ABSTRACT
OBJECTIVES: Previous studies have demonstrated that intravesical administration of apaziquone (EOquin) has ablative activity against superficial bladder cancer marker lesions with 8 out of 12 complete responses recorded. We present a comparison between the rates of tumor recurrence before and after treatment with apaziquone. METHODS: The rate of tumor recurrence after treatment with apaziquone was compared with each patient's historical record of recurrences obtained from a retrospective analysis of the patients' case notes. The time to each recurrence event before apaziquone treatment and the time to the first recurrence after apaziquone treatment were recorded, and the data were analyzed using a population-averaged linear regression model using Stata Release, version 9.2, software. RESULTS: Of the eight complete responses obtained in the Phase I study, tumor recurrence occurred in 4 patients and the remaining 4 patients remained disease free after a median follow-up of 31 months. The time to the first recurrence after apaziquone treatment was significantly longer (P <0.001) compared with the historical pattern and recurrence interval before apaziquone. Before apaziquone instillation, the mean +/- SE recurrence rate and tumor rate per year was 1.5 +/- 0.2 and 4.8 +/- 1.2, respectively, and these decreased to 0.6 +/- 0.25 and 1.5 +/- 0.8, respectively, after apaziquone treatment (P <0.05). CONCLUSIONS: The results of this study indicate that early recurrences after treatment with apaziquone are infrequent and the interval to recurrence is significantly greater compared with the historical recurrence times for these patients. Larger prospective randomised trials are warranted to confirm these results.
Subject(s)
Aziridines/therapeutic use , Carcinoma, Transitional Cell/drug therapy , Indolequinones/therapeutic use , Neoplasm Recurrence, Local/epidemiology , Urinary Bladder Neoplasms/drug therapy , Administration, Intravesical , Biopsy, Needle , Carcinoma, Transitional Cell/mortality , Carcinoma, Transitional Cell/pathology , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Follow-Up Studies , Humans , Immunohistochemistry , Male , Neoplasm Recurrence, Local/prevention & control , Neoplasm Staging , Probability , Retrospective Studies , Risk Assessment , Survival Analysis , Treatment Outcome , Urinary Bladder Neoplasms/mortality , Urinary Bladder Neoplasms/pathologyABSTRACT
PURPOSE: The quinone based bioreductive drug apaziquone (EO9) failed to demonstrate efficacy in previous phase II studies following intravenous administration. We determined the dose of apaziquone that can be safely administered intravesically and explored its activity for superficial bladder transitional cell carcinoma. MATERIALS AND METHODS: Six patients with multifocal, Ta/T1 and G1/G2 transitional cell carcinoma of the bladder received escalating doses of apaziquone formulated as EOquintrade mark (0.5 mg/40 ml up to 16 mg/40 ml) weekly for 6 weeks. A further 6 patients received weekly apaziquone at the highest nontoxic dose established. Pharmacokinetic parameters were determined in urine and blood, and the pharmacodynamic markers NQO1 (reduced nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase-1) and glucose transporter 1 were also characterized. Efficacy was determined against a marker lesion. RESULTS: Local toxicity (grades 2 and 3 dysuria, and hematuria) was observed at doses of 8 mg/40 ml and above but 4 mg/40 ml was well tolerated with no systemic or local side effects. Apaziquone in urine increased linearly with the dose but no apaziquone was detected in plasma. In 8 of 12 patients complete macroscopic and histological disappearance of the marker lesion occurred. A correlation between response and NQO1 and/or glucose transporter 1 expression could not be established. CONCLUSIONS: Intravesical administration of 4 mg/40 ml apaziquone was well tolerated and had ablative activity against superficial bladder cancer marker lesions.
