Authors:
Goetz TE. DVM , Diplomate, ACVIM; Long, M.T. DVM

Institution
Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois, Urbana 61801.

Title
Cimetidine for treatment of melanomas in three horses (continued)

Source

The prevalence of neoplasma in horses has been estimated to be from 1 to 3%. Sundberg et al found that melanomas comprised 3.8% of the total numbe of neoplasms diagnosed in horses. Melanomas develop most frequently in gray and white horses > 6 years old, and have also been described in white mules. Melanomas also develop in horses of other colors, where they tend to be more aggressive. Although it is uncommon, congenital melanomas are seen. Approximately 80% of gray horses > 15 years old will be afflicted with melanomas. A sex predication for melanomas has been suggested by some, and refuted by others.

Melanomas can develop anywhere on or within the body; however, they usually have an external predilection for the undersurface of the tail, near its root, the perineal and perianal regions, the male genitalia, the head below the entrance to the pinna, the ear margin, and the paratoid salivary gland.

Melanomas can be hard, soft, solitary, or multiple. Often they are located subcutaneously and are covered by normal haired skin, however, with time, they may become ulcerated and infected. Typically, when visible, they are dark brown to black o gray; some are unpigmented. Diagnosis of unpigmented melanomas (amelanotic) requires microscopic examination of biopsy specimens.

A complex system of grading melanomas which allows accuate pathologic classification, has been developed for dogs. At this time, however, equine melanomas are graded merely as benign or malignant.

In aging gray horses it appears that melanomas arise from disturbance of melanin metabolism. This disturbance stimulates the formation of new melanoblasts or increases their activity, resulting in local areas of overproduction of pigment in the dermis. With time, these hyperplastic melanoblasts usually undergo malignant transformation.

Clinically, equine melanomas tend to develop and behave in 1 of 3 distinct ways. The most common pattern is one of slow growth over a numbe of years without metastasis. Melanomas may be benign for as long as 10 to 20 years. The next most common pattern is for the benign growth to suddenly assume malignant characteristics and metastasize. Conversely, some melanotic tumors are malignant from their first appearance and readily metastasize. Metastasis to any region of the body is possible once malignant transformation occurs, but there appears to be a predilection for the serosal surface of the spleen, liver, and lungs.

Several modalities have been used in the treatment of equine melanomas: wide surgical excision, chemotherapy, bacille Calmette-Guerin, radiotherapy, and single or repeated crynecrosis. A satisfactory form of treatment still does not exist. Chemotherapy, radiotherapy, and bacille Calmette-Guerin have been of little clinical value. New melanomas often form in areas of surgical excision, and cryonecrosis (although of benefit) often has to be frequently repeated each time the tumorous tissue proliferates to unwanted size. In human beings, some malignant melanomas will regress without treatment.

Besides the threat melanomas pose to the life of affected horses, chronic benign melanomas are a therapeutic, economic, and practical nuisance. Benign melanomas can interfere with urination, defecation, and coitus, and can preclude saddle, bridle, and halter application when they develop on horse's backs and in bridle and halter paths.

Within the past 5 years, cimetidine has been recognized as a biological response modifier with antitumor properties effective in the treatment of various human and animal tumors including malignant melanoma. Because of reliable method of treatment for equine melanomas still does not exist, we evaluated the efficacy of cimetidine in the clinical management of these tumors in three horses.

The manner in which cimetidine manifests its effects on the host's antitumor defence mechanism is unknown and is still being pursued. One theory states that some patients with neoplastic disorders may have an overabundance of suppressor T cells that suppress the body's own antitumor defense mechanism. Recent in vitro studies have shown that histamine activates suppressor T cells through H2 histamine receptors, which suppress both cell-mediated and humoral immune responses. Cimetidine appears to block the activation of these suppressor cells, thus augmenting cell-mediated and humoral immune responses. Results of these studies suggest that cimetidine may be beneficial in vivo as a therapeutic immunomodulator inhibiting suppressor T cells pharmacologically. This inhibition could allow unchecked enhancement of the T contrasuppressor cell's antitumor influence on macrophage function.

Based on the information gained from treating horses 1 and 2, it appears that cimetidine may manifest its optimal effect after 3 to 4 months of treatment, however, it is still not known whether treatment for a shorter period might not be just as effective. Treatment for a longe period in horse 1 (a full year) did not appear to offer and therapeutic advantage.

Comparison of the response of horse 3 with those of horses 1 and 2 was complicated by the fact that the different dosages of cimetidine were used and that horse 3 was treated with a different H2 histamine antagonist, ranitidine, for 5 months. Nevertheless, some observations that may be important clinically should be stressed. The continued resolution of the masses in horse 3 suggests that a beneficial response may be possible with administration of cimetidine at a dosage of only 1.6 to 2.5 mg/kg once daily. A once-a-day treatment protocol would greatly decrease the treatment burden of the horse owner and substantially decrease the cost of the treatment. We wish to stress, however, that more horses will need to be treated with lower doses of cimetidine before specific treatment guidelines can be given. It is of interest to mention that the owner of horse 3 reported that the masses appeared to decrease in number and size more quickly when the horse was being treated with higher and more frequent doses of cimetidine.

On the basis of the response of horse 3, treatment with ranitidine does not appear to be a viable therapeutic option. Our clinical observations concerning ranitidine are in agreement with the veterinary and medical literature, which to our knowledge does not contain any information that supports the use of ranitidine in this fashion. However, it should be pointed out that ranitidine was evaluated in only one horse at one dose; this single dosage regimen was insufficient to definitively comment on the efficacy of ranitidine in the management of equine melanomas.

It was obvious from the cases reported here that response to treatment with cimetidine can be variable. Typically, cimetidine appears to stop the progression and decrease the number and size of the tumors by approximately one half. The response to horse 3, which is still under treatment, suggests that in some horses, treatment with cimetidine may lead to complete disappearance of the melanomas and that some horses may require an as-yet-undetermined low dose of cimetidine regularly to prevent exacerbation of the tumors.

In horses 1 and 2, cimetidine was administered at similar dosages, but with intervals longer than those used in the treatments of gastric ulcers. Even though the duration of treatment in all 3 horses was prolonged, none of the horses experienced any of the more common toxic effects of cimetidine (reversible confusional states, transient diarrhea).

Barring the expense and the inconvenience of prolonged administration, cimetidine may be a viable alternative singly or in conjunction with other treatment modalities for the clinical management of horses with melanomas.