It is a word that, when used in discussions involving one's health, carries a dreaded connotation. Cancer. Some of the world's most brilliant scientists have spent lifetimes seeking to understand and find a treatment for this disease. To be sure, there have been breakthroughs resulting in treatment modalities that have spared, or at least lengthened, the lives of many, but no one has yet come up with an overall preventive measure, and no one has developed a sure-fire cure.
Horses, too, can contract cancer. In the past, treatment of choice more often than not was surgery. However, research conducted by Alain P. Theon, DVM, MS, of the University of California, Davis, along with other researchers at the institution, indicates that some of the same treatment approaches that have been successful with humans will also work for horses, offering options other than radical surgery.
First, a few textbook facts about cancer. Basically, cancer can be described as a growth disorder of cells. It begins when an apparently normal cell starts to grow in an uncontrolled and invasive way. The result is a ball of cells known as a tumor that continues to expand in size.
When the tumor involves connective tissue, such as muscle, it is called a sarcoma.
If epithelial tissue, such as the skin, is involved, the tumor is called a carcinoma.
If its cells leave the mass and spread throughout the body, forming new tumors at distant sites, the spreading of the cells is called metastasis.
The abnormal growth of cells, both malignant and benign, is called neoplasia.
When there is neoplastic growth of cells involving the lymph nodes, the affliction is called lymphoma.
When the dark pigmented cells are involved, it is called melanoma. In humans, melanoma is frequently seen as skin cancer, often the result of over-exposure to the sun. In equines, it appears to be more prevalent in gray horses because of the dark skin pigmentation.
Frequently, both lymphoma and melanoma are synonymous with malignancy.
As mentioned above, for a number of years, the treatment of choice for horses with malignant or benign tumors has been radical surgery to remove all of the cancerous tumor. However, in many cases, even radical surgery would not prevent recurrence of the tumor. There have been instances where surgery actually accelerated growth of the neoplastic cells because there was an incomplete excision of the cancerous tissue.
In other cases where the surgeon made certain that all afflicted tissue was removed, the horse was left with both functional and cosmetic problems, such as mammoth scars or perhaps genitalia that no longer functioned appropriately.
Enter chemotherapy and radiation treatment.
One of the drugs of choice in chemotherapy, Theon believes, is cisplatin, described as a heavy metal compound that inhibits DNA synthesis by directly binding to DNA, which leads to the death of actively dividing cells.
Cisplatin, when used alone, is most effective, Theon says, for tumors that are three to five centimeters in size. Tumor types responsive to treatment with cisplatin, he said, include squamous (scaly) cell carcinoma/papilloma, sarcoid, soft tissue sarcoma, melanoma, lymphoma, and hamartoma (a benign tumor-like nodule composed of an overgrowth of cells and tissues).
The treatment, Theon feels, is ideal for tumors in locations where a complete surgical resection would result in cosmetic and functional problems. The most commonly indicated sites include the face--eyelid, lip, nose, ears, and lips--the lower extremities, and both male and female genitalia.
Surgery remains one of the most effective weapons against cancerous growths, but there are many tumors that simply are inoperable because of their location or the effect surgery would have on the animal's ability to function normally or the effect on its appearance.
Research, Theon says, has demonstrated that treatment with cisplatin is effective and the cosmetic results are excellent.
Use of Cisplatin
Cisplatin is not new to scientists, but in the past there had been a basic problem with the use of cisplatin in horses. While the drug had been proven effective for humans and other animals, its cost and toxic effects on equines when administered orally, intramuscularly, or intravenously, had made it an impossible treatment approach.
The reason is basic. Administration of the drug orally, intramuscularly, or intravenously usually causes the recipient to vomit. That's fine with people and dogs, but horses can't vomit.
Theon and colleagues at the University of California, Davis, decided to find a way around this problem. To do so, they conducted a study to determine if administering cisplatin directly into a tumor would enhance the drug's cancer fighting capability and, simultaneously, reduce its toxicity. The treatment approach was aimed at primary tumors confined to single organs or regions of the body.
Direct delivery of the drug to the tumor, it was reasoned, would provide advantages over systemic delivery, including a high concentration of drug in the tumor and a reduction in systemic
In order for the drug to be most effective, it must remain at the tumor site for a sustained length of time. This meant that another substance to hold the drug at the tumor site would have to be utilized.
Chosen to be administered with cisplatin was sesame oil, mixed with sterile water.
"The reason for using sesame oil in the formulation," Theon reports, "was that purified sesame oil is an established, safe vehicle for parenteral (injection) administration; it is biologically inert and non-irritating."
