Conventional cancer treatment utilizes chemotherapy at the maximally tolerated dose (MTD), or the highest dose shown to be both cytotoxic and tolerable for the patient. MTD chemotherapy targets rapidly dividing cells including: tumor cells and normal cells of the gastrointestinal tract and bone marrow1. Since MTD chemotherapy targets normal cells, a mandatory hiatus between treatments is required to allow these cells to recover and repopulate. During this recovery time, the tumor cells also have the opportunity to repopulate and acquire genetic changes which lead to drug resistance1.
In an attempt to avoid these pitfalls of conventional chemotherapy treatment, metronomic chemotherapy was developed. Much like a metronome keeps continuous rhythm; metronomic chemotherapy is the administration of low doses of chemotherapy at continuous, regular intervals2. Due to higher dosing frequency, the cytotoxic agent must be administered at dosages lower than MTD to ensure tolerability, and administered in a form that enables ease of use. The majority of metronomic chemotherapy protocols that have been studied in veterinary medicine use oral anti-neoplastic agents, such as cyclophosphamide, lomustine, or chlorambucil3-6. This relatively new method of chemotherapy administration is still under investigation, especially with regard to optimization of the proper drugs, dose, schedule, and tumor applications. However, the low cost, ease of administration, and acceptable toxicity profiles potentially associated with this therapeutic strategy make metronomic chemotherapy protocols attractive and suitable to veterinary patients.
How Does it Work?
The main mechanism of action of metronomic drug delivery is the inhibition of tumor angiogenesis2-7. The process of angiogenesis, or new blood vessel formation, is imperative for the tumor cells to grow and metastasize7. The metronomic strategy is based on the fact that blood vessel endothelial cells are highly sensitive to continuous exposure to low doses of chemotherapeutic drugs2-7. There are several proposed mechanisms for the anti-angiogenic effects of metronomic chemotherapy including5-7:
1. Targeting the drug-sensitive endothelial cells of tumors
2. 2. Inhibiting the mobilization of endothelial precursors from the bone marrow
3. Stimulating the production of thrombospondin-1, an endogenous anti-angiogenic protein
Metronomic chemotherapy has also been shown to alert the immune system of the tumor and exert anti-tumor immunity through inhibition of regulatory T cells (Tregs)8. Tregs are a subset of CD4+ lymphocytes that normally function to keep the immune system in check and prevent autoimmunity. Several studies have documented a high level of circulating Tregs in both human and canine cancer patients9-10. In these cases, Tregs prevent the patient’s endogenous immune system from attacking and destroying the cancer cells. Studies have shown that the administration of metronomic cyclophosphamide in both human and canine cancer patients selectively decreases circulating Treg numbers, thereby promoting the host immune response to destroy tumor cells8-10. A recent study demonstrated that toceranib (Palladia), a small molecule inhibitor which targets genetic mutations within the tumor cell, decreased the number of circulating Tregs in dogs with cancer after 2 weeks of therapy, and when combined with metronomic cyclophosphamide, the effect on Tregs was even more profound18.
The majority of metronomic chemotherapy protocols incorporate anti-inflammatory drugs, specifically cyclooxygenase (COX) inhibitors. COX is a prostaglandin synthase enzyme which has been implemented in tumor cell promotion and progression11. One of the proposed mechanisms by which this occurs is through upregulation of angiogenesis through the production of pro-angiogenic cytokines such as vascular endothelial growth factor (VEGF), transforming growth factor beta, and endothelin – 111. More recent research suggests cyclooxygenase may stimulate tumor cell production of Tregs, thereby downregulating anti-tumor immunity12. In veterinary patients, COX inhibitors, such as piroxicam or deracoxib, have been shown to elicit antitumor activity in patients with transitional cell carcinoma13-14, prostatic carcinoma15, oral squamous cell carcinoma16, oral malignant melanoma16, and inflammatory mammary carcinoma17. The potential anti-angiogenic effects of these drugs support their inclusion in metronomic protocols.
What Do the Experts Say?
