Recent strategies for the use of paclitaxel in the treatment of urological malignancies

Abstract

Paclitaxel, a natural anticancer drug, has gained widespread acceptance as an active broad-spectrum antitumor agent, including its use in urological malignancies, particularly urothelial tract cancer and testicular cancer. The mechanism of action, based on the premature stabilization of the microtubule assembly with disruption of the cytoskeletal framework, is completely different from those of DNA-damaging agents, e.g., cisplatin and ifosfamide. As a single agent, paclitaxel is one of the most active drugs in metastatic bladder cancer, with an overall response rate of 40–50% being obtained in previously untreated patients. These promising single-agent results have prompted the use of combination regimens including, in particular, cisplatin and paclitaxel. A high degree of activity for the cisplatin-paclitaxel combination as reflected by responses in 50–80% of patients, including a substantial number of complete responses (>30%), has been identified. The role of other agents such as vinorelbine, methotrexate, 5-fluorouracil, or ifosfamide as additions to this two-drug combination currently remains open. The combination of paclitaxel plus ifosfamide or vinorelbine in the absence of a platinum derivative has yielded rather disappointing results. Of particular interest may be the combination of paclitaxel and carboplatin. Both drugs can be given to patients with impaired renal function. Overall response rates of 45–60% have been reported in phase II studies. The so-called platelet-sparing effect of paclitaxel given in combination with carboplatin has resulted in a surprisingly low frequency of myelotoxicity, particularly thrombocytopenia. The combination of paclitaxel with carboplatin is being compared in an ongoing trial against the current standard MVAC regimen (methotrexate/vinblastine/Adriamycin/cisplatin) in patients with metastatic disease. Furthermore, the activity of paclitaxel-based combinations is currently being explored in the neoadjuvant setting in phase II studies, and the potential for the combination with the other new promising agent – gemcitabine – will be evalutated in a phase I setting. In prostate cancer, estramustine phosphate is widely used as palliative treatment for patients with hormone-refractory disease. In vitro synergistic activity has been observed between estramustine and paclitaxel in prostate-cancer cell lines, although paclitaxel has not demonstrated single-agent activity in patients with hormone-refractory prostate cancer. In clinical trials the combination of the two agents was associated with increased gastrointestinal toxicity. The addition of etoposide as a third drug has yielded prostate-specific antigen (PSA)-response rates of >50%, but data on quality of life and survival time have not been reported for these combinations. A true clinical role for paclitaxel in prostate cancer has therefore not been established. Paclitaxel has finally demonstrated single-agent activity in relapsed and/or cisplatin-refractory testicular cancer in recent phase II trials, indicating different mechanisms of resistance to cisplatin and paclitaxel. These results have formed the rationale for the introduction of paclitaxel as part of combination chemotherapy regimens in patients with relapsed but chemosensitive testicular cancer. Preliminary results demonstrate that paclitaxel can be safely included into these conventional-dose combination regimens. When it is used prior to high-dose chemotherapy, sufficient numbers of peripheral blood stem cells (PBSCs) for high-dose therapy can be collected. The final role of paclitaxel in risk-adapted chemotherapeutic strategies in testicular cancer is not defined, but it appears that paclitaxel-based combinations can achieve a substantial response rate in patients with relapsed disease.