The researchers also decided to use high dosages of cisplatin.
Theon explained it this way: "The high concentrations of cisplatin that can be achieved locally with intratumoral administration and the potentially long duration of exposure of tissues to cisplatin resulting from the use of a slow-release formulation formed the rationale for the study."
Involved in that study were 20 horses with 30 lesions. Treatment consisted of four sessions of intratumoral cisplatin chemotherapy at two-week intervals. Dosages varied, depending on the size of the tumor.
"Dosage tended to be slightly higher for smaller tumors and slightly lower for larger tumors," Theon says.
The horses selected for the study were those where other previous treatments had failed or the tumors were not considered amenable to conventional treatment.
Of the 30 tumors in the 20 horses, 19 were identified as sarcoid, seven as squamous cell carcinoma (a lesion of the skin characterized by crusty edges and lack of healing), and squamous cell papilloma, a benign form of tumor.
Nine horses with sarcoid had prior treatment, including surgery, laser vaporization, and other modalities.
None of the horses with carcinoma had received previous treatment.
Tumor locations included 12 sarcoid and three carcinomas around the eyes, three sarcoid and one carcinoma in the cheek area, four sarcoid in the trunk or limbs, two carcinomas in the female genitalia, and two carcinomas and three papillomas in the male genitalia.
Theon describes the treatment approach this way: "The goal of the treatment technique was to achieve a uniform distribution of cisplatin within the target volume. Using sterile injection techniques, a 20- to 25-gauge needle was inserted into the tissues, and the mixture (of cisplatin, sesame oil, and sterile water) was injected while the needle was withdrawn. Multiple injections were performed to cover the treatment field that encompassed the gross lesion with a margin of one centimeter of normal tissue. Depending on the shape or accessibility of the lesion, parallel-row or field block technique was used. (The parallel-row technique involves injections given in parallel lines on either side of the lesion as well as in the center. The field block method involves injections in a V-pattern as well as directly into the lesion.) For large tumors, multiple planes of injections were required. Injections were complete when the mixture extruded through the surface of the treated area."
The horses were evaluated each two weeks during the course of treatment, and followup examinations were performed two weeks, one month, six months, and one year after treatment.
The researchers used the terms complete, partial, and no response when describing the results of the test.
"Tumor response was categorized as complete," Theon reports, "when all clinical evidence of neoplasia completely disappeared for a minimum of four weeks, as partial when the largest cross-sectional area of neoplasm was reduced 50% for a minimum of four weeks, and as no response when the disease did not respond or progressed."
Seventeen of the 20 horses completed the planned treatment program.
First of all, the use of sesame oil and water in conjunction with cisplatin received a strong positive rating, both from the point of slow-release of the drug at the injection site and for nullifying toxic effect. Theon put it this way: "Water-in-oil emulsion of cisplatin appeared to be an effective and non-toxic formulation for slow release of cisplatin. The water-in-sesame oil emulsion is neutral; it does not compromise the antitumoral activity of cisplatin. The interaction between sesame oil and cisplatin is minimal, making the oily emulsion suitable as a passive carrier for the drug. The oil is thought to be cleared by local metabolic degradation as well as by venous and lymphatic absorption and phagocytosis. In this study, purified sesame oil without or with cisplatin, was well tolerated in tissues. Subcutaneous test injections of sesame oil prior to treatment did not result in inflammatory response or delayed foreign-body reactions.
"High local concentrations of cisplatin were achieved without attendant systemic toxicosis. Hypersensitivity reactions to sesame oil or cisplatin were not observed. However, potential for infection, as seen in one horse in this study, is unavoidable with this treatment technique. Tumors are often ulcerated and infected at time of examination. Treatment of grossly infected lesions should be postponed until the infection has resolved. Prophylactic administration of antibiotics is recommended after each treatment session."
So much for the treatment aftermath concerning tolerance and toxicity. How about the horses themselves? Was the cisplatin effective in reducing tumor size and stopping regrowth?
Here, too, the report was positive.
All horses had tumor regression (at least 50% reduction in size) during the treatment course.
In lesions that received the full course of treatment, complete response was found in 18 of 19 of the sarcoid, five of seven of the squamous cell carcinomas, and all four of the squamous cell papillomas. Three squamous cell papillomas on the penis of one of the horses resolved completely after only one treatment.
The researchers used another term to describe success or failure of the treatment--relapse-free interval, which was defined as the time elapsed between the end of treatment and tumor recurrence.
