Background: Invasive transitional cell carcinoma (InvTCC) of the urinary bladder has a propensity to metastasize, is only partially responsive to chemotherapy, and causes > 14,000 deaths yearly in the United States. The development of effective means to prevent the development and progression of InvTCC is crucial. Cyclooxygenase‐2 (Cox‐2) is over‐expressed in InvTCC in humans and animals. In a pilot study, a Cox‐2 inhibitor induced apoptosis of InvTCC in humans. Cox‐2 inhibitors may offer an avenue for prevention of InvTCC progression. The purpose of this study was to determine the effects of Cox‐2 inhibitor treatment in preventing the progression of InvTCC in a highly relevant animal model, canine InvTCC. Naturally‐occurring InvTCC in dogs closely mimics human InvTCC in cellular and molecular features (including Cox‐2 expression), sites and frequency of metastasis, and response to therapy.
Methods: Dogs with histologically confirmed InvTCC who failed or whose owner declined standard chemotherapy protocols, and with expected survival of > 6 weeks were prospectively enrolled. The Cox‐2 inhibitor deracoxib (Novartis, Greensboro, NC) was given as a single agent with a planned dose of 3mg/kg/day orally. Dogs were evaluated prior to and during therapy with abdominal ultrasound including mapping of the urinary bladder masses, thoracic radiographs, complete blood count, serum biochemistry profiles and urinalyses. Toxicity was assessed by clinical signs and serial blood work. Tumor response was defined as: complete remission (CR), no evidence of disease detected; partial remission (PR) ≥ 50% reduction in tumor volume; stable disease (SD) <50% change in tumor volume; or progressive disease (PD) ≥ 50% increase in tumor volume or new lesions. A whole blood assay was used to confirm selective Cox‐2 inhibition.
Results: Thirty‐nine dogs with InvTCC received deracoxib at a mean dose of 2.79 mg/kg/day (range 1.18 mg/kg/day to 4.08mg/kg/day). Of 39 dogs, 1 had nodal metastasis, and 3 had distant metastasis at diagnosis. Initial responses in 30 dogs with measurable disease included PR in 4 dogs (13%), SD in 17 dogs (57%), and PD in 3 dogs (10%); and in 6 dogs, response to therapy has not been determined. Mean time to subsequent PD (n=20) was 167 days (range 36 – 482 days). After PD was noted, 10 dogs went on to receive other therapy (leukeran, mitoxantrone, mitomycin‐C, 5 azacitidine, carboplatin). Of the 39 dogs treated, 9 had microscopic residual disease after surgical intervention. Of these 9 dogs, 4 had relapse (median time to relapse, 221 days), and 3 had not relapsed at the time of death from other causes (median time to death 772 days). The median survival times for dogs with measurable disease and microscopic disease were 349 and 772 days, respectively.
Conclusion: The results of this work help justify further study of the use of Cox‐2 inhibitors in preventing the progression of InvTCC.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):A48.