Abstract
Simple SummaryThe present article reviews the state of the art of metronomic chemotherapy use to treat the principal types of cancers, namely breast, non-small cell lung cancer and colorectal ones, and of the most recent progresses in understanding the underlying mechanisms of action. Areas of novelty, in terms of new regimens, new types of cancer suitable for Metronomic chemotherapy (mCHT) and the overview of current ongoing trials, along with a critical review of them, are also provided.Metronomic chemotherapy treatment (mCHT) refers to the chronic administration of low doses chemotherapy that can sustain prolonged, and active plasma levels of drugs, producing favorable tolerability and it is a new promising therapeutic approach in solid and in hematologic tumors. mCHT has not only a direct effect on tumor cells, but also an action on cell microenvironment, by inhibiting tumor angiogenesis, or promoting immune response and for these reasons can be considered a multi-target therapy itself. Here we review the state of the art of mCHT use in some classical tumour types, such as breast and no small cell lung cancer (NSCLC), see what is new regarding most recent data in different cancer types, such as glioblastoma (GBL) and acute myeloid leukemia (AML), and new drugs with potential metronomic administration. Finally, a look at the strategic use of mCHT in the context of health emergencies, or in low –and middle-income countries (LMICs), where access to adequate healthcare is often not easy, is mandatory, as we always need to bear in in mind that equity in care must be a compulsory part of our medical work and research.
Highlights
Molecular targeted agents differ from traditional chemotherapy agents in terms of administration schedules, toxicity profile and anticancer activity [1]. Metronomic chemotherapy treatment (mCHT) was coined for the first as the frequent administration of conventional chemotherapy drugs at low doses with no prolonged drug-free breaks in 2000’s by Kerbel [1] and Hanahan [2] in two different articles
Afterwards, numerous studies showed that mCHT inhibited the proliferation and circulation of endothelial cells (CECs) and endothelial progenitor cells (CEPs) and reduced the differentiation of immature endothelial cells, modulating proand anti-angiogenic molecules [6,8,9,10,11]. mCHT can shift the balance between pro-and antiangiogenic factors inducing the synthesis and release of anti-angiogenic factors, as shown by Bocci et al in in vitro studies on endothelial cells treated with diverse anticancer agents in the mCHT schedule and in in vivo in mice treated with low daily doses of cyclophosphamide (CTX)
Another relevant mechanism of action of mCHT consists in the recovery of the immune response, which acts against cancer cells by inhibiting T regulatory cells, myeloid-derived suppressor cells and stimulating dendritic cells [16]
Summary
Molecular targeted agents differ from traditional chemotherapy agents in terms of administration schedules, toxicity profile and anticancer activity [1]. mCHT was coined for the first as the frequent administration of conventional chemotherapy drugs at low doses with no prolonged drug-free breaks in 2000’s by Kerbel [1] and Hanahan [2] in two different articles. Preliminary results of mCHT in different cancer types, mainly breast and lung cancer, showed interesting and promising results: mCHT remained confined to palliative settings for a long period, as erroneously considered to be devoid of antitumor activity. Different metronomic drug concentrations and schedules can exert different actions, so far, they can be modulated according to the setting of use, cancer type and patients’ preferences. In this context, the most studied drugs for mCHT are cyclophosphamide (CTX), methotrexate (MTX), capecitabine (CAPE) and oral vinorelbine (VNR) in breast cancer, CAPE in gastro-intestinal cancers and oral VNR in NSCLC. With the advent of new drugs, especially immune checkpoint inhibitors, and a deeper knowledge of peculiar mechanisms of action of mCHT, it is advisable that these regimens become more widely used in clinical practice
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