Tumori, 80: 273-275, 1994 DOSE INTENSIFICATION OF CHEMOTHERAPY IN ADVANCED BREAST CANCER: A FEASIBILITY PHASE II STUDY Paolo Pedrazzoli1, Claudio Zamagni2, Angelo Martoni 2 , Anna Maria Capotorto 3 , Gian Antonio Da Prada\ Lorenzo Pavesi1, Pietro Preti1, Giorgio Lelli 3 , Franco Pannuti 2 , and Gioacchino Robustelli della Cuna 1 ('Division of Medical Oncology, "Clinica def Lavoro" Foundation, JRCCS, Pavia. 'Division of Medical Oncology, Ospedale S. Orsola-Malpighi, Bologna. 'Division of Medical Oncology, Casa Sollievo de/la Sofferenza, S. Giovanni Rotondo, (Foggia) Aims and background: Dose intensification of chemotherapy is associated with increased response rates in advanced breast cancer. Achievement of dose incrementation is usually limited by drug-dependent bone marrow toxicity. The recent availa- bility of recombinant human colony-stimulating factors (CSFs) have made it possibile to evaluate their potential in ameliorating chemoterapy-induced myelosuppression. The aim of this study was to evaluate tolerability and effectiveness of an intensified mitoxantrone, methotrexate and mitomycin- C (3M) regimen, given with G-CSF support in patients with advanced breast cancer (ABC). Study design: Twenty-eight eligible patients with advanced breast cancer were treated with mitomycin -C (7 mg/sqm iv every 4 weeks), methotrexate (35 mg/sqm iv) and mitoxantrone (7 mg/sqm iv every 2 weeks) for 6 cycles. Recombinant human granulocyte colony- stimulating factor (r-HuG-CSF, Filgrastim) (5 μg/kg/day) was given subcutaneously from day 2 to day 12 after each chemo- therapy administration to prevent leukopenia. Results: Of the 27 evaluable patients, 4 had complete response and 14 achie- ved partial response; the overall response rate was 63% (95% Cl; 46.8%-82.2%). The median duration of response was 8 months (range, 4-13+). Chemotherapy-related toxicity was mild: only 3 out of 163 courses had to be postponed due to myelotoxidty. Conclusions: The 3M regimen given at 2- week intervals is a feasible, active and well tolerate! treatment in patients not previously treated for metastatic breast cancer. Key words: Metastatic breast cancer, chemotherapy, granulocyte colonystimulating factor. Increasing the dose or frequency of administration of cytotoxic drugs leads to an improved therapeutic out- come of breast cancer, in metastatic disease and in adjuvant setting (5, 9, 14). However, increasing dose intensity is usually accom- panied by a concurrent increase in toxic effects, which generally limit the degree of dose escalation that might be achieved in clinical practice. The major dose-limiting toxic effect is myelosuppression, which can cause life- threating infection or hemorrhage. In recent years the availability for in vivo use of hemopoietic growth factors, a family of glycoproteins that stimulate proliferation and differentiation of hemopoietic progenitors as well as the biologic activity of their mature off springs, offers the possibility to over- come drug-related myelosuppression (4). In particular granulocyte colony-stimulating factor (CSF) has been shown to produce a lower absolute granulocyte nadir and shorten duration of absolute neutropenia in patients with various malignancies receiving standard- dose chemotherapy (2,7). Furthermore, the availability of CSFs allows direct testing of more intensive chemo- therapy regimens (1, 3, 6). We evaluated tolerability, as well as effectiveness, of an accelerated mitoxantrone, methotrexate and mito- mycin-C (3M) regimen, given with filgrastim support in patients with advanced breast cancer (ABC). Dose intensification over the originally described 3M regi- men (11) was obtained by reducing intervals between courses to 2 weeks. Patients and methods Women with histologically documented ABC at first relapse were enrolled in the study. All patients were required to have measurable or evaluable disease and a WHO performance status of 2 or less. In addition, patients had to meet standard criteria for renal, hepatic and hematologic status and had received no previous cytotoxic chemotherapy for advanced disease. Radia- tion therapy on involved bone segments was allowed. Prior to the start of chemotherapy, an interval was required of at least six weeks from adjuvant chemo-or endocrine therapy. Patients with a history of prior malignancy or severe concomitant medical or psychia- tric illness, documented brain metastasis or bone invol- vement as the only site of disease were ineligible. The study was approved by the ethic committees of the indi- vidual participating institution, and signed informed consent was obtained from all patients. Twenty-eight patients were enrolled in the study. To whom correspondence should be addressed: Dr. Paolo Pedrazzoli, Division of Medical Oncology, Fondazione Clinica del Lavoro, Via S. Boezio 26, 27100 Pavia, Italy. Received February 15, 1994; revised May 16, 1994. 273