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Carboplatin and Gemcitabine: Developing a More Gentle Approach for the Treatment of Advanced Transitional Cell Carcinoma
Abstract & Commentary
Synopsis: Transitional cell carcinoma frequently occurs in older patients and the current standard therapy, which includes cisplatin combinations, may be too toxic for some patients. In the current report, fairly impressive results with carboplatin-gemcitabine chemotherapy used in patients with advanced transitional cell carcinoma are described. This combination may be particularly effective therapy for older, more frail patients, or for those with significant comorbidities.
Source: Nogue-Aliguer M, et al. Cancer. 2003;97: 2180-2186.
Cisplatin-based chemotherapy is currently considered a standard approach for advanced transitional cell carcinoma. Until recently, the most commonly used regimen was M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin), which had proven superior when compared to single-agent cisplatin,1 but the associated toxicity (including nausea/vomiting, mucosal, bone marrow suppression and renal, cardiac and neurologic damage) has been substantial. More recently, a cisplatin gemcitabine doublet was compared to M-VAC and proved to be equally efficacious with regard to response rates and time to treatment failure and overall survival, but with less toxicity.2
The current report is of a phase II trial of carboplatin and gemcitabine in patients with advanced transitional cell carcinoma. Patients with lower performance status (ie, Karnofsky scores of 60 or greater) and with mild-to-moderate renal insufficiency (ie, creatinine clearances > 30 mL/min) were considered candidates. Gemcitabine (1000 mg/m2) was given on days 1 and 8, and carboplatin (area under the concentration time curve [AUC] of 5) was given on day 1 of each 21-day cycle.
Forty-one patients were enrolled and received an average of 5.5 cycles of drug. Creatinine clearance was below 60 in 54% of patients, and Karnofsky score was 70 or below in 37%, and 37% were older than age 70. Although grade 3/4 neutropenia occurred in 63%, there were only 3 episodes of febrile neutropenia. However, one patient died with neutropenic sepsis. Nonhematologic toxicity was mild, with asthenia the most frequently reported event. Six patients experienced complete responses and 17 partial responses for an overall response rate of 56.1% (95% CI, 40.6-71.6). Progression-free survival was 7.2 months (95% CI, 5.7-8.5), and median survival was 10.1 months (95% CI, 8.8-12.2).
Nogue-Aliguer and associates conclude that the combination of carboplatin and gemcitabine is an effective alternative treatment to cisplatin-based regimens and may offer the potential advantage of being less toxic.
Comment by William B. Ershler, MD
Transitional cell carcinoma occurs most commonly in elderly patients, with the median age of close to 70 years in both men and women. Although combination therapy has been shown to be effective, a fairly large segment of patients are not eligible for standard treatment, primarily because of existing comorbidities and associated impairment of renal or cardiac functions that preclude the use of aggressive, cisplatin-based combinations. Thus, the current report is of importance. It appears that the combination of carboplatin and gemcitabine achieves a similar result to doublets using cisplatin. Furthermore, the more favorable toxicity profile enables patients with impaired renal function and/or poor performance status to be treated. Short of a randomized trial comparing cisplatin-gemcitabine with carboplatin-gemcitabine, the latter combination offers a reasonable alternative for the typical patient with coexisting illnesses or organ impairment.
Dr. Ershler, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.
1. Loeher PJ, et al. J Clin Oncol. 1992;10:1066-1073.
2. von der Maase H, et al. J Clin Oncol. 2000;18: 3068-3077.