In horses with sarcoid, the mean relapse-free interval was 21.6 months. In horses with squamous cell carcinoma and papilloma, the mean relapse-free interval was 14 months.
In practical terms, this means that the majority of horses involved were given a renewed lease on life as a result of the chemotherapy.
In fact, the treatment procedure has become so successful that it is now used frequently by equine surgeons around the country.
Theon describes the use of cisplatin injections as a first-line treatment approach when dealing with equine cancer patients. At the same time, it also often is a "rescue" treatment--the treatment of choice when other modalities have failed.
A strong point for cisplatin is that it can be administered by licensed veterinarians, where as radiation treatments require the services of a specially licensed individual.
The Next Step
A year after the research outlined above, Theon and his colleagues took another step in their study. They looked at the effects of utilizing cisplatin in conjunction with surgery to eliminate tumors and prevent their recurrence.
The basic premise in combining surgery with intratumoral cisplatin treatment, Theon says, is that conservative surgery, combined with intratumoral chemotherapy, would be as effective as radical surgery.
Theon feels the two treatments are complementary because conservative surgery removes the tumor bulk while injecting cisplatin into the area eradicates the residual disease.
This type of surgery-chemotherapy combination, he says, is especially beneficial when dealing with large tumors located on the face, genitalia, extremities, perineum (the area between the anus and the scrotum), and tailbase, where radical surgery would have severe cosmetic consequences.
One of the concerns with use of combined treatment, Theon explains, is the risk of increased postoperative complications.
"Chemotherapeutic agents," he says, "can selectively sterilize dividing and metabolically active cells. Use of these agents may not only affect tumor growth, but also may substantially impair wound healing."
Involved in this study were 27 horses and one mule.
Treatments were planned to include surgery and four intratumoral treatment sessions with cisplatin administered at two-week intervals. The first treatment session was performed at the time of surgery and included the entire surgical wound. The second treatment came two weeks later.
Again, the results were positive.
"Healing of open granulating wounds was not compromised by the combined treatment modality," Theon reports, "and none of the wounds required surgical revision for coverage.
"The minor postoperative complications observed indicated that high local doses of cisplatin can be administered at the time of surgery. Perioperative (during the period of hospitalization) administration of cisplatin does not appear to inhibit or substantially compromise the healing of skin, mucosa, or subcutaneous tissues in horses.
"This may be explained by the fact that treatment affects a small volume of tissue, which allows sparing of the surrounding normal tissues for effective repopulation and regeneration.
"Results of the study reported here indicated that conservative surgery and perioperative intratumoral administration of cisplatin are safe and effective for treatment of cutaneous and subcutaneous tumors in horses."
The side effects of treatment, he says, were strictly local. All acute reactions, including inflammation, swelling, and ulceration, were resolved quickly. However, swelling frequently does occur after treatment, he says. It usually starts two to three days after each treatment and lasts about seven to 10 days.
Theon did add a word of warning when the drug is used in conjunction with more radical surgery.
"The risk of wound complications associated with cisplatin administered intraoperatively may be increased when more radical surgical procedures are performed. The importance of any impairment in wound healing varies with the site of surgery and extent of surgical procedure."
Overall, the results of combining surgery and chemotherapy have been excellent at the University of California, Davis. Records kept on 74 horses suffering from tumors around the eyes demonstrate that a combination of surgery and chemotherapy yielded excellent results. A two-year followup in the wake of surgery on the horses revealed a tumor control rate of 89% for squamous cell carcinomas and 94% for soft tissue sarcomas.
In still another study, Theon and his fellow researchers turned their attention to the effects of radiation treatment on cancerous growths in horses.
Used in this study were 115 horses with tumors around the eyes. A total of 52 of the tumors were squamous cell carcinomas, and 63 were sarcoid. The ages of the horses ranged from one to 28 years. There were 70 geldings, 43 mares, and two stallions involved.
The most common breeds were Quarter Horse--10 carcinomas, 35 sarcoid; Appaloosa--18 carcinomas, two sarcoid; Arabian--two carcinomas, 10 sarcoid; grade horses--eight carcinomas, two sarcoid; and Thoroughbred--three carcinomas, seven sarcoid.
Most of the tumors were on the eyelids.
All horses were evaluated clinically at Davis after treatment at two and three weeks. They also were evaluated at two, four, and six months, and approximately every six months thereafter.
The researchers used the term progression-free survival (PFS) in determining the success rate of the treatment. The progression-free survival time was defined as the interval between completion of radiation treatment and a measurable tumor growth or death of the horse.
The estimate of the five-year PFS rate for both carcinomas and sarcoid around the eye was listed at 66.4%.
