title: Methods to improve efficacy of intravesical mitomycin C: results of a randomized phase III trial.
abstract: 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.
authors: Ohio State University, 496 W. 12th Ave., Columbus, OH 43210, USA. au.1@osu.edu
authors: J L
authors: JL
authors: Au
authors: R A
authors: RA
authors: Badalament
authors: M G
authors: MG
authors: Wientjes
authors: D C
authors: DC
authors: Young
authors: J A
authors: JA
authors: Warner
authors: P L
authors: PL
authors: Venema
authors: D L
authors: DL
authors: Pollifrone
authors: J D
authors: JD
authors: Harbrecht
authors: J L
authors: JL
authors: Chin
authors: S P
authors: SP
authors: Lerner
authors: B J
authors: BJ
authors: Miles
mesh_terms: D000283:Administration, Intravesical; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016685:Mitomycin / Q000008:administration & dosage* / Q000009:adverse effects; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control; D011446:Prospective Studies; D012307:Risk Factors; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*
chemical_list: D000903:Antibiotics, Antineoplastic; D016685:Mitomycin