Metronomic anti-cancer therapy – an ongoing treatment option for advanced cancer patients

Abstract

The therapeutic concept of administering agents (cytotoxic/-static,non-cytotoxic and/or targeted drugs) continuously at lower doses -relative to MTDs in the case of cytostatic and cytotoxic drugs or continuously at tolerable doses as in the case of targeted drugs without drug-free breaks over extended periods -known as 'metronomic therapy' (MT), is increasingly being recognized as an experimental option for treating cancer. In comparison with MTD-defined chemotherapy (CHT) regimens, metronomic therapy has demonstrated reduced toxicity. More importantly, several phase II trials have shown that metronomic therapies showed anti-cancer activity in different cancer types with different drugs. The mechanistic basis of metronomic therapy using cytotoxic/static drugs is believed to be primarily anti-angiogenic, either by direct killing or inhibiting endothelial cells (ECs) in the tumor vasculature, killing bone-marrow-derived endothelial progenitor cells, stimulating the immune system, directly affecting tumor cells through a drug-driven effect as well as specificly inhibiting a target when targeting drugs were used in additional to metronomic therapy. The induction of senescence in cancer is another possible explanation for the principles behind 'metronomic therapy' .

Metronomic chemotherapy from rationale to clinical studies: A dream or reality?

“…Moreover, fatigue and gastrointestinal symptoms e.g. nausea, vomiting and diarrhea are more common when targeted drugs are added to metronomic chemotherapy, and high accumulation over time of etoposide, temozolomide and cyclophosphamide can lead to secondary leukemia, or myelodysplastic syndrome (MDS) [118].…”

Combining low-dose or metronomic chemotherapy with anticancer vaccines

“…These rest periods, however, also allow cancer cells to become resistant to chemotherapy and hence to drive a disease relapse 5 . A new therapeutic paradigm has recently been established based on the administration of low-dose chemotherapeutics at short intervals (so-called, metronomic chemotherapy), in the absence of prolonged drug-free periods 6 , 7 . Metronomic chemotherapy not only causes relatively mild and short-lived toxic effects, but also exerts an antiangiogenic activity had have been associated with robust antineoplastic effects in preclinical models of chemoresistant tumors 8 .…”

Next generation metronomic chemotherapy—report from the Fifth Biennial International Metronomic and Anti-angiogenic Therapy Meeting, 6–8 May 2016, Mumbai

“…Despite more than a decade of clinical studies, very little work has been published on the PK data related to low-dose chemotherapy, primarily due to an underestimation of the importance of plasma/tumour concentrations of drugs and their biological effects. This is particularly the case when there are multiple mechanisms of action for MC, and that these may be operative at different drug concentrations [2]. For example, in mice the anti-angiogenic activity of daily oral cyclophosphamide is apparent at doses of 20 mg/kg [3], yet the activation of innate anti-tumour immunity occurs on an intermittent six-day schedule and at a dose of 140 mg/kg [4].…”