[Show abstract][Hide abstract] ABSTRACT: M-VAC (cisplatin, methotrexate, adriamycin, vinblastine) combination chemotherapy has been the standard of care in fit patient with advanced urothelial tumors for long time. Phase III trials have evaluated new combinations such as gemcitabine/cisplatin, carboplatin/paclitaxel, docetaxel/cisplatin and interferon-alpha/5-fluorouracil/cisplatin. Even though these new regimens have failed to demonstrate superiority in terms of overall survival when compared to the classical M-VAC, the combination of gemcitabine/cisplatin has proved to be a new standard alternative showing more favorable toxicity profile and similar efficacy. Along the same line, the addition of a third agent (TCG) has been studied in a large phase III EORTC trial. This study shows a trend in favor of the triplet and suggests different patterns of chemosensitivity favoring primary bladder carcinoma. In addition to the new active drug combinations the role of targeted agents as monotherapy, in combination with chemotherapy or as maintenance post-chemotherapy is currently under study. Finally, chemotherapy optimization using clinical and molecular markers predicting chemosensitivity and prognosis are emerging.
[Show abstract][Hide abstract] ABSTRACT: Cisplatin, methotrexate, doxorubicin, and vinblastine (M-VAC) combination chemotherapy has been the historic standard of care in patients with advanced urothelial tumors. Phase III trials have evaluated new combinations such as gemcitabine/cisplatin (GC), carboplatin/paclitaxel, docetaxel/cisplatin, and interferon-alpha/5-fluorouracil/cisplatin. However, these new regimens have failed to demonstrate superiority in terms of overall survival when compared with classic M-VAC. The GC doublet has proved to be a new standard treatment alternative based on an improved toxicity profile and similar survival results. The addition of a third agent (paclitaxel) to this regimen is the focus of a phase III trial. However, long-term follow-up with classical and new regimens (doublets and triplets) still show limited efficacy and emphasize the need to identify more active treatment. For "unfit" patients, ie, those unable to receive cisplatin-based regimens, conventional regimens include methotrexate, carboplatin, and vinblastine (M-CAVI), carboplatin-gemcitabine, carboplatin-paclitaxel, gemcitabine-taxane, or monotherapy with either gemcitabine, carboplatin, or a taxane. New drugs, including pemetrexed and vinflunine, are now being studied for salvage therapy. In addition to new active drug combinations and targeted therapies, chemotherapy optimization using molecular characteristics to predict chemosensitivity is emerging.
Seminars in Oncology 05/2007; 34(2):135-44. DOI:10.1053/j.seminoncol.2006.12.008 · 3.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Customizing chemotherapy on the basis of chemosentitivity prediction may improve outcome in advanced bladder cancer patients. Since DNA damaging agents are the cornerstones of therapy, we hypothesized that levels of DNA repair genes could predict survival.
Messenger RNA expression levels of excision repair cross complementing 1 (ERCC1), breast cancer 1 (BRCA1), ribonucleotide reductase subunit M1 (RRM1) and caveolin-1 were determined by RT-PCR in tumor DNA from 57 advanced and metastatic bladder cancer patients treated with either gemcitabine/cisplatin or gemcitabine/cisplatin/paclitaxel (Taxol). Levels were correlated with survival, time to disease progression and chemotherapy response.
Median survival was significantly higher in patients with low ERCC1 levels (25.4 versus 15.4 months; P = 0.03) (median follow-up 19 months). A trend towards longer time to progression was observed in patients with tumors expressing low levels of all markers. Levels of RRM1, BRCA1 and caveolin-1, however, failed to predict the survival and a clear link with chemotherapy response could not be established. On multivariate analysis with pretreatment prognostic factors, ERCC1 emerged as an independent predictive factor for survival.
The results of the study indicate that ERCC1 may predict survival in bladder cancer treated by platinum-based therapy.
