Metronomic therapy
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.[1] Metronomic therapy is also cost-effective as a lower dose is used compared to conventional chemotherapy.[2] The use of metronomic therapy has been extensively investigated and can be advantageous in selected group of patients.[3] Yet, more clinical trials are necessary to generalize the method.[4]
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
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.
| Conventional chemotherapy | Metronomic therapy | |
|---|---|---|
| Dosage | Close to maximum tolerated dose | Much lower than maximum tolerated dose |
| Dosing interval | Less frequent | More frequent |
| Route of administration | Various e.g. intravenous, oral | Oral |
| Mechanisms of action | Cytotoxicity | Various e.g. anti-angiogenesis, immunomodulation |
| Side effects | More significant | Less severe |
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.[1] There is also emerging evidence that metronomic therapy may also act on tumor cells by inducing tumor dormancy and senescence.[8]
Anti-angiogenesis
Angiogenesis supports tumor growth by ensuring sufficient oxygen and nutrient supply to the rapidly-proliferating tumor cells.[9] 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.[8] This is probably mediated by increasing the expression of thrombospondin-1 (TSP-1), which inhibits angiogenesis.[5] 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.[1]
Immunomodulation
Tumor cells develop
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.[13]
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.[14] In fact, a recent study presented at American Association for Cancer Research (AACR) congress in 2017 announced the effect of metronomic regimens.[15] The study also encourages further studies about finding appropriate regimen and its optimal dosage.
Prostate cancer
While
Lung cancer
Metronomic therapy was discovered to be effective in treatment of
Ovarian cancer
Metronomic therapy has been investigated for treatment of metastatic ovarian cancer as it is less costly and it improves patients’ quality of lives compared to conventional therapy.[22] It may also be useful in patients who have platinum-resistant ovarian cancer.[1]
From 2012 to 2016, six ovarian cancer patients who could not be treated with conventional therapy were treated with metronomic cyclophosphamide.[23] Although the clinical outcomes do not only depend on metronomic therapy but also previous treatments they had received, the treatment provided the progress of ovarian cancers and one case was found to have nearly complete clinical remission. Despite the encouraging results, there are not many clinical trials using metronomic therapy for ovarian cancer. Most of the findings are from case reports and pre-clinical trials. Due to few clinical trials and lack of information about the applications, it is still risky and questionable to substitute conventional therapy used in treatment of ovarian cancer.[24]
Paediatric cancers
Paediatric cancers have been a challenge due to the expense of treatment. In fact, the cure rate in high-income countries and low-income countries are 80% and 10% respectively.[25][26] Therefore, lowering the expense of paediatric cancers is a key to improve the quality of life worldwide.[2] Metronomic therapy can be a good way to reduce the expense of cancer treatment. In terms of using metronomic therapy for paediatric cancers, it has been very effective as children have stronger immunity and tend to have fewer comorbidities compared to elderly cancer patients.[27] Despite a few clinical trials, some trials still highlighted the effectiveness of metronomic therapy as well as cost-effectiveness.[28][29]
Limitations
The use of metronomic therapy is still of limited use and requires further evaluation. Currently, most of the clinical studies are phase I and II trials.[28] There are only about ten studies which have proceeded to phase III.[4]
Heterogeneity of studies
The studies are heterogeneous in terms of patient selection, chemotherapeutic agents, dosage and dosing interval.[3] Correspondingly, the clinical outcomes are variable. Multiple reviews pointed out that further studies should be carried out to determine the most effective drugs, dosage and dosing interval according to tumor and patient characteristics.[3][28][29]
Lack of promising biomarkers
Different biomarkers for monitoring the patients’ response towards metronomic therapy have been tested, but the results showed that the biomarkers did not correlate well with the treatment response.[29] Without proper biomarkers, it is difficult to determine the optimal metronomic dose for the patients.
Blood biomarkers related to angiogenesis, such as VEGF, TSP-1, circulating endothelial cells (CECs) and CEPs, have been tested. It was reviewed that most studies did not show a significant correlation between the level of these biomarkers and the treatment response, in terms of clinical outcomes such as overall survival and progression-free survival.[30] This is likely due to the complex interplay of factors in angiogenesis.[30]
Besides blood biomarkers, an imaging called
Biomarkers related to the immunomodulatory effects of metronomic therapy are also under investigation. The most commonly studied one is Tregs. With advances in technologies, not only the number of Tregs but also other properties such as receptor profile and functioning of Tregs can be studied, which may aid in finding more suitable biomarkers in the future.[31]
History
The term “metronomic therapy” was first used by Douglas Hanahan in 2000.[32] In his commentary on two animal studies testing the effects of metronomic dosing of chemotherapeutic agents on tumor growth, he suggested that metronomic therapy was a potential new modality of chemotherapy with clinical value.[32][33][34]
See also
References
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