Phase I study of eniluracil and oral 5-fluorouracil in combination with docetaxel in the treatment of patients with metastatic breast carcinoma




The authors conducted a single-institution Phase I clinical trial to determine the maximum tolerated doses and to define the toxic effects of oral eniluracil and oral 5-fluorouracil (5-FU) combined with docetaxel in patients with metastatic breast carcinoma.


Patients with metastatic breast carcinoma were eligible if they had disease progression after anthracycline-based therapy and had never been exposed to taxanes. The starting doses of oral eniluracil and oral 5-FU were 11.5 mg/m2 and 1.15 mg/m2, respectively, twice daily on Days 1–14. Docetaxel was given intravenously at a starting dose of 50 mg/m2 on Day 1 only. The dose of docetaxel was escalated among cohorts until a maximum tolerated dose was reached. Courses were repeated every 21 days.


The authors treated 19 patients with Stage IV breast carcinoma, of whom 5 had received prior chemotherapy for their metastatic disease. Fifty-three percent had a performance status of 1, and 53% had bone or soft tissue involvement as the dominant site of disease. All patients had received prior therapy with doxorubicin. The dose-limiting toxicity was neutropenic fever. No episodes of sepsis were observed. Significant antitumor activity was observed with a total of two complete and nine partial responses. The recommended doses for Phase II studies are 72 mg/m2 docetaxel on Day 1 and 10.0/1.0 mg/m2 oral eniluracil/5-FU twice daily for a total of 14 days, with courses being repeated every 21 days.


The combination of oral eniluracil/5-FU and intravenous docetaxel is a safe and well tolerated regimen. Significant antitumor activity is associated with this combination. Cancer 2002;94:2321–6. © 2002 American Cancer Society.

DOI 10.1002/cncr.10488

Eniluracil is a potent inactivator of dihydropyrimidine dehydrogenase, the first enzyme in the degradative pathway of 5-fluorouracil (5-FU).1 In preclinical and early clinical studies, doses of eniluracil sufficient to inactivate greater than 99% of endogenous dihydropyrimidine dehydrogenase were nontoxic and exhibited no antiproliferative activity. Pretreatment with eniluracil significantly increased the bioavailability and half-life and reduced the pharmacokinetic variability of oral 5-FU. Eniluracil also increased the antitumor efficacy of 5-FU and increased the therapeutic index of 5-FU by up to sixfold in three rodent tumor models.2–5 5-Fluorouracil is commonly used for the treatment of breast carcinoma, in both the adjuvant therapy and metastatic disease settings, but its efficacy may be limited by its pharmacokinetics. Eniluracil holds promise as an agent to enhance the antitumor efficacy of 5-FU by alternating its plasma pharmacokinetics and inhibiting its intracellular catabolism. By enabling reliable oral absorption of 5-FU, eniluracil facilitates chronic administration of 5-FU.

Docetaxel, another widely used chemotherapeutic agent for the treatment of breast carcinoma, acts as a spindle poison, by promoting microtubule assembly and inhibiting disassembly.6–8 Response rates as high as 61% have been reported in patients with metastatic breast carcinoma who received docetaxel doses of 100 mg/m2.9 The drug currently is being evaluated in combination with a variety of other chemotherapeutic agents. Recent studies have demonstrated the superiority of docetaxel alone or in combination with agents such as doxorubicin when compared with combinations such as mitomycin/vinblastine and doxorubicin/cyclophosphamide.10, 11 Prior studies of docetaxel and 5-FU have shown this to be an efficacious and safe combination.12–15 The results of such studies, the known activity of docetaxel against breast carcinoma, and the observed preliminary results of Phase II studies evaluating the activity of eniluracil and oral 5-FU in breast carcinoma16, 17 led to further evaluation of this combination in patients with American Joint Committee on Cancer (AJCC)-tumor node metastases (TNM) Stage IV breast carcinoma.


Eligibility Criteria

Patients were eligible for the study if they had Stage IV breast carcinoma, had had anthracycline-based chemotherapy that failed, and had never been exposed to taxanes. Patients were allowed to have received a total of two prior chemotherapy regimens but no more than one for metastatic disease. Patients could have either measurable or evaluable disease, but bone marrow metastases, pleural effusions, or ascites could not be the only sites of disease. Patients were required to have a life expectancy of at least 12 weeks, to have a performance status of 0 or 1 on the Zubrod scale,18 and to be at least 18 years of age. Other eligibility criteria included adequate bone marrow function, defined as an absolute granulocyte count of greater than or equal to 1500/μL and a platelet count of greater than or equal to 100,000/μL, and adequate liver and renal function, defined as a bilirubin concentration of less than 1.5 mg/dL and estimated creatinine clearance of greater than or equal to 40 mL/minute according to the modified Cockroft and Gault formula.19 The study was approved by the institutional review board at our institution, and participants signed an informed consent form.