Annals of Oncology 04/2007; 18(3):522-8. DOI:10.1093/annonc/mdl435 · 6.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The understanding of cellular processes underlying tumour biology has allowed the development of novel molecular-targeted drugs with optimistic results in renal cell carcinoma (RCC). Mutations in the von Hippel-Lindau gene are found in 75% of sporadic RCCs, which results in upregulation of several genes involved in angiogenesis, e.g. vascular endothelial growth factor and platelet-derived growth factor. Other activated pathways in RCC are the epidermal growth factor receptor and the mTOR pathway, which regulate survival and cell growth. In addition to temsirolimus (an mTOR inhibitor) two different strategies have been studied to inhibit these targets: monoclonal antibodies, e.g. bevacizumab, and small molecule tyrosine-kinase inhibitors such as sorafenib, sunitinib and AG 013736. Phase II studies with these drugs reported substantial clinical activity in advanced RCC. Survival benefit was reported with temsirolimus, sunitinib and sorafenib in randomized trials, which led to the accelerated approval of sorafenib and sunitinib for advanced RCC by regulatory authorities in the USA and Europe. Nevertheless, as new therapies develop, new challenges arise for the optimum use of these targeted drugs. We discuss the rationale and the clinical development of these novel molecular-targeted agents, with special emphasis on updated information presented at recent meetings because of the relevance of the data reported and the potential future impact in the management of patients with RCC.
BJU International 03/2007; 99(2):274-80. DOI:10.1111/j.1464-410X.2006.06589.x · 3.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: M-VAC (cisplatin, methotrexate, adriamycin, vinblastine) combination chemotherapy has been for long time the standard of care in fit patient with advanced urothelial tumors. Gemcitabine/cisplatin with similar results and an improved toxicity profile has proved to be a new standard alternative. Whether or not we can improve survival with newer triplet regimens will depend upon the results of ongoing phase III trials. In addition to the new active drug combinations and targeted therapies, new approaches are emerging for treatment. Chemotherapy optimization using molecular markers predicting chemosensitivity are being applied. There is an obvious need to incorporate in clinical trials a systematic translational approach to explain both our successes and our failures.
[Show abstract][Hide abstract] ABSTRACT: The median survival of patients with metastatic cancer of the urothelium who receive best supportive care only in 4-6 months. With the introduction of combination chemotherapy regimens including cisplatin and methotrexate for the management of metastatic urothelial cancer, median overall survival has doubled. Nevertheless, death due to cancer ultimately occurs in more than 80% of these patients, thus more effective therapy is required. The new available treatment modalities range from new combinations of conventional chemotherapeutic agents to combinations incorporating novel drugs like gemcitabine and the taxanes. These new combinations incorporate the new active agents in two, three or multiple drug combinations, administered either in one regimen or sequentially in various combinations and schedules intended to improve the outcome of bladder cancer patients. Ongoing phase III studies will help to define the role of these new combinations in the treatment of advanced bladder cancer. The improved understanding of the molecular biology of urothelial malignancies is helping to define the role of new prognostic indices that can direct the most appropriate choice of treatment for advanced disease. In addition, advances in the molecular biology of urothelial malignancies may allow identification of specific genetic lesions and biochemical pathways upon which future therapeutic approaches can be focused. The integration of newer biologic agents, probably to supplement rather than to supplant chemotherapeutic drugs, should be a primary direction of research with the objective to interfere with multiple aspects of bladder cancer progression.
[Show abstract][Hide abstract] ABSTRACT: Transitional cell carcinoma of the urothelium is considered a chemosensitive malignancy. Until recently, the methotrexate, vinblastine, doxorubicin and cisplatin combination has been considered the standard for treating this disease. The development of new chemotherapeutic agents such as gemcitabine and the taxanes has opened up promising new perspectives in the treatment of this disease. However, the preliminary phase II data must be confirmed in adequately conducted phase III trials.
Current Opinion in Urology 10/2001; 11(5):517-22. DOI:10.1097/00042307-200109000-00011 · 2.12 Impact Factor