Abstract
Abstract 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. Patient inclusion criteria: 21-80 years old, more than 3 month of life expectancy, advanced breast cancer in progression after, at least, anthracyclines, taxanes and capecitabine treatments, at least one lesion according to RECIST criteria, ECOG scale β2, adequate bone marrow, hepatic, and renal function, normal calcemia, signed informed consent. Treatment: CY, 50 mg p.o./day + CEL, 200 mg p.o. bid. Study design: The trial has two stages with a final number of 25 patients, looking for a 25% general response rate (≥ error=0.10; ≤ error=0.05). 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. The time of permanence varied from 4 to 64 weeks (median=13). Presently, 4 patients are still in treatment. It was observed stable disease (SD) in 9/13 patients that lasted from 12 to 64 weeks (median=18) and partial response (PR) in 1/13. 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 2/10 patients, a worse score in 3/10 and a better one in 5/10. The % of circulating CEPs showed a significant increase in non-responder patients (p=0.008) The serum VEGF concentration decreased as a function of time (p=0.004). Patients with the lowest VEGF/TSP-1 ratios showed the highest permanence. We conclude that the treatment showed a low toxicity profile, the therapeutic response consisted of SD during different periods of time, and one PR with no modifications or improvement of the performance status in a high proportion of patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1749. doi:1538-7445.AM2012-1749
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