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ABSTRACT: • 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.
BJU International 02/2012; 109(4):496-505. · 2.84 Impact Factor
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ABSTRACT: 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.
To evaluate the effectiveness and toxicity of intravesical gemcitabine in preventing tumour recurrence and progression in non-muscle invasive bladder cancer (NMIBC).
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.
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.
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.
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.
Cochrane database of systematic reviews (Online) 01/2012; 1:CD009294. · 5.72 Impact Factor
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ABSTRACT: • To systematically review the literature on gemcitabine chemotherapy for advanced or metastatic bladder cancer.
• The Medical Literature Analysis and Retrieval System Onlinedatabase (MEDLINE), the Excerpta Medicadatabase (EMBASE), the Cumulative Index to Nursing and Allied Health Literature database(CIHNAL), the Cochrane database of randomized trials, the Literatura Latino-Americana e do Caribe emCiências da Saúdedatabase (LILACS), and Web of Science were searched to identify trials of gemcitabine for metastatic bladder cancer. Also searched were international guidelines on metastatic prostate cancer, trial registries, and recent systematic reviews. Data on trial design, survival, tumour response and toxicity outcomes were extracted from relevant studies.
• This review identified six randomized trials of combined chemotherapy with gemcitabine for the management of unresectable, locally advanced or metastatic bladder cancer. • One trial compared gemcitabine plus cisplatin (GCis) with methotrexate/vinblastine/doxorubicin/cisplatin(MVAC) and found no difference in overall survival (OS; hazard ratio 1.09) but a better safety profile with GCis, which was suggested as the treatment of choice. • A second trial evaluated GCis against gemcitabine plus carboplatin (GCarbo) and reported similar median OS (12.8 vs 9.8 months), disease progression (8.3 vs 7.3 months) and tumour response rates (66% vs 56%) for the two patient groups. • A third trial compared GCis with GCis plus paclitaxel (GCisPac) and showed no significant difference in median OS (12.3 vs 15.3 months) and response rates (44% vs 43%) but greater toxicity with GCisPac. • A fourth trial assessed GCarbo against methotrexate plus carboplatin plus vinblastine in patients unfit for cisplatin-based chemotherapy and found similar tumour response rates for each regime (38% vs 20%) but the triplet regime was more toxic. • Two other randomized studies compared a 2-weekly maintenance regime of gemcitabine plus paclitaxel with a 3-weelky regime given for a maximum of six cycles and found that the maintenance schedule did not confer any additional survival benefit. • In all, 53 observational studies of gemcitabine chemotherapy were identified that varied considerably in the drug combinations used and schedules. Overall response rates (17-78%) and median OS (6.4-24.0 months) were variable with no combination being clearly superior.
• Gemcitabine combined chemotherapy is active in the management of metastatic bladder cancer. • GCis may be considered an alternative regime to MVAC. • GCarbo should be considered for patients unfit for cisplatin-based therapy.
BJU International 07/2011; 108(2):168-79. · 2.84 Impact Factor
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ABSTRACT: 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.
Evaluate the effectiveness and toxicity of gemcitabine for the management of unresectable, locally advanced or metastatic bladder cancer.
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.
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 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.
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/m(2)) (grams per metre squared) plus paclitaxel (175 mg/m(2)) (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.
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.
Cochrane database of systematic reviews (Online) 01/2011; · 5.72 Impact Factor
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ABSTRACT: Prostate cancer mainly affects elderly men, and its incidence has steadily increased over the last decade. The management of this disease is replete with controversy. In men with advanced, metastatic prostate cancer, hormone therapy is almost universally accepted as the initial treatment of choice and produces good responses in most patients. However, many patients will relapse and become resistant to further hormone manipulation; the outlook for these patients is poor. Many have disease extending to the skeleton, which is associated with severe pain. Therapies for these men include chemotherapy, bisphosphonates, palliative radiotherapy, and radioisotopes. Systemic chemotherapy has been evaluated in men with hormone-refractory prostate cancer (HRPC) for many years, with disappointing results. However, more recent studies with newer agents have shown encouraging results. There is therefore a need to explore the value of chemotherapy in this disease.
The present review aims to assess the role of chemotherapy in men with metastatic HRPC. The major outcome was overall survival. Secondary objectives include the effect of chemotherapy on pain relief, prostate-specific antigen (PSA) response, quality of life, and treatment-related toxicity.
Trials were identified by searching electronic databases, such as MEDLINE, and handsearching of relevant journals and conference proceedings. There was no restriction of language or location.
Only published randomised trials of chemotherapy in HRPC patients were eligible for inclusion in this review. Randomised comparisons of different chemotherapeutic regimens, chemotherapy versus best standard of care or placebo, were relevant to this review. Randomised, dose-escalation studies were not included in this review.
Data extraction tables were designed specifically for this review to aid data collection. Data from relevant studies were extracted and included information on trial design, participants, and outcomes. Trial quality was also assessed using a scoring system for randomisation, blinding, and description of patient withdrawal.
Out of 107 randomised trials of chemotherapy in advanced prostate cancer identified by the search strategy, 47 were included in this review and represented 6929 patients with HRPC. Only two trials compared the same chemotherapeutic interventions and therefore a meta-analysis was considered inappropriate. The quality of some trials was poor because of poor reporting, low-patient recruitment, or poor trial design. For clarity, trials were categorised according to the major drug used, but this was not a definitive grouping, since many trials used several agents and would be eligible for inclusion in a number of categories. Drug categories included estramustine, 5-fluorouracil, cyclophosphamide, doxorubicin, mitoxantrone, and docetaxel. Only studies using docetaxel reported a significant improvement in overall survival compared to best standard of care, although the increase was small (< 2.5 months). The mean percentage of patients achieving at least a 50% reduction in PSA compared to baseline was as follows: estramustine 48%; 5-fluorouracil 20%; doxorubicin 50% (one study only); mitoxantrone 33%; and docetaxel 52%. Pain relief was reported in 35% to 76% of patients receiving either single agents or combination regimens. A three weekly regime of docetaxel significantly improved pain relief compared to mitoxantrone plus prednisone (the latter regimen approved as standard therapy for HRPC in the USA). All chemotherapeutics, either as single agents or in combination, were associated with toxicity; the major ones being myelosuppression, gastrointestinal toxicity, cardiac toxicity, neuropathy, and alopecia. Quality of life was significantly improved with docetaxel compared to mitoxantrone plus prednisone.
Patients with HRPC have not traditionally been offered chemotherapy as a routine treatment because of treatment-related toxicity and poor responses. Recent data from randomised studies, in particular those using docetaxel, have provided encouraging improvements in overall survival, palliation of symptoms, and improvements in quality of life. Chemotherapy should be considered as a treatment option for patients with HRPC. However, patients should make an informed decision based on the risks and benefits of chemotherapy.
Cochrane database of systematic reviews (Online) 02/2006; · 5.72 Impact Factor
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