The simultaneous administration of other chemotherapy, hormone therapy, immunotherapy, or radiotherapy was not allowed. All previous systemic therapy, except hormone therapy, had to have ended 3 weeks before entering this study, and patients must have recovered from the toxic effects of prior therapy.

Patients were not eligible for this study if they had received prior therapy with a taxane (paclitaxel or docetaxel), continuous infusion 5-FU, and/or fluorouracil-related drugs such as capecitabine or flucytosine. In addition, patients were not eligible if they had evidence of uncontrolled brain metastases or depletion of bone marrow reserves secondary to tumor involvement, irradiation, or high-dose chemotherapy followed by bone marrow transplant. They were not allowed to enter the study if they had evidence of other serious uncontrolled illnesses or if the control of an illness may have been jeopardized by the complications of this therapy.

Treatment Plan and Evaluation

Before study entry, patients underwent a complete history and physical examination, including evaluation of performance status and weight and documentation of all prior anticancer treatments and any residual side effects from prior therapies. Baseline imaging studies were obtained to define the extent of disease. Laboratory tests included a complete blood cell count with differential and platelet counts, urinalysis, blood chemistry studies including tumor marker studies, and a serum pregnancy test in women of childbearing potential.

The study was conducted using a standard Phase I design with sequential cohorts of patients. Docetaxel was given at a dose of 50 mg/m2 infused intravenously over 1 hour on Day 1 in cohort 1. In subsequent cohorts, the dose of docetaxel was escalated approximately 20% over the previous cohort's dose, until the maximum tolerated dose was reached (Table 1). Patients in the earlier cohorts received a fixed dose of oral eniluracil, 11.5 mg/m2 twice a day, together with a fixed dose of oral 5-FU, 1.15 mg/m2 twice a day (10:1 ratio of eniluracil to 5-FU) every day for 14 days starting on Day 1. In the last cohort, the dose of eniluracil and 5-FU were decreased to 10.0 and 1.0 mg/m2, respectively. Premedication with dexamethasone, 8 mg orally twice daily for 3 days, was given with each course starting on the day before chemotherapy. Courses were repeated every 21 days on an outpatient basis. Eniluracil and 5-FU were provided free of charge to the patients by Glaxo Wellcome Inc.

Table 1. Dose Levels
Cohort (no. of patients)Docetaxel (mg/m2)Eniluracil/5-FU (mg/m2)
  1. 5-Fu: 5-Fluorouracil.

1 (3)5011.5/1.15
2 (6)6011.5/1.15
3 (6)7211.5/1.15
4 (4)7210.0/1.0

The patients were treated until there was unacceptable toxicity or evidence of disease progression. Treatment also could be ended at the patients' request or investigator's discretion. Dose adjustments were made according to the greatest degree of toxicity. Toxicities were graded using the National Cancer Institute Common Toxicity Criteria, version 2.0. Unacceptable toxicity was defined as: any Grade 3 or higher nonhematologic toxicity (excluding nausea and vomiting) or Grade 2 or higher nonhematologic toxicity that had not resolved by Day 21, or Grade 4 hematologic toxicity lasting more than 7 days or associated with fever, infection, or thrombocytopenia. Patients were followed up with complete blood cell counts, differential counts, and platelet counts before each dose of docetaxel. Blood chemistry studies were repeated before each course or as frequently as needed to define drug toxicity. Serum tumor marker studies were repeated every two courses if levels were initially elevated. Radiologic assessments were performed after every two courses unless the clinical situation required earlier assessment.

