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Adjuvant Therapy for Melanoma in Dogs: Results of Randomized Clinical Trials Using Surgery, Liposome-encapsulated Muramyl Tripeptide, and Granulocyte Macrophage Colony-stimulating Factor¹

University of Wisconsin, School of Veterinary Medicine, Madison, Wisconsin 53706 [E. G. M., I. D. K., D. M. V., R. R. D., K. E., B. P.]; University of California, School of Veterinary Medicine, Davis, California 95616 [B. R. M., C. O. R., B. P., C. H. Z.]; Oakland Veterinary Referral Services, Bloomfield Hills, Michigan 48302 [J. O.]; Veterinary Specialists of Rochester, Rochester, New York 14623 [R. C. R.]; University of Florida, College of Veterinary Medicine, Gainesville, Florida 32610 [L. E. F.]; Veterinary Cancer Referral Group, Los Angeles, California 90064 [M. R.]; University of Missouri, College of Veterinary Medicine, Columbia, Missouri 65211 [C. H.]; and Special Veterinary Services, Berkeley, California 94704 [J. F.]

Spontaneous canine oral melanoma (COM) is a highly metastatic cancer, resistant to chemotherapy, and can serve as a model for cancer immunotherapy. Liposome-encapsulated muramyl tripeptide-phosphatidylethanolamine (L-MTP-PE) can activate the tumoricidal activity of the monocyte-macrophage system following i.v. injection. The objective of these studies was to evaluate the therapeutic effectiveness of L-MTP-PE administered alone and combined with recombinant canine granulocyte macrophage colony-stimulating factor (rcGM-CSF) in dogs undergoing surgery for oral melanoma.

Ninety-eight dogs with histologically confirmed, clinically staged, oral melanoma were entered into two randomized, double-blind, surgical adjuvant trials. In trial 1, 50 dogs were stratified based on clinical stage and randomized to once a week L-MTP-PE or lipid equivalent (control). When all of the clinical stages were combined, no difference in disease-free survival or in survival time (ST) were detected. However, within stage I, dogs receiving L-MTP-PE had a significant increase in ST compared with control, with 80% of the dogs treated with L-MTP-PE still alive at >2 years. Within each stage II and stage III, there was no difference detected between the treatment groups. In trial 2, 48 dogs were stratified on the basis of clinical stage and extent of surgery (simple resection or radical excision), treated with L-MTP-PE two times a week, and randomized to rcGM-CSF or saline (placebo) given s.c. daily for 9 weeks. Within each stage and when all of the stages were combined, there was no difference between the treatment groups. In both studies, stage I COM is associated with a better prognosis. No effect on survival was observed with regard to tumor location in the oral cavity, sex, type/extent of surgery, or age. In a subset of dogs tested, pulmonary alveolar macrophage cytotoxicity was enhanced with combined rcGM-CSF and L-MTP-PE but not in dogs treated with L-MTP-PE alone.

The present study indicates that after surgery, L-MTP-PE administered alone or combined with rcGM-CSF showed no significant antitumor activity in treating advanced stage COM. In early stage COM, L-MTP-PE was shown to result in a prolongation of ST. Furthermore, this study provides additional rationale for the use of the dog model for human malignant melanoma.

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