During the study period, 25 of the 115 horses had tumor recurrence. Of that number, nine were described as having marginal recurrence, while 16 were described as having an "in-field tumor recurrence."
Two of the horses which had tumor recurrence involving carcinomas developed regional metastasis (a spreading of the disease) at five months, and one horse developed metastasis 11 months after radiation treatment.
There were some side effects from the treatment. Local toxicoses during treatment, Theon reports, included swelling (75.6%) and infection (10.4%).
The reactions to the radiation dosages were described as being either acute or chronic. Included in the category of acute reactions, in addition to swelling and infection, were redness of the skin and scaly, shedding skin. Acute reactions to radiation were observed six to 30 days after treatment.
"The acute reactions," reports Theon, "were generally well-tolerated and self-limiting."
Chronic reactions included necrosis (3.4%); the formation of fibrous tissue (10.4%), which, in some horses, resulted in the turning inward of the edge or margin of the eyelid (3.2%) or restriction of eyelid use (5.2%); cataract (4.3%); and inflammation of the cornea and corneal ulceration (6.9%).
Cosmetic after-effects included loss of hair (21.7%) and disorders of the pigmentation of skin and hair, such as the hair turning white (78.3%).
Theon described his evaluation of radiation therapy involved in the research this way:
"The results of this study demonstrate that radiation therapy may be an optimal treatment or an effective alternative to surgery, immunotherapy, and cryotherapy (the therapeutic use of cold) for local control of small, periocular (around the eye) tumors. The relative advantages of each approach are frequently debated. Because of the radiation hazard involved in the procedures, interstitial irradiation is not widely available; special training for the operator and special facilities are required to obtain a radiation use license.
"Irradiation therapy is preferred to surgery, immunotherapy, and cryotherapy when suboptimal functional or cosmetic results are expected.
"Horses with large lesions may benefit from a treatment combination, including surgical excision and radiotherapy. The central ideal in combining the two modalities is that conservative surgical resection and irradiation is as effective as radical excision.
"This approach reduces the cosmetic or functional deficit of radical surgery. The main combinations of interstitial irradiation and surgery revolve around intraoperative and post-operative radiation therapy. Irradiation has its maximum effect in the early post-operative period, when the tumor burden is minimal.
"Studies in rodents, however, have shown that interstitial brachytherapy, performed within the first five post operative days, is associated with significant risk of wound complications after primary closure.
"Thus, for lesions that can be closed primarily (not left open for drainage or other reasons), post-operative irradiation is recommended. For open wounds with visible residual tumor, intraoperative irradiation may be recommended; the therapeutic benefit of initiating irradiation early may outweigh the potential risk of wound complication.
"Certainly, there is preliminary evidence that surgical cytoreduction and intraoperative irradiation is effective for treatment of periocular tumors.
"For locally advanced inoperable tumors, tumor control may be improved by using innovative treatment methods such as combinations of irradiation and intratumoral chemotherapy. Such a treatment protocol has been shown to be beneficial in dogs and may be modified for use in horses."
Since that research report was filed, Theon has been doing more studies on the combining of radiation and chemotherapy.
In a preliminary report at the American College of Veterinary Radiology Annual Scientific Meeting held last August in Hawaii, Theon reported that in a study that is still underway, a group of horses treated with a combination of cisplatin and radiation did not have tumor recurrence. Also, he reports, the addition of cisplatin did not increase the effects of radiation on normal tissues.
There is even more good news. What Theon has done, in essence, is bring together the two modalities on which he has been doing research--radiation treatment combined with chemotherapy.
What he has discovered is that he can reduce the dosage of both and get much better results. The reason, he says, is synergy. Cisplatin, in essence, magnifies the positive healing power of radiation. Less radiation and a lower drug dosage mean that there are fewer adverse side effects.
As is the case in human medicine, the research continues in finding a solution to equine cancer. No one at the University of California, Davis, is saying they have found a cure-all, but their research has definitely opened the doors to a variety of options for horse owners.
Much of the cancer research conducted, and being conducted, at Davis is supported by the Equine Research Laboratory, with funds provided by the Oak Tree Racing Association, the State of California Satellite Wagering Fund, and contributions from private donors.
About the Author
Les Sellnow is a free-lance writer based near Riverton, Wyo. He specializes in articles on equine research, and operates a ranch where he raises horses and livestock. He has authored several fiction and non-fiction books, including Understanding Equine Lameness and Understanding The Young Horse, published by Eclipse Press and available at www.exclusivelyequine.com or by calling 800/582-5604.
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