HIGHLIGHTS:
• Low-dose chemotherapy (LDC) is a promising new approach to treating hemangiosarcoma.
• LDC targets the endothelial cells feeding the tumor.
• Combining LDC with angiogenesis inhibitors may work synergistically to shrink tumors.
• Low-dose continuous oral administration of 3 drugs (cyclophosphamide, etoposide, piroxicam) was well tolerated as adjuvant therapy for stage II splenic HSA in dogs. 

Conventional adjuvant chemotherapy provides only a modest survival benefit for dogs with hemangiosarcoma (HSA), an aggressive and often rapidly fatal malignant tumor in dogs. A promising alternative to conventional therapy is continuously administered low-dose chemotherapy (LDC), also known a metronomic chemotherapy. Unlike traditional chemotherapy, which delivers the highest doses possible to cancer cells, the LDC approach targets the endothelial cells feeding the tumor rather than the actual tumor cells. HSA cells are believed to arise from endothelial cells and are highly vascularized. A study to evaluate long-term treatment with LDC in dogs with stage II HSA was conducted. Dividing endothelial cells may have a unique sensitivity to low doses of certain agents, so smaller doses of traditional chemotherapy drugs are administered more frequently, sometimes every day. Circulating endothelial progenitor cells from the bone marrow may also be targeted by LDC. Drug resistance is less likely to result with metronomic dosing because the endothelial cells are genetically stable and thus unable to mutate. Combining LDC with angiogenesis inhibitors, which are drugs that alter the blood supply to tumors, may work together to shrink tumors. There is some evidence that inhibition of cyclooxygenase enzymes (COX-1 and COX-2) by nonsteroidal antiinflammatory drugs can interfere with endothelial cell tube formation and vascular endothelial growth factor production. Piroxicam has demonstrated significant activity against a variety of types of cancer in dogs and is now commonly included in treatment protocols for a variety of canine tumors. In this small preliminary study, survival times after treatment with a 3-drug combination (cyclophosphamide, etoposide, piroxicam) were at least as good as those obtained after conventional therapy with doxorubicin.

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