Although the major objective of a Phase I study is to evaluate dosing and toxicity, an attempt was made to evaluate the efficacy of this drug combination in this patient population. The size of measurable lesions was reported as the product of the longest dimension and its perpendicular. Standard response criteria were applied.20 A complete response was defined as the disappearance of all measurable and unmeasurable but evaluable disease lasting 4 weeks or longer. A partial response was defined as a greater than or equal to 50% reduction in the sum of the products of perpendicular dimensions of all measurable lesions for 4 weeks or longer without the appearance of new lesions or the growth of any existing lesion. A minor response was defined as a decrease of less than 50% but greater than 25% in the above-mentioned sum for 4 weeks or longer with no new lesions or the growth of any existing lesion. Stable disease was defined as no change or no more than a 25% increase in the above-mentioned sum for 4 or longer weeks with no new lesions or the growth of any existing lesion. Disease progression was defined as the unequivocal appearance of any new lesion or a greater than or equal to 25% increase in the above-mentioned sum or in the estimated size of a nonmeasurable but evaluable lesion. Development of new brain lesions was considered progression of disease.

Statistical Analysis

The major objective of this trial was to determine the maximum tolerated dose of docetaxel in combination with eniluracil and oral 5-FU and to evaluate the toxic effects associated with this combination. The maximum tolerated dose was considered to have been reached if two patients at the same dose level experienced unacceptable Grade 3 or 4 toxicity. Toxicity in relation to dose escalation patterns was assessed through the use of descriptive statistics. The intent was to establish the doses of docetaxel and of eniluracil plus oral 5-FU to be recommended for combination therapy in a Phase II study.


Patient Characteristics

Between January 1999 and May 2000, 19 eligible patients were registered in this study. Demographic and clinical characteristics of all patients are listed in Table 2. The median age was 52 years, and the median Zubrod performance status was 1. The median number of metastatic sites was 1 (range, 1–6 sites). Most patients had bone and soft tissue involvement as their dominant site of disease. All 19 patients had received at least one prior chemotherapeutic regimen. Five patients had received prior chemotherapy for their metastatic disease. All 19 patients had received prior doxorubicin, and 17 patients had received prior bolus 5-FU. Fifteen patients had received prior hormonal therapy, 12 had prior radiotherapy, and all had prior surgery.

Table 2. Patient Characteristics
CharacteristicNo. of patients
Total no. of patients19
Age (yrs)
 Median52 y
Performance status
 Female gender19
Race/ethnic group
No. of metastatic sites
 ≥ 35
Dominant metastatic site
 Soft tissue6
No. total prior chemotherapy regimens
Prior hormonal therapy15
Prior radiotherapy12


A total of 149 courses of the combination were administered. The median number of courses received was 8 (range, 2–12). Toxicity was evaluated for all patients.

Hematologic toxicity

The dose-limiting side effect observed was neutropenic fever. Three patients in cohort 2 had six episodes of neutropenic fever. Two of these three patients had a total of two and three episodes each of neutropenic fever associated with infection (one had a perirectal abscess, and the other had pneumonia). The third patient had fever associated with a urinary tract infection. Five episodes of neutropenic fever were observed in a total of three patients in cohort 3. Two of these episodes were associated with positive blood cultures, and one was associated with stomatitis, and in two there was no obvious source of infection. No episodes of neutropenic fever or infection were reported in cohorts 1 and 4. None of the episodes of neutropenic fever occurred during the first cycle of chemotherapy. The mean nadir granulocyte and platelet counts for all first courses was 400/μL and 186,000/μL, respectively, and occurred on Day 10 in most patients.

There were a total of eight hospitalizations in five patients; six hospitalizations were for neutropenia associated with fever and/or infection. One patient in cohort 1 had to be admitted for pain control caused by a bone fracture. Another patient in cohort 2 was admitted with dehydration. A total of one hospitalization occurred in cohort 1, five hospitalizations in cohort 2, and two in cohort 3. No hospitalizations were observed in cohort 4.

Nonhematologic toxicity

Grade 4 nonhematologic toxic effects were not observed in any course in any patient. Nausea, vomiting, stomatitis, diarrhea, paresthesias, and excessive tearing were among the most commonly observed nonhematologic toxic effects (Table 3). Fatigue and fluid retention were not significant problems. Grade 1 or 2 palmar-plantar erythrodysesthesias (hand-foot syndrome) were observed in two patients.

Table 3. Nonhematologic Toxic Effects for All Courses According to Maximum Grade
ToxicityMaximum gradeNo. of patients (n = 19)No. of courses (n = 149)
Hand-foot syndrome2210
Excessive tearing348

Dose Modifications

Dose reduction of docetaxel was required in 13 courses received by a total of 9 patients, mostly because of neutropenic fever. Stomatitis was the reason for a dose reduction in two courses. One patient required a dose reduction because of stomatitis and neutropenic fever. No dose reductions were required for any of the patients in cohort 4.

