Metronomic Chemotherapy

“The definition of metronomic chemotherapy varies, but generally it refers to repetitive, low doses of chemotherapy drugs designed to minimize toxicity and target the endothelium or tumor stroma as opposed to targeting the tumor.” -Dr. Harold Burstein of the Dana-Farber Cancer Institute.

Principles of Metronomic chemotherapy

“For almost half a century, systemic therapy of cancer has been dominated by the use of cytotoxic chemotherapeutics.  Most of these drugs are DNA-damaging agents that are designed to inhibit or kill rapidly dividing cells.  They are often administered in single doses or short courses of therapy at the highest possible dosage without causing life-threatening levels of toxicity.  This is referred to as the “Maximum Tolerated Dose” (MTD).  MTD therapy requires prolonged breaks (generally 2-3 weeks in duration) between successive cycles of therapy.  Progress had been modest in terms of curing or significantly prolonging the lives of patients with cancer using MTD, particularly those with advanced-stage or metastatic disease.  The higher the dosage of chemotherapy, the more likely we are to kill the cancer, but the limiting factor is always the adverse side effects that occur with increasing dosages.  More recently, a lot of research has been directed towards a reappraisal of the best ways of administering chemotherapy.  Instead of using short bursts of toxic MTD chemotherapy interspersed with long breaks to allow recovery from the harmful side effects, there is now a shift in thinking towards the view that more compressed or accelerated schedules of drug administration using much smaller dosages than MTD might be more effective—not only in terms of reducing certain toxicities but perhaps even improving antitumor effects as well.” (Kerbel RS and Kamen BA, The Anti-Angiogenic Basis of Metronomic Chemotherapy, Nature Reviews Cancer 2004.)

There is a considerable body of evidence that even very low, nontoxic doses of chemotherapy drugs, when delivered frequently for a prolonged period of time (metronomic chemotherapy)  can retard tumor blood vessel growth (or angiogensis) by destroying endothelial cells.  Endothelial cells are the cells that line the blood vessels.  Angiogenesis, or the orderly formation of the endothelial cells into blood vessels, is necessary for tumors to grow and to spread.  Stopping this process, or anti-angiogenic therapy, has been shown to be an effective way to stop tumor growth and metastasis.  The endothelial cells that form the lining of newly formed blood vessels, such as those whose creation is orchestrated by tumors to fuel their growth are the targets for this type of therapy.  Simply put, if you starve the blood supply to the tumor, it is deprived of necessary oxygen and nutrients needed to survive. Drawing reproduced from The Stehlin Foundation for Cancer Research September 2003 newsletter.  

In veterinary medicine, there have been several studies published that give promise to the principle of metronomic or anti-angiogenic therapy.  In dogs with incompletely resected soft tissue sarcomas, Elmslie, et al. [J Vet Intern Med 2008;22(6):1373-9)]showed that the use of low dose daily cyclophosphamide (cytoxan) and piroxicam (feldene) extended the time to recurrence over patients treated with surgery alone.  In addition, Lana, et al. [J Vet Intern Med 2007;21(4):764-9] showed that in patients with hemangiosarcoma, the use of metronomic chemotherapy was associated with survival times equal to that of MTD chemotherapy.

Dr. Robert Kerbel (Toronto, Ontario) is one of the leaders in anti-angiogenic and metronomic therapy.  He has recently suggested that the clinical benefit and impact could be greater if the therapy were initiated at earlier stages of malignancy.  Therefore, at the Animal Cancer and Imaging Center, we recommend standard MTD chemotherapy combined with low dose metronomic therapy for many tumor types such as osteosarcoma and hemangiosarcoma.  For other tumor types, metronomic chemotherapy may be the primary modality of therapy or will start after standard therapy has ended.  We will discuss with you in detail what is the optimum use of this therapy for your pet as your pet’s individual condition and general health other than the cancer may have a impact on the schedule of treatment we utilize.  It must be kept in mind that the laboratory and clinical research with metronomic chemotherapy administration is ongoing but extremely promising.

Schematic of changes in tumor vasculature during the course of anti-angiogenic therapy.  A. Normal vasculature composed of mature vessels and maintained by the perfect balance of pro-and anti-angiogenic molecules, might not change during the course of anti-angiogenic therapy.   B. Abnormal tumor vasculature, composed largely of immature abnormal vessels. C. Judiciously applied direct or indirect anti-angiogenic therapies might prune immature vessels, leading to more normalized tumor vasculature.  This network should be more efficient for the delivery of therapeutics and nutrients.  D. Rapid pruning of, or coagulation in, tumor vasculature might reduce the vasculature to the point that it is inadequate to support tumor growth and might lead to tumor dormancy. This is the ultimate goal of anti-angiogenic/anti-vascular therapy.
From Nature Medicine 7, 987-989 (2001). 

How is treatment given?

Prior to beginning metronomic chemotherapy, some baseline information is needed to evaluate your pet’s cancer and their general health. Measurements of existing tumors, if present are necessary to determine response.  This may be a physical measurement of an obvious tumor on the outside of the body, or by radiographs or ultrasound for internal tumors.  A CBC, chemistry panel, and urinalysis are needed prior to starting treatment.  If test results are acceptable, then medications are dispensed.  It is important that you follow handling and administration guidelines provided for you at the time of starting chemotherapy.

what DRUGS ARE USED AND are the side effects of treatment?

 Our metronomic protocol most commonly consists of daily oral Cytoxan® (cyclophosphamide) OR Leukeran® (chlorambucil) and Feldene®(piroxicam).  Recently, the use of a tyrosine kinase inhibitor (Palladia® or toceranib) has been used in the metronomic setting for a variety of tumors.

Feldene® is a non-steroidal anti-inflammatory drug (NSAID) that can cause gastrointestinal upset.  For this reason, we also advise using Pepcid® (famotidine) or a similar medication to prevent gastrointestinal upset and potential gastrointestinal ulceration.  Although metronomic chemotherapy involves using dosages of close to one-tenth of standard chemotherapy doses, side effects, although minimal, can occur.  Gastrointestinal upset and myelosuppression (lowering of white blood cell counts) are uncommon.  With metronomic cyclophosphamide, patients should be monitored for the development of blood in the urine or urinary tract symptoms as sterile hemorrhagic cystitis, although very uncommon, can occur.    Although side effects to this type of therapy have been negligible, monthly CBCs (complete blood counts), serum chemistry panels, and urinalyses are advised.  We carefully watch renal function and monitor for blood in the urine, as these can be side effects of these drugs that are more typically seen at higher dosages, but are still possible with metronomic dosing. 

Our doctors will make recommendations for the most effective metronomic chemotherapy protocol to use for your pet's particular type of cancer and advise you on the most beneficial monitoring schedule. 

As always, if there are any concerns about symptoms your pet may be exhibiting after starting these drugs, please contact our office.