Metronomic therapy is a new type of chemotherapy in which anti-cancer drugs are administered in a lower dose than the maximum tolerated dose repetitively over a long period to treat cancers with fewer side effects. Metronomic therapy is shown to affect both tumor microenvironment and tumor cells to achieve its therapeutic effects. Metronomic therapy is also cost-effective as a lower dose is used compared to conventional chemotherapy. The use of metronomic therapy has been extensively investigated and can be advantageous in selected group of patients. Yet, more clinical trials are necessary to generalize the method.
Comparison with conventional chemotherapy
Conventional chemotherapy
In conventional chemotherapy, a dose close to the maximum tolerated dose is administered in a bolus manner to achieve cytotoxic effects on tumor cells. However, the side effects are often significant as the cytotoxic agents also kill the fast-dividing cells normally present in the body, such as bone marrow cells and epithelial cells of the gastrointestinal tract. A treatment break is thus required to allow recovery in these normal tissues.
Metronomic therapy
In metronomic therapy, a lower dose, typically varying from one-tenth to one-third of the maximum tolerated dose, is administered frequently to maintain a low concentration of the drugs in the plasma. It is commonly given in oral form, which is more convenient for patients and has a lower cost compared with intravenous form used in conventional chemotherapy. At a low concentration, the drugs primarily act on the tumor microenvironment including the tumor endothelial cells and immune cells. As a lower dose is used, the risk of having severe side effects, such as neutropenia, is lower.
Mechanisms of action
Multiple mechanisms of action have been studied in both pre-clinical and clinical settings. Instead of directly killing the tumor cells, the drugs in metronomic therapy suppress tumor growth mainly by inhibiting tumor angiogenesis and modulating the immune response against tumors. There is also emerging evidence that metronomic therapy may also act on tumor cells by inducing tumor dormancy and senescence.
Anti-angiogenesis
Angiogenesis supports tumor growth by ensuring sufficient oxygen and nutrient supply to the rapidly-proliferating tumor cells. Metronomic therapy can inhibit tumor angiogenesis by multiple mechanisms. It selectively inhibits the proliferation and induces apoptosis of tumor endothelial cells, without disrupting the endothelial cells of normal blood vessels. This is probably mediated by increasing the expression of thrombospondin-1 (TSP-1), which inhibits angiogenesis. Another target of metronomic therapy is the bone marrow-derived circulating endothelial progenitor cells (CEPs), which are involved in tumor angiogenesis. Metronomic therapy was found to decrease the level of CEPs.
Immunomodulation
Tumor cells develop various means to evade immunosurveillance of the host. The number of CD4+ CD25+ FOXP3+ regulatory T cells (Tregs) was found to increase in various types of tumors, suppressing both specific and innate immune responses. Metronomic therapy can selectively inhibit Tregs and therefore activate CD8+ cytotoxic T cells and CD4+ helper T cells responsible for tumor-specific immunity, as well as natural killer cells (NK cells) involved in innate immunity. This selective inhibition is not observed in conventional chemotherapy which reduces the number of all lymphocyte subsets. In addition, some chemotherapeutic agents including cyclophosphamide, methotrexate, vinblastine, paclitaxel and etoposide can promote maturation and antigen-presenting ability of dendritic cells, which in turn facilitate the T-cell mediated immune response against tumors.
Uses under investigation
Cancers in adults
Breast cancer
In the breast cancer settings, several drugs that are commonly used in conventional chemotherapy such as methotrexate, cyclophosphamide, vinorelbine and fluoropyrimidines have been tested either as monotherapy or in combination with other therapies including hormonal therapy, targeted therapy and vaccines.
Although there have been many cases that metronomic therapy did not create synergy with other therapies, a number of studies have proven the efficacy of metronomic therapy in treatment of intractable breast cancer. In fact, a recent study presented at American Association for Cancer Research (AACR) congress in 2017 announced the effect of metronomic regimens. The study also encourages further studies about finding appropriate regimen and its optimal dosage.