Abstract: Six relevant randomised trials were identified with the number of patients randomised in each trial varying from 30 to 341 (total 704). All trials compared gemcitabine to active controls and varied in the reporting of outcomes. One study compared a single post-operative instillation of intravesical gemcitabine with a saline placebo in 341 patients and found no significant difference in the rates of tumour recurrence (28% versus 39%, respectively) or recurrence-free survival (HR (hazard ratio) 0.95, 95% CI 0.64 to1.39, P = 0.77). The rate of progression to invasive disease was greater with gemcitabine (2.4% versus 0.8%). A further trial compared gemcitabine with intravesical mitomycin C and demonstrated that the rates of recurrence (28% versus 39%) and progression (11% versus 18%) were lower with gemcitabine but did not reach statistical significance. The global incidence of adverse events was significantly less with gemcitabine (38.8% versus 72.2%, P = 0.02). Three trials compared gemcitabine with intravesical BCG but a meta-analysis was not possible due to clinical heterogeneity. In untreated patients at intermediate risk of recurrence (primary Ta-T1 no CIS) one trial showed that gemcitabine and BCG were similar with respective recurrence rates of 25% and 30% (P = 0.92) and overall progression equal (P = 1.0). Dysuria (12.5% versus 45%, P < 0.05) and frequency (10% versus 45%, P < 0.001) were significantly less with gemcitabine. In a second trial of high risk patients the recurrence rate was significantly greater with gemcitabine compared to BCG (53.1% and 28.1%, P = 0.04) and the time to recurrence significantly shorter with gemcitabine (25.5 versus 39.4 months, P = 0.042). Finally in a third trial of high risk patients who had failed previous intravesical BCG therapy, gemcitabine was associated with significantly fewer recurrences (52.5% versus 87.5%, P = 0.002) and a longer time to recurrence (3.9 versus 3.1 months, P = 0.9) compared to BCG. Progression rates were similar in both groups (33% versus 37.5%, P = 0.12) with no significant differences in grade 2 or 3 toxicities. The final trial was a marker lesion study which reported greater response rates when intravesical gemcitabine (2 g) was given as three bi-weekly doses (36%) or six weekly doses (40%) compared to a single dose (9%). A single dose immediately following surgery is ineffective based on one study. Gemcitabine may be more active than mitomycin C with a lower toxicity profile. Compared to intravesical BCG therapy, gemcitabine had similar effects in intermediate risk patients, less effective in high risk patient and superior in BCG refractory patients. However, each randomised trial identified represents a different clinical setting in NMIBC and therefore the evidence base is limited. Consequently these data should be interpreted with caution until further corroborative evidence becomes available. The aim of intravesical therapy in NMIBC is to prevent tumour recurrence and progression and to avoid the morbidity associated with cystectomy. Intravesical gemcitabine is a promising drug that may add to the urologist's options in achieving this goal.

Plain-language summary: We searched the published literature for randomised clinical trials that evaluated intravesical gemcitabine in bladder cancer patients and found six trials. The first trial compared a single dose of gemcitabine with a placebo immediately following surgery and found no difference in the rate of tumour recurrence, although there was some concern over the trial methodology. Another study compared gemcitabine with the established anticancer drug mitomycin C and showed that gemcitabine was more active and less toxic. Three trials compared gemcitabine with intravesical BCG. The first enrolled patients with intermediate risk of recurrence and reported gemcitabine was as effective as BCG in preventing tumour recurrence and disease progression but with fewer side-effects. The second trial enrolled untreated patients with a high risk of recurrence and found gemcitabine to be inferior to BCG in preventing recurrence but again was less toxic than BCG. The third trial recruited patients who had previously received BCG but had not responded and this study showed that gemcitabine was superior to BCG in reducing the rate of tumour recurrence. These small numbers of trials indicate that intravesical gemcitabine has activity in delaying tumour recurrence and may have a role in patients who are not suitable for, or who have failed, BCG therapy. The final study suggested that multiple doses of gemcitabine gave better tumour responses compared to a single dose, although the clinical significance of this is unclear.