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Equine Melanoma


2014/08/03




By Nancy Brannon, Ph.D.

Equine melanomas occur most commonly in grey horses at age 5 years or older. Melanoma in grey horses is often a benign neoplasm (cancer) of melanocytes (pigment cells) that is usually found in the skin, although it can be found in other organs. In addition to the bulk of the tumors, the tumors can ulcerate and release a dark tarry discharge.

Gervais and Bartol (2013) describe the dubious origins of melanoma in horses: “The etiology of melanomas in horses has not been clearly determined. One dominant theory is that melanomas in older grey horses are due to disturbed metabolism of melanin. This is thought to lead to the development of new melanoblasts, or possibly to increased activity of melanoblasts in the area resulting in a central area of too much pigment production in the dermis.  It is controversial as to whether ultraviolet radiation (sun exposure) plays a role in equine melanoma as it does in humans.  Because most melanoma lesions occur in regions not exposed to the sun, it seems unlikely that the sun plays as significant a role as it does in human melanoma.”

In a study of 296 grey Lipizzaner horses, Seltenhammer, et al. (2003) found dermal melanomas present in 50% of the horses. In 75.6% of cases, melanotic tumors were detected underneath the tail. Individuals were classified according to their stage of disease using a 0–5 scale. Although melanoma-bearing grey horses were encountered up to stage 4, none of the affected individuals suffered any severe clinical effect or was handicapped in performance. They concluded that grey horse-specific genetic factors inhibiting metastatic processes may be responsible.

Beth Valentine studied a sample of 53 grey horses with cutaneous melanocytic tumors and found four distinct clinical syndromes, one of which was dermal melanoma. “Dermal melanomas were diagnosed in 20 grey horses with an average age of 13 years. Eight horses with an average age of 7 years had 1 or 2 discrete dermal melanomas. …Metastases occurred in 2 horses, and surgical excision was apparently curative in 4 horses. Dermal melanomatosis was diagnosed in 12 grey horses with an average age of 17 years; all 6 of these horses evaluated had internal metastases.”

The research on equine melanoma is a mixed bag regarding malignancy. Gorham and Robl (1986) reported that 66% of equine melanomas may become malignant. MacGillivray (2002) reported that only 14% of dermal melanomas may become malignant, but believed his figure may be an overestimate. The study of 296 Lipizzaners found a 50% incidence of melanomas, but no clinical evidence of malignancy.

However, Metcalfe, et al.(2013) published a case study of a 15-year-old Thoroughbred gelding that, following post-mortem examination, found multiple internal melanomas that confirmed a presumptive diagnosis of malignant melanoma. In retrospect, regarding treatment options, they stated: “By the time a definitive diagnosis in this case had been made, disease progression was too advanced to offer any reasonable treatment options. However the external melanomas were present for a number of years and earlier therapeutic options might have been possible.”

These treatments in the early stages include: “Sharp surgical excision, CO2 laser excision, and cryosurgery are often curative in cases of small well-demarcated dermal melanomas. However in advanced cases, the size and extensive invasion of local tissues may preclude complete removal.” Other treatment protocols may include: “Cicplatin, a heavy metal compound that inhibits DNA synthesis. … Cimetidine, a histamine H2-receptor antagonist, has been reported to have anti-neoplastic properties that may improve survival in patients with melanoma.” (Metcalfe, et al.2013)
 “Tumour cells express antigens recognizable as non-self by the immune system. These antigens are weakly immunogenic. Current research is focusing on the development of immunotherapeutic approaches: immunization or immune stimulation…” (Metcalfe, et al.2013)

Dr.  Jeffrey Phillips, of the Lincoln Memorial University College of Veterinary Medicine (LMUCVM), conducted a study two cohorts of patients, testing what is tentatively called a “Cancer Vaccine” to treat melanoma in horses. His research, funded by the Morris Animal Foundation, was to evaluate a vaccine that since 2006 has been solely licensed for dogs, and has reportedly been very effective in treating melanoma in dogs. In his study, “the vaccine was used in gradually escalating doses in horses that had been diagnosed with melanoma.  Horses were then evaluated for effective response to vaccine, immunologic response, and side effects.  Effective response to vaccine was determined based on changes in the size of the tumor. Immunologic response was evaluated using serum antibody titers and measures of cell-mediated response.

“In the first two cohorts of patients for this project, the horses were closely monitored for side effects and evidence of beneficial response. Virtually every horse demonstrated substantial improvement following treatment.  In some cases, benefit was seen as early as two weeks after initiation.  He is moving forward with the recruitment of additional cases and expects to demonstrate that the vaccine is safe and effective for the treatment of equine melanoma.”

When he’s not teaching at LMUCVM, Dr. Phillips is Head Oncologist at the Animal Emergency Specialty Center in Knoxville, TN. Dr. Phillips said the vaccine is a “form of gene therapy, stimulating the body to mount an immune response” to the melanoma cells. In his research, he has observed that “it works in as short a time period a four weeks.” He has recorded evidence-based benefits of the vaccine in “all measures of immune response. It was effective in 80% of the horses,” he said. He follows his patients, measures the [decrease in] size of the tumors, checks for side effects. “We’ve seen 30% and over reduction in the size of the tumor girths,” he reported.

