Metastatic breast cancer patients treated with low-dose metronomic chemotherapy with cyclophosphamide and celecoxib: clinical outcomes and biomarkers of response

Background Preclinical results showing therapeutic effect and low toxicity of metronomic chemotherapy with cyclophosphamide (Cy) + celecoxib (Cel) for mammary tumors encouraged its translation to the clinic for treating advanced breast cancer patients (ABCP). Patients and methods A single-arm, mono-institutional, non-randomized, phase II, two-step clinical trial (approved by Bioethics Committee and Argentine Regulatory Authority) was designed. Patients received Cy (50 mg po.d) + Cel (200 mg p.o.bid). Patient eligibility criteria included: ABCP who progressed to anthracyclines, taxanes and capecitabine, ≤4 chemotherapy schemes, with good performance status. Several pro- and anti-angiogenic molecules and cells were determined as biomarkers. Informed consent was signed by all patients. Primary endpoint was clinical benefit (CB). Results Twenty patients were enrolled. Main clinical outcomes were prolonged disease stabilization and partial remission in 10/20 and 1/20 patients, respectively. CB was 55 %, and time to progression (TTP) was 21.1 weeks. Median TTP in patients who achieved CB was 35.6 weeks, and mean overall survival was 44.20 weeks. There were no grade 3/4 toxicities associated with treatment. Circulating endothelial cells (CECs) increased at the time of progression in patients who showed CB (P = 0.014). Baseline CECs and circulating endothelial progenitor cells showed marginal associations with TTP. Serum VEGF decreased (P = 0.050), sVEGFR-2 increased (P = 0.005) and VEGF/sVEGFR-2 ratio decreased during treatment (P = 0.041); baseline VEGF and VEGF/sVEGFR-2 were associated with TTP (P = 0.035 and P = 0.030, respectively), while sVEGFR-2 did not. Conclusions Treatment was effective, showing low toxicity profile and excellent tolerability. The combination had anti-angiogenic effect. Increased levels of CEC could be useful for detecting progression. Baseline VEGF and VEGF/sVEGFR-2 values could be useful as early predictors of response. Trial registration ANMAT#4596/09.Fil: Perroud, Herman A. Institute of Experimental Genetics. School of Medical Sciences. National University of Rosario; Rosario; ArgentinaFil: Alasino, Carlos María. Institute of Oncology of Rosario; ArgentinaFil: Rico, María José. Institute of Experimental Genetics. School of Medical Sciences. National University of Rosario; Rosario; ArgentinaFil: Mainetti, Leandro Ernesto. Institute of Experimental Genetics. School of Medical Sciences. National University of Rosario; ArgentinaFil: Queralt, Francisco. Institute of Oncology of Rosario; ArgentinaFil: Pezzotto, Stella Maris. Research Council of the National University of Rosario (CIUNR); ArgentinaFil: Rozados, Viviana R. Institute of Experimental Genetics. School of Medical Sciences. National University of Rosario; Rosario; ArgentinaFil: Scharovsky, O. Graciela. Universidad Nacional de Rosario. Consejo de Investigaciones UNR, Facultad de Ciencias Médicas; Argentin

Clinical response in patients with ovarian cancer treated with metronomic chemotherapy

Ovarian cancer (OC) is the leading cause of death from gynaecological cancer. It is extremely hard to diagnose in the early stages and around 70% of patients present with advanced disease. Metronomic chemotherapy (MCT) is described as the chronic administration of, generally low, equally spaced, doses of chemotherapeutic drugs with therapeutic efficacy and low toxicity. This is an effective and low-cost way to treat several types of tumours, including ovarian cancer. Here, we present six cases of advanced ovarian cancer treated with MCT with low doses of cyclophosphamide, which showed clinical response and stable disease.Fil: Perroud, Herman A. Institute of Experimental Genetics. School of Medical Sciences. National University of Rosario; Rosario; ArgentinaFil: Scharovsky, Graciela Olga. Universidad Nacional de Rosario. Consejo de Investigaciones UNR, Facultad de Ciencias Médicas; ArgentinaFil: Rozados, Viviana R. Institute of Experimental Genetics. School of Medical Sciences. National University of Rosario; Rosario; ArgentinaFil: Alasino, Carlos María. Institute of Oncology of Rosario; Argentin

