An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guérin for non-muscle-invasive bladder cancer

Abstract

incidence estimates in the BCG group (p=0.005). There was a weak trend for fewer progressions (p=0.1) and cancer-specific deaths (p=0.2) in the cumulative incidence analysis, as 4 patients versus 10 patients progressed and 4 patients versus 9 patients died from the disease in the BCG group versus the MMC group, respectively. No difference existed in the overall mortality. The study population, however, was too small for conclusive evidence about progression or survival. Conclusions: An intensive intravesical BCG immunotherapy results in a sustained and significant long-term reduction in recurrence in frequently recurrent bladder carcinoma. The relatively low progression rate during the long follow-up suggests that it may be difficult to show significant differences in overall mortality with a substantially larger but otherwise similar study population. Trial Registration: Registration was not considered to be necessary at this stage of the follow-up because the study was initiated as early as 1984 and the last randomisation took place in July 1987, that is, long before the current requirements concerning study registrations were implemented. Editorial CommentThese data show the long-term results of a comparative trial that was initiated in 1984 in patients with intermediate risk bladder cancer. The present publication with roughly 20 years of overall follow-up focuses on the durability of the response and the possible impact of instillation therapy on progression and mortality. The recurrence rate before therapy was 2.54 and 1.99 in the BCG and the MMC arms, respectively, showing more rapidly recurrent patients in the BCG arm. The results are impressive; even with this extremely long follow-up and as few as 45 patients in the MMC arm and 44 patients in the BCG arm there was a statistically sound advantage of BCG therapy with regard to recurrence. Furthermore, this advantage was sustained over time with the probability of recurrence in the BCG arm vs. MMC was 50 vs. 70% after 5 years, 57 vs. 80% after 10 years and 59 vs. 80% after 15 years of follow-up, respectively (p = 0.005). Due to the low numbers of patients, data on progression and mortality should be regarded with caution and lack significance. Still, fewer patients had progression (4 vs. 10 pts.) and died of bladder cancer in the BCG arm than in the MMC trial arm. In retrospective, one might criticize the suboptimal monthly maintenance regimen in the BCG arm and the quite low concentration of MMC used in this trial. Still, these data support other results on the sustained long-term efficacy of BCG. Dr. Andreas Bohle Professor of Urology HELIOS Agnes Karll HospitalBad Schwartau, Germany E-mail: boehle@urologie-bad-schwartau.de An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guérin for non-muscle-invasive bladder cancer Malmström PU, Sylvester RJ, Crawford DE, Friedrich M, Krege S, Rintala E, Solsona E, Di Stasi SM, Witjes JA Uppsala University Hospital, ...

Mathematical model of MMC chemotherapy for non-invasive bladder cancer treatment

“…Despite improved management for decreasing the recurrence rate and prolonging the progression-free interval, the clinical effectiveness of MMC is often limited, as the estimated 5-year recurrence rate varied between 49% to 75%, with a risk of progression to the muscle-invasive stage (38)(39)(40)(41)(42)(43). Moreover, for this treatment modality, the length and frequency of repeat chemotherapy instillations are still controversial (38)(39)(40)(41)(42)(43).…”

“…Despite improved management for decreasing the recurrence rate and prolonging the progression-free interval, the clinical effectiveness of MMC is often limited, as the estimated 5-year recurrence rate varied between 49% to 75%, with a risk of progression to the muscle-invasive stage (38)(39)(40)(41)(42)(43). Moreover, for this treatment modality, the length and frequency of repeat chemotherapy instillations are still controversial (38)(39)(40)(41)(42)(43). Clinicians emphasize that the inability to define drug dosage, treatment frequency, and duration plays a significant role in the failure of MMC treatment, highlighting the absence of an ideal MMC regimen as a key issue (18,44).…”

“…Finally, MMC is currently considered one of the most effective chemotherapy treatments after TUR to prevent NMIBC. In this paper, we propose theoretical explanation for the fact that still, a substantial percentage of patients fail the treatment (38)(39)(40)(41)(42)(43). It is possible that treatment failure results from tumor size, as described in the literature (86,87) and shown in Figure 5, or from an improper selection of the drug dose, m 0 , that is implicitly reflected in the drug instillation rate, m, of the model.…”