by Edwin Brodsky, DVM, Diplomate ACVIM (Oncology)
In order for cancer to grow beyond 2mm in diameter, a tumor needs to recruit its own blood supply. This process is called angiogensis. A variety of growth factors are involved in this process, including vascular endothelial growth factor (VEGF), basic fibroblastic growth factor (bFGF) and platelet derived growth factor (PDGF). Cancer cells can directly produce these angiogenic growth factors or stimulate the normal cells in the area of the tumor to produce these angiogenic growth factors. Once a blood supply is established, the malignant tumor is allowed to grow and potentially metastasize causing further damage to the patient. The tumor blood supply provides an attractive target for anticancer therapy because the target cells (the vascular endothelium) are more genetically stable than the cancer cells and they are less likely to become resistant to chemotherapy. Angiogenesis is a normal body process and is important in adult animals, when recovering from surgery and during pregnancy as well as in young animals developing into adulthood. Therefore, there is little risk of adverse side effects from lack of angiogenesis in the majority of our cancer patients, as an adult animal does not require angiogenesis for normal daily functions.
Metronomic chemotherapy is continuous low dose oral chemotherapy. The metronomic protocol consists of multiple drugs including an oral chemotherapy agent, an antibiotic (doxycycline) and a non-steroidal anti-inflammatory (NSAID). The daily low dose oral chemotherapy is targeting the tumor vascular cells directly. It also stimulates the release of certain anti-angiogenic factors. Doxycycline is included in the protocol for its potential anticollagenase activity. Collagenase is an enzyme needed to breakdown the extracellular matrix to allow new tumor blood vessel formation. NSAIDS inhibit the enzymes COX-1 and COX-2. COX-1 and COX-2 over expression has been associated with increases in angiogenic growth factors and inhibition of the COX enzymes by NSAIDS has been shown to decrease these growth factors and decrease endothelial tube formation needed for new blood vessels. In addition to its anti-angiogenic effects, low dose oral chemotherapy has also been shown to be beneficial in increasing antitumor immunity by decreasing T regulatory cells. Metronomic chemotherapy is generally well-tolerated with minimal side effects. However, monitoring for chemotherapy induced cystitis (bladder inflammation) is needed with one of the oral chemotherapy agents, cyclophosphamide, used in metronomic chemotherapy protocols.
Metronomic chemotherapy was found to be effective in treating dogs with splenic hemangiosarcoma after splenectomy and in dogs with incompletely excised soft tissue sarcomas on the limbs. Metronomic chemotherapy may be effective in a wide variety of cancers, as all cancers require a blood supply to grow and metastasize. However, more studies are necessary to confirm this theory.
Metronomic chemotherapy may be more attractive than traditional cytotoxic chemotherapy in certain situations. Traditional chemotherapy commonly involves the administration of intravenous medications whereas metronomic chemotherapy involves oral medications given at home and thus requires less frequent visits to the veterinarian. Metronomic chemotherapy can be a cost effective treatment alternative for clients who cannot afford more expensive treatment options. Traditional cytotoxic chemotherapy tends to be very well-tolerated. However, for the rare pets who do not tolerate cytotoxic chemotherapy well, or for those moms and dads who are very risk adverse to side effects, metronomic chemotherapy may be a less toxic option. As with any treatment, metronomic chemotherapy is not risk free, but is well-tolerated by the majority of our patients.
Edwin Brodsky, DVM, Diplomate ACVIM (Oncology)
Veterinary Medical Center of Long Island
75 Sunrise Highway
West Islip, New York 11795
(631) 587-0800; fax (631) 587-2006