When less is more: the theory of metronomic chemotherapy

As the focus of cancer treatments shifts away from conventional chemotherapy to more targeted therapies, a new strategy for the treatment of cancer has become increasingly popular for both human and veterinary patients. The phrase that has been coined for this strategy is metronomic chemotherapy or low-dose chemotherapy.

The traditional strategy is to directly target cancer cells with the use of maximally tolerated doses (MTD) of chemotherapy. As we all know, this strategy can lead to deleterious side effects and a decreased quality of life. Treatments are given intermittently to allow for normal tissue recovery, which allows for recovery of tumor cells often resulting in re-population of the tumor with drug-resistant cells and tumor vasculature. As a result, this strategy does not result in cures for many solid tumors (Table 1).

Table 1: Comparison of MTD chemotherapy and etronomic chemotherapy

A different approach is to target normal cells such as endothelial cells and cells of the immune system. Metronomic chemotherapy still involves the use of chemotherapy drugs, but these drugs are given more frequently at a much lower dose. The targets of metronomic chemotherapy are circulating endothelial cells and other factors that control angiogenesis. Given that normal endothelial cells have a more stable genetic makeup, resistance is not likely to be an issue. In addition, this strategy requires lower doses of chemotherapy that minimize side effects (Table 1).

Review of angiogenesis

In normal tissues, the regulation of angiogenesis is a balance between proangiogenic factors and anti-angiogenic factors. Most tissues do not require on-going angiogenesis to any significant degree because normal vasculature does not have a high turnover rate. Exceptions to this would be during growth phases or wound healing.

It has long been recognized that tumor cells rely on angiogenesis to deliver nutrition so that tumors can continue to proliferate. Without a vascular supply, tumors are not able to grow beyond 1 to 2 mm in size. In order to grow, tumors must have some way of mobilizing vascular endothelial cells. Many tumors have the ability to secrete potent factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (BFGF) that promote angiogenesis.

Potential strategies that can be used to arrest angiogenesis would include targeting the growth factors that promote angiogenesis, promote the production of anti-angiogenic factors or directly inhibit or kill endothelial cells. Given the limited need for angiogenesis in mature organisms, it would be expected that significant side effects would be unlikely.

Metronomic chemotherapy

As part of the angiogenic process, endothelial cells are mobilized from the bone marrow into circulation in response to proangiogenic factors. These circulating endothelial cells are then attracted to the site of active angiogenesis and form tumor vasculature. Studies have shown that endothelial cells have intrinsic sensitivity to chemotherapy even when used in low doses. The doses required to inhibit endothelial cells are much lower than those that will inhibit bone marrow and gastrointestinal cells, thus, limiting side effects. The low doses of chemotherapy used in metronomic chemotherapy directly target endothelial cells as well as inhibit the release of endothelial cells from the bone marrow.

In addition, metronomic chemotherapy can also induce the production of thrombospondin-1, which is a potent anti-angiogenic factor. It has been shown that low-dose chemotherapy can selectively remove regulatory T lymphocytes that can lead to enhancement of immune function.

As is the case with MTD chemotherapy, it is felt that a combination of drugs would be more likely to be effective compared with a single agent. Metronomic chemotherapy is frequently combined with drugs that have different angiogenic targets. For example, in human patients, metronomic chemotherapy is combined with drugs such as bevacizumab, which is an antibody against VEGF. Multiple agents have been shown to have anti-angiogenic activity in vitro so they are logical agents to combine with metronomic chemotherapy. These agents would include cyclooxygenase-2 (COX-2) inhibitors, doxycycline and thalidomide.

COX-2 inhibitors are of particular interest as COX-2 has been shown to play a role in the development of certain tumors, and overexpression of COX-2 has been shown to be a negative prognostic factor. COX-2 is capable of inducing the production of several proangiogenic factors including VEGF and BFGF. Inhibitors of COX-2, such as piroxicam and celecoxib, can block the production of these factors and, thus, inhibit angiogenesis. COX-2 can also promote tumor growth through other pathways, such as decreasing apoptosis, increasing cell proliferation and increasing the number of regulatory T lymphocytes, so COX-2 inhibition can affect multiple pathways of tumor progression.

