**10. Pazopanib (GW786034)**

Pazopanib hydrochloride is an oral, angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-kit. In October 2009, the US Food and Drug Administration–approved pazopanib for the treatment of patients with advanced renal cell carcinoma. In the international, multicenter, randomized, double-blind trial, 435 patients were randomly assigned (2:1) to receive pazopanib (n = 290) or placebo (n = 145), [26]. The study demonstrated a median progression-free survival (the primary endpoint) of 9.2 months in the pazopanib arm vs 4.2 months in the placebo arm (hazard ratio [HR]: 0.46; P <.001). This effect was observed both in patients who had not received previous treatment (HR: 0.40) as well as patients pretreated with cytokine therapy (HR: 0.54). The median duration of responses was 13.5 months. The overall survival results were not mature yet and 40% of patients died by the time of final data cut-off. Based on this study, the recommended dose of pazopanib for the treatment of advanced renal cell carcinoma is 800 mg administered orally once daily without food (at least 1 hour before or 2 hours after a meal).

### **11. BAY 73-4506**

BAY 73-4506 is an orally active, potent multikinase inhibitor targeting both tumor cell proliferation and tumor vasculature through inhibition of receptors of tyrosine kinases (VEGFR, KIT, RET, FGFR, and PDGFR) and serine/threonine kinases (RAF and p38MAPK). Previously untreated patients with predominantly clear cell RCC and measurable disease according to RECIST were enrolled in this multicenter, open-label, phase II study. Eligibility criteria included ECOG performance status 0–1, low or intermediate risk MSKCCC prognostic profiles, and adequate bone marrow and organ function. Treatment consisted of BAY 73-4506 160mg once daily on a 3 weeks on/1 week off schedule. The primary endpoint was overall response rate. Preliminary efficacy data of the 33 patients evaluable for response show a 27% partial response (PR) and a 42% stable disease (SD) rate [27].

Combinations of VEGF-targeting agents have undergone initial testing. Several combina‐ tions of these targeted agents were studied, including temsirolimus with either bevacizu‐ mab or sorafenib. Bevacizumab was also combined with sunitinib, and PTK787/ ZK222584. These combinations have frequently demonstrated enhanced toxicity, prevent‐ ing the use of the maximum single-agent doses. However, temsirolimus and bevacizu‐ mab in combination could be given at full doses of each agent without enhanced toxicity

Current Perspectives in Metastatic Renal Cell Carcinoma Treatment: The Role of Targeted Therapies

http://dx.doi.org/10.5772/54856

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The combination of sorafenib and bevacizumab showed preliminary evidence of antitumor activity, but the full doses of each agents were not reached due to dose-limiting toxicity related

Additional preclinical data have described potentially favorable immunomodulation with sunitinib therapy. Such data may provide a rationale for combination strategies with immu‐

At this point, such combinations cannot be recommended for routine use outside of a clinical trial setting.A greater understanding of the pleiotropic effects of targeted agents is needed to

Surgery is the mainstay of therapy across renal cell carcinoma stages, and surgical innovation has resulted in less invasive approaches to localized disease while preserving oncologic efficacy. Renal cell carcinoma has become a model for solid tumors in which a better under‐ standing of biologic pathways has led to systemic therapies that have dramatically improved patient outcomes. Given the availability of multiple treatment options, each with a slightly different profile of risk and benefit, there are currently multiple options for therapy. The approach to treatment requires appreciation of the risks and benefits of each of these agents,

The goal for every metastatic renal cell carcinoma patient upon presentation is to maximize overall therapeutic benefit, meaning delaying for as long possible a lethal burden of disease

primarily to hand-foot syndrome, functional stomatitis, anorexia, and fatigue.

and with encouraging clinical activity.

notherapy to optimize antitumor effect.

**14. Future directions and conclusions**

as well as knowledge of the limitations of the current data.

while maximizing quality of life and patient convenience.

V. Michalaki, M. Balafouta, D. Voros and C. Gennatas

Oncology Unit Areteion Hospital Univesity of Athens, Greece

rationally build combinations.

**Author details**
