RECENT STRATEGIES FOR THE USE OF PACLITAXEL IN THE TREATMENT OF UROLOGICAL MALIGNANCIES

Paclitaxel, a natural anticancer drug, has gained widespread acceptanc e as an active broad-spectrum antitumor agent, including its use in ur ological malignancies, particularly urothelial tract cancer and testic ular cancer. The mechanism of action, based on the premature stabiliza tion of the microtubule assembly with disruption of the cytoskeletal f ramework, 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 r esponse rate of 40-50% being obtained in previously untreated patients . These promising single-agent results have prompted the use of combin ation regimens including, in particular, cisplatin and paclitaxel. A h igh degree of activity for the cisplatin-paclitaxel combination as ref lected by responses in 50-80% of patients, including a substantial num ber of complete responses (>30%), has been identified. The role of oth er agents such as vinorelbine, methotrexate, 5-fluorouracil, or ifosfa mide as additions to this two-drug combination currently remains open. The combination of paclitaxel plus ifosfamide or vinorelbine in the a bsence of a platinum derivative has yielded rather disappointing resul ts. Of particular interest may be the combination of paclitaxel and ca rboplatin. Both drugs can be given to patients with impaired renal fun ction. 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 frequ ency of myelotoxicity, particularly thrombocytopenia. The combination of paclitaxel with carboplatin is being compared in an ongoing trial a gainst the current standard MVAC regimen (methotrexate/vinblastine/Adr iamycin/cisplatin) in patients with metastatic disease. Furthermore, t he activity of paclitaxel-based combinations is currently being explor ed in the neoadjuvant setting in phase II studies, and the potential f or the combination with the other new promising agent - gemcitabine - will be evalutated in a phase I setting. In prostate cancer, estramust ine phosphate is widely used as palliative treatment for patients with hormone-refractory disease. In vitro synergistic activity has been ob served between estramustine and paclitaxel in prostate-cancer cell lin es, although paclitaxel has not demonstrated single-agent activity in patients with hormone-refractory prostate cancer. In clinical trials t he combination of the two agents was associated with increased gastroi ntestinal toxicity. The addition of etoposide as a third drug has yiel ded prostate-specific antigen (PSA)-response rates of >50%, but data o n quality of life and survival time have not been reported for these c ombinations. A true clinical role for paclitaxel in prostate cancer ha s therefore not been established. Paclitaxel has finally demonstrated single-agent activity in relapsed and/or cisplatin-refractory testicul ar cancer in recent phase II trials, indicating different mechanisms o f resistance to cisplatin and paclitaxel. These results have formed th e rationale for the introduction of paclitaxel as part of combination chemotherapy regimens in patients with relapsed but chemosensitive tes ticular cancer. Preliminary results demonstrate that paclitaxel can be safely included into these conventional-dose combination regimens. Wh en it is used prior to high-dose chemotherapy, sufficient numbers of p eripheral blood stem cells (PBSCs) for high-dose therapy can be collec ted. The final role of paclitaxel in risk-adapted chemotherapeutic str ategies in testicular cancer is not defined, but it appears that pacli taxel-based combinations can achieve a substantial response rate in pa tients with relapsed disease.