There have been several published reports evaluating metronomic protocols for spontaneously developing tumors in dogs3-6, 18-20 and only one in cats21. When evaluating these studies, it is important to keep in mind that the majority are retrospective in nature, an appropriate control group may be lacking (using historical controls or no control group at all), and in many, the sample size is low. These factors make it difficult for most veterinary oncologists to offer metronomic therapy as a ‘first-line’ treatment option for our patients. In most cases, surgery, radiation and/or MTD chemotherapy is offered as ‘standard of care’ for the majority of tumor types; while metronomic chemotherapy may be offered as a ‘maintenance’ therapy after standard of care treatment is complete, or offered as a more conservative treatment option, in cases where a client declines standard of care.
One of the first reports evaluated the safety and efficacy of metronomic cyclophosphamide, etoposide, and piroxicam as adjuvant therapy for dogs with stage II splenic hemangiosarcoma6. A total of nine dogs were enrolled in the study. Their treatment outcomes were compared to historical controls consisting of 24 dogs with stage II splenic hemangiosarcoma treated with the standard of care chemotherapy, adjuvant doxorubicin. The study found that the treatment protocol was well tolerated by the majority of dogs and that the disease-free interval was improved in dogs receiving the metronomic protocol over the dogs receiving doxorubicin. The authors concluded that the results showed promising preliminary evidence that metronomic protocols are safe and may be effective, however the results should be interpreted with caution due to the small number of dogs included as well as the use of historical controls.
Metronomic cyclophosphamide and piroxicam in dogs with incompletely excised soft tissue sarcomas has been evaluated5. Eighty-five dogs were included in the study, 55 dogs were used as contemporary controls while 30 dogs were given treatment. The majority of the patients in both arms of the study had grade 2 tumors. 40% of the treated dogs developed mild side effects including: anorexia, vomiting, increase serum creatinine concentration, and sterile hemorrhagic cystitis. The study revealed that dogs receiving treatment had a longer disease-free interval of approximately 400 days compared to dogs that received surgery alone (disease-free interval of 211 days). The authors of this study concluded that this treatment protocol was fairly well tolerated and it was effective in delaying tumor recurrence in dogs with incompletely resected soft tissue sarcomas. These results should be interpreted with caution due to the retrospective nature of the study.
The tolerability of metronomic lomustine has been evaluated in eighty-one dogs with a variety of naturally occurring primary or metastatic tumors.4 Treatment was discontinued in nearly 30% of dogs due to severe toxicosis. Side-effects described include: gastrointestinal, thrombocytopenia, increased alanine transferase, neutropenia, and progressive azotemia. Nearly 10% of dogs developed some degree of azotemia during the treatment protocol. The authors concluded that metronomic lomustine was tolerated in dogs without pre-existing renal compromise but that caution should be used when administering this agent as the risk for side effects was fairly high in this study.
Another recent study evaluated the safety and efficacy of metronomic chlorambucil in dogs with cancer3. Thirty-six dogs with a variety of tumors were included in the study. The majority of patients tolerated the treatment well with only 11% of dogs reporting low grade gastrointestinal side effects. Complete remission was achieved, and lasted over 35 weeks in three dogs (mast cell tumor, soft tissue sarcoma and thyroid carcinoma). Partial remission was noted in 1 dog with histiocytic sarcoma (39 weeks duration). The overall remission rate for the study was 11% (4 of 36 dogs). Stable disease was noted in 17 dogs (47%) with various other cancers. The median progression-free interval was 61 days, and the median survival time was 153 days. The authors concluded that chlorambucil given in a metronomic protocol showed low toxicity profile and antitumor activity in dogs with a variety of naturally occurring cancers. The results of the study should be interpreted with caution due to variety of tumor types included and the small sample size in each tumor population.
