Cancer chemotherapy in dogs and cats has traditionally involved administration of chemotherapy agents at the maximum tolerated dose. Cytotoxic chemotherapy has an acceptably low risk of serious toxicity, but an obligatory rest period must be included to allow for recovery of drug-sensitive normal cell populations. This rest period can also allow significant recovery of tumor cells. Metronomic chemotherapy is characterized by more frequent administration of lower doses of oral drugs and appears to halt or slow tumor progression through multiple mechanisms. This approach may be at least as effective as conventional chemotherapy with a lower risk of toxicity.

Keywords

Low-dose chemotherapy

Canine neoplasia

Angiogenesis

Immune modulation

Tumor biomarkers

Key points

Introduction

Conventional cytotoxic chemotherapy has been the mainstay of systemic anticancer therapy for more than 50 years. For both human and veterinary patients, most protocols involve administration of single or multiple antiproliferative agents delivered at doses close to the maximum tolerated dose (MTD). Because neoplastic cells are rapidly dividing compared with normal tissues, MTD chemotherapy is intended to kill as much of the neoplastic cell population as possible. A critical aspect of all MTD protocols is inclusion of breaks between drug administrations to allow for recovery of drug-sensitive normal tissues, particularly bone marrow progenitors and gastrointestinal epithelial cells. Without these gaps between treatments, unacceptable drug toxicities occur. However, this approach also permits recovery of tumor cells and can lead to tumor regrowth and the development of drug-resistant or metastatic disease. Although conventional chemotherapy has been associated with significant gains in survival for many cancers, it infrequently results in permanent tumor control, particularly in the face of demonstrable metastatic disease.

Research over the past several decades has brought about an exponential increase in understanding of the molecular pathways and mechanisms of cancer metastasis and drug resistance. This work has revealed many reasons for the failure of conventional chemotherapy to limit cancer progression. These reasons include the dynamic heterogeneity and instability of tumor cells, the protective action of the tumor microenvironment, and suppression of antitumor immune responses. However, awareness of these shortcomings is enabling the development of more targeted approaches to cancer therapy including a form of chemotherapy known as metronomic chemotherapy (MC). In contrast with conventional chemotherapy, MC is characterized by the continuous or uninterrupted administration of chemotherapy drugs at doses that are significantly lower than MTD therapy (Box 1).1 As discussed in this article, MC can be thought of as a multitargeted approach and is rapidly emerging as an attractive adjunct or alternative to conventional drug delivery. Although many questions regarding the application of MC to human and veterinary oncology patients await investigation, favorable tumor control and excellent safety profiles support the significant promise of this new anticancer approach.

Targets of MC

Tumor Angiogenesis

Tumor growth is critically dependent on the process of angiogenesis, which occurs through the development of new blood vessels from preexisting, larger vessels. Tumors can also stimulate vasculogenesis, which is defined as new blood vessel formation from bone marrow–derived progenitor cells including circulating endothelial progenitor cells (CEPs).2–4 Regardless of the pathway, the rapidly dividing tumor cell population requires a blood supply to deliver nutrients and oxygen and to remove waste products; without it, tumor volume is limited to only a few millimeters in size.5,6

Because angiogenesis is so important to their survival, tumors are adept at disrupting the normal balance between proangiogenic and antiangiogenic molecules that characterizes the physiologic angiogenesis of organ system development, wound healing, and other normal processes. Also referred to as the angiogenic switch, tumor formation drives the upregulation of a large number of growth factors, including vascular endothelial growth factor (VEGF), fibroblast growth factor, and platelet-derived growth factor (PDGF). Of these, VEGF is most important, stimulating angiogenesis through direct effects on endothelial cell proliferation and migration and through mobilization of CEPs from the bone marrow to sites of neovascularization.7,8

The other important aspect of the angiogenic switch is tumor-induced inhibition of naturally occurring antiangiogenic molecules such as thrombospondin-1 (TSP-1). Inhibition of TSP-1 activity is an effective tumor survival strategy because TSP-1 has direct suppressive effects on endothelial cell proliferation and apoptosis and is therefore a potent VEGF antagonist.9 In human patients with cancer, increased serum or intratumor concentrations of VEGF and decreased levels of TSP-1 are associated with poor outcome for many malignancies, including carcinomas of lung, breast, and bladder.10,11

Although it may seem surprising, drugs from nearly every class of conventional chemotherapy agents have been found to have antiangiogenic activity based on the results of various in vitro and in vivo assays.12,13 Similar to the neoplastic cell population, the endothelial cells recruited to support tumor growth are also rapidly dividing and as such are susceptible to cytotoxic chemotherapy.13 Some drugs, including vinblastine and paclitaxel, inhibit endothelial cell proliferation at doses lower than those required to inhibit tumor cell proliferation.14,15 Why then are the antiangiogenic effects of MTD chemotherapy not more clinically relevant? The answer to this question arises from the discovery by Browder and colleagues16 that the long, but necessary, break periods between MTD dosing permit regrowth and recovery of damaged tumor vasculature at a pace that outweighs any benefit of the drugs’ antiangiogenic effects. When the alkylating agent cyclophosphamide (CYC) (Cytoxan) was given at the MTD to mice with lung cancer, apoptosis of endothelial cells in the tumor vasculature occurred even before tumor cell death did. However, this antiangiogenic activity had no therapeutic benefit because damage to the vasculature was repaired during the recovery periods between successive cycles of chemotherapy. When CYC was given at a lower dose (about one-third of the MTD in these studies) and without interruption, then even large, well-established tumors were found to regress.16

Since this ground-breaking work many preclinical studies have confirmed the antiangiogenic effects of metronomic dosing of CYC and other chemotherapy agents. Some drugs, such as the microtubule inhibitors vinblastine and paclitaxel, inhibit endothelial cell proliferation or migration directly.15,17,18 Other drugs, including CYC and 5-fluorouracil, seem to have...