Phase 1/2 study of intravenous paclitaxel and oral cyclophosphamide in pretreated metastatic urothelial bladder cancer patients.

Cisplatin-based combination regimens represent the standard treatment for patients with metastatic urothelial cancer. Nevertheless, nearly all responding patients develop disease recurrence within the first year, with a median survival of 12 months. Thus, the need for the development of new and tolerable agents is urgent and clinical trials for second-line chemotherapy are warranted. Taxane-based chemotherapy is currently the most commonly used regimen for salvage chemotherapy. Paclitaxel was reported to yield a 42% response rate as first-line therapy. However, against previously treated patients, the response rate was found to be only 10%. Metronomic chemotherapy, defined as the administration of low doses of cytotoxic chemotherapy at frequent intervals, suppresses tumor growth in experimental models, possibly by inhibiting angiogenesis by stimulating the release of thrombospondin. Although it is believed that metronomic cyclophosphamide acts primarily through blockade of angiogenesis, it cannot be completely excluded that part of the activity might rely on its cytotoxic properties. Recently, promising studies have been published with metronomic low-dose cyclophosphamide in different cancer types. To our knowledge, no study to date has been reported on oral cyclophosphamide in urothelial cancers. This phase 1/2 study was performed to evaluate the combination of paclitaxel and cyclophosphamide in pretreated patients with metastatic bladder cancer.