Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels

Abstract

Continuously low-dose CTX and MTX is minimally toxic and effective in heavily pretreated breast cancer patients. A drop in VEGF was associated with the treatment and so alternative hypotheses, other than that of direct toxicity on tumor cells, must be favored when trying to explain the anticancer effect.

A pharmacokinetic and pharmacodynamic study on metronomic irinotecan in metastatic colorectal cancer patients

“…In our study, the individual plasma VEGF concentrations of patients initially increased when compared to the baseline values in the first 3 weeks and then at lower doses constantly decreased. Despite the presence of a high variability, VEGF plasma levels may reflect both the initial elevated hypoxia of tumour tissue caused by the antiangiogenic therapy, as previously shown (Bocci et al, 2004;Motzer et al, 2006), and the low rate of VEGF secretion by tumour or tumourassociated stromal cells due to the long-term therapy (Colleoni et al, 2002). This PK/PD study underlines the importance to conduct further comparative studies with BSC or bevacizumab to establish the feasibility of metronomic irinotecan approach.…”

“…However, the heterogeneous patient population, the drugs that were involved and the lack of a preclinical investigation of the doses that were used, and combination of drugs used all could have affected the outcome of the results. Colleoni et al (2002) described a reduction in serum VEGF of both responders and non-responders in breast cancer metastatic patients treated with metronomic CTX. In our study, the individual plasma VEGF concentrations of patients initially increased when compared to the baseline values in the first 3 weeks and then at lower doses constantly decreased.…”

“…Colleoni and co-workers have used the metronomic/antiangiogenic strategy, mainly based on the use of daily oral cyclophosphamide (CTX) in combination with low-dose methotrexate given 2 days/week, in clinical trials for the treatment of metastatic breast cancer patients, and reported promising clinical activity in the absence of serious adverse events (Colleoni et al, 2002(Colleoni et al, , 2006Orlando et al, 2006a, b). Moreover, the lowtoxicity profile (Kerbel and Kamen, 2004) and the low costs (Bocci et al, 2005b) of the metronomic CTX regimens enhanced the quality of life of patients and suggested immediate potential use in various clinical settings.…”

Upregulation of endogenous angiogenesis inhibitors: A mechanism of action of metronomic chemotherapy

“…1 Such regimen involves the frequent administration of conventional chemotherapeutic agents (e.g., cyclophosphamide, vinblastine, topotecan, cisplatin) at very low doses to target activated endothelial cells in tumors, the advantages of which include minimal adverse effects and scarce chance of developing acquired drug resistance. Indeed, preclinical [2][3][4][5] and clinical studies [6][7][8] have demonstrated the antitumor efficacy and the superiority of metronomic chemotherapy compared with its maximum tolerated dose (MTD) counterpart. Endostatin, tumstatin, and thrombospondins are endogenous proteins or protein fragments with antiangiogenic property.…”

Immunomodulatory effects of low dose chemotherapy and perspectives of its combination with immunotherapy

“…56 CTX has also been used with low-dose methotrexate in the treatment of early breast cancer and the inhibition of angiogenesis is caused by a decrease in vascular endothelial growth factor. 57 …”