Metronomic chemotherapy (Proceedings)

The veterinary profession and more specifically, oncologists are taking an interest in the concept of metronomic chemotherapy. What is it? How does it work? Will it help pets with cancer? Metronomic chemotherapy (mCTx) is the use of very low doses of anticancer drugs given at a constant daily or alternate day schedule with no rest periods. Although there are no randomized clinical trials to prove that mCTx is effective in dogs and cats, there is enough research rationale to justify its use in veterinary medicine. In theory, mCTx given on a long term basis may help patients live longer achieving, durable stable disease. It may be effective in the inhibition of common mechanisms and pathways of malignancy such as angiogenesis, mitosis, and metastasis. Metronomic chemotherapy is a viable palliative option for veterinary cancer patients with resistant, inoperable or advanced cancer. Cancer patients that are entered into "Pawspice" (pet hospice) management programs may derive benefit from metronomic chemotherapy.

Metronomic Chemotherapy as an Option

The battle against cancer often involves initial skirmishes using surgery, chemotherapy or radiation therapy to make the cancer retreat into remission. Recurrences are fought along the way until the cancer claims the victim with its fatal agenda. In veterinary medicine, metronomic chemotherapy may be the best option to pursue in selected patients or in all patients depending on the disposition of the pet owner. Certainly when cancer recurs, the attending doctor and the family must regroup and evaluate the patient. Using the recommended framework for ethical decision making, as described in the over-treatment session in the previous hour would be very helpful http://www.ethics.ubc.ca/people/mcdonald/conflict.htm. There comes a time when the pet's family declines previously successful standard recommendations such as salvage surgery, rescue chemotherapy or radiation therapy. The family may feel that the first round of treatments took a lot out of their pet and that the pet might not be able to handle further aggressive treatments. Other pet owners may feel that they just do not want to put their pet through the demands of another round chemotherapy again.

The good news about metronomic chemotherapy is that it is very well tolerated by the majority of veterinary cancer patients due to its inherent low toxicity. (Liptack, et al, 2004) This author uses low dose, increased frequency therapy as a kinder, gentler way to help fragile and geriatric cancer patients with compromising comorbidities, dehydration, cachexia or malnourishment.

Antiangiogenesis Effect of mCTx

Metronomic chemotherapy is documented to target growing tumor vascular endothelial cells. Since it targets tumor vasculature, it may achieve an antiangiogenesis effect and stabilization of disease. Other agents which might also have antiangiogenic action such as NSAIDs and doxycycline are often added to mCTx protocols. This author has used oral antineoplastic agents such as Cytoxan™, Leukeran™, Xeloda™, Alkeran™ and lomustine along with various nutraceuticals such as Agaricus mushroom and Inositol Hexaphosphate in combination with NSAIDs and doxycycline to enhance overall anti-tumor effects. Some oncologists use chemo preventive agents such as Tamoxifen™ in combination with mCTx as well. Theoretically, mCTx incorporates an evidence based and scientific method of therapy, although the exact mechanisms of action are not fully understood.

Lymphoma

Dogs and cats with resistant lymphoma or with families who cannot afford the routine chemotherapy protocols may receive metronomic chemotherapy, although the benefits are anecdotal and published data for benefit is lacking. It is important to know that using mCTx for lymphoma patients is not intended to induce remissions. It is best to use mCTx following induction protocols when the patient is in clinical remission. Using continuous low dose cytoxan, chlorambucil, melphalan, procarbazine, and/or dexamethasone may be helpful in sustaining longer remissions or partial remissions. It may help some patients achieve stable partial remissions. However, when the patient relapses; more aggressive drugs are required for re-induction.

Carcinoma

Canine cancer patients with any type of carcinoma, may benefit from the use of low dose oral Xeloda™ (capecytabine), a derivative of 5-fluro-uracil) on a daily basis along with low dose cytoxan given on an alternate day basis. Take precautions to never use 5-F-U or its derivatives or its topical cream in cats because it is neurotoxic in this species. Cats develop seizures at surprisingly low doses. Cats given 5-F-U topical cream or low dose intralesional injections may develop seizures and die. Xeloda™ can be given in the range of 250mg per meter squared body surface area in dogs on a daily basis or 500mg/M2 on an alternate day basis. These doses are well below the maximum tolerated dose (MTD) for capecytabine. At this low dose, canine cancer patients may receive it indefinitely on a continuous schedule. All cancer patients on mCTx must have routine hematologic parameters evaluated at least every two or three weeks. The patient may continue with the mCTx drug protocol if their CBC values remain within or just below normal limits.

In addition, this author has experienced benefits for patients using a combination of mCTx and routine chemotherapy. For instance, we use a protocol with metronomic Xeloda™ and IV injections of Gemzar™ at 200 mg/M2 on alternate weeks for dogs with hepatocellular, intestinal, pancreatic, and anal sac carcinoma.