Comparative Effectiveness of Two Metronomic Chemotherapy Schedules. Our Experience in the Preclinical Field

Metronomic chemotherapy refers to the chronic, equally spaced, delivery of low doses of chemotherapeutic drugs, without extended interruptions. Previously, we developed two combined metronomic schemes for the treatment of murine mammary tumors. The aim of this study was to compare their effects on tumor and metastasis growth, survival, and toxicity. Metronomic chemotherapy with Cyclophosphamide + Celecoxib (Cy + Cel) showed higher antimetastatic power than Cyclophosphamide + Doxorubicin (Cy + Dox), while being similar in other aspects. That difference, plus the advantage that represents its oral administration, suggests that the Cy + Cel combination is more suitable than Cy + Dox for metronomic chemotherapy of mammary tumors and could be proposed to the translation to the clinic.Fil: Rico, María José. Institute of Experimental Genetics. School of Medical Sciences. National University of Rosario; Rosario; ArgentinaFil: Perroud, Herman A. Institute of Experimental Genetics. School of Medical Sciences. National University of Rosario; Rosario; ArgentinaFil: Mainetti, Leandro Ernesto. Institute of Experimental Genetics. School of Medical Sciences. National University of Rosario; ArgentinaFil: Rozados, Viviana R. Institute of Experimental Genetics. School of Medical Sciences. National University of Rosario; Rosario; ArgentinaFil: Scharovsky, Graciela Olga. Universidad Nacional de Rosario. Consejo de Investigaciones UNR, Facultad de Ciencias Médicas; Argentin

Association between baseline VEGF/sVEGFR-2 and VEGF/TSP-1 ratios and response to metronomic chemotherapy using cyclophosphamide and celecoxib in patients with advanced breast cancer

Background: Metronomic chemotherapy (MCT) with cyclophosphamide (Cy) and celecoxib (Cel) has therapeutic efficacy and low toxicity profile in advanced breast cancer patients (ABCP), but no reliable biomarkers of response have been found yet that allow patient selection for treatment. AIM: To investigate the potential role as biomarkers of pro- and antiangiogenic parameters and evaluate their response in ABCP receiving metronomic Cy 50 mg p.o./day + Cel 400 mg p.o./day. Materials and Methods: Serum levels of vascular endothelial growth factor-C (VEGF-C), soluble VEGF receptors 2 and 3 (sVEGFR-2, sVEGFR-3), were measured at different time points in 13/15 patients included in a phase II trial of MCT with Cy+Cel. Results: Serum levels of sVEGFR-2 and sVEGFR-3 increased significantly during treatment (P = 0.0392; P = 0.0066, respectively). VEGF-C showed no significant modifications. Previous determinations of VEGF and TSP-1 in the same patients were utilized. VEGF/sVEGFR-2, VEGF/TSP-1, and VEGF-C/sVEGFR-3 ratios decreased significantly along the treatment (P = 0.0092; P = 0.0072; P = 0.0141, respectively). Nonsignificant variations were observed for VEGF-C/sVEGFR-2 ratio. Baseline values of VEGF/sVEGFR-2 and VEGF/TSP-1 ratios were associated with time to progression (TTP) (P = 0.0407; P = 0.0394, respectively) meanwhile baseline VEGF was marginally significant (P = 0.0716). Patients with values lower than the 50 th percentile for both ratios showed longer TTP. Conclusions: We have identified the baseline VEGF/sVEGFR-2 and VEGF/TSP-1 ratios as potential biomarkers of response in ABCP treated metronomically with Cy+Cel. This finding warrants its confirmation in a higher number of patients.Fil: Perroud, Herman A. Institute of Experimental Genetics. School of Medical Sciences. National University of Rosario; Rosario; ArgentinaFil: Rico, María José. Institute of Experimental Genetics. School of Medical Sciences. National University of Rosario; Rosario; ArgentinaFil: Alasino, Carlos María. Institute of Oncology of Rosario; Rosario; Argentina.Fil: Pezzotto, Stella Maris. Research Council of the National University of Rosario (CIUNR); Rosario; Argentina.Fil: Rozados, Viviana R. Institute of Experimental Genetics. School of Medical Sciences. National University of Rosario; Rosario; Argentina.Fil: Scharovsky, Graciela Olga. Institute of Experimental Genetics. School of Medical Sciences. National University of Rosario; Rosario; Argentina

