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© 2000 American Society for Clinical Oncology Low-Dose Oral Fluorouracil With Eniluracil as First-Line Chemotherapy Against Advanced Breast Cancer: A Phase II StudyFrom the Royal Marsden Hospital, Sutton and London; The Kent Cancer Centre, Maidstone; Royal Bournemouth Hospital, Bournemouth; and Glaxo Wellcome Research and Development, Middlesex, United Kingdom. Address reprint requests to Ian E. Smith, MD, Department of Medicine, Royal Marsden Hospital, Fulham Road, London SW3 6JJ.
PURPOSE: Eniluracil (776C85) is an effective inactivator of dihydropyrimidine dehydrogenase that allows continuous low-dose oral fluorouracil (5-FU) to be given with predicable oral bioavailability. We have assessed this as first-line oral chemotherapy for patients with advanced/metastatic breast cancer. PATIENTS AND METHODS: Patients with histologically proven, locally advanced or metastatic breast cancer without previous chemotherapy for advanced disease were entered onto this open-label phase II study. Patients received oral 5-FU 1.0 mg/m2 with eniluracil 10 mg/m2, both given twice daily for the first 28 days of each 35-day cycle, continuing until disease progression or unmanageable toxicity. RESULTS: Thirty-three patients were entered, with a median age of 53 years. Sixteen partial responses were seen in twenty-nine assessable patients (55%; 95% confidence interval, 37% to 73%), including responses in four (40%) out of 10 patients who had received prior adjuvant 5-FU. Seven patients had stable disease for at least 3 months with symptom improvement. Median response duration was 14 months (range, 10 to 18+ months). Toxicity was low. There were only two episodes of drug-related grade 3 nonhematologic toxicity (diarrhea and infection), and only 6%, 3%, and 3% of patients developed granulocytopenia, thrombocytopenia, and neutropenic sepsis, respectively. Mild (grade 1/2) diarrhea occurred in 39% of patients, hand-foot syndrome in 15%, nausea in 27%, and mucositis in 18%. Toxicity-associated delay and dose reduction occurred in only 2% and 5% of courses, respectively. CONCLUSION: First-line treatment with the combination of oral 5-FU and eniluracil has high activity in patients with advanced breast cancer comparable with the most active conventional cytotoxic agents but with strikingly less toxicity.
FLUOROURACIL (5-FU) has been widely used in the treatment of patients with breast cancer for several decades. It is usually given as a bolus injection, although it is recognized that this is unlikely to be the best schedule for a cycle-specific S-phase–dependent drug with a short half-life of 10 to 20 minutes.1 Continuous infusion 5-FU chemotherapy has been developed in an attempt to improve efficacy.2 A series of small phase II studies of continuous infusion 5-FU in metastatic breast cancer, usually in heavily pretreated patients, have reported response rates of up to 54%,3 with an overall response rate in all studies of 29%.4 These included some responses in patients previously treated with bolus 5-FU. Recently, a retrospective series of continuous infusion 5-FU in 106 heavily pretreated patients with metastatic breast cancer reported a response rate of 21%, with a further 29% of patients achieving stable disease and 44% of patients, overall, achieving useful symptomatic improvement.5 Continuous infusion single-agent 5-FU has never been reported as first-line treatment for patients with advanced breast cancer. Oral administration has obvious practical and economic advantages over long-term continuous infusion treatment. The problem with oral 5-FU is its highly variable bioavailability, ranging from 0% to 80%.6-8 Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme involved in the catabolism of 5-FU; it is found mainly in the liver but also in other organs, including the intestinal mucosa where its activity is particularly variable.9,10 It is likely that this largely explains why oral 5-FU bioavailability is so unpredictable. Eniluracil (776C85), a uracil analog with an ethynyl substitution at the 5 position, acts as an effective inactivator of DPD.9 In preclinical studies, a single oral dose of eniluracil achieved near total inhibition of DPD activity for 6 hours,9 increased the plasma half-life of oral 5-FU 10-fold, and produced 100% oral bioavailability.11 In a phase I clinical trial, single daily oral doses of eniluracil inhibited DPD without toxicity.12 In another phase I study with eniluracil plus 5-FU given orally for 5 days every 28 days, the terminal half-life (mean ± SD) of 5-FU was prolonged to 4.5 ± 1.6 hours, and the maximum-tolerated dose of 5-FU was 25 mg/m2 daily for 5 days with neutropenia being the principal toxicity.13 Therefore, low-dose oral 5-FU with eniluracil is potentially a simpler and more convenient alternative to continuous infusion 5-FU with its risk of central line complications.14 The activity of this combination in patients with advanced breast cancer refractory to anthracyclines and taxanes is being assessed elsewhere in a multicenter phase II study.15 Here, we report a phase II study to assess oral 5-FU with eniluracil as first-line chemotherapy for patients with advanced/metastatic breast cancer.
