A clinical phase I/II trial with the monoclonal antibody cG250 (RENCAREX®) and interferon-alpha-2a in metastatic renal cell carcinoma patients.

PURPOSE: To evaluate the efficacy and safety of WX-G250, a chimeric monoclonal antibody that binds to carboxy anhydrase IX, combined with low-dose interferon-alpha (LD-IFNα) in patients with progressive metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Thirty-one patients, nephrectomized for the primary tumor, clear cell progressive mRCC, were enrolled to receive weekly infusions of WX-G250 (20 mg i.v.; week 2-12) combined with LD-IFNα (3 MIU s.c. 3 times/week; week 1-12). At week 16, patients were evaluated for response and stratified into two groups: (a) responders into the extended treatment group for an additional 6 weeks of treatment or (b) the progressive group with no further study treatment. RESULTS: Of the 31 treated patients, 26 were evaluable for response to treatment. Two patients showed partial remission and 14 patients had stable disease as assessed in week 16. One patient experienced partial remission resulting in a complete remission lasting at least 17 months. Nine patients had durable stable disease of 24 weeks or longer. Clinical benefit was obtained in 42% (11/26) patients. The median overall survival achieved was 30 months and the 2-year survival was 57%. Patients receiving extended treatment showed a significantly longer 2-year survival rate than discontinued patients (79 vs. 30%; P=0.0083). In general, treatment was well tolerated with little toxicity. CONCLUSION: Treatment with the antibody WX-G250 in combination with LD-IFNα is safe, well tolerated, led to clinically meaningful disease stabilization and demonstrated clinical benefit in this progressive mRCC patient population.

[Systemic therapy of renal cell carcinoma]. / Systemische Therapie beim Nierenzellkarzinom.

Systemic therapy of metastatic renal cell carcinoma has completely changed in the last 5 years. Although a cure for the disease is still not achieved with systemic treatment in the majority of cases immunotherapy is no longer used. The therapeutic regiments are mainly based on angiogenic inhibitors such as sunitinib, sorafenib, pazopanib, everolimus and temsirolimus as well as the combination of bevacizumab with interferon. This article gives an overview of these treatment options and the clinical setting for their usage. To achieve a prolonged progression-free survival, a continuous therapy based on the new drugs is necessary. The major goal of the treatment remains to keep the disease stable as complete remission is only seen in 2-4% of cases. With these lengthy treatment regimes a schedule for sequenced administration of drugs is necessary for most of the patients. The optimal treatment sequence is unknown and should be chosen based on the individual course of the disease and the side effects as well as comorbidities. The role of neoadjuvant and adjuvant therapies remains unclear.

Sorafenib after combination therapy with gemcitabine plus doxorubicine in patients with sarcomatoid renal cell carcinoma: a prospective evaluation.

BACKGROUND: Sarcomatoid renal cell cancer (RCC) is a distinct histological variant of RCC that is associated with rapid progression and a poor prognosis. The optimal treatment for patients with sarcomatoid RCC remains to be defined. Gemcitabine plus doxorubicine (GD) has shown some efficacy, however durability of response is limited. We carried out a prospective, open-label study to investigate the efficacy and safety of sorafenib in patients after GD failure in sarcomatoid RCC. METHODS: Fifteen patients with pure sarcomatoid RCC and objective progressive disease were treated with GD (gemcitabine 1500 mg/m², doxorubicine 50 mg/m² administered by weekly intravenous infusion) until progression of disease. Subsequently 9 patients were switched to sorafenib (400 mg twice daily). Tumor response was measured by physical examination and computerized tomography scans and evaluated according to Response Evaluation Criteria in Solid Tumors criteria. RESULTS: Median time to progression (TTP) under GD was 6.6 months (range 0.8 - 8 months). During GD treatment there were no remissions and 6 patients died from progressive disease. Median TTP for the 9 patients switched to sorafenib was 10.9 months (range 0.6 - 25.5 months). During sorafenib therapy one patient had a partial remission lasting for 3 months and 4 patients experienced stable disease with a duration of 3 to 9 months. Four patients immediately progressed on sorafenib treatment but had a slower dynamic of tumor progression than under GD. Dosing in both treatment phases was generally well tolerated with manageable toxicities and no requirement for dose reduction. CONCLUSIONS: Chemotherapy with GD was ineffective in our patients with pure sarcomatoid RCC. Subsequent anti-angiogenic treatment using the multi-tyrosine kinase inhibitor sorafenib resulted in additional progression-free survival in 5 of 9 patients. Further evaluation of targeted anti-angiogenic agents for the treatment of sarcomatoid RCC is warranted.

