Comparisons of Intravesical Treatments with Mitomycin C, Gemcitabine, and Docetaxel for Recurrence and Progression of Non-Muscle Invasive Bladder Cancer: Updated Systematic Review and Meta-Analysis

Abstract

Background: Non-muscle-invasive bladder cancer (NMIBC) comprises about 75% of all bladder cancers. Although NMIBC is treatable, it poses significant costs and burdens to patients due to high recurrence rates. We conducted an updated meta-analysis of studies that evaluated the efficacy of and outcomes after treatment with mitomycin C (MMC), gemcitabine (GEM), and docetaxel (DOCE) for NMIBC recurrence and progression. Methods: We searched the PubMed and Cochrane databases for observational cohort studies and randomized clinical trials (RCT) conducted between 2009 and 2022 that assessed the efficacy of GEM, DOCE, or MMC, alone or in combination, regarding NMIBC outcomes. A total of 49 studies that met the inclusion criteria were reviewed for their quality, sample size, outcomes, and potential for bias, and relevant data were extracted for the meta-analysis. Separate meta-analyses were performed to assess the risks of recurrence or progression when comparing GEM/DOCE or MMC vs. other treatments. Study heterogeneity was assessed by I² statistics. Results: Among 31 studies comparing GEM or MMC to other treatments for NMIBC recurrence, there were statistically significant risk reductions of 24% for GEM (pooled relative risk (RR) of 0.76; 95% confidence interval (CI) 0.64-0.87) and 37% for MMC (pooled RR = 0.63; 95% CI 0.58-0.68). Recurrence-free survival (RFS) for GEM or MMC alone was 69.5% (95% CI 66.6-72.3%) and 67.2% (95% CI 66.2-68.2%), respectively. Studies assessing the combination of treatments had a pooled RFS of 44.6% (95% CI 40.4-48.7%). Fewer studies examined the risk of NMIBC progression, with large variability and inconclusive results across them. Conclusions: Our findings corroborate recent guidelines indicating that both GEM and MMC are effective treatments that reduce tumor recurrence and improve survival of NMIBC, although with large variability across the studies. Fewer studies evaluated DOCE treatment, with inconclusive results. Women and minorities were generally underrepresented, raising concerns about the generalizability of the findings and highlighting the importance of including a broader patient population in future RCTs.

Keywords: docetaxel (DOCE); gemcitabine (GEM); meta-analysis; mitomycin C (MMC); non-muscle-invasive bladder cancer (NMIBC); progression; recurrence; systematic review.

Figure 1

Flowchart of study selection for this updated systematic review and meta-analysis.

Figure 2

Forest plot of studies comparing the efficacy of gemcitabine (GEM) and/or docetaxel (DOCE) vs. other treatments in relation to the risks of recurrence (a) and of high-grade disease persistence and progression (b) for non-muscle-invasive bladder cancer (NMIBC). (a) NMIBC recurrence. Summary pooled RR = 0.76 (95% CI 0.64–0.87)—favors gemcitabine (GEM). Overall heterogeneity: I² = 80.4% (p < 0.0001). Included studies comparing GEM alone (n=13) or a combination of GEM/BCG (n = 1) or GEM/DOCE (n = 1) to other treatments. Studies were weighted by their sample size; studies with a larger number of patients, indicated by larger grey boxes, received greater weights. (b) High-grade NMIBC persistence and progression. Summary pooled RR = 0.60 (95% CI 0.22–0.97)—favors GEM. Overall heterogeneity: I² = 57% (p = 0.03). Included studies comparing GEM or GEM/BCG to other treatments that reported risks of progression or high-grade disease persistence. Bohle et al.’s RCT study [24] was removed from this analysis due to an unstable RR of 3.0 with a very large 95% CI (0.32–28.45).

Figure 2

Forest plot of studies comparing the efficacy of gemcitabine (GEM) and/or docetaxel (DOCE) vs. other treatments in relation to the risks of recurrence (a) and of high-grade disease persistence and progression (b) for non-muscle-invasive bladder cancer (NMIBC). (a) NMIBC recurrence. Summary pooled RR = 0.76 (95% CI 0.64–0.87)—favors gemcitabine (GEM). Overall heterogeneity: I² = 80.4% (p < 0.0001). Included studies comparing GEM alone (n=13) or a combination of GEM/BCG (n = 1) or GEM/DOCE (n = 1) to other treatments. Studies were weighted by their sample size; studies with a larger number of patients, indicated by larger grey boxes, received greater weights. (b) High-grade NMIBC persistence and progression. Summary pooled RR = 0.60 (95% CI 0.22–0.97)—favors GEM. Overall heterogeneity: I² = 57% (p = 0.03). Included studies comparing GEM or GEM/BCG to other treatments that reported risks of progression or high-grade disease persistence. Bohle et al.’s RCT study [24] was removed from this analysis due to an unstable RR of 3.0 with a very large 95% CI (0.32–28.45).