The treatment he used was an initial four doses IM over a period of two weeks. He said the immune response peaks 2-3 weeks after the final vaccine. Repeat boosters are given at 3-month intervals, when he saw a “profound immune response!”

He said the vaccine originated from work at Memorial Sloan Kettering Cancer Center in NYC. Physicians there collaborated with a veterinary oncologist for expanded applications. The vaccine is called Oncept, released by Merial in 2007.

While generally optimistic about this treatment for melanoma, he said the huge downside of the vaccine is the cost. It is only available through a veterinary oncologist and costs can range from $540 - $800 per dose or more. He said the pharmaceutical company is going forward with label extension for horses.

Another oncologist has been critical of Oncept. Robyn Elmslie, DVM, DACVIM (Oncology) at Veterinary Cancer Specialists in Englewood, Colorado, describes how Oncept works. “The Merial melanoma vaccine for dogs consists of DNA encoding the gene for the human melanocyte protein tyrosinase. When administered to dogs, the vaccine triggers the dog’s immune system to mount an immune response against the human tyrosinase protein. Because the human tyrosinase protein is very similar to the dog tyrosinase protein, the immune response triggered by the vaccine cross-reacts with the dog tyrosinase protein expressed at high levels in the dog’s melanoma tumor cells. This is thought to trigger an immune response against the dog’s tumor. The immune response may also cause an attack against the dogs own skin cells…”

She argues use of the vaccine is controversial: “Though several clinical trials have been performed, culminating in the USDA granting licensure for the canine melanoma vaccine in 2010, use of the vaccine remains controversial.  The primary reason for the controversy is that none of the clinical studies performed to date have been done in a manner to truly test the efficacy of the vaccine.  What has been missing thus far is properly performed randomized clinical trials, which are considered the gold standard studies to prove that a treatment or vaccine is effective.  These studies are required by the FDA prior to approval of drugs or vaccines.  However, the USDA (which approved the canine melanoma vaccine) has no requirement for such studies and thus the Merial vaccine was approved based on much less convincing trial data,” she says.

It is not certain if Elmslie was aware of Dr. Phillips’ study when she wrote her article in January 2013. Dr. Phillips disagrees with Dr. Elmslie’s critique and praises her as “an excellent oncologist and her husband is faculty at CSU veterinary school.” He says that “the line of reasoning that Dr. Elsmlie espoused, while well intentioned, ignores common veterinary practice of every veterinary oncologist…” He  says his study “was well controlled and solid work that provides a rock solid foundation for the use of the vaccine in horses.”

Acupuncture
Dr. Kathy Mitchener, Veterinary Oncologist at Angel Care Cancer Clinic for Animals in Memphis, TN has praise for the effectiveness of the treatment in dogs. She has found positive results using Oncept with dogs.  In addition to medicinal care, another therapy that she uses with her cancer patients is acupuncture. She recently applied the “needles” to James Bond 007, a 24-year-old grey Thoroughbred gelding, who has metastasized melanoma that originated as a few “innocuous” bumps under his tail approximately ten years ago

Dr. Mitchener applied needles around James’ head and neck area, “basically to help reduce some of the swelling in his sinuses and to reduce the pain he was experiencing in his neck and back.  Acupuncture works by changing the way in which the nervous system processes and responds to painful and abnormal stimuli.  The technical term is neuromodulation.  You stimulate an area close to a peripheral nerve and that information is carried to the spinal cord first, and to upper centers in the brain second.  Once stimulated, the central nervous system (spinal cord and brain) respond by sending outgoing signals, again through the nerves, back to the location of stimulus, thus modulating the disease process or painful process.  It’s easiest to understand with pain, as the reflex response is to activate a nerve that dampens the pain.  In addition, acupuncture needles placed in myofascial trigger points which are very painful areas of muscle spasm, will help to alleviate the spasm and relax the muscle, thus reducing the pain almost immediately. In addition, those signals that are carried to the brain (higher centers) cause a ‘balancing’ of neurotransmitters as well as the parasympathetic and sympathetic nervous system, so you just flat feel better – whether a horse, dog, cat, or person!”

Mitchener continued:  “According to the National Cancer Institute, acupuncture may cause physical responses in nerve cells, the pituitary gland, and parts of the brain. It is proposed that, by stimulating physical responses in these areas, acupuncture positively affects blood pressure and body temperature, boosts immune system activity, and causes the body's natural painkillers, such as endorphins, to be released.”

For James, her plan is to first alleviate the pain that he is experiencing. “Likely some of the discomfort is coming from the local area where his sinuses are not functioning adequately because of the physical presence of the disease. Acupuncture alters blood flow, reduces congestion and inflammation, and helps relieve any headache,” she said. In addition, “acupuncture helps with any tension and pain he is experiencing and can improve his autonomic nervous system balance.  In any stressful situation (cancer being one) we see the sympathetic nervous system (fight or flight) ramped up and the parasympathetic nervous system (calming, immune function, digestive function) ramped down.  Acupuncture balances these so the whole body is essentially ‘better’, i.e., better immune function, digestion, etc.”