[Clinical approach to renal trauma]. / Klinische Vorgehensweise bei Nierentraumata.

Management of kidney injuries is an uncommon challenge to urologists. Therapy has evolved in recent years from mainly surgical to predominantly conservative treatment. Immediate surgical intervention for renal trauma is now only necessary in rare instances. This overview is based on the guidelines of the European Association of Urology and the Societé International d'Urologie as well as clinical experience and is intended to provide practical advice for treatment of renal trauma.

[Diagnostic algorithm in cystic renal masses]. / Diagnostischer Algorithmus bei zystischen Nierenläsionen.

Cystic renal lesions can be classified as either simple or complicated cysts, which might occur as solitary as well as multifocal lesions. The Bosniak classification (I-IV), which characterizes renal cysts on the basis of ultrasound or computer tomographic criteria, is very useful for further decision-making about the therapeutic approach. The method of choice for diagnosis of renal cysts is ultrasound. Besides the conventional B-mode ultrasound, contrast enhanced ultrasound with SonoVue provides a promising new technique for distinguishing cysts according to the Bosniak classification. This review describes cystic renal lesions with emphasis on the etiology and significance of these pathologies in a methodological comparison of conventional B-mode, contrast enhanced ultrasound and computer tomography.

Carcinoma of the collecting ducts of Bellini of the kidney: adjuvant chemotherapy followed by multikinase-inhibition with sunitinib.

INTRODUCTION: Carcinoma of the collecting ducts of Bellini of the kidney (CDC) is very rare but among the most aggressive urological entities. Standard therapy is not well defined with questionable efficacy. METHODS: We present two cases of male patients (49 and 66 years old) with pT3a pN2 CDC treated with a combination of cisplatin plus gemcitabine in an adjuvant setting. Following recurrence the multi-kinase inhibitor sunitinib was administered. RESULTS: Radical nephrectomy with lymphadenectomy revealed CDC in stage pT3a pN2 M0 G3 R0 in both patients. 4 courses of adjuvant chemotherapy with cisplatin 70 mg/m superset2 and gemcitabine 1,500 mg/m superset2 were given. Side effects according to the NCI 3.0 common toxicity criteria were limited to grade 2 asthenia and grade 2 thrombozytopenia/leucopenia. Restaging revealed local recurrence and lymph node metastases. Both patients were re-operated and metastatic CDC was found. Second line therapy with sunitinb malatat (Sutent superset, Pfizer Inc. U.S.) at 50mg p.o. was given. Grade 3 leucopenia and thrombocytopenia and grade 2 asthenia and mucositis were not dose-limiting. After two cycles multiple liver, lung and bone metastases and mediastinal lymphopathy occured. 8 weeks later the patients died with a survival of 8 months from initial diagnosis. CONCLUSIONS: Adjuvant gemcitabine plus cisplatin did not delay recurrence of CDC after surgery. Metastasectomy either had no influence on the course of disease. Anti-angiogenetic therapy with sunitinib treatment was not effective, possibly related to a low vascular density (CD31 expression) in CDC.

[Systemic therapy of metastasizing renal cell carcinoma]. / Systemische Therapie des metastasierten Nierenzellkarzinoms.

Once surgical options have been exhausted, systemic therapy is indicated for metastasizing renal cell carcinoma. Until recently this was carried out using mainly immunotherapeutic concepts with unsatisfactory results. Since the majority of clear cell renal cell carcinomas are well vascularised, angiogenetic inhibition offered an alternative therapy goal. To date, four substances have been approved to control angiogenesis in the therapy of renal cell carcinoma: sunitinib, sorafenib, temsirolimus, as well as a combination of bevacizumab and interferon alpha. Other substances, such as everolimus, pazopanib and axitinib, are currently the subject of clinical trials. Initial data on tolerance and efficacy was presented at this years annual conference of the American Society of Clinical Oncology (ASCO). This article examines current therapy options and ASCO data and discusses future trends.

