Long-term Treatment of Equine Sarcoid in a Mare Senior Seminar Paper Elsa Kanner April 9, 2014 Advisors: Dr. Richard Hackett & Dr. Hayley Lang Cornell University College of Veterinary Medicine Key words Equine sarcoid, immunotherapy, chemotherapy, surgical debulking, ethical considerations Abstract This paper outlines a case report of equine sarcoids and the specifics of the various treatments attempted over 13 years in an extraordinary presentation of this disease in a Warmblood mare. The ethical implications of the continued treatment of a disease of this severity are also discussed. Case Report The patient, a 19 year old intact female Warmblood, presented to Cornell University Hospital for Animals on February 20, 2014 for a sixth surgical debulking of her equine sarcoids, which were primarily present on her left flank and right axillary region. The patient had a 13 year history of treatment for her sarcoids at Cornell and with her primary care veterinarian. On presentation, her sarcoids were the only problems noted on her physical examination and problem list. She was bright and alert, friendly, in good body condition, and had an excellent appetite. The masses were very large, friable, pedunculated in some areas, and necrotic in many places. Other smaller more nodular sarcoids were present in her pectoral region, on her left flank, and above her right eye. Her right ear was mostly hairless as a result of a sarcoid that had been present and had subsequently healed on that ear. 2 Lesions on left flank, 20 Feb 2014 Lesions on right axilla, 20 Feb 2014 3 2001-2002 The patient’s initial lesions developed in 2001 at approximately age 3. Her first sarcoids were flat (occult), and after examination by her RDVM it was decided to monitor the lesions and not to pursue treatment at that time. The lesions remained static for about a year, when they abruptly became much more aggressive and the patient was referred to Cornell. After her initial presentation to in 2002, she began what turned out to be a life-long battle with the disease. 2003-2007 Early in the disease from 2003 - 2007when her tumors were smaller, they could be controlled with removal by cautery and use of antibiotics to prevent secondary bacterial infections. However, the tumors became more aggressive in 2007 and at that time alternate therapies were pursued. Besides surgical procedures, immunotherapy is one of the mainstays of equine sarcoid treatment. The theory behind this type of therapies is to stimulate the immune system so that it will recognize the sarcoids as foreign and mount an immune response sufficient to cause regression of the lesions1. 2007-2009 The first type of immunotherapy used in our patient from 2007-2009 involved injections of Propionoibacterium acnes (EqStim, Neogen Corp., Lexington , KY), an anaerobic gram + rod primarily involved in the skin condition acne. This procedure bacteria which has been studied primarily at Kansas State and is meant to stimulate the innate immune system, in particular natural killer cells, T-lymphocytes, and other cytokines. Some studies have shown it to be 4 effective in the treatment of Equine Respiratory Disease Complex (ERDC), but it has not been shown to be an effective treatment for equine sarcoids2. In our patient, it appeared to have a short term positive effect, but was eventually discontinued when it failed to cause significant regression of the sarcoids. 2009 After the EqStim injections were discontinued, injections of a particular strain of the Pythium fungus called the “Texas Strain” were tried. Such injections have been shown to modulate an effective immune response in various diseases in horses such as equine sarcoids, exuberant granulation tissue, navicular disease and laminitis. It has also been used successfully to help manage canine mast cell tumors, inflammatory bowel disease in dogs, and certain allergies in dogs, cats, horses, and humans3. In our patient, Pythium injections showed some effect initially, but were discontinued when the lesions continued to grow. 2010 After the Pythium treatments stopped having an effect, BCG, (Bacille de Calmette et Guerin) another common immunomodulator was tried. This is a Mycobacterium bovis derived vaccine developed for treatment of human tuberculosis in 1921. This vaccine is still used worldwide to prevent TB in humans, and is also used as an immunostimulant in several types of human cancer and more recently equine sarcoids4. In our patient, it did not have an appreciable effect. After these more traditional treatments failed to cause regression of the sarcoids, the goals of treatment shifted from regression of the sarcoids to palliative treatment aimed at maximizing the comfort of the patient. 5 A trial use of systemic chemotherapy was used in the patient to see if it would have any effect on the tumors using the injectable agents cyclophosphamide and doxorubicin. While there appeared to be a slight improvement in the surface composition of the tumors in that they bled less readily, the chemotherapy did not significantly reduce the size of the tumors. As the tumors had now grown to a size that they were becoming pendulous, and parts were becoming necrotic and causing discomfort to the patient, the decision was made to attempt surgical debulking of the lesions despite the risk of of stimulating the tumors to grow more rapidly. Despite the fact that the tumors bled readily during the surgery and that they were not able to be fully removed in many places, the patient recovered very well from anesthesia and was bright, responsive, and much more comfortable soon after the surgery. In order to avoid another surgical debulking, another round of systemic chemotherapy was attempted with another combination of drugs, cyclophosphamide and vincristine. However, part way through this protocol the tumors began to grow aggressively, and the chemotherapy was discontinued. Whether the chemotherapy was the cause of the aggressive growth is unknown. 