Doxorubicin and BAY 12-9566 for the Treatment of Osteosarcoma in Dogs: A Randomized, Double-Blind, Placebo-Controlled Study

Abstract

Background: This study was designed to assess the efficacy of a matrix metalloproteinase inhibitor in prolonging posttreatment survival for dogs with appendicular osteosarcoma after treatment with amputation and doxorubicin chemotherapy. Hypothesis: Survival will be prolonged in dogs receiving BAY 12–9566. Animals: The study included 303 dogs with appendicular osteosarcoma. Methods: Dogs were treated with doxorubicin (30 mg/m2) every 2 weeks for 5 treatments starting 2 weeks after amputation. Dogs were randomly allocated to receive a novel nonpeptidic biphenyl inhibitor of matrix metalloproteinases (MMPs, BAY 12–9566; 4-[4–4-(chlorophenyl)phenyl]-4-oxo-2S-(phenylthiomethyl) butanoic acid) or placebo after doxorubicin chemotherapy. Results: Median survival for all 303 dogs was 8 months; and 1-year, 2-year, and 3-year survival rates were 35%, 17%, and 9%, respectively. Treatment with BAY 12–9566 did not influence survival. Multivariate analysis revealed that increasing age (P= .004), increasing weight (P= .006), high serum alkaline phosphatase (ALP) (P= .012) and high bone ALP (P < .001) were independently associated with shorter median survival times. Additional analyses on available data indicated that as the number of mitotic figures in the biopsy increased (P= .013), and as plasma active MMP-2 concentrations increased (P= .027), the risk of dying increased. Conclusions and Clinical Importance: Doxorubicin is an effective adjuvant to amputation in prolonging survival for dogs with appendicular osteosarcoma.