UROLOGICAL ONCOLOGY

doi: 10.1590/S1677-55382011000200024

Sequential intravesical chemoimmunotherapy with mitomycin C and bacillus Calmette-Guérin and with bacillus Calmette-Guérin alone in patients with carcinoma in situ of the urinary bladder: results of an EORTC genito-urinary group randomized phase 2 trial (30993)
Oosterlinck W, Kirkali Z, Sylvester R, Silva FC, Busch C, Algaba F, Collette S, Bono A
Department of Urology, Ghent University Hospital, Ghent, Belgium
Eur Urol. 2011; 59: 438-46

• Background: Bacillus Calmette-Guérin (BCG) is the intravesical treatment of choice for carcinoma in situ (CIS).
  Objective: Our aim was to assess if sequential mitomycin C (MMC) plus BCG after transurethral resection (TUR) is worthy of further study in non-muscle-invasive bladder cancer patients with CIS.
  Design, Setting, and Participants: In a noncomparative phase 2 study, 96 patients with primary/secondary/concurrent CIS of the urinary bladder were randomized to sequential MMC plus BCG or to BCG alone after TUR.
  Intervention: Patients received six weekly instillations of MMC followed by six weekly instillations of BCG or six weekly instillations of BCG, 3 wk rest, and three further weekly instillations of BCG. Complete responders received three weekly maintenance instillations at 6, 12, 18, 24, 30, and 36 mo in accordance with the initial randomization.
  Measurements: End points were complete response (CR) rate at the first control cystoscopy 16-18 wk after start of treatment, disease-free interval, overall survival, and side effects.
  Results and Limitations: Ninety-six patients were randomized, 48 to each treatment group. Ten patients were ineligible, and three did not start treatment. In all randomized patients, CR rates on MMC plus BCG and BCG alone were 70.8% and 66.7%, respectively. In 83 eligible patients who started treatment, CR rates were 75.6% and 73.8%, respectively. Based on a median follow-up of 4.7 yr, 25 patients (52.1%) on MMC plus BCG and 22 patients (45.8%) on BCG alone were disease free. Twelve patients stopped treatment due to toxicity: three during induction (two MMC plus BCG, one BCG) and nine during maintenance (three MMC plus BCG, six BCG).
  Conclusions: In the treatment of patients with CIS, sequential chemoimmunotherapy with MMC plus BCG had acceptable toxicity. CR and disease-free rates were similar to those on BCG alone and to previous publications on sequential chemoimmunotherapy.
  Trial Registration: This study was registered with the US National Cancer Institute clinical trials database (protocol ID: EORTC-30993). http://www.cancer.gov/search/ViewClinicalTrials.aspx?cdrid=68869&version=HealthProfessional&protocolsearchid=7920643.
  
• Editorial Comment
  Carcinoma in situ (CIS) of the bladder is relatively rare, still an aggressive disease and treatment options are scarce. Intravesical BCG has proven to be better than chemotherapy in several trials. The authors sought to clarify if a combination of both would improve the outcome. Interestingly, they used an unusual statistical method and claimed their study a phase 2 noncomparative trial in which randomization was not done for the purpose of making a treatment comparison but to provide a simultaneous screening of the two treatments. Thus, no p values were given for the end points.
  The differences between both treatment arms were small, if any. Side effects were mostly local and not severe. 48.6% of patients had recurred after 5 years on mitomycin C + BCG versus 56.4% on BCG alone.
  The authors conclude correctly that the present study and data from the literature do not support the use of sequential intravesical chemotherapy and BCG of CIS.
  Furthermore, this study design and conduct shows that if applied carefully, interesting alternatives for large-scale randomized trials do exist.

Dr. Andreas Bohle
Professor of Urology
HELIOS Agnes Karll Hospital
Bad Schwartau, Germany
E-mail: boehle@urologie-bad-schwartau.de