Phase I Clinical Trial and Pharmacokinetics of Intravesical Mitomycin C in Dogs with Localized Transitional Cell Carcinoma of the Urinary Bladder

Abstract

Background: Transitional cell carcinoma (TCC) is the most common cancer of the urinary tract in dogs. The most frequent cause of death is urinary obstruction from the primary tumor. Standard medical therapy for TCC is only partially effective.Hypothesis/Objectives: Intravesical administration of mitomycin C (MMC) in dogs with invasive TCC will result in antitumor activity against the primary tumor and minimal systemic drug absorption.Animals: Thirteen privately owned dogs with naturally occurring, histopathologically diagnosed TCC of the urinary bladder. Methods: A prospective phase I trial was performed. MMC was given intravesically (600 mg/mL initial concentration) for 1 h/d for 2 consecutive days each month. The MMC concentration was escalated to a maximum of 800 mg/mL in groups of 3 dogs until the maximum tolerated dose (MTD) was determined. Serum assays for MMC were performed to determine the extent of systemic absorption of the MMC.Results: The MTD of MMC based on local toxicoses was 700 mg/mL (1-h dwell time, 2 consecutive days). In addition, 2 dogs had severe myelosuppression and appeared to have systemic absorption of MMC. Five dogs had partial remission, and 7 dogs had stable disease.Conclusions: Intravesical MMC has antitumor activity in dogs with invasive TCC. Further study is needed to determine the cause of the myelosuppression associated with MMC administration, and to develop strategies to minimize this risk.

Tumors of the Urinary System

“…58 The reported tumor responses included two (5%) CR, eight (21%) PR, and 19 (50%) SD. 57 Tumor response was assessed in 12 of 13 dogs, and responses included five PR and seven SD. Other emerging therapies that have shown promise include singleagent vinblastine 52 and metronomic chlorambucil.…”

Targeting Folate Receptors to Treat Invasive Urinary Bladder Cancer

“…Toxicity was assessed by complete blood counts (CBC), serum chemical profiles, urinalyses, physical exams, and owner observations, and was classified by the Veterinary Cooperative Oncology Group (VCOG) criteria (28). Urologic toxicity was categorized as previously described (29). The MTD was defined as the highest dose that resulted in 0 of 6 dogs having grade 4 toxicity and 0 or 1 of 6 dogs having grade 3 toxicity.…”

Randomized Phase III Trial of Piroxicam in Combination with Mitoxantrone or Carboplatin for First‐Line Treatment of Urogenital Tract Transitional Cell Carcinoma in Dogs

“…The PFI in dogs with TCC treated with cisplatin alone is 75–84 and is 124 days when combined with piroxicam 17, 18. Multiple other chemotherapeutic agents have been described for the treatment of TCC in dogs and response rates to cisplatin, doxorubicin, mitomycin C, gemcitabine, vinblastine, and chlorambucil range from 3 to 71% with PFI ranging from 75 to 329 days 10, 16, 17, 18, 19, 20, 21, 22, 23…”

“…17,18 Multiple other chemotherapeutic agents have been described for the treatment of TCC in dogs and response rates to cisplatin, doxorubicin, mitomycin C, gemcitabine, vinblastine, and chlorambucil range from 3 to 71% with PFI ranging from 75 to 329 days. 10,[16][17][18][19][20][21][22][23] Reported response of dogs with TCC to piroxicam combined with either mitoxantrone or carboplatin is similar, with overall response rates of 35% and 38%, respectively. 14,15 However, these combinations have not yet been compared in a randomized prospective trial, and it is currently not known whether either drug may provide superior duration of response and thus be indicated as first-line treatment.…”