Metronomic Chemotherapy: Changing the Paradigm That More Is Better

Abstract

The introduction of the “maximum tolerated dose” in usual treatment protocols (and its concomitant overt toxicity) made necessary the imposition of rest periods between cycles of therapy—a practice that not only involves re-growth of tumour cells, but also growth of selected clones resistant to the therapy. To avoid the problems caused by traditional chemotherapeutic regimens, a new modality of drug administration called “metronomic chemotherapy” has been proposed. This name makes reference to the chronic, equally spaced administration of (generally) low doses of various chemotherapeutic drugs without extended rest periods. The novelty of this treatment modality lies not only in its antitumour efficacy with very low toxicity, but also in a cell target switch, now aiming at tumour endothelial cells. The knowledge acquired in the experimental field of metronomic chemotherapy, plus the increasing experience that is being obtained in the clinical setting, will help to lead a change in the design of therapeutic protocols against cancer.

Dose/dense metronomic chemotherapy with fractioned cisplatin and oral daily etoposide enhances the anti-angiogenic effects of bevacizumab in advanced non-small-cell-lung cancer patients

“…The rationale of this combination is derived from preclinical models where cytotoxic drugs like etoposide and cyclophosphamide, administered on metronomic modality, with short and regular inter-cycle intervals, chronically and generally at low doses, 15 showed cytotoxic activity on activated endothelial cells (anti-angiogenic activity), immunosuppressive blood cell populations like immunoregulatory T lymphocytes (with a CD4 + CD25 + FoxP3 + immunophenotype) and immunosuppressive myeloid precursors (immuno-modulating activity). These drugs given with dose/dense schedules became additionally able to force cancer cells to acquire a less aggressive phenotype (epigenetic effect).…”

Efficacy of Metronomic Vinorelbine in Elderly Patients with Advanced Non-Small-Cell Lung Cancer and Poor Performance Status

“…Continuous administration of the drug in low doses also lessens tumour angiogenesis and inhibits circulating endothelial progenitor cells 23 . Thus, metronomic chemotherapy could be good choice in certain cancer types and in selected patients, as well as in some combination or maintenance therapies.…”

Phase II trial of bevacizumab and dose/dense chemotherapy with cisplatin and metronomic daily oral etoposide in advanced non-small-cell-lung cancer patients

“…Phase II trial of bevacizumab and dose/dense chemotherapy with cisplatin and metronomic daily oral etoposide in advanced non-small-cell-lung cancer patients [21][22][23][24][25][26][27] Our study was also based on the results of a previous phase II trial which showed the low level of toxicity and the antitumor activity of a metronomic chemotherapy doublet with cisplatin and daily oral etoposide (mPE regimen) in patients with high risk advanced NSCLC. 27 The results of the previous phase I mPEBev trial provided preliminary evidence of antitumor activity in advanced NSCLC including squamous cell histology; additionally, they allowed the identification of the most active biological dose (MABD) and the maximal tolerated dose (MTD) of bevacizumab within the mPEBev regimen, in a range between 5 and 7.5 mg/kg, to be used for further studies.…”