Adjuvant therapy for melanoma in dogs: Results of randomized clinical trials using surgery, liposome-encapsulated muramyl tripeptide, and granulocytemacrophage colony-stimulating factor

Spontaneous canine oral melanoma (COM) is a highly metastatic cancer, resis tant to chemotherapy, and can serve as a model for cancer immunotherapy. Li posome-encapsulated muramyl tripeptide-phosphatidylethanolamine (L-MTP-PE) can activate the tumoricidal activity of the monocyte-macrophage system fol lowing i.v. injection. The objective of these studies was to evaluate the t herapeutic effectiveness of L-MTP-PE administered alone and combined with r ecombinant canine granulocyte macrophage colony-stimulating factor (rcGM-CS F) in dogs undergoing surgery for oral melanoma. Ninety-eight dogs with histologically confirmed, clinically staged, oral me lanoma were entered into two randomized, double-blind, surgical adjuvant tr ials. In trial 1, 50 dogs were stratified based on clinical stage and rando mized to once a week L-MTP-PE or lipid equivalent (control). When all of th e clinical stages mere combined, no difference in disease-free survival or in survival time (ST) mere detected. However, within stage I, dogs receivin g 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 sta ge 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 bot h 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 alv eolar 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 trea ting advanced stage COM. In early stage COM, L-MTP-PE was shown to result i n a prolongation of ST. Furthermore, this study provides additional rationa le for the use of the dog model for human malignant melanoma.