The same group looked prospectively at a population of 31 dogs with bladder transitional cell carcinoma (TCC), 29 dogs were not previously treated (naïve) and 2 dogs had tumors that progressed in the face of prior treatments19. This group of dogs received metronomic chlorambucil, toxicity and tumor responses were evaluated. 70% of the dogs had partial remission (3%) or stable disease (67%) for a median progression free interval of 119 days (range, 4-728 days) and median survival time (from time of chlorambucil treatment to death) of 221 days (range, 7-747 days). One only dog discontinued the study because of toxicosis. This group concluded that metronomic chlorambucil is a viable option for dogs with TCC; however the majority of the dogs on study had stable disease only, treatment with this protocol did not provide remission for the majority of cases.
One group evaluated metronomic cyclophosphamide and piroxicam in conjunction with MTD chemotherapy for dogs with osteosarcoma who had received amputation20. A total of 30 dogs were evaluated retrospectively. Nearly half received MTD carboplatin and the other half received combination of MTD doxorubicin and carboplatin. Both groups received the metronomic protocol at the start of MTD chemotherapy. Results indicated that more dogs in the carboplatin alone group had side effects with the protocol compared to the other group. The survival times for both groups were similar to historical controls for dogs with osteosarcoma, receiving amputation and MTD chemotherapy. In other words, it did not appear that the metronomic protocol provided benefit to this group; however the results must be interpreted with caution due to retrospective nature and small sample size.
To the author’s knowledge there is only one published study evaluating metronomic chemotherapy in pet cats with cancer21. This study evaluated 24 cats receiving metronomic cyclophosphamide for a variety of tumor types. The majority of cases were advanced stage disease, with nearly 30% with metastasis and 70% with bulky disease (non-resectable tumors). The study found that metronomic cyclophosphamide was well tolerated for the majority of cats; however follow-up longer than 1-month occurred in only 15 cases, due to the advanced stage of most cases (cases not available for study due to tumor progression, death, etc). The results of this study must be interpreted with caution due to retrospective nature, small sample size, and limited follow-up period.
In summary, preliminary veterinary studies3-6, 18-21 have shown promise for metronomic chemotherapy although both the human and veterinary medical community has a great deal to learn, especially with regard to optimization of the proper drugs, dose, schedule, and tumor applications. The low cost, ease of administration, and acceptable toxicity profiles make these protocols attractive and suitable to veterinary patients. These protocols, however, should be used with caution as they are still considered investigational and the studies noted above3-6, 18-21 just skim the surface on safety and efficacy. Larger, case-controlled, prospective trials are needed before these protocols become widely accepted or considered ‘first-line’ therapies. These protocols should not be used in place of the standard of care treatment and clients should understand the investigational nature of these protocols before initiating treatment on their pet.
Submitted by: Dr Kate Vickery, VMD, MS, DACVIM (Oncology), CVA
Hope Veterinary Specialists
- Cancer Chemotherapy and Biotherapy. 3rd ed. 2001.
- Buckstein, R, et al. High-dose celecoxib and metronomic ‘low-dose’ cyclophosphamide is an effective and safe therapy in patients with relapsed and refractory aggressive histology
Non-Hodgkin’s Lymphoma. Clin Cancer Res 2006; 12(17): 5190-5198. http://www.ncbi.nlm.nih.gov/pubmed/term=Highdose+celecoxib+and+metronomic+%E2%80%98lowdose%E2%80%99+cyclophosphamide+is+an+effective+
- Leach TN, et al. Prospective trial of metronomic chlorambucil chemotherapy in dogs with naturally occurring cancer. Vet Comp Oncol. 2012 Jun;10(2):102-12.
- Tripp CD, et al. Tolerability of metronomic administration of lomustine in dogs with cancer. J Vet Intern Med. 2011 Mar-Apr;25(2):278-84.
- Elmslie RE, et al. Metronomic therapy with cyclophosphamide and piroxicam effectively delays tumor recurrence in dogs with incompletely resected soft tissue sarcomas.
J Vet Intern Med. 2008 Nov-Dec;22(6):1373-9.
- Lana S, et al. Continuous low-dose oral chemotherapy for adjuvant therapy of splenic hemangiosarcoma dogs. J Vet Intern Med. 2007 Jul-Aug;21(4):764-9.
