title: Intravesical gemcitabine for non-muscle invasive bladder cancer.
abstract: BACKGROUND
  Intravesical immunotherapy or chemotherapy for non-muscle invasive bladder cancer is a well established treatment for preventing or delaying tumour recurrence following 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.
  
  
  OBJECTIVE
  To evaluate the effectiveness and toxicity of intravesical gemcitabine in preventing tumour recurrence and progression in non-muscle invasive bladder cancer (NMIBC).
  
  
  METHODS
  A search strategy was developed for MEDLINE to identify randomised trials of intravesical gemcitabine for the treatment of non-muscle invasive bladder cancer. The searches were from 1947 to May 2011. Other databases searched included EMBASE, CINAHL, the Cochrane Central Register of Controlled Trials, LILACS, SCOPUS, BNI, Biomed Central, Web of Science and BIOSIS. Handsearching of meeting proceedings, international guidelines and trial registries was also carried out.
  
  
  METHODS
  The titles and abstracts of the combined electronic and handsearching were manually screened by three authors independently to determine if they met the inclusion criteria for this review. Studies were selected if they were randomised, controlled trials or quasi-randomised clinical trials that included intravesical gemcitabine in at least one arm of a comparative study.
  
  
  METHODS
  Data extraction was carried out by three reviewers. The information retrieved included the author's details, the study design, the characteristics of the recruited patients, details of the interventions and data relating to the primary, and secondary outcome measures.
  
  
  RESULTS
  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%).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cochrane ProstaticDiseases and Urological Cancers Unit, Research Department, Velindre NHS Trust, Cardiff, UK.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Jones
authors.forename: Anne
authors.initials: A
authors.lastname: Cleves
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Wilt
authors.forename: Malcolm
authors.initials: M
authors.lastname: Mason
authors.forename: Howard G
authors.initials: HG
authors.lastname: Kynaston
authors.forename: Mike
authors.initials: M
authors.lastname: Shelley
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000283:Administration, Intravesical; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects; D001500:BCG Vaccine / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D018450:Disease Progression; D004334:Drug Administration Schedule; D006801:Humans; D016685:Mitomycin / Q000008:administration & dosage / Q000009:adverse effects; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control; D016032:Randomized Controlled Trials as Topic; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D000093542:Gemcitabine
chemical_list: D000276:Adjuvants, Immunologic; D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D001500:BCG Vaccine; D003841:Deoxycytidine; D016685:Mitomycin; D000093542:Gemcitabine