Metronomic Therapy in Oral Squamous Cell Carcinoma

Metronomic therapy is characterized by drug administration in a low-dose, repeated, and regular manner without prolonged drug-free interval. The two main anticancer mechanisms of metronomic therapy are antiangiogenesis and immunomodulation, which have been demonstrated in several delicate in vitro and in vivo experiments. In contrast to the traditional maximum tolerated dose (MTD) dosing of chemotherapy, metronomic therapy possesses comparative efficacy but greatlydecreases the incidence and severity of treatment side-effects. Clinical trials of metronomic anticancer treatment have revealed promising results in a variety cancer types and specific patient populations such as the elderly and pediatric malignancies. Oral cavity squamous cell carcinoma (OCSCC) is an important health issue in many areas around the world. Long-term survival is about 50% in locally advanced disease despite having high-intensity treatment combined surgery, radiotherapy, and chemotherapy. In this article, we review and summarize the essence of metronomic therapy and focus on its applications in OCSCC treatment.

Angiogenesis and chemotherapy resistance: optimizing chemotherapy scheduling using mathematical modeling

Chemotherapy remains a widely used cancer treatment. Acquired drug resistance may greatly reduce the efficacy of treatment and means to overcome it are a topic of active discussion among researchers. One of the proposed solutions is to shift the therapeutic paradigm from complete eradication of cancer to maintenance, i.e., to treat it as a chronic disease. A concept of metronomic therapy (low chemotherapy doses applied continuously) emerged in early 2000s and was henceforth shown to offer a number of benefits, including targeting endothelial cells and reducing acquired drug resistance. Using mathematical modeling and optimal control techniques, we investigate the hypothesis that lower doses of chemotherapy are beneficial for patients. Our analysis of a mathematical model of tumor growth under angiogenic signaling proposed by Hahnfeldt et al. adapted to heterogeneous tumors treated by combined anti-angiogenic agent and chemotherapy offers insights into the effects of metronomic therapy. Firstly, assuming constant long-term drug delivery, the model suggests that the longest survival time is achieved for intermediate drug doses. Secondly, by formalizing the notion of the therapeutic target being maintenance rather than eradication, we show that in the short term, optimal chemotherapy scheduling consists mainly of a drug applied at a low dose. In conclusion, we suggest that metronomic therapy is an attractive alternative to maximum tolerated dose therapies to be investigated in experimental settings and clinical trials.