BERKELEY, CA (UroToday Inc.) - In the United States urothelial carcinoma is primarily of transitional cell (TCC) histology. There are 57,000 new cases of bladder cancer annually with about 12,000 deaths. Few advances have improved the survival of patients with metastatic TCC.

The standard chemotherapeutic regimen for advanced TCC has been methotrexate, vinblastine, doxorubicin and cisplatin (MVAC). MVAC results in a median survival of 12 months with approximately 3.7% long-term survivors.

Gemcitabine is a pyrimidine antimetabolite and has a 25% overall response rate as single-agent therapy for advanced TCC. Paclitaxel is a mitotic spindle agent with a single agent response rate of 42%. Dr. Li and collaborators in the Hoosier Oncology Group from Indiana University and other sites in Indiana conducted a Phase II trial of paclitaxel and gemcitabine in patients with advanced TCC. Their findings are reported in the February 2005 issue of the Journal of Clinical Oncology.

Thirty-six patients with metastatic or unresectable TCC were enrolled in this trial between 1998 and 2003. Initially, patients were given paclitaxel 110mg/m2 over 1 hour on days 1, 8, and 15 of each 28-day cycle. Gemcitabine 1,000mg/m2 was administered similarly intravenously for 30 minutes on days 1, 8, and 15 of each 28-day cycle.

Therapy was continued for at least two courses unless there was disease progression or dose-limiting toxicity. However, the paclitaxel and gemcitabine doses were reduced to 90 and 800mg/m2, respectively for the last 12 patients due to pulmonary toxicity. Disease re-evaluation was performed every two cycles.

The primary study objective was to determine the efficacy of combining gemcitabine and paclitaxel. A 35% response rate was considered worthy of further evaluation. The second study objective was to determine the safety of the proposed drug combination.

Median enrolled patient age was 64.5 years, and 64% were male. Visceral metastases were present in 58% and loco-regional disease in 42% of enrolled patients. Patients received a median of five cycles of treatment, with 92% receiving at least two cycles.

An overall response rate of 69.4% was achieved, with a complete response in 41.7% and a partial response in 27.8%. Median duration of response was 5.3 months and median time to progression was 7.6 months. The response rate was higher for those with loco-regional disease (93%) as compared with 52% for those with visceral metastases. A median follow-up time of 38.7 months demonstrated a median survival time of 15.8 months.

The most common grade 3 and 4 toxicities were hematological, with a 36% incidence of grade 3 to 4 granulocytopenia and 8.3% incidence of grade 3 to 4 thrombocytopenia. Grade 3 to 4 neuropathy was recorded in 16.7% of patients and 6 patients developed significant pulmonary toxicities. Three of these patients presented with a clinical scenario of adult respiratory distress syndrome and one of these patients died.

The efficacy of the paclitaxel and gemcitabine chemotherapy combination was notable, and better in patients with loco-regional disease. However, grade 3 to 5 pulmonary toxicities in 5 patients lead the authors to conclude that this regimen and dosing schema results in an unacceptable level of toxicity.

J Clin Oncol 2005;23:1185-1191