Gemcitabine and docetaxel as first-line treatment for advanced urothelial carcinoma: a phase II study

The purpose of the study was to investigate the toxicity and efficacy of the combination of gemcitabine and docetaxel in untreated advanced urothelial carcinoma. Patients with previously untreated, locally advanced/recurrent or metastatic urothelial carcinoma stage-IV disease were eligible. Patients with Performance status: PS ECOG >3 or age >75 years or creatinine clearance <50 ml min−1 were excluded. Study treatment consisted of docetaxel 75 mg m−2 (day 8) and gemcitabine 1000 mg m−2 (days 1+8), every 21 days for a total of six to nine cycles. A total of 31 patients with urothelial bladder cancer, 25 men and six women, aged 42–74 (median 64) years were enrolled. The majority of patients had a good PS (51.6%; PS 0). In all, 15 (48.3%) patients had locally advanced or recurrent disease only and 16 (54.8%) presented with distant metastatic spread, with multiple site involvement in 22.5%. Toxicity was primarily haematologic, and the most frequent grade 3–4 toxicities were anaemia 11 (6.7%) thrombocytopenia eight (4.9%), and neutropenia 45 (27.6%), with 10 (6.1%) episodes of febrile neutropenia. No toxic deaths occurred. A number of patients had some cardiovascular morbidity (38.7%). Nonhaematological toxicities except alopecia (29 patients) were mild. Overall response rate was 51.6%, including four complete responses (12.9%) and 12 partial responses (38.7%), while a further five patients had disease stabilisation (s.d. 16.1%). The median time to progression was 8 months (95% CI 5.1–9.2 months) and the median overall survival was 15 months (95% CI 11.2–18.5 months), with 1-year survival rate of 60%. In conclusion, this schedule of gemcitabine and docetaxel is very active and well tolerated as a first-line treatment for advanced/relapsing or metastatic urothelial carcinoma. Although its relative efficacy and tolerance as compared to classic MVAC should be assessed in a phase III setting, the favourable toxicity profile of this regimen may offer an interesting alternative, particularly in patients with compromised renal function or cardiovascular disease

Targeting angiogenesis in renal cell carcinoma

Angiogenesis is an important factor for cancer development and progression in humans. Hereditary and sporadic renal cell carcinoma are characterized by inactivation of the Von-Hippel Lindau (VHL) gene, which results in hyperactivity of the hypoxia-inducible factor-a (HIFa). As a consequence, there is a production of angiogenic factors, such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). The activity of these factors is associated with oncogenesis, growth, and metastatic potential of renal-cell carcinoma. These data indicate that angiogenic factors are the promising therapeutic targets in this disease. Surgery can cure the patients with renal cancer if disease is diagnosed at an early stage. On the contrary, inoperable or metastatic disease is not curable. Until recently, the only drugs approved for the treatment of advanced disease were the cytokines, interferon, and interleukin. Nevertheless, only a minority of patients (about 15%) would benefited from this treatment, while the toxicity was considerable. During the last 5 years a new era of biological agents, with considerable activity has been developed and tested in clinical trials and (some of them) have been approved in USA and Europe. These agents are: Sunitinib, Bevacizumab, Sorafenib and Temserolimus. Bevacizumab is an anti-VEGF monoclonal antibody, Sunitinib and Sorafenib are multi- tyrosine kinase inhibitors (TKIs), while Temserolimus is a mTOR inhibitor. The common these in their development is the inhibition of angiogenesis, which may explain their significant activity in renal-cell carcinoma. All the agents have been proven more effective than the interferon as first or second-line treatment. This review will focus in these recent developments and the intense continuing clinical research in this field. © 2008 Bentham Science Publishers Ltd

Sunitinib treatment in patients with severe renal function impairment: a report of four cases by the Hellenic Cooperative Oncology Group.

Sunitinib is approved for the treatment of metastatic renal cell carcinoma (RCC). No data are available on sunitinib use specifically in patients with significantly impaired renal function. We evaluated the safety and efficacy of sunitinib in patients with advanced RCC and Grade 4 renal function impairment. Four patients had a calculated creatinine clearance of 15 - 29 ml/min/1.73 m2 prior to initiation of sunitinib. Three patients tolerated treatment well with no renal toxicity: 2 received 17 and 5 cycles of sunitinib at full dose, while 1 received 5 cycles with a dose reduction due to myelotoxicity. We observed one partial response and two patients had stable disease for 24 and 4 months, respectively. The 4th patient had a creatinine clearance of 18 ml/min/1.73 m2 and had treatment discontinued during the first cycle due to poorly controlled hypertension and deterioration of his renal function. We conclude that sunitinib can be administered to the majority of patients with RCC and significant renal function impairment. © 2009 Dustri-Verlag Dr. K. Feistle

Diagnosis and management of hypertension in advanced renal cell carcinoma: Prospective evaluation of an algorithm in patients treated with sunitinib

Hypertension may complicate treatment with antiangiogenic agents, leading to dose reductions and treatment delays. To prospectively evaluate the frequency and management of hypertension in 10 patients with advanced kidney cancer receiving sunitinib, we used 24-h blood pressure monitoring (BPM) and home BPM and homogenously treated hypertension according to guidelines of the European Society of Hypertension. Normal BP was ensured prior to sunitinib initiation with the successive use of hydrochlorothiazide + irbesartan, nebivolol, amlodipine. During treatment, additional antihypertensive therapy was introduced, if necessary. Sunitinib dose was modified only if BP was not controlled with four anti-hypertensive agents. Four patients had baseline hypertension, while 5 of 6 normotensive patients required antihypertensive treatment during sunitinib administration. One patient permanently discontinued sunitinib due to hypertensive crisis but 9 patients received full dose. Sunitinib-associated hypertension is more frequent than previously reported. Aggressive BP monitoring and treatment of hypertension may achieve uninterrupted, full-dose therapy in most patients treated with sunitinib. The application of such protocols instead of commonly used toxicity criteria should be further validated. © E.S.I.F.T. srl

Diagnosis and management of hypertension in advanced renal cell carcinoma: prospective evaluation of an algorithm in patients treated with sunitinib

Hypertension may complicate treatment with antiangiogenic agents, leading to dose reductions and treatment delays. To prospectively evaluate the frequency and management of hypertension in 10 patients with advanced kidney cancer receiving sunitinib, we used 24-h blood pressure monitoring (BPM) and home BPM and homogenously treated hypertension according to guidelines of the European Society of Hypertension. Normal BP was ensured prior to sunitinib initiation with the successive use of hydrochlorothiazide + irbesartan, nebivolol, amlodipine. During treatment, additional antihypertensive therapy was introduced, if necessary. Sunitinib dose was modified only if BP was not controlled with four anti-hypertensive agents. Four patients had baseline hypertension, while 5 of 6 normotensive patients required antihypertensive treatment during sunitinib administration. One patient permanently discontinued sunitinib due to hypertensive crisis but 9 patients received full dose. Sunitinib-associated hypertension is more frequent than previously reported. Aggressive BP monitoring and treatment of hypertension may achieve uninterrupted, full-dose therapy in most patients treated with sunitinib. The application of such protocols instead of commonly used toxicity criteria should be further validated. © E.S.I.F.T. srl