In people with tumors of the superficial layer of the urinary bladder (namely non-muscle invasive bladder cancer [NMIBC]), how does gemcitabine that is put into the bladder compare to other medicines after the tumor has been removed?
NMIBC can be taken out of the bladder using small instruments and a light source (called transurethral surgery). However, these tumors often come back (recurrence) with an aggressive feature such as spread into the deep layers of the bladder. To prevent this, we can put various medicines into the bladder. In this review, we wanted to know whether gemcitabine (a chemotherapy medication) was better or worse than other medicines.
The evidence is current to 11 September 2020. We included only studies in which chance determined whether people received gemcitabine or other medicines. We found seven studies with 1222 participants. Two studies compared gemcitabine versus saline. One study compared gemcitabine versus mitomycin (a chemotherapy medication). Three studies compared gemcitabine versus BCG (Bacillus Calmette-Guérin; a medicine used to help keep cancer from growing). One study compared gemcitabine versus one-third dose BCG.
Gemcitabine may reduce the risk of recurrence over time, but may have a similar effect on progression (cancer getting worse) and severe unwanted effects compared to saline. Gemcitabine may prevent recurrence and progression compared to mitomycin. We are very unsure about the effect of gemcitabine on the severe unwanted effects compared to mitomycin. In people who had a high-risk NMIBC with the cancer coming back after one course of treatment with BCG, gemcitabine may cause less tumor recurrence and progression compared to giving BCG again. We are very unsure about the effect of gemcitabine on the severe unwanted effects compared to BCG retreatment. The review also includes information on how gemcitabine compares to BCG and how it compares to one-third dose BCG.
Reliability of the evidence
The reliability of the evidence was low or very low for most of the treatments we compared, meaning that we were often uncertain about whether the findings were true. Further research will likely change these findings.
Based on findings of this review, gemcitabine may have a more favorable impact on recurrence and progression-free survival than mitomycin but we are very uncertain as to how major adverse events compare. The same is true when comparing gemcitabine to BCG in individuals with high risk disease who have previously failed BCG. The underlying low- to very low-certainty evidence indicates that our confidence in these results is limited; the true effects may be substantially different from these findings; therefore, better quality studies are needed.
It remains unclear whether people with non-muscle invasive bladder cancer (NMIBC) benefit from intravesical gemcitabine compared to other agents in the primary or recurrent setting following transurethral resection of a bladder tumor. This is an update of a Cochrane Review first published in 2012. Since that time, several randomized controlled trials (RCTs) have been reported, making this update relevant.
To assess the comparative effectiveness and toxicity of intravesical gemcitabine instillation for NMIBC.
We performed a comprehensive literature search of the Cochrane Library, MEDLINE, Embase, four other databases, trial registries, and conference proceedings to 11 September 2020, with no restrictions on the language or status of publication.
We included RCTs in which participants received intravesical gemcitabine for primary or recurrent NMIBC.
Two review authors independently assessed the included studies and extracted data for the primary outcomes: time to recurrence, time to progression, grade III to V adverse events determined by the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0), and the secondary outcomes: time to death from bladder cancer, time to death from any cause, grade I or II adverse events determined by the CTCAE v5.0 and disease-specific quality of life. We performed statistical analyses using a random-effects model and rated the certainty of the evidence using GRADE.
We included seven studies with 1222 participants with NMIBC across five comparisons. This abstract focuses on the primary outcomes of the three most clinically relevant comparisons.
1. Gemcitabine versus saline: based on two years' to four years' follow-up, gemcitabine may reduce the risk of recurrence over time compared to saline (39% versus 47% recurrence rate, hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.54 to 1.09; studies = 2, participants = 734; I2 = 49%; low-certainty evidence), but the CI included the possibility of no effect. Gemcitabine may result in little to no difference in the risk of progression over time compared to saline (4.6% versus 4.8% progression rate, HR 0.96, 95% CI 0.19 to 4.71; studies = 2, participants = 654; I2 = 53%; low-certainty evidence). Gemcitabine may result in little to no difference in the CTCAE grade III to V adverse events compared to saline (5.9% versus 4.7% adverse events rate, risk ratio [RR] 1.26, 95% CI 0.58 to 2.75; studies = 2, participants = 668; I2 = 24%; low-certainty evidence).
2. Gemcitabine versus mitomycin: based on three years' follow-up (studies = 1, participants = 109), gemcitabine may reduce the risk of recurrence over time compared to mitomycin (17% versus 40% recurrence rate, HR 0.36, 95% CI 0.19 to 0.69; low-certainty evidence). Gemcitabine may reduce the risk of progression over time compared to mitomycin (11% versus 18% progression rate, HR 0.57, 95% CI 0.32 to 1.01; low-certainty evidence), but the CI included the possibility of no effect. We are very uncertain about the effect of gemcitabine on the CTCAE grade III to V adverse events compared to mitomycin (RR 0.51, 95% CI 0.13 to 1.93; very low-certainty evidence). The analysis was only based on recurrent NMIBC.
3. Gemcitabine versus Bacillus Calmette-Guérin (BCG) for recurrent (one-course BCG failure) high-risk NMIBC: based on 6 months' to 22 months' follow-up (studies = 1, participants = 80), gemcitabine may reduce the risk of recurrence compared to BCG (41% versus 97% recurrence rate, HR 0.15, 95% CI 0.09 to 0.26; low-certainty evidence) and progression over time (16% versus 33% progression rate, HR 0.45, 95% CI 0.27 to 0.76; low-certainty evidence). We are very uncertain about the effect of gemcitabine on the CTCAE grade III to V adverse events compared to BCG (RR 1.00, 95% CI 0.21 to 4.66; very low-certainty evidence).
In addition, the review provides information on the comparison of gemcitabine versus BCG and gemcitabine versus one-third dose BCG.