Gemcitabine for unresectable, advanced or metastatic bladder cancer

When bladder cancer has spread beyond the bladder and is unresectable or metastatic, the possibility of cure is severely diminished. Treatment at this stage of the disease aims to reduce the disease-related symptoms and to improve quality of life. Chemotherapy is the main treatment offered to patients with this condition and one drug that has recently shown activity is gemcitabine. This review aimed to determine the effectiveness and toxicity of gemcitabine by looking at the evidence published from randomised clinical trials. Patients receiving gemcitabine combined with cisplatin had a similar overall survival but less toxicity when compared to the well-established chemotherapeutic treatment of MVAC (methotrexate, vinblastine, doxorubicin, cisplatin). This suggests that gemcitabine plus cisplatin may be considered an alternative chemotherapy schedule to MVAC for advanced bladder cancer but the evidence is limited to one trial only. For patients who have poor kidney function or poor performance status the combination of gemcitabine plus carboplatin may be considered.

Authors' conclusions: 

A review of the published evidence found that one trial reported gemcitabine plus cisplatin had a better safety profile than MVAC and may be considered the first choice for treatment of metastatic bladder cancer. However, the data are limited to one trial only. Patients unable to tolerate cisplatin may benefit from gemcitabine plus carboplatin.

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Background: 

The prognosis for unresectable, locally advanced or metastatic transitional cell carcinoma of the bladder is poor with most patients succumbing to their disease within 2 to 3 years. Clinical management at this stage of the disease is palliative with systemic chemotherapy the main treatment of choice. A number of cytotoxic agents have shown activity in metastatic disease including cisplatin, methotrexate, doxorubicin and vinblastine. However, response rates still need improving and toxicities may sometimes be severe, and so the search for newer agents with improved benefit-to-risk ratios is constantly being pursued. One such agent that shows promise is gemcitabine.

Objectives: 

Evaluate the effectiveness and toxicity of gemcitabine for the management of unresectable, locally advanced or metastatic bladder cancer.

Search strategy: 

A search strategy was developed for MEDLINE to identify randomised trials of gemcitabine for the treatment of unresectable, locally advanced or metastatic bladder cancer. The searches were from 1966 to July 2010.  Other databases searched included EMBASE, CINAHL, the Cochrane Database of Systematic Reviews, LILACS, and the Web of Science®. There were no language or location restrictions.

Selection criteria: 

The titles and abstracts of the combined electronic and hand searching searches were manually screened by two authors to determine if they met the inclusion criteria of this review. Studies were selected if they were randomised, controlled trials or quasi-randomised clinical trials that included gemcitabine in at least one arm of a comparative study.

Data collection and analysis: 

Data extraction was carried out in duplicate by two authors. 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 outcomes measures.

Main results: 

Three randomised trials used gemcitabine plus cisplatin (GCis) as one of the arms in each trial. The first randomised trial compared GCis with MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) and showed no significant difference in overall survival (hazard ratio1.09, 95% CI 0.88 to 1.34, P = 0.443) however the GCis regime had fewer incidences of neutropenic sepsis (1% versus 12%, P = 0.001) and mucositis (1% versus 22%, P = 0.001). A second randomised trial compared GCis to gemcitabine plus carboplatin (GCarbo) and reported an improved, but non-significant 1-year survival rate with GCis (64% versus 37%). A third randomised trial compared GCis with gemcitabine plus cisplatin plus paclitaxel (GCisPac) and again found no significant difference in overall survival (respective medians 49 weeks versus 61 weeks).

One randomised trial evaluated GCarbo against methotrexate plus carboplatin plus vinblastine (MCarboV) in patients "unfit" for cisplatin-based chemotherapy. There were more overall responses (38% versus 20%) and less severe acute toxicities (14% versus 23%) with GCarbo.

In one randomised study evaluating 3-weekly gemcitabine plus paclitaxel (GPac3) versus a 2-weekly regimen overall survival was not significantly different (respective medians 13 and 9 months) however toxicities were worse with GPac3 especially alopecia (76% versus 32%).

A larger trial compared gemcitabine (1 g/m2) (grams per metre squared) plus paclitaxel (175 mg/m2) (milligrams per metre squared) as a 3-weekly schedule for 6 cycles with a 2-weekly maintenance schedule. There was no significant difference in response rates, progression-free survival, disease-specific survival, and overall survival.

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