Metronomic chemotherapy with cyclophosphamide (CY) and doxorubicin (DOX) inhibits tumor growth and metastases development of mouse mammary adenocarcinoma M-406.

LE MAINETTI,; MV FERNÁNDEZ ZENOBI, ; VR ROZADOS; OG SCHAROVSKY

San Antonio

Congreso; San Antonio Breast Cancer Symposium; 2011

Metronomic chemotherapy (MCT), the chronic administration at regular intervals, of low doses of chemotherapeutic drugs, without extended rest periods, allows chronic treatment with therapeutic efficacy and low toxicity. Its molecular target is mainly the endothelial cell which is less prone to develop drug resistance. The aim of the present two-stage, phase I/II trial study was to determine the safety and efficacy of MCT with Cy plus Cel in metastatic breast cancer (MBC) patients progressing after standard chemotherapy and to identify early markers of therapeutic response. Methods: Patient patient with advanced breast cancer, 21-80 years old, more than 3 month of life expectancy, in progression after, anthracyclines, taxanes and capecitabine treatments, at least one lesion according to RECIST criteria, ECOG 0, 1 or 2, normal hepatic and renal function, normal calcemia and blood count, signed informed consent. Treatment: oral CY, 50 mg/day + oral CEL, 400mg/day. Study design: The trial has two stages with a final number of 25 patients, looking for a 25% general response rate (β error=0.10; α error=0.05). Primary endpoint: Primary end point: clinical response, safety and tolerability. Toxicity: all the serious adverse events are registered by CTCAE criteria and followed until their resolution. Angiogenesis parameters: the serum level of vascular endothelial growth factor (VEGF) and thrombospondin 1 (TSP-1) were determined by ELISA, and the circulating endothelial cells (CECs) and circulating endothelial progenitor cells (CEPs) by flow cytometry. This protocol was authorized by the School of Medicine Bioethics Committee and by A.N.M.A.T. (National Regulatory Authority). During the first stage we have incorporated 13 patients. Patients time of permanence in the protocol varied from 4 to 64 weeks (median=13). Presently, 4 patients are still in treatment. It was observed stable disease (SD) in 10/13 patients that lasted from 2 to 56 weeks (mean=14.3; median=8). Treatment toxicity was very low: hematologic (2/13, grade I and II), gastric (4/13, grade I). There was no evidence of hepatic, renal or cardiac toxicities associated with the therapy. The performance status evaluated with the ECOG scale showed no modifications in 3/11 patients, a worse score in 2/11 and a better one in 6/11, during SD. The % of circulating CECs and CEPs showed no association with SD duration.. We conclude that the treatment showed a very low toxicity profile, the terapeutic response consisted of SD in a high proportion of patients, during different periods of time, with an improvement of the performance status.