It should be cautioned that despite the potential benefit of metronomic therapy, there are also several limitations. With metronomic therapy, tumors do not always regress, and if they do, it can be slowly over a period of time. Patients with rapidly progressing tumors are not likely to benefit from the metronomic strategy. It can be difficult to evaluate responses objectively, particularly in those tumors that remain stable. Further studies need to evaluate other biologic endpoints such as numbers of circulating endothelial cells and levels of VEGF as well as clinical response. At the current time, most of the individual drug dosages, drug combinations and schedules are empiric, and there is a need to identify what would be considered optimal.

Metronomic chemotherapy use in veterinary medicine

Metronomic chemotherapy is being increasingly used in veterinary medicine, although currently there are few published studies. There are several scenarios in which metronomic therapy may be indicated. The first would be after completion of a standard course of chemotherapy. Some oncologists are now advocating the routine use of metronomic chemotherapy after MTD chemotherapy for several types of cancer including osteosarcoma and hemangiosarcoma. The second scenario would be as a primary treatment option (i.e., tumors for which there is no standard of care) or as an alternative to standard therapy (i.e., for those owners that decline standard treatment). A third application would be for those patients that have failed conventional therapy.

The most commonly used chemotherapy drug for metronomic therapy in veterinary oncology is cyclophosphamide as it is low-cost, readily available and orally administered. Methotrexate, another oral chemotherapy drug, has been used in metronomic therapy. Cyclophosphamide is frequently combined with a COX-2 inhibitor such as piroxicam and/or doxycycline. Side effects are limited, though hemorrhagic cystitis has been reported in dogs treated with low-dose cyclophosphamide, which can become a significant side effect in those patients. This would necessitate discontinuation of the cyclophosphamide.

In one study, low-dose daily dosing of cyclophosphamide was combined with piroxicam for incompletely excised soft-tissue sarcomas (Elmslie 2008). Incompletely excised soft tissue sarcomas can successfully be treated with radiation therapy. Control rates are between two to five years. However, radiation therapy is not always accessible or affordable. In this study, 30 dogs received cyclophosphamide and piroxicam after surgical excision, while 55 dogs received surgery only. In both groups, the tumor was reduced to a microscopic level of disease. The disease-free interval in the control dogs was 211 days, while the disease-free interval had not yet been reached in the treated group of dogs. The minimum disease-free interval was calculated at 410 days. Toxicity was reported in 40 percent of dogs in the treated group, although this was generally mild and did not require discontinuation of treatment. The most common side effects were anorexia, vomiting or hemorrhagic cystitis.

In a second study, metronomic chemotherapy was used instead of doxorubicin chemotherapy after splenectomy for hemangiosarcoma (Lana 2007). Doxorubicin is considered the standard of care for hemangiosarcoma. However, even with treatment, survival times are still only four to six months. Nine dogs with splenic hemangiosarcoma were given a combination of low-dose oral cyclophosphamide and etoposide (another chemotherapy drug) and piroxicam. The median survival time for this group of dogs was 178 days, which was significantly longer than the median survival time of 133 days for the control group receiving doxorubicin alone.

Metronomic chemotherapy is an attractive option because it is less toxic, easier to administer and less expensive than MTD chemotherapy. Currently, a large number of clinical trials are underway in both human and veterinary medicine to determine the optimal conditions for the use of metronomic therapy. We should expect to hear more about this form of therapy in the near future.

Suggested Reading

» Mutsaers AJ. Chemotherapy: new uses for old drugs. Vet Clin North Am Small Animal Pract 2007;37:1079-1090.

» Elmslie RE, Glawe P, Dow SD. 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.

» 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.