant metastatic breast cancer. J Clin Oncol 13(12):2886-2894, 1995.

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4. Clinical Pharmacology Monograph: Docetaxel. Gold Standard Multimedia, Inc./Resources/Clinical Pharmacology Online. (http://www.gsm.com/resources/cponline and choose docetaxel or Taxotere) January 15, 1997, page 1.

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7. Vogel M, Hilsenceck SG, Debenbrock H, et al: Preclinical activity of Taxotere (RP 56976, NSC 628503) against freshly explanted clonogenic human tumor cells: Comparison with Taxol and conventional antineoplastic agents. Eur J Cancer 29A:2009-2014, 1993.

8. Hanauske AR, Degen D, Hilsenbeck SG, et al: Effects of Taxotere and Taxol on in vitro colony formation of freshly explanted human tumor cells. Anticancer Drugs 3:121-124, 1992.

9. Bellet R, Riva A, Ravdin P, et al: Docetaxel (Taxotere): A new active agent in anthracycline resistant breast cancer, in Kubista E, Staffen A, Zielinski C, (eds): 2nd European Congress on Senology, pp 609-613. Bologna, Italy, Monduzzi Editore, 1993.

10. Eckardt JR: New approaches to the treatment of advanced breast cancer. Anticancer Drugs 7(suppl 2):41-46, 1996.

11. Bissery M-C, Vrignaud P, Bayssas M, et al: Taxotere synergistic combination with cyclophosphamide, etoposide and 5-fluorouracil in mouse tumor models (abstract). Proc Am Assoc Cancer Res 34:299, 1993.

12. Bissery M-C, Vrignaud P, Bayssas M, et al: Docetaxel (RP56976, Taxotere) efficacy as a single agent or in combination against mammary tumors in mice (abstract). Proc Am Assoc Cancer Res 35:327, 1994.

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