Chemotherapy options in cisplatin-unfit patients with advanced urothelial cell cancer
Ronald de Wit, Erasmus University Medical Center and Daniel den Hoed Cancer Center Rotterdam, The Netherlands
Several decades of single-arm phase II and prospective randomized clinical trials involving patients with advanced urothelial cancers have led to the conclusion that urothelial tract tumors are chemosensitive and that the treatment regimen should be a cisplatinum- based combination. Through the 1990s, the combination of methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) was the widely accepted treatment standard and proved to be superior in terms of prolonging life. Toxicities associated with this treatment, including diminished renal function, cardiovascular side effects, neutropenia and sepsis and mucositis tempered the use in the considerable group of patients who are comprised functionally (performance score (PS) <2) and have compromised renal function and other comorbididity conditions. The gemcitabine/cisplatin (GC) regimen has been shown a valuable alternative chemotherapy option, providing similar response rates and survival, with the benefit of fewer side effects. Even in elderly patients (>75 years) GC is a feasible option, provided that patients are still basically healthy (no or minor cardiovascular comorbidity) and have good renal function.
For individuals with a compromised renal function (creat clear 30-60 ml/min) a carboplatin-based combination (in lieu of cisplatin) is recommended, with dosing based on the estimated renal function of the individual patient. The single agent activity of carboplatin is 12%, which seems slightly inferior to that of cisplatin which was associated with an overall response rate of 17%. Carboplatin combination chemotherapy studies have shown median survival durations of 8-10 months, which again suggests inferiority as compared with the 14-15 months obtained with MVAC and GC (1,2). Regrettably, carboplatin and cisplatin have never been directly compared in randomised trials that were sufficiently powered to test for superiority or non-inferiority.
A confounding factor in interpreting the data from non-randomized studies is the proportion of patients with adverse prognostic factors for survival in phase II trials. The 2 predominant factors for survival following MVAC therapy are the presence of visceral disease in liver or bone and impaired PS (Bajorin risk groups; 0, 1, or 2 factors present, corresponding with 0%, 11% and 33% 5year survival rates ). Patients with no risk factors have a median survival of 18 months versus 4,4 months for those with the least favorable combination of adverse features present. (3). Decreasing the proportion of patients with adverse prognostic factors in phase II trials will thus impact outcome and may provide flattering results. In this light it is also difficult to interpret the non-randomized phase II data obtained with platinum-free combination chemotherapy, particularly taxanes with gemcitabine. Apart from myelotoxic effects these regimens seems to be well tolerated, but the true merit of these combinations can only be answered in randomized trials.
The EORTC and Spanish Oncology Genitourinary Group have reported the phase II data of the randomized phaseII/III trial of gemcitabine/ carboplatin(G/carbo) vs carboplatin/methotrexate/vinblastine (M-CAVI), in patients deemed unfit for cisplatin due to PS 2 and/or or impaired renal function (creat clear <60ml/min) (4). Overall response rates were 42% for G/carbo and 30% for M-CAVI and severe acute toxicity (SAT) was manageable. Patients, however, with both stratification parameters present (poor PS plus poor renal function), or poor PS plus visceral disease (Bajorin risk group 2) had a response rate of only 26% and 20% and an unacceptable SAT rate of 26 and 25%, respectively. Carboplatin combinations are active in this group of cisplatin-unfit patients. However patients with multiple adverse prognostic factors (Impaired PS, Impaired renal fuction, visceral metastasis) are not likely to benefit from combination chemotherapy. Alternative treatment modalities should be sought for this subgroup of very poor risk patients.
1. de Wit R, Bellmunt J. Chemotherapy in metastatic urothelial cancer. Am J Cancer 2002;1:23-31.
2. GalskyMD, Chen GJ, Oh WK, Bellmunt J, Roth BJ, Petrioli R, Dogliotti L, Dreicer R, Sonpavde G. Comparative effectiveness of cisplatin-based and carboplatin-based chemotherapy for treatment of advanced urithelial carcinoma. Annals of Oncol 2011;21543626
3. Bajorin DF, Dodd PM, Mazumdar M. Long-term survival in metastatic transitional-cell carcinoma and prognostic factors predicting outcome of therapy. J Clin Oncol 1999;17:3173-3181
4. de Santis M, Bellmunt J, Mead G. Randomized phase II/III trial assessing gemcitabine / carboplatin and methotrexate / carboplatin and methotrexate / carboplatin / vinblastine in patients with advanced urothelial cancer “unfit” for cisplatin-based chemotherapy: phase II-results of EORTC study 30986. J Clin Oncol 2009;27:5634-5639
Posted with the author’s permission.
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