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Metronomic Chemotherapy

Conventional dosing of chemotherapy is intended to kill rapidly cells and cancer cells tend to divide much more quickly than normal tissue.  It typically involves a treatment every few weeks with an injection or pill.  Metronomic chemotherapy involves the long-term administration of a low dose oral chemotherapy drug every 1-2 days with a nonsteroidal anti-inflammatory drug.  Metronomic chemotherapy does not directly kill tumor cells. It works via:

  1. Angiogenesis:  Angiogenesis if the formation of blood vessels from existing vasculature. Angiogenesis plays a critical role in the growth and spread of cancer and tumor blood vessels are more proliferative than normal tissue.  Metronomic chemotherapy inhibits angiogenesis which therefore deprives the tumor of oxygen and nutrients which can result in cancer cell death.
  2. Immunomodulation: Regulatory T cells (Tregs) are cells of the immune system that are immunosuppressive.  Tregs are recruited by cancer cells to help it evade detection and killing by the immune system.  It has been demonstrated the metronomic chemotherapy can suppress Tregs in dogs with soft tissue sarcomas.
  3. Tumor dormancy/cancer stem cells: Dormancy is a stage in the development of a tumor in which the cancer cells are present but inactive.  If the tumor cells are in a dormant state, eventually a switch will occur, and the tumor will start to grow again and/or spread.   Cancer stem cells are a robust population of cells within a tumor. They are thought to be the source of all the cancer cells within the tumor and they can regrow despite treatment.  It is thought that metronomic chemotherapy may be able to target cancer stem cells and dormant tumor cells.

The chemotherapy drugs used most commonly in metronomic protocols are cyclophosphamide and chlorambucil.  Less commonly used drugs include etoposide and thalidomide.  Side effects associated with low-dose chemotherapy are rare but include gastrointestinal upset and bone marrow suppression.  Cyclophosphamide is associated with an increased risk for irritation of the bladder called sterile hemorrhagic cystitis (SHC). This has been reported to occur in up to 30% of dogs receiving metronomic cyclophosphamide.  SHC can resolve in a few weeks but in some cases can be prolonged and it can be very difficult to manage.  Therefore, I typically recommend chlorambucil instead since it does cause SHC.  NSAIDS can cause GI toxicity and can affect kidney or liver function in rare cases.  Lab work should be performed every 8-12 weeks while a pet is on metronomic chemotherapy.  If there are concerns about side effects, I recommend stopping the medications and contacting your veterinarian. Chemotherapy medication should be handled wearing gloves and the tablets should never be split or crushed.

Metronomic chemotherapy tends to be affordable and the follow-up appointments are less often.  It is not as intense of a treatment compared to conventional chemotherapy.  Since metronomic chemotherapy does not kill rapidly dividing cancer cells, a notable response can take months.  Therefore, it may not be a good option for pets with tumors that are growing quickly.  Metronomic chemotherapy has not been as well studies in cats, but it seems to be well tolerated in general.

Indications for metronomic chemotherapy in dogs include:
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  • Hemangiosarcoma
  • Incompletely excised soft tissue sarcomas
  • Transitional cell carcinoma
  • Pulmonary carcinoma
  • Thyroid carcinoma
  • Other solid tumors


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