Phase I/II study of paclitaxel, carboplatin, and methotrexate in advanced transitional cell carcinoma: A well-tolerated regimen with activity independent of p53 mutation

Objectives. To evaluate the feasibility and activity of paclitaxel, carbopl atin, and methotrexate in advanced transitional cell carcinoma (TCC) of the urothelium and to relate the activity of this combination to the mutationa l status of p53. Methods. In the Phase I portion, paclitaxel 200 mg/m(2) (3-hour infusion), carboplatin dosed to an area under the curve (AUC) of 6 mg/mL . min, and me thotrexate 10 mg/m2, increasing in 10-mg/m(2) increments, were administered on day 1 and every 21 days thereafter with granulocyte colony-stimulating factor (C-CSF) and leucovorin support. Subsequently, a Phase II study was i nitiated in which the carboplatin dose was lowered to an AUC of 5 to allow treatment without G-CSF. p53 expression was evaluated using immunohistochem istry. Results. Thirty-three patients were accrued. Median age was 66 years. No do se-limiting toxicities were seen in the Phase 1 portion despite escalation of the methotrexate to 60 mg/m(2). Principal toxicities were myelosuppressi on and neuropathy. The overall response rate (Phase I and II) was 56% (95% confidence interval 38% to 74%). Median survival was 15.5 months; 88% of pa tients overexpressed p53 at the primary site. Conclusions. Paclitaxel, carboplatin, and methotrexate were well tolerated and active in advanced TCC. The high response rate to this regimen despite frequent p53 mutation is consistent with the p53-independent mechanism of p aclitaxel. Whether this regimen is superior to methotrexate/vinblastine/dox orubicin/cisplatin, other paclitaxel-based regimens, or to paclitaxel alone will require comparative trials. UROLOGY 55: 521-525, 2000. (C) 2000, Else vier Science Inc.