Docetaxel in Combination With Flourouracil: Study Design and Preliminary Results

June 1, 1997

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.

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]

Introduction

Treatment of patients with advanced cancer--local or systemic--remainslargely a matter of palliation, with increases in survival measured inmonths, rather than years. The term "salvage chemotherapy" reflectsthe limitation of current treatments for these individuals. For patientswith previously untreated metastatic breast cancer, first-line treatmentwith anthracyclines as a component has so far produced the greatest improvementin 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, withresponse rates ranging from 7% to 40%.[2]

Although a breakthrough with significant impact on advanced cancer survivalis still in the future, current work has focused on improving the therapeuticindex of the agents administered, especially to patients who have receivedprior anthracycline-based chemotherapy. One of the most important recentadditions to the armamentarium is docetaxel (Taxotere).

Phase I clinical trials of docetaxel began in 1990.[3] The agent receivedFDA approval in May 1996 for the treatment of patients with locally advancedor metastatic breast cancer that has progressed during anthracycline therapyor has relapsed during anthracycline-based adjuvant therapy.[4] There havebeen vigorous, ongoing clinical investigations of docetaxel, used aloneand in combination, as first- or second-line treatment, in many cancertypes. These studies have yielded impressive data for the drug as a singleagent; use of docetaxel in combination with various other agents is stillunder investigation.[3,5,6]

This report presents the design and preliminary results of a phase Iclinical trial testing the feasibility of docetaxel in combination withfluorouracil (5-FU).

Rationale

One important goal of the development of combination regimens is toimprove response rates, palliation, and survival of patients with locallyadvanced or disseminated cancer. The many patients in whom response toanthracycline regimens is incomplete or temporary have a tremendous needfor better options. Mitomycin and vinblastine, alone or in combination,have been commonly used as second- or third-line therapy for anthracycline-resistantmetastatic breast cancer and, as mentioned, demonstrate a range of activitywith response rates of 7% to 40%.[2]

Docetaxel, when used alone, has demonstrated significant antineoplasticactivity against tumor cells of advanced breast, ovarian, and lung cancer.[6-8]Phase II trials have shown that the agent produces the highest reportedantitumor response rate in anthracycline-resistant metastatic breast cancer,generally showing a range of 29% to 50%,[9,10] with one study reportingan objective response rate of 53%.[2]

Preclinical investigations of docetaxel used in combination with 5-FUhave been encouraging. Taxoids and 5-FU have demonstrated true synergy,[6,11]and the combination has reached approximately 70% of the maximum toleratedsingle-agent dose for each agent.[12] Docetaxel and 5-FU have differentmechanisms of action, and their toxicity profiles do not significantlyoverlap. These positive indicators provide a rationale for this combinationin clinical trials, particularly in patients with recurrent and anthracycline-resistantmetastatic breast cancer and other neoplasms (eg, esophageal, stomach)in which both agents are active.

This investigation, which focused on clinical feasibility, was designedto determine the maximum tolerated dose and principal toxicities of thedocetaxel/5-FU combination regimen.

Patients and Study Procedures

Study Design

This phase I, nonrandomized trial involved the Cancer Therapy and ResearchCenter, Brooke Army Hospital and their affiliated institutions in San Antonio.Patients with all types of locally advanced solid tumors and those withmetastatic 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 chemotherapywith an alkylating agent (except platinum), no more than two cycles ofchemotherapy with mitomycin or a nitrosurea, or radiation to 30% or lessof body mass. All patients were required to have adequate bone marrow andhepatic and renal function, as well as a Karnofsky performance status of60% or greater.

Treatment

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 fora total of 3 days, every 28 days
  • Docetaxel administered over 1 hour by intravenous infusion on day 1and given every 28 days
  • 5-FU given as a simple intravenous bolus beginning immediately afterdocetaxel, repeated daily for 5 consecutive days, every 28 days

The regimen consisted of five levels (I through V), with increasingdoses of docetaxel, 5-FU, or both, at each subsequent level (Table1). The first two increases, to level II and then to level III, wereincreases of both agents. At level IV, only the docetaxel dose increased,with the dose of 5-FU remaining constant. At level V, the docetaxel dosewas constant, whereas the dose of 5-FU increased.

Assessments

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 whichthree patients, of a maximum of six, experienced a dose-limiting toxicity.The recommended dose is the dose level just below the maximum tolerateddose.

Results

Patient Characteristics

Initially, 27 patients were enrolled in the study. There were no patientswith breast cancer in the initial cohort (four patients, three of whomhad breast cancer, were subsequently added at the time of this report).Patients generally presented with refractory cancer. The majority of patientshad prior chemotherapy; 33% had more than one prior regimen of the typeour inclusion criteria permitted. These patients had a fairly wide burdenof tumor, with generally two or three organs involved, and significantvisceral involvement.

Patient characteristics by dose level are shown in Table1. Tolerability of the combination did not seem to depend on the Karnofskyscale, number of organs involved, or presence or absence of visceral disease.

Hematologic Toxicity

The major toxicity, to date, has been neutropenia. Of the initial 27patients enrolled in the study, 5 have been treated at the highest doselevel, and 4 of these 5 patients experienced grade 4 neutropenia at somepoint during their successive courses of chemotherapy.

To date, none of the first 27 patients experienced grade 4 neutropenialasting more than 7 days. Two of the first five patients experienced febrileneutropenia 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 levelrecommended for phase II studies. The projection is based on the low incidenceof febrile neutropenia and the general toleribility of this dose in thispatient population, but this will be determined definitely following accrualof additional patients.

Nonhematologic Toxicity

One patient, during one course, experienced grade 4 diarrhea, and anotherpatient experienced a sporadic and isolated course of stomatitis at thehighest dose level, which was also associated with febrile neutropenia.Of the chronic nonhematologic events, neither fluid retention nor neurosensorytoxicity was clinically significant in the dose range studied.

Discussion

Based on the preliminary experience with all patients enrolled to date,the maximum tolerated dose is projected as 60 mg/m² of docetaxel for1 day and 300 mg/m² of 5-FU for 5 days. Additional patients are beingtreated to determine whether this dose can be recommended as an initialdose in clinical practice based on the brevity and reversibility of toxicitiesat this dose level. No unexpected toxicities have been observed. The principaltoxicity was granulocytopenia, and the major dose-limiting toxicity wasfebrile neutropenia.

Following clear definition of the maximum tolerated dose and recommendeddose on the present schedule, the protocol will be amended to use 5-FUon a 3-day dosing regimen as a potentially more feasible alternative ingeneral clinical practice.

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