Safety and therapeutic effect of metronomic chemotherapy with cyclophosphamide and celecoxib in advanced breast cancer patients

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. Our pre-clinical results suggested that combined MCT with cyclophosphamide (CY) and celecoxib (CEL) could inhibit breast cancer growth. The aim of this study was to determine the toxicity, safety and efficacy of the oral chronic administration of CY 50 mg p.o. daily, plus CEL 400 mg (200 mg p.o. bid) in advanced breast cancer patients (ABCP). The therapeutic response consisted in stable disease in a high proportion of patients and one partial response. The overall clinical benefit rate obtained was 66.7%. Toxicity was low. Evaluation of quality of life showed no changes during the response period. MCT with CY + Cel is safe and shows therapeutic effect in ABCP.Fil: Perroud, Herman A. Institute of Experimental Genetics. School of Medical Sciences. National University of Rosario; Rosario; ArgentinaFil: Rico, María José. Institute of Experimental Genetics. School of Medical Sciences. National University of Rosario; Rosario; ArgentinaFil: Alasino, Carlos María. Institute of Oncology of Rosario; ArgentinaFil: Queralt, Francisco. Institute of Oncology of Rosario; ArgentinaFil: Pezzotto, Stella Maris. Research Council of the National University of Rosario (CIUNR); ArgentinaFil: Rozados, Viviana R. Institute of Experimental Genetics. School of Medical Sciences. National University of Rosario; Rosario; ArgentinaFil: Scharovsky, O. Graciela. Universidad Nacional de Rosario. Consejo de Investigaciones UNR, Facultad de Ciencias Médicas; Argentin

Achievements and challenges in the use of metronomics for the treatment of breast cancer

Two interesting therapeutic proposals for cancer treatment emerged at the beginning of the 21st century. The first one was metronomic chemotherapy, which refers to the chronic administration of chemotherapeutic agents, in low doses, without extended drug-free periods. Then, the idea of drug repositioning in oncology, the use of well-known drugs that were created for other uses to be utilized in oncology, gained strength. Shortly after, the two strategies were merged in one, named metronomics. Both approaches share several features which make metronomics an appealing choice for cancer treatment: use of known and approved drugs, thus diminishing the time necessary to enter to the clinic, therapeutic effect, low toxicity, oral administration, better life quality, low costs because of the use of, generally, out of patent drugs, possibility of use, even in countries with very low economic resources. Many chemotherapy and repurposed drugs were tested with metronomics approaches for the treatment of mammary cancer, the most common malignancy in women worldwide, leading to high rates of mortality. The wide range of therapeutic models studied, paralleled the wide range of responses obtained, like tumor growth and metastasis inhibition, overall survival increase, lack of toxicity, better life quality, among others. The accomplishments reached, and the challenges faced by researchers, are discussed.Fil: Scharovsky, O. Graciela. Universidad Nacional de Rosario. Consejo de Investigaciones UNR, Facultad de Ciencias Médicas; ArgentinaFil: Rico, María José. Institute of Experimental Genetics.School of Medical Sciences. National University of Rosario; Rosario; ArgentinaFil: Mainetti, Leandro Ernesto. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; ArgentinaFil: Perroud, Herman A. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; ArgentinaFil: Rozados, Viviana R. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; Argentin

Patrón de consumo alimentario en una muestra de adultos con Enfermedad Colelitiasica (EC)

