Exploring the role of novel agents in the treatment of renal cell carcinoma

Oncology Center, Sirio Libanês Hospital, São Paulo, Brazil.
Cancer Treatment Reviews (Impact Factor: 7.59). 10/2008; 34(8):750-60. DOI: 10.1016/j.ctrv.2008.07.002
Source: PubMed


Renal cell carcinoma represents nearly 3% of all cancers, predominantly affecting individuals >or=50 years of age, and until recently, few treatments options were available for metastatic disease. The 5-year median survival for these patients with metastatic renal cell carcinoma has been estimated at <10%. This review explores the data of the most relevant trials focusing on new approaches with novel agents, including sunitinib, sorafenib, bevacizumab, temsirolimus, as well as their combinations with traditional agents. We describe mechanisms of action, activity, and toxicity profile of those agents, as well as administration schedules that have been studied in clinical trials.

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    • "Current treatment approaches utilising novel targeted agents At present, treatment for mRCC with molecularly targeted agents can be broadly divided into the following categories: previously untreated patients, those refractory to immunotherapy or chemotherapy, and those who have failed treatment with VEGF-targeted therapy [9]. An important consideration that influences treatment decisions is the Memorial Sloan-Kettering Cancer Centre (MSKCC) prognostic risk stratification system, which is widely used to define patient profiles and provide an indication of overall survival (OS) [10] [11] [12]. "
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    ABSTRACT: ContextFew treatment options were available for metastatic renal cell carcinoma (mRCC) until the development of novel targeted agents directed against angiogenesis and tumour growth.
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    ABSTRACT: In 1971, J. Folkman started his crusade on the therapeutic targeting of tumor angiogenesis [1]. This strategy gained an increasing number of sustainers showing promising, if not sensational results in animal models. Numerous potential targets were identified on the endothelial cell, causing the sensation to have no more secrets to disclose. Times were mature for an optimistic clinical transfer. This transfer immediately appeared a disaster: most molecules showed high toxicities, without appreciable therapeutic effects. Several trials were suddenly discontinued by the pharmaceutical industry, was it the end of “antiangiogenesis”? Fortunately, among numerous endothelial targets, one survived as potentially interesting: vascular endothelial growth factor (VEGF) and its receptor. Today we know that bevacizumab, a humanized anti VEGF antibody, significantly improves patients' life expectancy, when associated to the chemotherapy of colon and other solid cancers. In addition synthetic inhibitors of tyrosine kinase receptors (TKR) - like sunitinib and sorafenib- are deeply investigated. While these molecules have “saved” the anti angiogenic theory and will be perfected, we could ask why so many promising drugs failed in clinic. Among several answers, one can resume the others: the milestones of the anti-angiogenic theory were misunderstood by its clinical application. Born for chemoprevention, angiogenesis was targeted in advanced cancers, frequently as monotherapy. This implied the study of a MTD in phase I trials causing severe side effects, while an “optimal dose for chronic scheduling” (ODCS) should be tested instead. The evaluation of rapidly evolving cancers with an already established vascularization was a clear limit to those anti-angiogenic molecules unable to affect a completed angiogenic process. In addition it was immediately clear that classic response evaluation protocols were inadequate for anti-angiogenic assessment, due to the short time of the screening, and the lack of surrogate markers. In this review we revisit the different therapeutic strategies historically developed to target tumor vessels, describe the state of the art for VEGF and TKR inhibitors, comment recent trials based on molecules with known anti angiogenic activities and finally suggest possible guidelines for improving basic research and clinic experimentation.
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    ABSTRACT: The outcome prediction for renal cell cancer (RCC) remains controversial, and although many parameters have been tested for prognostic significance, only a few have achieved widespread acceptance in clinical practice. The TNM staging system defines local extension of the primary tumour (T), involvement of regional lymph nodes (N), and presence of distant metastases (M). This review focuses on reassessing the current TNM staging system for RCC. A literature search in English was performed using the National Library of Medicine database and the following keywords: renal cell cancer, kidney neoplasm, and staging. We scrutinized 1952 references, and 62 were selected for review based on their pertinence, study size, and overall contribution to the field. The prognostic significance of tumour size for localized RCC has been investigated in a large number of studies. As a consequence, many modifications of the TNM staging system were primarily made to the size cut points between stage I and II tumours. The latest three revisions of the TNM system are systematically reviewed. For the heterogeneous group of locally advanced RCCs, involving different anatomic structures surrounding the kidney, the situation is still the subject of controversial scientific dispute. In detail, perirenal fat invasion, direct infiltration of the ipsilateral adrenal gland, invasion of the urinary collecting system, infiltration of renal sinus fat, and vena cava and renal vein thrombosis are disputed. Finally, staging of lymph node metastases and distant metastatic disease is discussed. Special emphasis should be put on renal sinus invasion for stage evaluation. Retrospective studies relying on material collected at a time when no emphasis was placed on adequate sampling of the renal sinus should be treated with caution. In view of new treatment opportunities, the current TNM staging system of RCC and any other staging system must be dynamic.
    Full-text · Article · Aug 2009 · European Urology
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