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
» 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.