2011 When the patient was returned for a second surgical debulking for the larger lesions on her left flank and right axilla, her owner reported that she had been using a proprietary bloodroot and zinc oxide preparation (XXterra Herbal Paste, Larson Labs, Ft. Collins, CO) with some success on her smaller lesions Its proposed mechanism of action is to cause inflammation of the surface of the sarcoid by the zinc chloride, and alteration of the tumor cells by the bloodroot alkaloids such that they become antigenic to the host, and the immune system will then respond and cause 6 regression of the tumors5. Unfortunately, the caustic nature of Xxterra makes application painful, and was discontinued when the mare started to become resistant to handling for her treatments. A third surgical debulking was then undertaken, with similar results to the first, followed by a fourth at the end of 2011. 2012 A fifth surgical debulking was undertaken in the fall of 2012, with similar results to the others. 2013 Although efforts at this point in the mare’s treatment were palliative, it was decided to try autologous tumor implantation, which is a treatment that has been shown to have success in the treatment of some sarcoids. This treatment involves removing a piece of sarcoid from the horse, cutting the sample into small 0.5 x 0.5 cm cubes, freezing those in liquid nitrogen, and implanting the cubes surgically beneath the skin of the neck under the mane in the region of the nuchal ligament. Unfortunately, this treatment did not cause regression of our patient’s sarcoids6. 2014 At her last surgical debulking, it was decided to do a trial of intralesional chemotherapy with cisplatin and carboplatin to see if that would reduce the frequency of surgeries required for the patient. These drugs are prepared in a lipid (sesame oil) emulsion and injected into the tumors 7 after debulking. The emulsion is meant to keep the drugs in the tumor sites longer before they are absorbed and excreted by the body. We are waiting to see if this latest treatment has any effect in our patient. As of today, our patient’s bill is over $14,000 dollars, and she is continuing treatment. Initial prognosis for this patient was fair, as many cases of equine sarcoid are able to be resolved with treatment. However, it soon became clear after trials of the most common treatments for this condition that regression of the lesions was not probable. Our current goal with treatment is to keep the patient comfortable so she can enjoy a good quality of life. Discussion Given the current status of our patient and her prognosis, her case raises two big categories of questions. The first involves the limitations in our veterinary knowledge about this disease. Why was this mare in particular refractory to the traditional treatments used for equine sarcoid, and why were her sarcoids so aggressive? As far as we understand, when equine sarcoids do not respond to treatment, it is largely due to a failure of the patient’s immune system to respond to the disease7. At this time, we do not understand why this mare’s immune system does not allow her to control her sarcoids, but has allowed her to remain systemically healthy throughout her struggle with this disease. 8 The other category of questions involves the ethical considerations in a case of this type. The most obvious of these is the question of her quality of life. Almost everyone that has seen this mare has an initial reaction somewhere from disbelief to horror that we are continuing treatment. However, since we cannot accurately measure levels of discomfort in animals, we have to rely on observations of their attitude, general health parameters, energy, and appetite to determine if they have a “good” quality of life. In this patient’s case, her owner has considered euthanasia several times when the tumors have been at their worst, but the patient has largely remained bright, maintained her weight, had a healthy appetite, and on a daily basis happily eats grass, relaxes with her pasture mates on the farm where she lives, and enjoys attention from her human companions. Conclusion Although I am not sure I would have made the same treatment decisions in the place of the client, I feel comfortable with our continued treatment of this extraordinary patient. 9 References 1- Larson, Erica. "Evidence-Based Equine Sarcoid Treatments Reviewed." The Horse 19 Apr. 2012: n. pag. Print. 2- Rohrbach, Barton W., VMD, MPH, DACVPM, et al. Effects of adjunctive treatment with intravenously administered Propionibacterium acnes on reproductive performance in mares with persistent endometritis. Journal of the American Veterinary Medical Association. Volume 231, Number 1, July 1 2007, pp. 107-13. 3- Mendoza, Alberto L., Robert L. Glass, and Richard D. Hansen. Pythium Immunotherapy. Board of Trustees, Michigan State University, assignee. Patent 12/647,971. 30 June 2011. Print. 4- United States. Centers for Disease Control and Prevention. Division of Tuberculosis Elimination. World Health Organization. Issues Relating to the Use of BCG in Immunization Programmes - A Discussion Document. N.p.: n.p., 1999. Print. 5 - Larson, Ken. "Xxterra." Larson Laboratories. Vetline, Inc., n.d. Web. 5 Apr. 2014. 6 - Espy, Benjamin M.K. "How to Treat Equine Sarcoids by Autologous Implantation." AAEP Proceedings 54 (2008): 68-73. Print. 7 - Taylor, S., and G. Haldorson. “A Review of Equine Sarcoid.” Equine Veterinary Education 25.4 (2013): 210-16. Print. 10