Seventeen-year follow-up of the prospective randomized Nordic CIS study: BCG monotherapy versus alternating therapy with mitomycin C and BCG in patients with carcinoma in situ of the urinary bladder.
OBJECTIVE
The aim of this study was to compare the long-term efficacy of BCG monotherapy to alternating therapy of mitomycin C (MMC) and BCG in patients with carcinoma in situ (CIS).


METHODS
Between 1992 and 1997, 321 patients with CIS were randomized from Finland, Norway and Sweden in a prospective multicenter trial into two treatment groups. The alternating therapy comprised six weekly instillations of MMC 40 mg followed by 10 instillations of BCG (Connaught 120 mg) or MMC alternating monthly for 1 year. BCG monotherapy followed the same 6 + 10 schedule. Stratification was done by nationality and CIS category. Primary endpoints were time to first recurrence and time to progression. Secondary endpoints were disease-specific mortality and overall survival. The main statistical methods were the proportional subdistribution hazards model and Cox proportional hazards model with the cumulative incidence and Kaplan-Meier analyses.


RESULTS
The median follow-up time was 9.9 years (maximum 19.9 years) in the BCG group and 8.9 years (maximum 20.3 years) in the alternating group. The risk of recurrence was significantly lower in the BCG group than in the alternating group (49 vs 59% at 15 years, respectively; hazard ratio 0.74, 95% confidence interval 0.54-1.00, p = 0.048). There were no significant differences in the other endpoints. Patients who progressed after 2 years were particularly prone to dying from bladder carcinoma. Younger patients performed worse than older ones.


CONCLUSIONS
BCG monotherapy including monthly maintenance was effective and better than the alternating therapy. The risk of dying from bladder carcinoma after progression was high.
a Department of Surgery , Hyvinkää Hospital, Hyvinkää and Helsinki University Hospital , Helsinki , Finland ;
Eero
E
Kaasinen
b Department of Urology , Karolinska University Hospital Huddinge , Stockholm , Sweden ;
Hans
H
Wijkström
c Department of Urology , Helsinki University Hospital , Helsinki , Finland ;
Erkki
E
Rintala
d Section for Urology, Surgical Division , University of Stavanger , Stavanger , Norway ;
Oddvar
O
Mestad
e Department of Urology, IKE , University Hospital Linköping, Linköping University , Linköping , Sweden ;
Staffan
S
Jahnson
f Department of Surgical Sciences , University Hospital Uppsala , Uppsala , Sweden.
Per-Uno
PU
Malmström
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D001500:BCG Vaccine / Q000627:therapeutic use*; D002278:Carcinoma in Situ / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D016685:Mitomycin / Q000627:therapeutic use*; D011446:Prospective Studies; D013997:Time Factors; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*
D000276:Adjuvants, Immunologic; D000903:Antibiotics, Antineoplastic; D001500:BCG Vaccine; D016685:Mitomycin
BCG; carcinoma in situ; combination therapy; immunotherapy; instillation therapy; long-term efficacy; mitomycin C; randomized controlled trial; urinary bladder