Patients Women aged 18 years or older with histologically confirmed adenocarcinoma of the breast (locally advanced and/or metastatic) were eligible for entry onto this study (FUMB2005), provided they fulfilled the following treatment requirements: no previous chemotherapy for the treatment of advanced breast cancer or adjuvant chemotherapy in the 12 months before the first dose of the study drug; no prior treatment with continuous infusion 5-FU (ie, for more than 4 consecutive days); no previous hormonal therapy in the week before the first dose of study drug; and no treatment with flucytosine or any investigational drug in the 2 weeks before the first dose of study drug. In general, patients were offered entry onto this study for one of the following reasons: metastatic disease that was not immediately life threatening (where standard combination chemotherapy would be recommended); reluctance to undertake conventional intravenous chemotherapy. At least one bidimensionally measurable lesion was required. Other eligibility criteria included Karnofsky performance status  70; life expectancy 12 weeks; no known CNS metastases; absolute granulocyte count 1.5 x 109/L, platelet count 75 x 109/L, haemoglobin 9 g/dL; estimated creatinine clearance 50 mL/min as calculated by the modified Cockcroft and Gault formula; total bilirubin  1.5 times upper limit of normal unless caused by tumor; alanine aminotransferase 3 times upper limit of normal unless caused by tumor; no history of another malignancy; and no history of malabsorption syndrome or other disease significantly affecting gastrointestinal function.
Study Design
Drug Dosage and Administration
Dose Modifications for Toxicity
Treatment delay.
Patients were required to meet all the following criteria to begin the next course of treatment: platelets
Dose Modifications for 5-FU
Because eniluracil changes the metabolism of 5-FU such that it is excreted primarily by the kidneys, further modification of the 5-FU dose was required for patients with an estimated creatinine clearance of 40 to 49 mL/min on the following basis: 100% 5-FU dosage was reduced to 80%; 80% 5-FU dosage was reduced to 60%; and 60% 5-FU dosage was reduced to no further treatment.
Once the mg/m2 dosage of 5-FU was decreased, it remained at that dosage or was reduced further on subsequent dosing, as described above. However, patients who completed one 5-week course at the 60% dosage level without experiencing any grade 2 or greater drug-related toxicity and had an estimated creatinine clearance of Treatment with study drugs was to be withdrawn if a patient developed both grade 4 hematologic and grade 4 nonhematologic toxicity. If the patient was allowed to continue treatment, the mg/m2 dosage of 5-FU was reduced by 50%, and the actual dose was calculated as described above. Treatment was to be withdrawn if the patient required a dosage reduction to 60% based on toxicity and had an estimated creatinine clearance of 40 to 49 mL/min. At the investigator’s discretion, treatment could be withdrawn for patients with grade 4 nonhematologic toxicity.
Dose Modifications for Eniluracil
Assessment of Response and Toxicity
Response was defined by modified SWOG criteria,16 and response duration was measured from the start of treatment. Measurable disease included lesions bidimensionally measurable by one of the following methods: direct measurement; medical photograph (skin or oral lesions) or plain x-ray, with at least one diameter
Patients assessable for response were defined as those patients who took at least 75% of the total prescribed amount of study drug in course 1 (or a total of 21 days on which any drug was taken) and had at least one disease assessment after baseline. Complete response was defined as complete disappearance of all measurable and assessable disease with no new lesions based on at least two consecutive assessments at least 4 weeks apart. Partial response was defined as patients with at least one measurable lesion who had
Statistical Assessment This study was approved by the research ethics committee of each of the institutions involved. Written informed consent was obtained from all patients.
