Intravesical gemcitabine therapy for non‐muscle invasive bladder cancer (NMIBC): a systematic review
Authors: Shelley Mike D. , Jones Gabriel , Cleves Anne , Wilt Timothy J. , Mason Malcolm D. , Kynaston Howard G. 
Published: February 2012

What's known on the subject? and What does the study add?

The standard treatment for non‐muscle invasive bladder (NMIBC) is transurethral resection followed by intravesical therapy. Intravesical agents, e.g. bacille Calmette‐Guérin (BCG) or mitomycin C (MMC), have activity in delaying and reducing the incidence of tumour recurrence after surgery but have significant side‐effects and are not effective in all patients. Clinical data suggests that gemcitabine has activity in this disease in terms of tumour response and is less toxic, and warrants further study.

This systematic review comprehensively presents the available clinical evidence on intravesical gemcitabine for NMIBC. The limited data from randomised trials suggest that gemcitabine may have role in intermediate‐risk patients, as an alternative to MMC, and in high‐risk, BCG‐refractory patients. Data from observational studies indicate that minimal systemic absorption occurs with intravesical administration and that gemcitabine is active in reducing tumour recurrence.

Intravesical immunotherapy or chemotherapy for non‐muscle invasive bladder cancer is a well‐established treatment for preventing or delaying tumour recurrence after tumour resection. However, up to 70% of patients may fail and new intravesical agents with improved effectiveness are needed. Gemcitabine is a relatively new anticancer drug that has shown activity against bladder cancer.

To systematically review the literature on the effectiveness and toxicity of intravesical gemcitabine for non‐muscle invasive bladder cancer (NMIBC).

MEDLINE, EMBASE, CINAHL, the Cochrane database of systematic reviews, LILACS, SCOPUS, BNI, Biomed Central, Web of Science and BIOSIS were searched to identify trials of intravesical gemcitabine for the treatment of NMIBC. Also searched were meeting proceedings, international guidelines and trial registries. Data on authors, study design, patient characteristics, interventions and outcome data relating to tumour recurrence, disease progression, survival and adverse events were extracted from relevant studies.

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.

The first was a marker lesion study which reported greater tumour response rates when intravesical gemcitabine (2 g) was given as three bi‐weekly doses (36%) or six weekly doses (40%) compared with a single dose (9%).

One study compared a single postoperative instillation of intravesical gemcitabine with a saline placebo in 341 patients and found no significant difference in the rates of tumour recurrence (28% vs 39%, respectively) or recurrence‐free survival (hazard ratio 0.95, 95% confidence interval 0.64–1.39, P= 0.77). The rate of progression to invasive disease was greater with gemcitabine (2.4% vs 0.8%).

A further trial compared gemcitabine with intravesical mitomycin C (MMC) and reported that the rates of recurrence (28% vs 39%) and progression (11% vs 18%) were lower with gemcitabine but did not reach statistical significance. The overall incidence of adverse events was significantly less with gemcitabine (38.8% vs 72.2%, P= 0.02).

Three trials compared gemcitabine with intravesical bacille Calmette‐Guérin (BCG) but a meta‐analysis was not possible due to clinical heterogeneity.

In untreated patients at intermediate risk of recurrence (primary Ta–T1, no carcinoma in situ) one trial showed that gemcitabine and BCG were similar with respective recurrence rates of 25% and 30% (P= 0.92) and overall progression equal. Dysuria (12.5% vs 45%, P < 0.05) and frequency (10% vs 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 with BCG (53.1% vs 28.1%, P= 0.04%) and the time to recurrence significantly shorter with gemcitabine (25.5 vs 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% vs 87.5%, P= 0.002) and a longer time to recurrence (3.9 vs 3.1 months, P= 0.9) compared with BCG. Progression rates were similar in both groups (33% vs 37.5%, P= 0.12) with no significant differences in grade 2 or 3 toxicities.

The data from several observational studies confirm the pharmacology of gemcitabine as an intravesical agent whilst others report the activity of gemcitabine in terms of tumour recurrence. However, these studies are inherently biased and these data should be interpreted appropriately.

In conclusion a single study suggests that in NMIBC multiple doses of intravesical gemcitabine reduce tumour recurrences to a greater extent than a single dose.

In contrast, a single dose immediately after surgery is ineffective based on one study. Gemcitabine may be more active than MMC with a lower toxicity profile.

Compared with intravesical BCG therapy, gemcitabine had similar effects in intermediate‐risk patients, less effective in high‐risk patients 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.

Intravesical gemcitabine is a promising drug that may add to the urologist's options in treating patients with NMIBC.