Metronomic chemotherapy: an attractive alternative to maximum tolerated dose therapy that can activate anti-tumor immunity and minimize therapeutic resistance

Abstract

The administration of chemotherapy at reduced doses given at regular, frequent time intervals, termed 'metronomic' chemotherapy, presents an alternative to standard maximal tolerated dose (MTD) chemotherapy. The primary target of metronomic chemotherapy was originally identified as endothelial cells supporting the tumor vasculature, and not the tumor cells themselves, consistent with the emerging concept of cancer as a systemic disease involving both tumor cells and their microenvironment. While anti-angiogenesis is an important mechanism of action of metronomic chemotherapy, other mechanisms, including activation of anti-tumor immunity and a decrease in acquired therapeutic resistance, have also been identified. Here we present evidence supporting a mechanistic explanation for the improved activity of cancer chemotherapy when administered on a metronomic, rather than an MTD schedule and discuss the implications of these findings for further translation into the clinic.

Keywords: Angiogenesis; Anti-tumor immunity; MTDL alternative; Mechanisms of metronomic chemotherapy; Therapeutic resistance.

Figure 1. Role of the tumor microenvironment during tumor progression

Therapeutically resistant tumors engage their microenvironment as cancer cells recruit normal tissue cells, such as fibroblasts, pericytes, histiocytes, platelets and hematopoetic progenitor cells. Through engagement and modification of their microenvironment, cancer cells ‘simulate’ the conditions of a wound, evoking normal physiological responses such as new blood vessel formation without allowing for angiogenesis termination.

Figure 2. Dose-response curves for cancer cells and tumor endothelial cells (TECs)

The dosage of therapeutic agents that achieve maximal cell kill of TECs can be orders of magnitude lower than the dosage necessary to inflict significant damage on cancer cells. Therefore, damaging tumor-supporting endothelial cells may inflict equal damage on all tumor cells, effectively preventing selection for resistant cell clones.

Figure 3. Impact of metronomic chemotherapy frequency and dose on anti-tumor innate immune responses

A) Impact of metronomic frequency on tumor NK cell response. Chemotherapy administration that is too frequent (daily and Q3d in the glioma models studied; [17]) causes ablation of responding NK cells, while chemotherapy administration that is insufficiently frequent (Q9d and Q12d schedules), while initially effective at activating an innate immune response, leads to abrogation of the anti-tumor immune response and tumor escape [95]. In these models, maximal immunostimulatory and therapeutic responses have been observed on a 6-day schedule. B) Metronomic activation of anti-tumor immunity on a 6-day schedule is impaired when VEGFR2 signaling is inhibited [24, 25]. C) NK cell dose response on a 6-day schedule is dose-dependent: reduction in dose causes insufficient immune stimulation [17], while a dose that is too high increases NK cell mortality [95].

Figure 4. Predicted response to changes in tumor size over time after MTD compared to metronomic chemotherapy

MTD therapy induces early onset, short-term tumor regression, which is frequently followed by a relapse. Metronomic administration of chemotherapy may have a delayed anti-tumor effect; it may initially lead to tumor growth stasis or even an increase in tumor size, followed by a slow but persistent decrease in overall tumor mass, yielding a potentially alarming short-term effect but superior long-term outcome.