Patient Characteristics Thirty-three patients were entered onto the trial, with a median age of 53 years (range, 37 to 81 years). Eighteen patients (55%) had received prior adjuvant chemotherapy, including 10 (30%) who had received prior adjuvant 5-FU therapy. Three patients (9%) had locally advanced disease, and the remaining 30 (91%) had metastatic disease. Details of patient characteristics and sites of disease are listed in Table 2.
Response Details of response are listed in Table 3. Four of the 33 patients were nonassessable for response for the following predefined protocol reasons: two patients had less than 21 days of the first course of treatment (one developed grade 4 respiratory infection, and the other withdrew herself to switch to conventional therapy); one had no measurable baseline disease (but continued on treatment for 3.5 months with stable disease); and one withdrew herself from the study at the end of her first 28-day course. Of the remaining 29 patients, there were no complete responders and 16 partial responders (55%; 95% CI, 37% to 73%). Seven patients (24%) had stable disease for at least 3 months with symptom improvement, and the remaining six patients (21%) had progressive disease. Responses were seen in all sites of disease except bone. Results on an intent-to-treat basis involving all 33 patients were as follows: 16 patients had partial response (48%; 95% CI 31% to 66%), 10 had stable disease (30%), and seven had progressive disease or were nonassessable (21%).
Response Duration The median response duration was 14 months, with a minimum of 10 weeks and a maximum of 18 months and continuing (Fig 1). Stable disease for the seven patients involved lasted a median of 6 months (range, 4.5 to 11+ months). The median time to disease progression for all 33 patients was 7 months (Fig 2).
Toxicity and Compliance This combination of low-dose 5-FU with eniluracil was, in general, well tolerated. Only two patients (6%) had grade 3 granulocytopenia, and one patient had grade 3 thrombocytopenia (Table 4). Twelve patients (36%) had grade 1/2 anaemia, six patients (20%) had grade 1/2 granulocytopenia, and 12 patients (36%) developed grade 1/2 thrombocytopenia. One patient had severe grade 4 neutropenic infection, a streptococcal pneumonitis against a background of pre-existing pulmonary metastases, and stopped treatment after 16 days. There were two episodes of drug-related grade 3 nonhematologic toxicity (one case of lower respiratory tract infection and one case of diarrhea); specifically there were no grade 3/4 toxicities for hand-foot syndrome or mucositis (Table 5). The most common grade 1/2 toxicities were malaise, reported in 15 patients (45%), and diarrhea, reported in 13 patients (39%). Only five patients (15%) experienced grade 1 hand-foot syndrome. Compliance was good, and only two patients (6%) withdrew themselves without a clinical indication.
Dose Reductions and Delays One hundred eighty-six courses of treatment were given to 33 patients. The median number of courses per patient was six (range, one to 15 courses). Of these 186 courses, only four (2%) were delayed because of toxicity, and only 10 (5%) required dose reductions because of toxicity. The dose reductions required because of toxicity included diarrhea, granulocytopenia, thrombocytopenia, and mucositis.
These results suggest a high activity for low-dose oral 5-FU with eniluracil, and the response rate of approximately 50% in previously untreated patients is comparable with that of the most active standard cytotoxic drugs used in breast cancer. Doxorubicin, the most widely used agent and a yardstick for assessment, has a reported single-agent response rate of 40% to 50% in previously untreated patients.18-20 Epirubicin, a doxorubicin analog, and mitoxantrone, an anthraquinone derivative, are both widely used in Europe; their respective response rates in previously untreated patients are reported as 62%21 and 35%.22 Among the newer agents, paclitaxel was initially reported as having a 56% to 62% response rate in anthracycline-pretreated patients23,24 at a dose of 250 mg/m2 in a 24-hour infusion; subsequent studies and trials at a lower dose of 175 mg/m2 have shown lower response rates of 29%.25 Randomized data indicate a higher response rate of 42% for paclitaxel when given in combination with trastuzumab (Herceptin; Genentech, San Francisco, CA) in a pretreated HER2-positive patient subgroup.26 Docetaxel, one of the most active current agents against breast cancer, has a reported response rate of 72% in previously untreated patients at a dose of 100 mg/m2 but with severe toxicity. When the dose was reduced to 75 mg/m2, the response rate was 50% but still with significant toxicity.27 Vinorelbine, a semi-synthetic vinca alkaloid, has a response rate in previously untreated patients of 41% in two studies28,29 and 38% in