Chapter 8 - Metronomic chemotherapy and antiangiogenic drugs: Preclinical and clinical data

Abstract

Metronomic chemotherapy (MC) is the frequent, regular administration of chemotherapeutic drugs that maintain a low, prolonged and active range of plasma concentrations with a favorable toxicity profile. MC regimens were developed to optimize the antitumor efficacy of agents that could impact multiple targets, including the tumor vasculature, regulatory T cells, and cancer cells. In the last two years, MC has become increasingly used in the clinical research setting due to a number of successful randomized phase II-III clinical trials in nasopharyngeal carcinoma, head and neck carcinoma, small-cell lung cancer, and epithelial ovarian cancer. The combination of MC and the antiangiogenic drug has seen its major development in the preclinical setting, where these regimes achieved high antitumor activities. Initially, the preclinical combination treatments included preferentially the anti-VEGFR-2 monoclonal antibody DC101, later the research interest focused on VEGFR-2 small tyrosine kinase inhibitors such as pazopanib, sorafenib, and sunitinib because of their oral administration route. Moreover, in the last ten years, several phase I and phase II clinical trials have combined MC and antiangiogenic drugs (e.g., bevacizumab or tyrosine kinase inhibitors, targeting VEGFR-2 and other angiogenic factor receptors), reporting mixed results (promising clinical efficacy or no clinical advantage) involving different types of cancer. In conclusion, MC has shown both preclinical and clinical activity in different types of cancer. The addition of antiangiogenic drugs into MC schedules greatly enhanced the therapeutic activity in preclinical models but these results were not completely confirmed in all the clinical trials based on the same combination. Additional phase III clinical trials will hopefully validate the promising preclinical results obtained by the combination of MC and antiangiogenic drugs.