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Vinflunine recently obtained approval by EMEA as second line chemotherapy in metastatic urothelial cancer. Since it is the first time a drug is registered in this specific indication it may lead to a change in hospital and general clinical practice
Transitional cell carcinoma of the urothelial tract (TCCU), arising either in the bladder or the ureter or the renal pelvis accounts for approximately 49 000 deaths a year in Europe.
The recommended standard of care for metastatic TCCU is cisplatin based chemotherapy, allowing a median overall survival in the range of 12-15 months., However, the majority of patients with advanced urothelial cancer are elderly, have a past history of tabacco smoking and they may have an obstructive renal function impairement. Half of the patients do not present with a renal function and a performance status allowing cisplatin administration. Carboplatin is then usually administered instead of cisplatin although it has been proved inferior, with an overall survival in the range of 9-10 months. The evaluation of newer generation cytotoxics was generally conducted in the salvage setting, many drugs demonstrating objective response rates with no evidence of improved survival or quality of life. Considering that the population of patients with metastatic TCCU eligible for a second line chemotherapy was scarce, research then focused on including these new drugs in first line regimens which would be a combination of cisplatin and one or 2 new drugs. While this strategy led to regimens which could be proved less toxic than the reference combination of doxorubicin, methotrexate, vinblastin and cisplatin (MVAC),  it always failed to demonstrate more efficacy (Figure I).,  Unfortunatly, the median overall survival of these patients has remained unchanged for the last two decades and is mosly related to the initial prognostic factors. It is in this context that vinflunine was developed as a second line chemotherapy.
Two phase II studies of vinflunine in metastatic TCCU were performed, yielding overall response rates of 18% (95% CI: 8.4-30.9%), and 15% (95% confidence interval, 9%-21%) and median survivals of 9 months and 8.2 months respectively.,  These results were not dramatically different from those of other agents like ifosfamide, docetaxel or pemetrexed.,,However, most phase II series are small with substantial heterogeneity in terms of eligibility criteria, definition of second line therapy and patient’s characteristics precluding any formal assumption of the actual benefit provided by the study drugs. In the setting of development of the new drug vinflunine, a large multicentric randomised study was designed to show a survival benefit of 2 months in patients with metastatic TCCU receiving vinflunine and best supportive care versus best supportive care alone after first line chemotherapy. This trial was designed to include patients previously treated for a metastatic disease but not patients who had received peri-operative chemotherapy (before or after surgery) at a stage of disease supposed to be potentially curable. Indeed, the response rates were shown to be noticeably different in these 2 groups of patients in previous studies o new drugs in TCCU patients in a salvage setting. The vinflunine study was performed in 370 patients and showed a statistically non-significant 2-month survival advantage favouring the vinflunine arm of treatment (6.9 versus 4.6 months). If the results of the study were restricted to the 357 eligible patients, excluding 13 patients who should not have been included in the study since they had received first line chemotherapy perioperatively but not for a metastatic disease, the results became statistically significant. Other criteria of evaluation of the study, which were objective response rates, disease control and its duration and progression free survival significantly favoured patients treated with vinflunine. Toxicity of vinflunine was considered acceptable. It was mostly haematological but also included nausea, vomiting, constipation, abdominal pain and fatigue. Quality of life was assessed and treatment with vinflunine did not lead to a decrease in health related quality of life when compared to best supportive care alone.
From the perspective of a practicing clinician, it is reasonable to ask whether these results will alter the current management of patients with metastatic TCCU. Will the results of this study establish the role of second line therapy? If so, will vinflunine be a standard of care in this setting? Both questions are debatable.
Despite the lack of demonstrable progress in the management of advanced TCCU, more patients are treated earlier in the disease course in the perioperative or metastatic setting. Despite the lack of evidence of clinical benefit, in countries where health insurance regulations allow this approach, many clinicians offerfirst line or second line cytotoxic chemotherapy with the goal of delaying or improving disease related symptoms. The best supportive care option is then reserved
for unfit patients. The results of this study may be interpreted
as providing justification for this approach but there is no evidence that vinflunine is superior to other antineoplastic agents with similar activity in phase II salvage studies. However, the interest in pursuing additional comparative studies of other agents versus vinflunine is impaired by the evidence of our current inability to significantly impact on these patients outcomes with any type of conventional chemotherapy.
In countries where second line chemotherapy was not available so far for patients with metastatic TCCU, theresults of a large randomised study of vinflunine + best supportive care versus best supportive care alone leading to an EMEA approval in this setting will most probably have an impact on hospital practice policy. Even in countries where second line chemotherapy was already available, vinflunine will probably become a reference second line chemotherapy , the gemcitabine + cisplatin or carboplatin being administered most often as first line treatment.
However, the current developments should not hinder the inclusion of such patients in clinical trials of novel classes of drugs. Further research remains indeed warranted since chemotherapy is hardly ever curative for patients with metastatic TCCU.
Bladder Cancer Advocacy network BCAN
American Association of Clinical Oncology (ASCO) Genito
Urinary (GU) Symposium : March 2010 5-7, San Francisco
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