Figure 3

Forest plot of studies comparing the efficacy of mitomycin C (MMC) vs. other treatments in relation to the risks of recurrence (a) and of high-grade disease persistence and progression (b) for non-muscle-invasive bladder cancer (NMIBC). (a) NMIBC recurrence. Summary pooled RR = 0.63 (95% CI 0.58–0.68)—favors MMC. Overall heterogeneity: I² = 78% (p < 0.0001). Studies included comparing MMC alone or MMC and BCG therapy to other treatments. Studies with a larger sample size (i.e., number of patients), as indicated by larger grey boxes, received greater weight. This meta-analysis was highly influenced by a large study [49] that contributed 61% of all weight. (b) High-grade NMIBC persistence and progression: summary pooled RR = 1.19 (95% CI 0.30–2.07). Overall heterogeneity: I² = 0% (p = 0.58).

Figure 4

Recurrence-free survival (RFS) during follow-up of NMIBC patients receiving either gemcitabine (GEM) alone (a), mitomycin C (MMC) alone (b), or the combination of treatments (c). (a) GEM treatment: summary pooled RFS = 69.5% (95% CI 66.6–72.3%). Overall heterogeneity: I² = 92% (p < 0.0001). Studies included evaluating RFS among patients receiving GEM treatment only. Studies with a larger number of patients, as indicated by larger grey boxes, received greater weights. (b) MMC treatment: summary pooled RFS = 67.2% (95% CI 66.2–68.2%). Overall heterogeneity: I² = 86.6% (p < 0.0001). Studies included evaluating RFS among patients receiving MMC alone or MMC/BCG treatment. (c) Combination of treatments: summary pooled RFS = 44.6% (95% CI 40.4–48.7%). Overall heterogeneity: I² = 56% (p = 0.033). Studies included evaluating RFS among NMIBC patients receiving various combinations of treatments (e.g., GEM/BCG, GEM/MMC or GEM/DOCE). Studies with a larger number of patients, as indicated by larger grey boxes, received greater weights.

Figure 4

Recurrence-free survival (RFS) during follow-up of NMIBC patients receiving either gemcitabine (GEM) alone (a), mitomycin C (MMC) alone (b), or the combination of treatments (c). (a) GEM treatment: summary pooled RFS = 69.5% (95% CI 66.6–72.3%). Overall heterogeneity: I² = 92% (p < 0.0001). Studies included evaluating RFS among patients receiving GEM treatment only. Studies with a larger number of patients, as indicated by larger grey boxes, received greater weights. (b) MMC treatment: summary pooled RFS = 67.2% (95% CI 66.2–68.2%). Overall heterogeneity: I² = 86.6% (p < 0.0001). Studies included evaluating RFS among patients receiving MMC alone or MMC/BCG treatment. (c) Combination of treatments: summary pooled RFS = 44.6% (95% CI 40.4–48.7%). Overall heterogeneity: I² = 56% (p = 0.033). Studies included evaluating RFS among NMIBC patients receiving various combinations of treatments (e.g., GEM/BCG, GEM/MMC or GEM/DOCE). Studies with a larger number of patients, as indicated by larger grey boxes, received greater weights.

Figure 4

Recurrence-free survival (RFS) during follow-up of NMIBC patients receiving either gemcitabine (GEM) alone (a), mitomycin C (MMC) alone (b), or the combination of treatments (c). (a) GEM treatment: summary pooled RFS = 69.5% (95% CI 66.6–72.3%). Overall heterogeneity: I² = 92% (p < 0.0001). Studies included evaluating RFS among patients receiving GEM treatment only. Studies with a larger number of patients, as indicated by larger grey boxes, received greater weights. (b) MMC treatment: summary pooled RFS = 67.2% (95% CI 66.2–68.2%). Overall heterogeneity: I² = 86.6% (p < 0.0001). Studies included evaluating RFS among patients receiving MMC alone or MMC/BCG treatment. (c) Combination of treatments: summary pooled RFS = 44.6% (95% CI 40.4–48.7%). Overall heterogeneity: I² = 56% (p = 0.033). Studies included evaluating RFS among NMIBC patients receiving various combinations of treatments (e.g., GEM/BCG, GEM/MMC or GEM/DOCE). Studies with a larger number of patients, as indicated by larger grey boxes, received greater weights.