Methods to improve efficacy of intravesical mitomycin C: Results of a randomized phase III trial

Background: Intravesical chemotherapy (i.e., placement of the drug directly in the bladder) with mitomycin C is beneficial for patients with superfici al 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: Pat ients with histologically proven transitional cell carcinoma and at high ri sk for recurrence were eligible for the trial. Patients in the optimized-tr eatment arm (n = 119) received a 40-mg dose of mitomycin C, pharmacokinetic manipulations to increase drug concentration by decreasing urine volume, a nd urine alkalinization to stabilize the drug. Patients in the standard-tre atment arm (n = 111) received a 20-mg dose without pharmacokinetic manipula tions or urine alkalinization, Both treatments were given weekly for 6 week s. Primary endpoints were recurrence and time to recurrence, Treatment outc ome was examined by use of Kaplan-Meier analysis with log-rank tests. Stati stical tests were two-sided. Results: Patients in the two arms did not diff er in demographics or history of intravesical therapy. Dysuria occurred mor e frequently in the optimized arm but did not lead to more frequent treatme nt termination. In an intent-to-treat analysis, patients in the optimized a rm showed a longer median time to recurrence (29.1 months; 95% confidence i nterval [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 a rm (11.8 months; 95% Cf = 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 recur rence. Conclusions: This study identified a pharmacologically optimized int ravesical mitomycin C treatment with statistically significantly enhanced e fficacy.