Breast Cancer Research and Treatment 11:269-271 (1988) © Kluwer Academic Publishers - Printed in the Netherlands

Brief communication

Cisplatin and 5-flnorouracil in refractory breast cancer patients: a phase II study

Domenico Amoroso, Paolo Pronzato, Gianfilippo Bertelli, Pietro Gallotti, Gisella Pastorino, Maria Pia Cusimano, Marco Merlano, Pier Franco Conte and Riccardo Rosso Istituto Nazionale per la Ricerca sul Cancro, Divisione di Oncologia Medica; North West Oncology Group (G.O.N.O.); Vie. Benedetto XV, 10-16132 Genova, Italy

Key words: breast cancer, chemotherapy, cisplatin/5-fluorouracil synergism, salvage therapy

Summary

24 patients with a median of 3 prior chemotherapy regimens were treated in our department with cisplatin 20 mg/m 2 (with pre- and posthydration) and 5-fluorouraci1200 mg/m 2 i.v. on day 1-5, every three weeks. 23 patients are evaluable; one had early death. 4 patients (17%) achieved a partial response, 8 had stable disease, and 11 progressed. Toxicity observed was moderate and no renal toxicity was noted. This study therefore shows tolerable toxicity but limited usefulness of adding cisplatin to 5-fluorouracil according to this schedule in these highly pretreated patients.

Introduction

Breast cancer seems to be moderately sensitive to cisplatin (CDDP). Phase II studies of CDDP alone in pretreated patients have shown conflicting re- sults: some authors failed to demonstrate activity of CDDP therapy [1], while others observed a re- sponse rate ranging from 12 to 20% [2-4]. More interesting results were obtained in untreated pa- tients, both with CDDP alone [5, 6], and in combi- nation therapy [7].

CDDP and 5-fluorouracil (5-FU) in combination have demonstrated synergistic effects in experi- mental systems [8] and high efficacy in the treat- ment of various malignancies, such as non small cell lung cancer, colon carcinoma, and head and neck tumors.

We have carried out a study with CDDP and 5-FU given for 5 consecutive days, to evaluate ac-

tivity and toxicity of this combination in pretreated metastatic breast cancer patients.

Patients and methods

Twenty-four patients with histologic diagnosis of breast cancer and evaluable progressive disease on more conventional therapy, entered the study. Pa- tients were required to have normal renal, cardiac, and hepatic function, and performance status <3 (ECOG scale). Treatment schedule was the fol- lowing: CDDP (20 mg/m z) for 5 consecutive days was administered after prehydration (40 mg of fu- rosemide + 500 ml of saline infusion + 5 mEq/L of KC1 over 30 minutes). CDDP was given if diuresis was >200 ml/30 minutes. Posthydration consisted of 1.5 L of NaC1 solution + 5 mEq/L of KC1 over a 90 minute infusion. 5-FU (200 mg/m 2 for 5 consec- utive days) was administered by i.v. bolus after the

Address for offprints: Domenico Amoroso, M.D. Instituto Nazionale per la Ricerca sul Cancro, Viale Benedetto XV, 10-16132 Genova, Italy

270 A m o r o s o D et al.

end of posthydration. Methylprednisolone or Me- toclopramide were given at the time of CDDP in- fusion for nausea and vomiting control. This sched- ule was repeated every 3 weeks. Therapy was con- tinued until progression of disease occurred. Re- sponse and toxicity were assessed according to WHO criteria.

All patients had been pretreated with chemo- therapy regimens containing 5-FU; no patient had previously received CDDP. Characteristics of eli- gible patients are summarized in Table 1.

R e s u l t s

23/24 patients are evaluable for response and toxic- ity; one patient had early death. Complete re- sponse was never obtained. Four patients (17%, with a 95% confidence interval of 5-39 %) achieved a partial response (PR), two with lung metastases and the others with liver lesions. Responses lasted 6--8 months. Eight patients had stable disease (SD), and 11 progressed. One patient, whose re- sponse was classified as SD, obtained a substantial reduction of CEA levels after 4 courses of therapy (from 2400 mg/ml to 470 mg/ml). Median progres- sion-free survival for PR and SD patients was 6 months, with a median survival from beginning of therapy of 8 months.

Major toxicities observed were nausea and vom- iting, grade II-III, in 80% of patients, and leukope- nia, grade II-III, in 70% of patients. One patient experienced hair loss (grade II), and another devel- oped mucositis (grade II). No renal toxicity, mea-- sured by BUN or creatinine levels, was observed.

D i s c u s s i o n

According to in vitro and in vivo experiments, addi- tive or synergistic efficacy was observed when CDDP was used with other antineoplastic agents; however, the combination of CDDP with other drugs in pretreated breast cancer patients pro- duced only 20-36% response rates. The University of Pittsburgh [9] evaluated a combination with 5- FU plus CDDP (96 hours infusion) in 14 pretreated

Table 1. Characteristics of patients.

Characteristics N. of patients

Response

CR PR SD PD

Evaluable pts 23 Median age: 55 (29-72) Postmenopausal 23 Dominant site of metastasis:

soft tissue 5 bone 5 liver 5 lung 8

Prior chemotherapy, median of regimens: 3 (range 1-4) Median courses of CDDP and 5-FU: 3 (range 1-7)

2 3 - 2 3 2 2 1 2 2 4

metastatic breast cancer patients, obtaining 5 ob- jective responses. Nevertheless, toxicity was high, with nausea and vomiting in 100% of patients and acute renal failure in 3 patients.

The current study was undertaken to evaluate the activity of a CDDP and 5-FU combination for 5 consecutive days. Our modified scheduling was easily adaptable to outpatients, reducing the cost of hospitalization and improving patient compliance to therapy. Unfortunately, this report has failed to demonstrate an improved response rate by adding CDDP to 5-FU. The response rate observed with this schedule (17%) was low and comparable to single agent activity of 5-FU; however, our patients had far advanced disease and all had previously received 5-FU containing chemotherapy. Toxicity was moderate, and in particular this schedule pre- vented CDDP-related renal failures.

This study, showing a limited usefulness with acceptable toxicity of CDDP plus 5-FU in heavily pretreated patients, adds information to the debate on the role of CDDP in refractory breast cancer [101.

A c k n o w l e d g e m e n t s

Supported by a grant of Associazione Italiana per la Ricerca sul Cancro (A.I.R.C.).

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C D D P and 5-FU in breast cancer 271

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