Soft Tissue Sarcoma

Dogs and cats with soft tissue sarcomas, including hemangiosarcoma, may benefit from metronomic chemotherapy using NSAIDs and doxycycline, and/or in combination with other antineoplastic drugs such as low dose cyclophosphamide, Tamoxifen, SAHA or other histone deacetylase inhibitors. (Cohen 2004) (Bryan 2008)

Expanding mCTx to include Immunonutrition & Chemoprevention

In many ways, one may consider that consistently administered supplements and nutraceuticals that have known anticancer therapy is another form of mCTx.

Expanding the Philosophy of mCTx

There is a need to avoid administering certain chemotherapeutic drugs that predictably cause a high rate of adverse events at their maximum tolerated dose (MTD). Chemotherapy has a bad reputation in human medicine due to the adverse effects of drugs given at much higher doses than we use in veterinary medicine. Several commonly used chemotherapeutic drugs have inherent toxicity. This author would like to take the opportunity to ask that you consider expanding the metronomic philosophy into every day chemotherapy treatments. When dealing with drugs that have a high risk of adverse events, it is reasonable to divide the MTD into 2-4 smaller doses which can be administered over 2 to 7 days. It is easy to explain to the client with the parallel example of drinking a pint of liquor all at one time or sipping it over a few days.

The first drug that comes to mind would be lomustine. This chemotherapeutic drug may cause severe leukopenia and thrombocytopenia for some patients when administered at the maximum tolerated dose of 60-90 mg/M2. For cats, this author may divide the 10 mg capsules into two or four doses that may be administered over a 4-8 day period. This drug lasts up to 6 weeks in the body and there is no need to assault the patient with the MTD and risk predictable and avoidable adverse events.

Adriamycin™ (doxorubicin) and related anthracyclines are well known for cardio toxicity. Small dogs and cats have the danger of being overdosed using the meter squared body surface method while large and giant breeds have the danger of being under dosed with the MTD of 30mg/M2. This author uses a "split-dose" method to avoid adverse events and to deliver adequate adriamycin to large and giant breed dogs. We administer two doses of adriamycin at 20mg/M2 over 15-20 minutes by slow infusion one week apart for large and giant breed dogs. We have virtually eliminated adriamycin-induced cardio toxicity from our oncology practice. Since adriamycin has a 21 day period of action, the adverse events and leukopenia during the nadir is almost completely avoided.

Cisplatin has notorious renal toxicity properties and it kills cats. This author refuses to use it in practice. Instead, we use carboplatin as a chemotherapeutic agent for our cancer patients with both soft tissue sarcomas and carcinomas. If the patient has comorbidities, anemia, dehydration, weight loss, renal disease or a previous history of being sensitive to this drug, we will split the dose and administer the first half on day 1 and the second half a few days or a week later.

Summary

The concept of metronomic chemotherapy provides a viable palliative option in the management of animals with cancer. In the future, small molecule kinase inhibitors, that will target various malignant pathways, will probably be considered mCTx because this type of therapy will need to be given consistently. It is important to educate the family about the fact that the current use of mCTx has no intent to cure and will not induce remissions or make solid tumors shrink. We must educate our clients to be satisfied with achieving less grandiose goals when using metronomic chemotherapy. It is best to encourage pet owners to appreciate and to assign a new value to the achievement of realistic goals such as, partial remissions, stable disease or slowing down the progression of disease. We need to counsel and guide our clients to enjoy their pet's current wellness rather than dwell on the anticipation of the pet's death. (Myers 2000) We must also diligently monitor the cancer patient's hemogram and quality of life during the administration of metronomic chemotherapy.

References and Resources

Bryan, J.N., DNA Methylation in Cancer: Techniques and Preliminary Evidence of Hypermethylation in a Canine Gene, www.cancer-therapy.org, Theilen Tribute Symposium Proceedings, June 15, 2008.

Cohen, L.A., Powers, B., Amin, S., Desai, D., Treatment of Canine Hemangiosarcoma with Suberoylanilide Hydroxamic Acid, a histone deacetylase Inhibitor, Veterinary and Comparative Oncology, Vol. 2, No. 4, December 2004, p 243-248.

Liptak, J.M., Monnet, E., Dernell, W.S., Withrow, S.J., Pulmonary Metastatectomy in the Management of Four Dogs with Hypertrophic Osteopathy, Veterinary and Comparative Oncology, Vol. 2, No. 1, March 2004).

Myers, B., Anticipatory Mourning and the Human Animal Bond, Research Press, 2000.

Timmons, R., Family Practice, American Association of Human Animal Bond Veterinarians Newsletter. Vol. 12, Winter 2005.

Villalobos, A.E., Canine and Feline Geriatric Oncology: Honoring the Human-Animal Bond, Wiley-Blackwell Publishing, Hoboken, NY, 2007.

Withrow S.J., Vail D.M., Withrow & MacEwen's Small Animal Clinical Oncology, 4th Edition, Saunders/Elsevier, St. Louis, MS, 2007.