360 Phase I/II study with paclitaxel in combination with weekly high dose 5-FU/Folinic acid in the treatment of metastatic breast cancer

Abstract

Introduction Based on the results of a phase II study with a weekly (x6) schedule of a 24 h infusion of high dose 5-FU/Folinic acid (HDFU/FA) demonstrating high efficacy (RR 41% 13/32 pts) and low toxicity in intensively pretreated metastatic breast cancer patients (pts), we added Paclitaxel (P) to HDFU/FA in a phase I/II trial. P was chosen because of its activity in pretreated metastatic breast cancer pts, different mode of action than HDFU/FA and the lack ofoverlapping hematologic toxicities between the combination partners. Since 9/93, 51 pts with at least one prior chemotherapy regimen were entered. Treatment Pts were treated with HD5-FU (24 h infusion)/FA (2 h infusion prior to FU) weekly for six weeks (dl, 8, 15, 22, 29, 36) and P (3 h infusion) was administered additionally on day 1 and day 22. Each cycle comprised of six weeks followed by two weeks rest. Number of cycles depending on response and toxicity. All pts were treated under outpatient conditions using i. v. port systems and portable pumps. During Phase I we chose the following dose levels (dl): Fixed doses of FA dl1–4 500 mg/m 2 followed by HDFU 24 h infusion dl1: 1.5, dl2: 1.8, dl3 and d14: 2.0 g/m 2 .3 h infusion of P, given prior to HD5-FU/FA on d.l and d.22 dl1–dl3: 135, d14: 175 mg/m 2 . Dl4 was chosen to be further evaluated during phase II. Patient Characteristics 51 pts entered this ongoing trial. Up to now 48 pts were evaluable for response and toxicity. 12 ps entered dl1–3 (4 pts each dl) and 39 pts dl4; age 47 yrs (26–63). WHO PS 1 (0–2), metastatic disease sites 2 (1–4). All pts had bidimensionally measurable disease. Pretreatment Pts had adjuvant chemotherapy 17/51, prior chemotherapy for metastatic disease 12/51, chemotherapy both adjuvant and for metastatic disease 22/51; prior treatment with anthracyclines 34/51, resistance to anthracyclines with disease progression while treatment prior to study entry 29/51. Toxicity (n = 51). No dose limiting toxicities occurred during dl1–3. 153 treatment cycles at dl4 had the following toxicities (WHO grade) in (n) cycles: leucopenia 3°/4° (28); mucositis 2° (49); diarrhea 2° (35), 3° (15); hand-foot syndrome 2° (85); PNP 2° (41); nausea/vomiting 2° (37); myalgia 2° (66). Results (n = 48). CR 4% (2/48), PR 58% (28/48), SD 34% (16/48), PD 4% (2/48). RR (Response rate) 62%, 95% confidence interval 48–76%. Responses (PR) at dl1–3: 2/4 patients. Response concerning 29 patients with anthracycline refractory disease (26 pts were evaluable for response so far): RR 58% (15/26),95% confidence interval 3878%. Time to maximum response 2 months (1–5), remission duration 8+ months (2–11). Median survival time not yet reached. Conclusions The combination of P with weekly HDFU/FA is well tolerated and indicates high efficacy also in anthracycline refractory metastatic breast cancer. In addition the regimen can safely be administered under outpatient conditions.