At his second treatment, James had made phenomenal progress in pain reduction. Dr. Mitchener was able to apply needles all along the top sides of James’ back. These reduce pain in that area as well as stimulate the immune system. A third treatment is upcoming in early August.

Sources:
Elmslie, Robyn, DVM, DACVIM (Oncology). “The Controversy Surrounding the Melanoma Vaccine For Dogs.” January 2013. VetCancerSpecialists blog. http://www.vetcancerspecialists.com/blog/2013/1/31/the-controversy-surrounding-the-melanoma-vaccine-for-dogs/
Gervais, Taryn, DVM and Jacqueline Bartol, DVM, DACVIM. 2013. “Equine Melanoma.”New England Equine Medical and Surgical Center, Dover, NH.  http://newscenter.equinesite.com/equinehealth/174-equine-melanoma.html
Gorham S, Robl M. 1986. “Melanoma in the grey horse: the darker side of equine ageing.”Vet Med. 81:446-448. OpenURL
Leopoldo F. Montes, J. Thomas Vaughan, and Gwen Ramer. 2006. “Equine Melanoma.” Journal of Cutaneous Pathology. Vol. 6 issue 3. Pp. 234-235. June 1979.
MacGillivray, KC, RW Sweeney, F. Del Piero. 2002. “Metastatic melanoma in horses.” Journal of  Veterinary Internal Medicine. 16:452-456.
Metcalfe, Lucy VA, Peter J. O’Brien, Stratos Papakonstantinou, Stephen D. Cahalan, Hester McAllister, and Vivienne E. Duggan. 2013. “Malignant Melanoma in a Grey Horse: case presentation and review of equine melanoma treatment options.” Irish Veterinary Journal. 66:22.
Seltenhammer, M.H., M. Simhofer, S. Scherzer, P. Zechner, I Curik. J. Solkner, S.M. Brandt, B. Jansen, H. Pehamberger, and E. Eisenbenger. 2003. “Equine Melanoma in a Population of 296 Grey Lipizzaner Horses.” Equine Veterinary Journal. Vo. 25, issue 2. Pp. 153-157. March.
Seltenhammer, Monika Heidemarie, Elisabeth Herre-Ress, Sabine Brandt, Thomal Druml, Burkhard Jansen, Hubert Pehamberger, and Gert Wilhelm Niebauer. 2004. “Comparative Histopathology of Grey-Horse Melanoma and Human Malignant Melanoma. Pigment Cell Research. Vol. 17, issue 6. Pp. 674-681. December.
Valentine, Beth. 2008. “Equine Melanocytic Tumors: A Retrospective Study of 53 Horses (1988-1991).” Journal of Veterinary Internal Medicine. Vol. 9, issue 5. Pp. 291-297. February.
 
Equine Melanoma Studies and Articles
Drug: Talimogene Laherparepvec, Amgen, April 4, 2014
“Amgen Provides Update On Phase 3 Study Of Talimogene Laherparepvec In Patients With Metastatic Melanoma”
http://www.amgen.com/media/media_pr_detail.jsp?releaseID=1915897
Critique of Amgen’s drug: “Amgen's viral cancer vaccine misses its survival goal in melanoma PhIII”
April 4, 2014 | By Damian Garde
 
Huffington Post: “Cancer Vaccine For Advanced Melanoma Effective In Late-Stage Study”
March 14, 2014
http://www.huffingtonpost.com/2014/03/16/advanced-melanoma-cancer-vaccine_n_4967119.html
 
WebMD “Experimental Melanoma Vaccine Shows Promise”
July 11, 2013
 http://www.webmd.com/melanoma-skin-cancer/news/20130711/experimental-melanoma-vaccine-shows-promise-in-study
 
Veterinary Practice News: “Canine Melanoma Vaccine Gets Conditional OK”
By Marissa Heflin
http://www.veterinarypracticenews.com/vet-dept/canine-practice/canine-melanoma-vaccine-gets-conditional-ok.aspx
Oncept Canine Melanoma Vaccine website: http://www.petcancervaccine.com/Pages/default.aspx
 
From Hagyard Pharmacy:
http://www.hagyard.com/custdocs/Equine%20Melanomas.pdf
 
From Univ. of Florida College of Veterinary Medicine:
http://research.vetmed.ufl.edu/clinical-trials/large-animal/vaccine-study-for-gray-horses-with-melanoma/
 
From Douglas Novick, DVM
http://novickdvm.com/treating-equine-melanomas/
 
From TheHorse.com and LMUCVM news: New 'Cancer Vaccine' for Horses in the Works (AAEP 2011)By Stacey Oke, DVM, MSc
March 27, 2012
http://www.thehorse.com/articles/28888/new-cancer-vaccine-for-horses-in-the-works-aaep-2011
http://vetmed.lmunet.edu/news/Posted on January 18, 2013 by vetmedadmin

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