Adverse side effects associated with the use of low-dose metronomic chemotherapy

Abstract

The benefit of cancer therapies can be characterized by the therapeutic index incorporating the balance between antitumor activities and treatment-associated toxicities. Low-dose metronomic (LDM) chemotherapy is a novel treatment strategy that was developed to overcome resistance to maximum-tolerated dose (MTD) chemotherapy, while using conventional chemotherapeutics. Published findings suggest that the therapeutic index of LDM chemotherapy is particularly beneficial given the combination of excellent antitumor activity with a toxicity profile that is considered to be superior to MTD chemotherapy. In fact, a systematic analysis of 66 published phase I/II clinical LDM chemotherapy trials providing detailed toxicity data confirms the excellent safety profile of LDM chemotherapy. Severe (grade 3 or 4) side effects were rare, and the toxicity profiles seemed to be associated with the type of LDM regimen studied. Overall, incidences of any severe adverse effects were limited to less than 10 % of patients. Severe lymphopenia and neutropenia were the most frequent side effects reported, occurring in 6.44 % and 5.71 % of patients. Furthermore, three comparative studies reporting the rates of adverse events associated with LDM versus MTD regimens indicate superior tolerance and safety of LDM chemotherapy, while still displaying comparable antitumor effects. By making treatments more tolerable and thus accessible to a broader range of cancer patients, LDM chemotherapy is an example that less can sometimes be more. However, in the absence of validated predictive or pharmacodynamic markers of LDM chemotherapy, additional clinical studies are warranted to further improve the therapeutic index of LDM chemotherapy.