This article describes the design and early results of an open-label, nonrandomized phase I/II trial of oral UFT plus leucovorin therapy in combination with bolus injections of epirubicin and cyclophosphamide in patients with advanced or metastatic breast cancer. This study was designed as a cohort dose-escalation study with the principal aims being to determine dose-limiting toxicity, overall toxicity, maximum tolerated dose, tumor response, and time to disease progression.
ABSTRACT: This article describes the design and early results of an open-label, nonrandomized phase I/II trial of oral UFT plus leucovorin therapy in combination with bolus injections of epirubicin and cyclophosphamide in patients with advanced or metastatic breast cancer. This study was designed as a cohort dose-escalation study with the principal aims being to determine dose-limiting toxicity, overall toxicity, maximum tolerated dose, tumor response, and time to disease progression. Currently there are 22 patients randomized in the study. Overall response rate to date is 56% (66% in the locally advanced group). Based on the preliminary data, the dose-limiting toxicity appears to be neutropenia and the optimum dose of UFT for use in a phase II study appears to be 300 mg/m². [ONCOLOGY 14(Suppl 9):47-49, 2000]
The Royal Marsden Hospital has developed a chemotherapeutic regimen consisting of continuous ambulatory fluorouracil (5-FU) with injections of epirubicin (Ellence) and cisplatin (Platinol) administered every 3 weeks. This regimen has excellent activity in patients with carcinoma of the breast, with response rates of 86% in patients with advanced disease. A subsequent study has shown that cyclophosphamide (Cytoxan, Neosar) can readily be substituted for cisplatin in this combination with similar efficacy, less toxicity, and no inpatient requirements. Response rates for epirubicin/cyclophosphamide/5-FU (EcycloF) were 63% for metastatic disease and 83% for locally advanced disease.
The principal disadvantage of the infusional regimen is the need for Hickman lines, which are associated with complications such as thrombosis, infection, and pneumothorax. Complication rates of up to 13% have been reported in some series. Therefore, the availability of an effective oral 5-FU agent to use in combination could potentially be advantageous to patients and eliminate the costs associated with the use of ambulatory pumps and Hickman lines.
This study was designed to evaluate the use of oral UFT (uracil and tegafur) plus oral leucovorin (a combination being developed under the trade name Orzel), (which has activity comparable to intravenously administered 5-FU), in combination with epirubicin and cyclophosphamide (ECU) in patients with locally advanced or metastatic carcinoma of the breast. The primary objective was to determine the maximum tolerated dose and phase II dose of UFT. Additionally, secondary objectives included the evaluation of time to disease progression and response rate.
The study was designed as a nonrandomized, open-label, dose-escalation trial in patients with locally advanced or metastatic carcinoma of the breast. Inclusion criteria are detailed in Table 1. Patients with brain metastases are excluded from the study. The drugs were administered on an every-3-week dosing schedule for a maximum of six cycles as follows: epirubicin 60 mg/m² intravenously (IV) on day 1 every 21 days and cyclophosphamide 600 mg/m² IV and UFT orally days 1 through 14. In cohort 1, the starting dose for UFT was 250 mg/m² (taken in three divided doses); cohort 2 was 300 mg/m²; and cohort 3 was 350 mg/m².
At least six patients were treated in each cohort and the cohort size expanded according to toxicity.
Patients were assessed every 3 weeks for symptoms and side effects and, if applicable, tumor size. Radiologic assessments were performed every 6 weeks. Patients showing evidence of progressive disease or unacceptable toxicity were taken off study.
To date, 22 patients have been randomized: six with locally advanced disease and 16 with metastatic disease. The median age of patients in the study is 53 years (range: 34–73 years). Of the patients being treated for metastatic disease, 10 had received no prior chemotherapy, three had received prior adjuvant cyclophosphamide/methotrexate/5-FU, and three had received neoadjuvant epirubicin/cisplatin/5-FU.
Of the 22 randomized patients, 17 have completed two or more cycles of chemotherapy. The response rate among these patients was 56%. In the patients presenting with locally advanced disease, the response rate was 66%; there was no progressive disease in this group. In total, 17 of those patients have completed treatment: of these, 10 patients completed the full six courses, one patient received five courses, two patients received four courses, one patient received three courses, one patient two courses, and two patients one course only. Of patients stopping prematurely, two stopped because of progressive disease, one stopped because of noncompliance, three stopped because of toxicity, and one stopped because of problems swallowing the tablets.
There were two dose-limiting toxicities in cohort 2, so the cohort was expanded to include 12 patients. The main toxicities experienced were neutropenia and gastrointestinal toxicities, which are summarized in Table 2 and Table 3. Although cohort 3 has only recently opened, two of three of the Royal Marsden Hospital patients have suffered dose-limiting hematologic toxicity and grade 3 gastrointestinal toxicity.
This paper describes the design and preliminary results of the epirubicin/cyclophosphamide/UFT (ECU) study. The primary objective was to determine the maximum tolerated dose and phase II dose of UFT in this regimen. The dose-limiting toxicity appears to be neutropenia. From the results to date, a UFT dose of 300 mg/m² (ie, that used in cohort 2) would appear to be the most appropriate to employ in a phase II study. The other main toxicity experienced was gastrointestinal, principally diarrhea and abdominal cramps.
The stated secondary objectives of the study were to evaluate time to progression and response rate. To date, there are insufficient data to comment on time to progression. Overall response rate was 56%, with a 66% response rate in the group of patients treated for locally advanced disease (however, numbers in this group are small [n = 6]). This is not much different from the 63% response rate in metastatic disease quoted for the EcycloF regimen. This is encouraging as it suggests that the UFT combination has equivalent efficacy to the infusional regimen without the potential complications of the Hickman line.
In summary, the ECU combination would appear to have activity in locally advanced and metastatic breast cancer. However, toxicity with a UFT dose above 300 mg/m² in combination with epirubicin and cyclophosphamide is probably unacceptable. The dose of UFT recommended for phase II studies in this combination is 300 mg/m².
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