Intravesical gemcitabine therapy for non-muscle invasive bladder cancer (NMIBC): a systematic review.

• 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.

Management of venous thromboembolism in patients with advanced cancer: a systematic review and meta-analysis.

Venous thromboembolism is common in patients with cancer. However, no management guidelines exist for venous thromboembolism specific to patients with advanced progressive cancer. To help develop recommendations for practice, we have done a comprehensive review of anticoagulation treatment in patients with cancer, with particular focus on studies that included patients with advanced disease. Data from 19 publications, including randomised, prospective, and retrospective studies suggest that: long-term full-dose low-molecular-weight heparin (LMWH) is more effective than warfarin in the secondary prophylaxis of venous thromboembolism in patients with cancer of any stage, performance status, or prognosis; warfarin should not be used in patients with advancing progressive disease; and in patients at high risk of bleeding, full-dose LMWH for 7 days followed by a long-term decreased fixed dose long term can be considered. The optimum treatment duration is unclear, but because the prothrombotic tendency will persist in patients with advanced cancer, indefinite treatment is generally recommended. For patients with contraindications to anticoagulation, inferior-vena-caval filters can be considered, but their use needs careful patient selection. Ultimately, the decision to initiate, continue, and stop anticoagulation will need to be made on an individual basis, guided by the available evidence, the patient's circumstances, and their informed preferences.

Intravesical therapy for superficial bladder cancer: a systematic review of randomised trials and meta-analyses.

BACKGROUND: In 2002 there were estimated to be 357,000 new cases of bladder cancer worldwide and 145,000 deaths making bladder cancer the 9th most common malignancy globally. At diagnosis, 60-80% of tumours are superficial and endoscopic resection is the initial treatment for this disease. In patients with low, medium or high risk disease, about 20%, 40% and 90%, respectively, will develop tumour recurrence. To delay or prevent recurrence, intravesical therapy is routinely used. Commonly used intravesical agents include immunotherapy with BCG and chemotherapy with cytotoxics such as Mitomycin C, Adriamycin, Epirubicin and Gemcitabine. However, controversy exists as to which agent and schedule should be used. METHODS: An overarching search of the literature was used to identify relevant studies to assess the clinical benefit of intravesical therapy and provide clinical guidance in a comprehensive systematic review of randomised trials and meta-analyses of intravesical therapy for superficial bladder cancer. Findings and interpretation the search identified over 80 randomised trials and 11 meta-analyses. The extensive evidence suggests that an immediate post-operative instillation of a chemotherapeutic agent, such as Mitomycin C or Epirubicin, is effective in reducing tumour recurrence. In intermediate or high risk patients, further intravesical induction and maintenance therapy with BCG is recommended. CONCLUSION: Intravesical chemotherapy with either Mitomycin C or Epirubicin would be an option for those patients failing or who are unsuitable for BCG therapy. Intravesical BCG is superior to chemotherapy in terms of complete response and disease-free survival. However, there is no conclusive evidence that one agent is superior in terms of overall survival.

Should the Gleason grading system for prostate cancer be modified to account for high-grade tertiary components? A systematic review and meta-analysis.

The Gleason system for grading prostate cancer assigns a score on the basis of the most prevalent and second most prevalent grade. Several studies have investigated the clinical significance of a tertiary grade in radical prostatectomy samples. A systematic search of the published work identified seven studies that reported the prognostic value of a tertiary Gleason grade. Three studies correlated the presence of a tertiary grade with pathological stage, and six with prostate-specific antigen recurrence or clinical progression. In the small number of studies available, the frequency of a tertiary grade was consistently higher in samples characterised with pathological variables of poor outcome, such as extra-prostatic extension and positive surgical margins, but not lymph-node metastases. In five studies the presence of a tertiary grade increased the risk of prostate-specific antigen recurrence after radical prostatectomy by a factor of 2.5. However, modification of the Gleason score to include a tertiary grade in Gleason 4+3 tumours might overestimate the risk of seminal-vesicle or lymph-node invasion. This systematic review has established the association of a tertiary grade with poorer outcome than that associated with no tertiary grade. A tertiary grade should, therefore, be included in the pathological reporting of prostate cancer and be considered in the interpretation and design of clinical trials. However, all studies assessed for this review were retrospective, potentially affected by selection bias, and based on radical prostatectomy samples or transurethral resections rather than biopsy samples. Therefore, more evidence is needed to warrant the adaptation of the Gleason system to account for the presence of a tertiary grade, especially when scoring prostatic biopsies and applying predictive algorithms.