[Injuries of the renal pelvis and ureter. Diagnosis and management]. / Verletzungen des Nierenbeckens und des Ureters. Diagnostik und Management.

About 5% of injuries of the urinary tract affect the renal pelvis and ureter and constitute a severe complication. Around 75% of these injuries are iatrogenic and only about 25% are caused by blunt abdominal trauma or perforation. To avoid complications and improve prognosis, immediate diagnosis and therapy are essential. The diagnostic accuracy of preoperative studies is low, therefore frequently injuries are detected during explorative laparotomy. The management of upper urinary tract lesions depends on severity and localization, whereas the ultimate ambition should always be the preservation of the kidney. As a basic rule, ureteral stenting is mostly sufficient for small lesions, and only larger injuries require open reconstructive techniques. Longitudinal studies document a high degree of functional reconstitution if adequate and immediate treatment is carried out.

[Managing the side effects of angiogenetic inhibitors in metastatic renal cell carcinoma]. / Antiangiogenetische Therapie beim Nierenzellkarzinom. Management der Nebenwirkungen.

Sunitinib and Sorafenib are both effective angiogenetic inhibitors for the treatment of renal cell carcinoma. With these drugs of a new class of chronic therapy is performed. During chronic treatment, the inherent side effects may necessitate stopping the application of these drugs thus preventing the required effective therapy. Most of the effects can be avoided or attenuated by prophylaxis. In this paper the published data are reviewed and added with our experience in 138 patients over up to two and a half years.

[Therapy strategies for advanced renal cell carcinoma]. / Therapiestrategien des fortgeschrittenen Nierenkarzinoms.

The therapeutic regimen for metastatic renal cell cancer has changed substantially in the last years. Formerly, metastatic disease was regarded as being inoperable and had a disastrous prognosis. Nowadays, radical nephrectomy is the accepted urologic-oncologic standard therapy in metastatic primaries, if technically feasible. A complete resection of metastases may be curative, or can achieve a substantial palliative benefit. A better understanding of prognostic parameters helps in the selection of patients with a chance of benefiting from systemic immunochemotherapy. For patients with rapidly progressing tumors or sarcomatoid dedifferentiation, new effective chemotherapy regimens are available. New angiogenesis inhibitors such as sutent, avastin or sorafenib can potentially be effectively used in future therapeutic regimens.

Targeted agents for the treatment of advanced renal cell carcinoma.

Renal cell carcinoma (RCC) is a highly treatment-resistant tumor type; however, advances in elucidating the molecular pathophysiology underlying RCC has led to the identification of promising targets for therapeutic intervention. In clear-cell RCC, mutations to the von Hippel-Lindau (VHL) gene results in the up regulation of many proteins necessary for tumor growth and survival--such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and platelet derived growth factor (PDGF), which are involved in tumor-initiated angiogenesis. Carbonic anhydrase IX and signaling via the epidermal growth factor receptor (EGFR) are involved in tumor cell proliferation and are also up regulated by mutation in the VHL gene. The intracellular messenger pathways phosphoinositide 3-kinase (PI3K) and Raf/MEK/ERK act as convergence points for positive growth signaling; the Raf/MEK/ERK pathway is also implicated in apoptosis. Several agents in development target VEGF (bevacizumab), the VEGF receptor (PTK787, SU11248, VEGF-trap, and BAY 43-9006), the PDGF receptor (SU11248 and BAY 43-9006), or the EGF receptor (gefitinib, cetuximab, ABX-EGF, and erlotinib). The intracellular Raf/MEK/ERK signaling cascade has been targeted at either the level of Raf (BAY 43-9006, ISIS 5132) or MEK (CI-1040, PD184352 and ARRY-142886), and PI3K signaling is disrupted by CCI-779. WX-G250 targets the G250 antigen, and PS-341 disrupts the 26S proteasome mediating the degradation of intracellular proteins. Given that multiple pathways contribute to tumor growth, anti-tumor activity may be increased by agents targeting multiple pathways, or by combining agents to allow horizontal or vertical inhibition of multiple pathways.