- Kerbel RS. The anti-angiogenic basis of metronomic chemotherapy. Nature Reviews. Cancer 2004; 4: 423-436. http://www.nature.com/nrc/journal/v4/n6/full/nrc1369.html
- Burton JH, et al. Low-dose cyclophosphamide selectively decreases regulatory T cells and inhibits angiogenesis in dogs with soft tissue sarcoma. J Vet Intern Med. 2011 Jul-Aug;25(4):920-6. http://www.ncbi.nlm.nih.gov/pubmed/?term=Low-dose+cyclophosphamide+selectively+decreases+regulatory+T+cells+and+inhibits+angiogenesis+in+dogs+with+soft+tissue+sarcoma.+J+Vet+Intern+Med.+2011
- Wilke CM, et al. Prognostic significance of regulatory T cells in tumors. Int J Cancer 2010; 127: 748-758.
- Biller, BJ. Use of FoxP3 expression to identify regulatory T cells in healthy dogs and dogs with cancer. Vet Immunol Immunopathol 2007; 116: 69-78.
- Flory, AB, et al. The role of cyclooxygenase in carcinogenesis and anticancer therapy. Compendium for Continuing Education Aug 2005; 616-627.
- Baratelli, F, et al. Prostaglandin E2 induces FoxP3 gene expression and T regulatory cell function in human CD4+ T cells. J Immunol 2005; 175: 1483-1490.
- Henry CJ, et al. Clinical evaluation of mitoxantrone and piroxicam in a canine model of human invasive urinary bladder carcinoma. Clin Cancer Res. 2003 Feb;9(2):906-11.
- McMillan SK, et al. Antitumor effects of deracoxib treatment in 26 dogs with transitional cell carcinoma of the urinary bladder. J Am Vet Med Assoc. 2011 Oct 15;239(8):1084-9.
- Sorenmo KU, et al. Evaluation of cyclooxygenase-1 and cyclooxygenase-2 expression and the effect of cyclooxygenase inhibitors in canine prostatic carcinoma. Vet Comp Oncol. 2004 Mar;2(1):13-23. http://www.ncbi.nlm.nih.gov/pubmed/?term=Evaluation+of+cyclooxygenase-1+and+cyclooxygenase2+expression+and+the+effect+of+cyclooxygenase+inhibitors+in+canine+prostatic+carcinoma.+Vet+Comp+Oncol.+2004
- Boria PA, et al. Evaluation of cisplatin combined with piroxicam for the treatment of oral malignant melanoma and oral squamous cell carcinoma in dogs. J Am Vet Med Assoc. 2004 Feb 1;224(3):388-94.
- de M Souza, et al. Inflammatory mammary carcinoma in 12 dogs: clinical features, cyclooxygenase-2 expression, and response to piroxicam Can Vet J. 2009 May;50(5):506-10.
- Mitchell L, et al. Clinical and immunomodulatory effects of toceranib combined with low-dose cyclophosphamide indogs with cancer. J Vet Intern Med. Mar-Apr;26(2):355-62.
- Schrempp DR, et al. Metronomic administration of chlorambucil for treatment of dogs with urinary bladder transitional cell carcinoma. J Am Vet Med Assoc. Vol. 242, No. 11, Pages 1534-1538.http://www.ncbi.nlm.nih.gov/pubmed/?term=Metronomic+administration+of+chlorambucil+for+treatment+of+dogs+with+urinary+bladder+transitional+cell+carcinoma.+J+Am+Vet+Med+Assoc.+2013
- Bracha S, et al. Evaluation of toxicities from combined metronomic and maximal-tolerated dose chemotherapy in dogs with osteosarcoma. J Sm Anim Pract. 2014. Vol 55,Issue 7, pages 369–374.
- Chiara L. Evaluation of low-dose metronomic (LDM) cyclophosphamide toxicity in cats with malignant neoplasia. J Fel Med Surg. 2014. V 16no. 8, pages 671-678.