a further study in patients 60 years of age.30 A striking additional advantage for low-dose oral 5-FU with eniluracil over other active agents is its low toxicity. Grade 3/4 hematologic toxicity was rare, and only one patient (3%) had a grade 4 neutropenic infection, a streptococcal pneumonitis against a background of pre-existing pulmonary metastatic disease. There were two episodes of drug-related grade 3 nonhematologic toxicity, one case each of diarrhea and lower respiratory tract infection. Specifically, anticipated toxicities were mild (grade 1/2); these included diarrhea (39%), mucositis (18%), and hand-foot syndrome (15%, all grade 1). Because of this, responding patients were able to continue on treatment for many months, up to a maximum so far of 18 months. Low toxicity with eniluracil/5-FU has also been reported in a series of 35 patients previously treated with anthracyclines and some also with a taxane.15 Even in this heavily pretreated group, only two patients each experienced grade 4 granulocytopenia or thrombocytopenia. Diarrhea (41%) was the most commonly reported toxicity, but only three patients experienced grade 3/4 diarrhea. No other serious toxicities were seen, and only 11% of courses were delayed because of toxicity. Clinical activity in this group was inevitably less, but three (11%) of 27 assessable patients achieved partial response, and 14 (52%) achieved stable disease, with a median progression-free survival of 30 weeks. Eniluracil/5-FU (10:1 ratio) at 5-FU doses of 1.0 or 1.5 mg/m2 twice daily for 28 days of a 5-week course has also been reported as first-line treatment in the management of metastatic colorectal carcinoma, with partial response rates of 24% and stable disease in 47% of 45 patients.31 Grade 3/4 toxicities were low and included diarrhea (30%), stomatitis (3%), and granulocytopenia (3%). Low toxicity was confirmed in a further similar study for which response rates have not yet been published.32 Against this background of low toxicity, it is reasonable to consider that the 30% of patients who only achieved stable disease (no progression for at least 3 months with improvement in pre-existing symptoms) in our study also benefited from treatment. The analogy here is with oral endocrine therapy, where approximately 30% of unselected patients achieve objective tumor response, but a further 20% also show stable disease, with an overall clinical benefit of approximately 50%. By these criteria, continuous oral 5-FU and eniluracil in this study achieved an objective response rate of approximately 50% but an overall clinical benefit nearer 80%. Other oral agents that mimic continuous infusion 5-FU are also currently under study or are registered for the treatment of advanced breast cancer. UFT is a similar oral fluorinated pyrimidine combination consisting of uracil and tegafur (1-[2-tetrahydrofuryl]-5-FU) in a molar ratio of 4:1. Uracil partially inhibits DPD and enhances 5-FU concentration, possibly more specifically within tumor than with normal tissues. UFT is already commercially available in some parts of the world, including the Far East, Spain, and Portugal. Phase II activity has been shown in combination with leucovorin against metastatic colorectal carcinoma,33 and UFT is currently under study against advanced breast cancer. Capecitabine is an oral, selectively tumor-activated fluoropyrimidine carbamate and acts as a prodrug for 5-FU. A 20% partial response was reported in 135 patients with paclitaxel-refractory breast cancer, with a further 40% achieving stable disease.34 Capecitabine has also been reported as having a higher response rate than cyclophosphamide, methotrexate, and fluorouracil (CMF) (25% v 16%, respectively) in a randomized phase II study involving patients over the age of 55.35 Capecitabine, unlike eniluracil/5-FU, is associated with grade 3/4 plantar palmar syndrome in a minority of patients. The next step is the assessment of low-dose oral 5-FU with eniluracil as part of combination chemotherapy regimens. Studies are underway, looking particularly at combinations with doxorubicin and cyclophosphamide, based on standard cyclophosphamide, doxorubicin, and fluorouracil schedules. The main problem with this approach is that one of the main advantages of 5-FU/eniluracil, the low incidence of side effects, could be lost in combination chemotherapy. It is important not to overlook the possibility that oral 5-FU with eniluracil might have an important role as single-agent palliative therapy, particularly in frail patients, or those with indolent metastatic disease no longer controllable with endocrine therapy but not immediately life-threatening. Trials addressing this question by comparing oral 5-FU and eniluracil with conventional combination chemotherapy in this context seem appropriate.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
