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The treatment of metastasized bladder cancer has been evolving during recent years. Cisplatin based chemotherapy combinations are still gold standard in the treatment of advanced and metastasized bladder cancer. But new therapies are approaching. Based to this fact biological markers will become more important for decisions in bladder cancer treatment. A systematic MEDLINE search of the key words "cisplatin", "bladder cancer", "DNA marker", "protein marker", "methylation biomarker", "predictive marker", "prognostic marker" has been made. This review aims to highlight the most relevant clinical and experimental studies investigating markers for metastasized transitional carcinoma of the urothelium treated by cisplatin based regimens.

Purpose: Cisplatin-based chemotherapy is standard first-line treatment for metastatic urothelial carcinoma. However, cisplatin is frequently avoided in elderly patients due to concerns regarding toxicities. We analyzed the efficacy, and tolerability, of cisplatin-based chemotherapy in elderly patients., Methods: Individual patient data were pooled from 8 phase II and III trials evaluating cisplatin-based first-line chemotherapy in patients with metastatic urothelial carcinoma. Adverse events, treatment delivery, response proportions, and survival outcomes were compared between patients aged<70 vs. ≥ 70 years., Results: Of the 543 patients included, 162 patients (30%) were ≥ 70 years old. The majority (93%) of elderly patients were aged 70 to 79 years. There was no significant difference in the proportions of patients experiencing Grade 3 to 4 renal failure, febrile neutropenia, or treatment-related death between younger and older patient cohorts. The median survival of the patients ≥ 70 years was 12.1 months compared to 12.8 months for patients<70 years (P = 0.91). There was no significant difference in survival between age groups when controlling for baseline performance status or the presence of visceral metastases or both., Conclusions: Fit septuagenarians, with adequate renal function, tolerate cisplatin-based chemotherapy similarly to their younger counterparts and achieve comparable clinical outcomes., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Although urothelial cancer is more common in men, women with urothelial cancer have inferior survival outcomes. The potential existence of gender-related disparities in patients with metastatic urothelial cancer has not been extensively explored., Patients and Methods: Individual patient data were pooled from 8 phase II and phase III trials evaluating first-line cisplatin-based combination chemotherapy in patients with metastatic urothelial carcinoma. Adverse events, treatment delivery, response proportions, and survival outcomes were compared between male and female patients., Results: Of the 543 patients included in the analysis, 100 patients (18%) were women. There was no significant difference in the number of cycles of chemotherapy administered or in the proportions of patients experiencing severe toxicities when comparing male and female patients. There was no difference in the survival distributions between male and female patients (P = .08); the median survival of male patients was 11.7 months (95% confidence interval [CI], 10.5-13.2) compared with 16.2 months for female patients (95% CI, 12.8-20.4). There was no significant difference in survival between men and women when controlling for baseline performance status and/or the presence of visceral metastases., Conclusion: Female patients with metastatic urothelial cancer tolerate cisplatin-based chemotherapy similarly to male patients and achieve comparable clinical outcomes. Although gender-associated survival disparities in patients with metastatic urothelial cancer cannot be completely ruled out, if such disparities exist, they are unlikely related to tolerability or efficacy of chemotherapy., (Copyright © 2013 Elsevier Inc. All rights reserved.)

This phase II trial assessed temsirolimus, an inhibitor of mammalian target of rapamycin (mTOR), as second-line therapy in patients with metastatic transitional carcinoma of the urothelium (TCCU) after failure of platinum containing therapy. From June/2009 to June/2011, we enrolled 15 patients in this trial. Primary endpoint was overall survival, as secondary endpoints we defined time to disease progression, safety and QoL along treatment. Patients with progressive TCCU after prior platinum-based chemotherapy received weekly 25 mg of temsirolimus for 8 weeks. Evaluation for response was accomplished every 8 weeks according to the RECIST criteria, QoL assessment was done every 4 weeks using the QLQ-C30 questionnaire, adverse events (AEs) were recorded and graded using NCI-CTC criteria. Fifteen patients were enrolled in this study, of whom 14 (93%) were available for activity, safety and QoL assessment. We treated 10 (71%) male and 4 female (29%) patients. Median age was 64,7 years (45-76). Patients received on average 13 (3-15) infusions of temsirolimus. As per protocol, no sufficient benefit on overall survival was observed, we early stopped the study after 14 patients. Median time to progression was 2.5 months (77 days), median overall survival was 3.5 months (107 days). Four patients with stable disease were observed. QoL assessment along treatment revealed a reduction of EORTC-QLQ-C30, Global Health Status subscale, from initial 7.86 to 5.00. Temsirolimus was well tolerated. As Grade 3-4 adverse events, we observed fatigue (n=2), leukopenia (n=2) and thrombopenia (n=2). All other adverse events were graded 1-2 in nature. Temsirolimus seems to have poor activity in patients with progressive metastasized TCCU after failure of platinum containing first-line therapy.

The treatment of metastasized urothelial cancer has been evolving in recent years. In particular, in the second-line setting after the failure of platinum-containing therapy, options are few and besides vinflunine, the recently approved standard in Europe, well-designed highly selective clinical trials may be possible alternatives for patients in this palliative situation. However, targeted therapy approaches have not achieved the same results in urothelial cancer as for instance in renal cell carcinoma. Many of the new targeted drugs have been investigated as single agents in phase II clinical trials without convincing oncologic outcome. This review aims to highlight the most relevant clinical studies examining targeted agents in the second-line setting of metastasized transitional carcinoma of the urothelium.

Relapse after initial first-line chemotherapy shows a poor prognosis in metastatic urothelial cancer. Currently, several chemotherapeutic agents and targeted drugs are under evaluation for platin-resistant advanced urothelial carcinoma. Vinflunine has been approved for second-line treatment in this indication. We present a patient with initial T4 advanced and subsequently metastasized bladder cancer, who has shown prolonged survival of 44 months after radical cystectomy. During her clinical course, the patient received two different platinum-containing therapies, temsirolimus within a phase II protocol and subsequent vinflunine chemotherapy. Treatment duration was 15 weeks with temsirolimus and 9 weeks with vinflunine, respectively, with a stable disease period of 3.8 months under temsirolimus therapy. This case is an example of how patients can derive a survival benefit from adequate sequencing of surgery and medical treatment including the newest therapies, even in advanced disease.

The potent inhibitor of the mammalian target of rapamycin, temsirolimus, comprises for cell cycle, angiogenesis and proliferation and has proven beneficial in the treatment of advanced renal cell carcinoma (RCC). Temsirolimus is officially approved for first line therapy in high risk previously untreated mRCC patients. This review summarizes the current clinical role of temsirolimus in the treatment of advanced renal cell carcinoma with regard to pharmacological features, toxicity and tolerability. It particularily discusses quality of life issues as important outcome parameters in palliative treatment of patients with mRCC and gives an outlook on current clinical developments regarding possible future combining/ sequencing strategies of temsirolimus.