En un estudio realizado en una muestra aleatoria de adultos de Rosario se encontró una tasa de prevalencia de Enfermedad Colelitiásica (EC) del 20,5%. Con el objetivo de determinar el patrón de consumo alimentario de estas personas y compararlo con las Raciones Dietéticas Recomendadas (RDA) se entrevistaron 44 de dichas personas con EC. Se les realizó una encuesta sobre hábitos alimentarios 5 años previos al diagnóstico, empleando un cuestionario semi-cuantitativo de frecuencia de consumo (FFQ) y un Atlas fotográfico de porciones estandarizadas. Se calcularon los promedios (± desvío estándar) de la edad, del Índice de Masa Corporal (IMC), del consumo de cada nutriente y de la energía total consumida (Kilocalorías). La significación estadística de las diferencias entre sexos se evaluó aplicando pruebas t de student. La edad de las personas estudiadas (18 varones y 26 mujeres) fue 63,8±13,8 años y el IMC fue 28,2±5,8. Consumos promedio diarios: Kcalorias 2941±791,1 ; Carbohidratos 295,3±96,9 g; Proteínas 131,6±36,8 g; Grasa 128,9± 43 g; Ácidos grasos saturados 41,9±18,6 g; Ácidos grasos poliinsaturados 13,8±8,7 g; Colesterol 455,4±186,8 mg; Sodio 2730±1552,1 mg; Potasio 2912,8±1001,4 mg; Calcio 719,3±403,3 mg; Hierro 16±4,6 mg; Fósforo 801,6±320,3 mg; Vitamina A 3121,7±1811,9 mcg; Vitamina B1 0,80±0,30 mg; Vitamina B2 1,9±0,8 mg; Vitamina C 157,6±114,1 mg; Niacina 6,9±2,7 mg; Fibra total 12± 5,3 g; Café 70,7±104,3 cc. Se concluye que el patrón alimentario de las personas con EC se caracterizó por un alto consumo de Grasas, Ácidos grasos saturados y Colesterol, no alcanzando las recomendaciones para Carbohidratos, Calcio, Niacina y Fibra

Therapeutic efficacy of metronomic chemotherapy with cyclophosphamide and doxorubicin on murine mammary adenocarcinomas

Metronomic chemotherapy (MCT) involves the chronic administration of doses of chemotherapy drugs that are below the maximum tolerated dose (MTD), at frequent and regular intervals, without extended rest periods [1]. It aims to achieve a balance between efficacy in tumor killing and lack of toxicity. The inhibition of angiogenesis would explain its therapeutic effect [2, 3]. We have demonstrated the antitumor efficacy of MCT with cyclophosphamide (Cy) as a single drug [4] and in combination with celecoxib on mice mammary adenocarcinomas (MA) [5]. Considering the high incidence of mammary tumors in humans, in this study, we analyze the therapeutic efficacy, toxicity and mechanism/s of action of MCT combining Cy and doxorubicin (Dox), in mouse MA tumor-models.Fil: Mainetti, Leandro Ernesto. Institute of Experimental Genetics. School of Medical Sciences. National University of Rosario; ArgentinaFil: Mainetti, Leandro Ernesto. Departments of Urology and Pathology. Wayne State University School of Medicine; Detroit; MI; USAFil: Rico, María José. Institute of Experimental Genetics. School of Medical Sciences. National University of Rosario; Rosario; ArgentinaFil: Fernández Zenobi, María Virginia. Institute of Experimental Genetics. School of Medical Sciences. National University of Rosario; Rosario; ArgentinaFil: Perroud, Herman A. Institute of Experimental Genetics. School of Medical Sciences. National University of Rosario; Rosario; ArgentinaFil: Roggero, Eduardo. Institute of Experimental Genetics. School of Medical Sciences. National University of Rosario; Rosario; ArgentinaFil: Rozados, Viviana R. Institute of Experimental Genetics. School of Medical Sciences. National University of Rosario; Rosario; ArgentinaFil: Scharovsky, Graciela Olga. Institute of Experimental Genetics. School of Medical Sciences. National University of Rosario; Rosario; Argentin