Metronomic chemotherapy: possible clinical application in advanced hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a hypervascular highly angiogenic tumor usually associated with liver cirrhosis. Vascular endothelial growth factor plays a critical role in vascular development in HCC. In contrast to the treatment of early-stage HCC, the treatment options for advanced HCC are limited and prognosis is often poor, which contributes to this tumor type being the third leading cause of cancer-related deaths worldwide. Metronomic chemotherapy, which was originally designed to inhibit angiogenesis, involves low-dose chemotherapeutic agents administered in a frequent regular schedule with no prolonged breaks and minimizes severe toxicities. We reviewed the potential effects and impact of metronomic chemotherapy in preclinical studies with HCC models and in patients with advanced HCC, especially when combined with a molecular targeted agent. Metronomic chemotherapy involves multiple mechanisms that include antiangiogenesis and antivasculogenesis, immune stimulation by reducing regulatory T cells and inducing dendritic cell maturation, and possibly some direct tumor cell targeting effects, including the cancer stem cell subpopulation. The total number of preclinical studies with HCC models shows impressive results using metronomic chemotherapy-based protocols, especially in conjunction with molecular targeted agents. Four clinical trials and two case reports evaluating metronomic chemotherapy for HCC indicate it to be a safe and potentially useful treatment for HCC. Several preclinical and clinical HCC studies suggest that metronomic chemotherapy may become an alternative type of chemotherapy for advanced unresectable HCC and postsurgical adjuvant treatment of HCC.

Figure 1

Mechanisms of action of metronomic chemotherapy. The beneficial effects of metronomic chemotherapy are mediated through inhibition of vasculogenesis and angiogenesis, activation of immunity, and probably direct inhibition of tumor cell proliferation. Inhibition of vasculogenesis and angiogenesis plays a critical role in metronomic chemotherapy. Inhibition of vasculogenesis and angiogenesis includes direct inhibition of endothelial cell proliferation, up-regulation of endogenous angiogenic inhibitor such as TSP-1, suppression of HIF-1?, and inhibition of EPC homing in tumor tissues. Metronomic chemotherapy also stimulates antitumor immunity by reducing the number of Treg cells and possibly inducing dendritic cell maturation.