Long-term outcome of patients with frequently recurrent non-muscle-invasive bladder carcinoma treated with one perioperative plus four weekly instillations of mitomycin C followed by monthly bacillus Calmette-Guérin (BCG) or alternating BCG and interferon-α2b instillations: prospective randomised FinnBladder-4 study.
BACKGROUND
Recurrent TaT1 non-muscle-invasive bladder cancer (NMIBC) patients should be treated with immediate instillation of chemotherapy after transurethral resection of bladder tumour followed by instillation therapy.


OBJECTIVE
To present long-term results of a study exploring the effect of initial mitomycin C (MMC) instillations followed by two types of immunotherapy for patients with frequently recurring NMIBC.


METHODS
Between 1992 and 1996, 236 patients with frequently recurring TaT1 grade 1-2 NMIBC were enrolled in the prospective randomised multicentre FinnBladder-4 study.


METHODS
One perioperative plus four weekly instillations of MMC followed by monthly bacillus Calmette-Guérin (BCG) or alternating BCG and interferon (IFN)-α2b instillations for up to 1 yr.


METHODS
Primary end points were time to first recurrence and time to progression. Secondary end points were disease-specific mortality and overall survival. The principal statistical methods were the proportional subdistribution hazards model and Cox proportional hazards model plus cumulative incidence and Kaplan-Meier analyses.


CONCLUSIONS
The median follow-up was 10.3 yr (maximum: 19.8 yr) in the MMC-BCG group and 8.6 yr (maximum: 19.8 yr) in the MMC-BCG/IFN group. The probability of recurrence was significantly lower in the MMC-BCG group than in the MMC-BCG/IFN group (43% vs 78% at 10 yr and 45% vs 80% at 15 yr, respectively; hazard ratio: 2.86; 95% confidence interval, 1.98-4.13; p<0.001). There were no significant differences in the probability of progression, disease-free mortality, or overall survival.


CONCLUSIONS
Perioperative plus four weekly MMC instillations followed by monthly BCG, instead of alternating BCG and IFN-α2b instillations, significantly reduce long-term recurrence.


RESULTS
We demonstrated in non-muscle-invasive bladder cancer patients with exceptionally frequent recurrences that the risk of long-term recurrence was reduced from 78-80% to 43-45% if one perioperative plus four weekly mitomycin C instillations were followed by monthly bacillus Calmette-Guérin (BCG) instillations for 1 yr instead of alternating instillations of BCG and interferon-α2b.


BACKGROUND
The registration was not considered necessary at this stage of the follow-up because the study was initiated as early as in 1992 and the last randomisation took place in 1996, before the current requirements concerning study registrations were implemented.
Department of Urology, Helsinki University Hospital, Helsinki, Finland. Electronic address: riikka.jarvinen@hus.fi.
Riikka
R
Järvinen
Department of Urology, Seinäjoki Central Hospital, Seinäjoki, Finland.
Timo
T
Marttila
Department of Surgery, Hyvinkää Hospital, Hyvinkää, Finland.
Eero
E
Kaasinen
Department of Urology, Helsinki University Hospital, Helsinki, Finland.
Erkki
E
Rintala
Department of Urology, Kuopio University Hospital, Kuopio, Finland.
Sirpa
S
Aaltomaa
Department of Urology, Tampere University Hospital, Tampere, Finland.
Jukka
J
Kallio
Department of Surgery, Mikkeli Central Hospital, Mikkeli, Finland.
Tapani
T
Liukkonen
Department of Urology, South Carelia Central Hospital, Lappeenranta, Finland.
Veli-Matti
VM
Puolakka
Department of Surgery, Satakunta Central Hospital, Pori, Finland.
Marjo
M
Seppänen
Department of Urology, Kuopio University Hospital, Iisalmi, Finland.
Kari
K
Tuhkanen
Department of Urology, Oulu University Hospital, Oulu, Finland.
Markku
M
Vaarala
Department of Urology, North Carelia Central Hospital, Joensuu, Finland.
Jouko
J
Viitanen
Department of Urology, Turku University Hospital, Turku, Finland.
Peter J
PJ
Boström
D000283:Administration, Intravesical; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001500:BCG Vaccine / Q000008:administration & dosage* / Q000009:adverse effects; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D005387:Finland; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000009:adverse effects; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D016685:Mitomycin / Q000008:administration & dosage* / Q000009:adverse effects; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology
D001500:BCG Vaccine; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D016685:Mitomycin
Bacillus Calmette-Guérin; Instillation therapy; Interferon α-2b; Long-term efficacy; Mitomycin C; Recurrent; Superficial bladder cancer