Metronomic chemotherapy (MC) is the oral administration of anticancer drugs at low, minimally toxic doses on a frequent or continuous schedule. This is commonly executed using a combination of cyclophosphamide (cytoxan) and piroxicam, however several other protocols have been published, including chlorambucil, etoposide and thalidomide. It is often an attractive option for clients due to its relatively low toxicity profile, moderate cost, and less intensive recheck schedule. In contrast to more traditional chemotherapy administered at maximally tolerated doses (MTD), the anticipated outcome with metronomic chemotherapy is disease stabilization or dormancy, therefore it is often pursued as a maintenance therapy, following surgery and/or MTD chemotherapy.
Mechanisms of Action
Antiangiogenic – Angiogenesis, which is the formation of new blood vessels from larger preexisting vessels, is critical for tumor development. This involves the migration, growth and differentiation of vascular endothelial cells, which line blood vessels. Tumor angiogenesis is regulated by inhibiting anti-angiogenic factors and activating pro-angiogenic factors. Metronomic cytoxan administration has been associated with a significant decrease in tumor microvessel density in dogs with soft tissue sarcomas. It also was shown to decrease anti-angiogenic factors VEGF and thrombospondin-1 in a mouse model.
Immunoregulatory – In patients with cancer, immunosuppressive T regulatory (Treg) cells are recruited by the tumor and present at high levels. This suppresses the anti-cancer immune responses and induces tolerance, allowing tumors to evade the immune system. Metronomic cytoxan and chlorambucil have been shown to reduce circulating Treg numbers in dogs with soft tissue sarcomas.
Inhibition of cancer stem cells and tumor dormancy – Cancer stem cells are a subpopulation of cancer cells that act like normal stem cells and can initiate tumor growth. It is theorized that metronomic chemotherapy can target cancer stem cells thereby inducing tumor dormancy, causing a prolonged period of stable disease.
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Potential Side Effects
Metronomic chemotherapy is well tolerated with minimal risk for bone marrow suppression or gastrointestinal (GI) upset. However, higher cumulative doses of Cytoxan have been associated with an increased risk of developing sterile hemorrhagic cystitis (SHC), which has been reported in 3.6 – 32% of dogs receiving metronomic cytoxan. Acrolein, a breakdown product of cyclophosphamide, is known to irritate the bladder epithelium. Symptoms of SHC include pollakiuria, stranguria and hematuria. In a 2017 study the addition of daily furosemide at 0.5 – 1 mg/kg/day significantly decreased the incidence of SHC with metronomic cytoxan.
Metronomic chemotherapy is often administered in conjunction with an NSAID, such as piroxicam, therefore we can see toxicity associated with these medications. Piroxicam alone has been reported to cause GI toxicity in 6-23% and nephrotoxicity in approximately 5% of cancer-bearing dogs.
The management of multiple different cancers using metronomic chemotherapy has been reported in the literature. One of the most common applications is in preventing local recurrence in dogs with incompletely excised soft tissue sarcomas. Another protocol using cytoxan, etoposide and piroxicam showed similar survival times to doxorubicin alone when treating dogs with hemangiosarcoma post splenectomy, with a median survival time of 178 days. Metronomic chlorambucil has be trialed in dogs with transitional cell carcinoma of the bladder in dogs, with 70% having a response or sustained stable disease for median of 119 days. Recently, a combination of cytoxan, piroxicam and thalidomide was shown to significantly prolong survival times in dogs with advanced primary lung tumors. Lastly reports of a response in dogs with a mast cell tumor, thyroid carcinoma and histiocytic sarcoma have been published.