الفهرس 
PathologyOnly 14 pages are availabe for public view
Abstract
Renal cell cancer (RCC) is the most lethal urologic malignancy, and its incidence is currently rising. RCC is now thought to be a clinicopathologically heterogeneous disease that can be classified into clear cell, papillary, chromophobe, collecting duct carcinoma, medullary carcinoma, and unclassified categories. Clear cell RCC is the most common adult RCC, representing 70% of all RCCs. Papillary RCC accounts for 10%–15%, chromophobe RCC for 4%–6%, collecting duct carcinoma for less than 1%, and unclassified lesions for 4%–5% of RCCs.
Radical nephrectomy remains the standard and only curative therapy for patients with localized RCC. However, at initial diagnosis, one third of RCC patients exhibit visceral metastasis, and up to half of remaining patients eventually develop distant metastases.
For a long time, the only effective therapeutic and preventive agents for distant metastases and local recurrence have been interferon (IFN) and interleukin (IL)-2, high-dose IL-2 therapy can provoke an immune response against RCC, resulting in lasting, complete remission in approximately 10% of patients. However, use of high-dose IL-2 is limited by its
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severe toxicity, including hypotension, cardiac arrhythmias, metabolic acidosis, renal failure, neurotoxicity, and dermatologic complications. Patients must receive high-dose IL-2 in a facility that can provide blood pressure support, and only patients with good or intermediate prognosis by Memorial Sloan-Kettering Cancer Center (MSKCC, New York, New York) criteria and excellent organ function are candidates for therapy. Although these agents only achieve a response rate of 15%.
Major recent break-throughs have broadened our knowledge of the genetics and transduction pathways involved in various malignancies, including RCC. This greater understanding of the molecular biology of RCC has led to the identification of the vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and mammalian target of rapamycin (mTOR) signaling pathways as rational targets for anticancer therapy for metastatic RCC. Currently, two major subgroups of molecular-targeted agents are available in clinical practice: angiogenesis inhibitors, which include sorafenib, sunitinib, bevacizumab, pazopanib, and axitinib; and two specific inhibitors of the mTOR kinase, temsirolimus and everolimus.
The current mRCC treatment paradigm is typically composed of sequential monotherapy with targeted agents.
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Guidelines continue to evolve regarding which agent to use as first-line therapy in treatment-naïve patients and as second-line therapy after relapse.
For treatment-naïve patients, first-line options supported by the highest level of clinical evidence (category 1) include sunitinib, bevacizumab plus IFN-α, and pazopanib (risk classifications not specified). Temsirolimus is recommended specifically for poor-prognosis patients (high risk). Thus, for most patients with mRCC, VEGF-based therapies have become standard of care first-line treatment. However, benefits are transient. Durable response is rarely achieved, and most patients eventually develop progressive disease. Resistance to VEGF-TKIs develops at a median of 6–11 months. Second-line recommendations with highest clinical evidence (category 1) include axitinib following 1 previous systemic therapy; sorafenib, sunitinib, and pazopanib following previous cytokine therapy; and everolimus following previous VEGF-TKI therapy.
Recommendations based on lower-level clinical evidence (eg, nonrandomized controlled trials) suggest sorafenib, sunitinib, pazopanib, bevacizumab plus IFN- α, or temsirolimus as second-line treatment following relapse on VEGF-TKIs, and bevacizumab plus IFN-α or temsirolimus after failure on cytokine therapy.
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Thus, a broad range of treatment sequencing choices for first and second-line therapy, leaving clinicians with several options when making treatment decisions.