Metronomic Scheduling of Anticancer Treatment

Why a Multitarget Treatment?

The development of more effective therapies using complementary drug combinations requires the complexity and heterogeneity of tumor tissues to be acknowledged, and a full understanding of the interactions within the tumor microenvironment, as well as their impact on tumor growth and treatment response.

Several Targets at the Same Time

We are advocating for a paradigm change. To optimize antitumor efficacy, treatments should not only be aiming to impair the function of several targets in cancer cells (i.e., the microtubule network, DNA replication, mitochondria and tyrosine kinase receptors), but also target many, and ultimately all, tumor components (Figure 2). In turn, understanding how a given therapeutic combination affects each tumor compartment could unveil new anticancer mechanisms of action and, therefore, pave the way for specifically developing new drugs or strategies.^[14]

(Enlarge Image)

Figure 2.

Tumor as a multifaceted tissue. Over the past few decades, studies have demonstrated that cancer is a complex entity with multiple components that are all implicated in the tumor's life (growth, invasion and metastasis) and response to treatment. These components are also more generically termed 'the tumor microenvironment'. It includes endothelial cells, pericytes, fibroblasts, dendritic cells, macrophages, leucocytes (Tregs), platelets and elements of the ECM. All of these components interact with each other and with tumor cells. A specific set of interactions occurs in the so-called vascular niche that implicates cancer stem cells.
ECM: Extracellular matrix; HIF: Hypoxia-inducing factor; PEC: Progenitor endothelial cell; Treg: Regulatory T cell; TSP: Thrombospondin; VEGFR: VEGF receptor.

Multitarget therapy cannot be solely based on a combination of chemotherapeutics given at concentrations near or at the maximum tolerated dose (MTD). Although the potential benefits of high-dose combination chemotherapy in certain types of tumors, such as lymphoma, should not be dismissed, such an approach is not likely to lead to a cure or long-term control of the disease.^[15–18] Moreover, the overall toxicity of MTD-based combinational approaches usually requires each drug to be administered at doses below its MTD, thus potentially decreasing its efficacy. Finally, MTD-based chemotherapy may also hamper the efficacy of the other agents used in combination therapy. For example, it may prevent the restoration of immunosurveillance in the case of severe hematologic toxicity, thus inhibiting the potential immunostimulatory effects of other compounds used in a given combination.^[16]

No Rest for the Tumor

It seems obvious that if one aims to design a treatment protocol that targets several tumor components, one will need to use several agents. If we confine our tools to spaced-out MTD chemotherapy, in addition to the limitations previously mentioned, some cells within the tumor that have a longer cell cycle or are in a quiescent state will most likely be resistant to the treatment. In addition, beyond the toxicities that thwart the efficacy and prolonged use of MTD chemotherapy, the emerging concept of long-term treatment for cancer must be taken into consideration.^[15] Indeed, the importance of the historical use of maintenance therapy in acute leukemia is currently being extended to other types of malignancies and clinical settings. For example, it has recently been demonstrated that treatment of gastrointestinal stromal tumors with Gleevec® (Novartis, NJ, USA) should not be stopped before completing a 3-year treatment.^[19] Elsewhere, it has been reported that patients with non-small-cell lung cancer had an increased overall survival when receiving 'switch maintenance' or 'continuation-maintenance' therapy.^[20,21] In children with anaplastic large cell lymphoma, maintenance therapy with vinblastine can also delay relapses.^[13,22] Taken together, these recent studies provide a strong rationale for the development of long-term cancer treatments. Thus, well-tolerated therapeutic strategies allowing treatment to be given frequently and for an extended period of time appear to be mandatory.

Future Oncol. 2011;7(3):385-394. © 2011 Future Medicine Ltd.

Cite this: Metronomic Scheduling of Anticancer Treatment - Medscape - Mar 01, 2011.