The recommended doses for a Phase II study were deemed to be 72 mg/m2 of docetaxel, 10.0 mg/m2 of eniluracil, and 1.0 mg/m2 of oral 5-FU. At this dose level, the regimen was well tolerated. Grade 3 or 4 hematologic and nonhematologic toxic effects were not reported during any of the 25 courses received by 4 patients at this dose level (cohort 4).


Evaluation of response was not considered the primary end point of this study. However, significant antitumor activity was observed, with a total of 2 complete, 9 partial, and 4 minor responses among 15 patients evaluated for response. Four patients with bone disease only could not be evaluated for response. However, three of those patients had improvement of their symptoms with a decrease in their pain level as well as a decrease in tumor marker levels. The fourth patient had evidence of disease progression after two cycles of chemotherapy. Responses were observed in all four cohorts. Patients had evidence of response in soft tissue, bone, and visceral sites. The lymph nodes and lungs were the sites of metastatic disease in the two patients who were reported to have a complete response. Twelve patients were removed from the study because they had achieved the maximum response to chemotherapy, five patients because of toxicity, and two because of disease progression. At last follow-up, three patients have died of disease progression.


This study demonstrated that docetaxel can be safely combined with oral eniluracil and 5-FU at doses of 72, 10.0, and 1.0 mg/m2, respectively. Docetaxel is known for its noncumulative dose-related neutropenia. Febrile neutropenia has been reported to occur in approximately 12% of breast carcinoma patients treated with docetaxel.9 Conversely, oral eniluracil and 5-FU, at doses of 10.0 and 1.0 mg/m2 or 11.5 and 1.15 mg/m2, have been reported to cause minimal myelosuppression and no episodes of febrile neutropenia in breast carcinoma patients.16, 17 In our study, the observed episodes of febrile neutropenia could have very well been attributed to the escalating doses of docetaxel. However, the finding that febrile neutropenia was not reported at the highest docetaxel dose combined with the decreased doses of oral eniluracil and 5-FU (10.0 and 1.0 mg/m2) could indicate that febrile neutropenia was related more to the combination than to any single drug.

Docetaxel has been evaluated previously in combination with 5-FU given as a continuous infusion or intravenous bolus every 3–4 weeks.12–15 The dose-limiting toxicities in those studies were neutropenia and mucositis. In our study, even though mucositis was reported, it was not considered to be of major importance. In most previous studies, the dose of docetaxel either was not escalated or was associated with significant toxicity when given beyond 60 mg/m2. In our study, no Grade 3 or 4 toxicity was observed at 72 mg/m2 of docetaxel, 10.0 mg/m2 of oral eniluracil, or 1.0 mg/m2 of oral 5-FU. This can be explained by the finding that this new oral combination of eniluracil plus 5-FU is associated with an improved toxicity profile compared with intravenous 5-FU.

Although response rate was not the primary end point of this study, antitumor activity, including two complete responses, was observed with this combination, suggesting a possible additive or even synergistic effect with these agents. However, that would have to be further evaluated in a Phase II or III study. Docetaxel was also recently evaluated in combination with capecitabine, an oral prodrug of 5-FU. Capecitabine was designed to mimic continuous infusion 5-FU, and it had been shown to be an active and tolerable treatment for patients with metastatic breast carcinoma.21 The combination of oral capecitabine, 1250 mg/m2 twice daily on Days 1–14, and intravenous docetaxel, 75 mg/m2 on Day 1 only, was compared in a large Phase III study to intravenous docetaxel, 100 mg/m2, in the treatment of metastatic breast carcinoma patients who had no response to anthracycline-based therapy. The results of the study favored the combination over docetaxel alone in terms of response rate, time to progression, and survival. However, the study lacked a capecitabine-only arm that would have enabled demonstration of the superiority or inferiority of this agent compared with docetaxel or the combination of the two drugs.22

In conclusion, the evaluation of various chemotherapy combinations to increase antitumor activity and thus increase the survival of patients continues to be a major area of research. The combination of docetaxel with oral eniluracil and 5-FU has been shown to be safe and well tolerated and to have promising activity. It would be of interest to evaluate this combination in larger Phase II and III studies to further document its activity and possible role in the treatment of breast carcinoma.