An increasing knowledge of cancer biology, coupled with the emerging era of targeted drug therapy, has inspired investigation of specific anti-cancer effects inherent in traditional cytotoxic chemotherapy drugs. The prolonged administration of low doses of chemotherapy with a greatly reduced break period between doses has come to be known as metronomic administration. This strategy represents an attempt to capitalise on effects that chemotherapy may have on the tumour microenvironment. The low cost, ease of administration, and generally well-tolerated adverse event profile has made metronomic administration of chemotherapy drugs appealing in veterinary oncology. However, to date formal clinical evaluation of this treatment strategy is in the early stages and a complete understanding of the types of cancers that are sensitive to treatment, as well as the optimal drugs and dosages to utilize requires further study in rigorous clinical trials.

Conventional dose and scheduling of chemotherapy has generally followed the principle of maximum tolerated dose (MTD), in which the administered dose is defined by the highest allowable toxicity to rapidly dividing normal tissues, such as cells in the bone marrow and intestinal epithelium. As such, there is an unavoidable break period between doses to allow for repair of these cells. In veterinary oncology, high-grade toxicity is not an acceptable component of treatment and doses are adjusted accordingly, but break periods are built in to protocols to allow for normal tissue repair, should repair be required. The principal goal of metronomic administration of chemotherapy is reduction or elimination of the break period between doses. As such, reduction of each individual dose is required to accomplish the goal of continual administration.

Mechanisms

In addition to a direct tumour cell cytotoxic effect, which may still represent a significant mechanism of action, metronomic administration of certain chemotherapy drugs has been shown to modulate specific aspects of the tumour microenvironment. The two most studied areas within the microenvironment have been a reduction in tumour angiogenesis by various mechanisms, and stimulation of anti-tumour immunity through alterations of T cell subset populations. Belief in the anti-angiogenic mechanisms of low-dose cyclophosphamide and other drugs is largely based on studies that demonstrate upregulation of the endogenous angiogenesis inhibitor thrombospondin-1 (TSP-1), downregulation of pro-angiogenic factors such as vascular endothelial growth factor (VEGF), and direct endothelial cell cytotoxicity at very low chemotherapy concentrations. Immunotherapeutic mechanisms for metronomic cyclophosphamide are based on reduction in circulating T regulatory cells that suppress the immune response, and possible concomitant increases in T helper subset 17 (Th17) cells, which translates to a boost in anti-tumour immunity. Not all metronomic chemotherapy drugs and regimens are likely to be equally efficacious, despite the fact that sustained angiogenesis and immune evasion are general hallmarks of tumour growth. Different drugs and schedules are associated with differing mechanisms of action.

Clinical Trials

Of the many cytotoxic chemotherapy drugs available, prolonged administration of alkylating agents, such as cyclophosphamide, chlorambucil, and lomustine have arguably received the most investigation. Preliminary studies of metronomic schedules with each of these drugs have been reported. Metronomic cyclophosphamide with piroxicam has been shown to delay or prevent the regrowth of incompletely excised canine soft tissue sarcomas. A metronomic "chemo-switch" regimen of cyclophosphamide and etoposide may also have activity in canine hemangiosarcoma. The list of chemotherapy agents that may have utility when administered in a metronomic fashion likely extends beyond alkylating agents. The ability to provide frequent administration, most often necessitating oral dosing, is a key component to drug suitability. Platinum agents, taxanes, anthracyclines, antimetabolites, among other drug families, are potential candidates for exploration of metronomic scheduling, but each requires proper evaluation.

Combination Therapy

As is often the case in oncology, combination therapy may result in superior efficacy. As more clinical results are reported, we will gain an increased understanding of drug combinations and schedules that will be most beneficial to patients. Many early clinical trials have evaluated combinations of drugs, usually a chemotherapy drug coupled with a non-steroidal anti-inflammatory agent such as piroxicam. This practice may hamper the ability to properly evaluate relative efficacy if these agents/doses/schedules have not first been evaluated clinically in a single agent context. The use of low dose metronomic chemotherapy protocols does not necessarily equate to an abandonment of the principles of maximum tolerated dose administration, as these approaches have been applied in combination in preclinical studies and anecdotally in veterinary oncology. Metronomic chemotherapy administration may also be a promising approach to combination therapy with emerging targeted agents, such as receptor tyrosine kinase inhibitors. Both strategies utilize drugs given in a chronic fashion at optimal biologic doses that may be considerably less than the maximum tolerated dose.

Side Effects

Conventional MTD chemotherapy protocols have not necessarily been designed for, or evaluated after, chronic application. Low dose metronomic protocols have generally been well tolerated in the short term. However, when using a metronomic treatment strategy, clinicians must be mindful of side effects that may only occur after prolonged drug exposure. The most concerning side effect encountered to date has been sterile cystitis with cyclophosphamide use, although the occurrence has not been reported to be higher than that observed with conventional protocols.

Patient Selection and Monitoring

Much work is required in the area of biomarkers to predict optimal biologic dose, and cancer types or subtypes that may benefit most from metronomic chemotherapy protocols. Candidate biomarkers that have received preliminary evaluation, both clinically and preclinically, include plasma VEGF levels, tumour vascular density, as well as circulating endothelial cells and their precursor cells (CEC/CEP). Veterinary evaluation of these potential biomarkers has begun, and functional imaging studies, such as dynamic contrast MRI and PET-CT may also be useful.

Drug Resistance

Resistance to metronomic therapy is likely to be a significant problem, not unlike resistance to other oncology treatments. This is true despite early predictions that anti- angiogenic and immunotherapy approaches should evade resistance by targeting genetically stable endothelial cell and lymphocyte populations, respectively. Use of a "chemo-switch" regimen, where exposure to one drug is alternated with another, is one strategy aimed at addressing this problem. A recent preclinical study with prostate cancer xenografts has suggested that onset of resistance to continuous low doses of cyclophosphamide does not select for resistance to the same drug administered at the maximum tolerated dose.

References

1.  Burton JH, Mitchell L, Thamm DH, et al. Low-dose cyclophosphamide selectively decreases regulatory T cells and inhibits angiogenesis in dogs with soft tissue sarcoma. J Vet Intern Med. 2011;25:920-926.

2.  Elmslie RE, Glawe P, Dow SW. Metronomic therapy with cyclophosphamide and piroxicam effectively delays tumor recurrence in dogs with incompletely resected soft tissue sarcomas. J Vet Intern Med. 2008;22:1373-1379.

3.  Lana S, U'ren L, Plaza S, et al. Continuous low-dose oral chemotherapy for adjuvant therapy of splenic hemangiosarcoma in dogs. J Vet Intern Med. 2007;21:764-769.

4.  Leach TN, Childress MO, Greene SN, et al. Prospective trial of metronomic chlorambucil chemotherapy in dogs with naturally occurring cancer. Vet Comp Oncol. 2012;10:102-112.

5.  Marchetti V, Giorgi M, Fioravanti A, et al. First-line metronomic chemotherapy in a metastatic model of spontaneous canine tumour: a pilot study. Invest New Drugs. epub April 2011.

6.  Mutsaers AJ. Antiangiogenic and metronomic therapy. In: Withrow SJ, Vail DM, Page RL (eds.) Small Animal Clinical Oncology. 5th ed. Philadelphia: WB Saunders Co, in press 2012.

7.  Tripp CD, Fidel J, Anderson CL, et al. Tolerability of metronomic administration of lomustine in dogs with cancer. J Vet Intern Med. 2011;25:278-284.