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Evolving Role of Novel Targeted Agents in Renal Cell Carcinoma

Evolving Role of Novel Targeted Agents in Renal Cell Carcinoma

ABSTRACT: ABSTRACT: The treatment of metastatic renal cell carcinoma (RCC) has changed dramatically over the past few years. An improved understanding of the biology of RCC has resulted in the development of novel targeted therapeutic agents that have altered the natural history of this disease. In particular, the hypoxia-inducible factor (HIF)/vascular endothelial growth factor (VEGF) pathway and the mammalian target of rapamycin (mTOR) signal transduction pathway have been exploited. Sunitinib malate (Sutent), sorafenib tosylate (Nexavar), bevacizumab (Avastin)/interferon alfa, and temsirolimus (Torisel) have improved clinical outcomes in randomized trials by inhibiting these tumorigenic pathways. Combinations and sequences of these agents are being evaluated. Other novel multitargeted tyrosine kinase inhibitors (pazopanib and axitinib) and mTOR inhibitors (everolimus) are in clinical development. Recently reported and ongoing clinical trials will help further define the role of these agents as therapy for metastatic RCC.

In the United States, more than 50,000 new cases of renal cell carcinoma (RCC) and 13,000 associated deaths are predicted for 2007.[1,2] Although surgery is a potential cure for patients with localized RCC, many patients experience recurrence after surgery or have metastatic disease at the time of initial diagnosis. In these patients, few treatment options have been available. A highly vascular disease, RCC is known to be resistant to chemotherapy, with no single agent showing significant antitumor activity.[3,4] Interferon alfa (IFN-α) and interleukin-2 (IL-2, Proleukin) have been widely utilized as treatment for metastatic RCC. However, the majority of patients do not benefit from IFN-α or IL-2, and the few responses seen are not durable—only about 10% of patients remain progression-free at 3 years.[5,6]

An improved understanding of the biology of RCC has resulted in the development of novel targeted agents that are changing the natural history of this disease. In particular, the hypoxia-inducible factor (HIF)/vascular endothelial growth factor (VEGF) pathway and the mammalian target of rapamycin (mTOR) signal transduction pathway have been exploited. Sunitinib malate (Sutent), sorafenib tosylate (Nexavar), bevacizumab (Avastin)/IFN-α, and temsirolimus (Torisel) have improved clinical outcomes in randomized phase III trials (Table 1), leading to the first new drug approvals for the treatment of advanced RCC in almost 2 decades.

Combinations and sequences of these agents are being evaluated. Other novel targeted agents have also demonstrated activity in early studies (Table 2). Given the availability of multiple treatment options, many questions emerge as to how to best integrate these new therapies into the management of metastatic RCC. Ongoing and planned clinical trials should help answer important questions that will allow the selection of patients most likely to respond to these agents. Herein, we review the rapidly evolving role of targeted therapy for RCC.

Prognostic Factors and Risk Stratification

Although pathologic stage (TNM stage) is the most powerful predictor of survival in RCC, other tumor- and patient-related factors have been demonstrated to be significant predictors of outcome in multivariate analysis. The widely used Memorial Sloan-Kettering Cancer Center (MSKCC) risk group categorization in untreated patients with metastatic RCC defines the five poor-risk features as a Karnofsky performance status (KPS) < 80, a serum calcium level > 10 mg/dL (corrected for albumin), a hemoglobin below normal, absence of prior nephrectomy, and a lactate dehydrogenase (LDH) > 1.5 times the upper limit of normal.[8,9] In the original MSKCC analysis, the median survivals were 20, 10, and 4 months for good-risk (no risk factors), intermediate-risk (1-2 risk factors), and poor-risk patients (≥ 3 risk factors), respectively.

Similar prognostic factors were subsequently demonstrated to be important for pretreated patients.[10] Pretreatment features associated with a shorter survival were low KPS, low hemoglobin, and high serum calcium. The median time to death in patients with zero risk factors was 22 months, with one of these prognostic factors was 11.9 months, and with two or more risk factors was 5.4 months. The application of the MSKCC risk group categorization or its modification has been widely applied in the pivotal trials of targeted therapy for RCC. Patient selection has allowed for risk group stratification that will enable the practicing oncologist to more appropriately select treatment options for utilizing targeted approaches in the patient cohort most likely to benefit.

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