PubMed · 10407950
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B Truniger. 1999-05-15. [Fatal cure].. https://pubmed.ncbi.nlm.nih.gov/10407950/
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BACKGROUND: Intravesical chemotherapy (i.e., placement of the drug directly in the bladder) with mitomycin C is beneficial for patients with superficial bladder cancer who are at high risk of recurrence, but standard therapy is empirically based and patient response rates have been variable, in part because of inadequate drug delivery. We carried out a prospective, two-arm, randomized, multi-institutional phase III trial to test whether enhancing the drug's concentration in urine would improve its efficacy. METHODS: Patients with histologically proven transitional cell carcinoma and at high risk for recurrence were eligible for the trial. Patients in the optimized-treatment arm (n = 119) received a 40-mg dose of mitomycin C, pharmacokinetic manipulations to increase drug concentration by decreasing urine volume, and urine alkalinization to stabilize the drug. Patients in the standard-treatment arm (n = 111) received a 20-mg dose without pharmacokinetic manipulations or urine alkalinization. Both treatments were given weekly for 6 weeks. Primary endpoints were recurrence and time to recurrence. Treatment outcome was examined by use of Kaplan-Meier analysis with log-rank tests. Statistical tests were two-sided. RESULTS: Patients in the two arms did not differ in demographics or history of intravesical therapy. Dysuria occurred more frequently in the optimized arm but did not lead to more frequent treatment termination. In an intent-to-treat analysis, patients in the optimized arm showed a longer median time to recurrence (29.1 months; 95% confidence interval [CI] = 14.0 to 44.2 months) and a greater recurrence-free fraction (41.0%; 95% CI = 30.9% to 51.1%) at 5 years than patients in the standard arm (11.8 months; 95% CI = 7.2 to 16.4 months) and 24.6% (95% CI = 14.9% to 34.3%) (P =.005, log-rank test for time to recurrence). Improvements were found in all risk groups defined by tumor stage, grade, focality, and recurrence. CONCLUSIONS: This study identified a pharmacologically optimized intravesical mitomycin C treatment with statistically significantly enhanced efficacy.
Cyclooxygenase-1 and cyclooxygenase-2 mRNAs and proteins and prostaglandin E(2) production are evaluated in a rat model of inflammation in which Escherichia coli lipopolysaccharide is intraperitoneally injected or intravesically instilled into the bladder. While cyclooxygenase-1 mRNA and protein and cyclooxygenase-2 mRNA do not change in bladders treated with lipopolysaccharide, cyclooxygenase-2 protein is elevated in bladders from rats intravesically instilled with lipopolysaccharide or phosphate buffered saline (PBS) or intraperitoneally injected with lipopolysaccharide. Urinary prostaglandin E(2) levels and prostaglandin E(2) synthesis in bladder particulates are elevated by intravesical instillation and intraperitoneal injection of lipopolysaccharide. The nitric oxide donor, S-nitroso-N-acetyl-D,L-penicillamine, increases prostaglandin E(2) synthesis in bladders from lipopolysaccharide intravesically instilled and intraperitoneally injected rats. Lipopolysaccharide increases prostaglandin E(2) synthesis by increasing cyclooxygenase-2 protein levels in rat bladder and prostaglandin E(2) synthesis may be further elevated by increases in nitric oxide caused by an up-regulation of inducible nitric oxide synthase (iNOS).