Targeted Approaches for Treating Advanced Clear Cell Renal Carcinoma

Abstract

The mainstay of any curative treatment in renal cell carcinoma (RCC) is surgery. In the case of metastatic disease at presentation, a radical nephrectomy is recommended to good performance status patients prior to the start of cytokine treatment. Interferon (IFN)-a offers in a small but significant percentage of patients advantage in overall survival. Interleukin (IL)-2-based therapy gives similar survival rates. To date, hormonal therapy and chemotherapy do not have a proven impact on survival. Recent insights demonstrate that the majority of clear cell RCC harbor abnormalities of the von Hippel-Lindau (VHL) gene. This gene plays a key role in the stimulation of angiogenesis by vascular endothelial growth factor (VEGF) in this highly vascularized tumor. This opens interesting new treatment strategies including blockade of VEGF with the monoclonal antibody bevacizumab (Avastin?) and inhibition of VEGF receptor tyrosine kinases with small oral molecules such as sunitinib (SU11248, Sutent?) or PTK787. Likewise, inhibition of the Raf kinase pathway with oral sorafenib (Bay 43-9006, Nexavar?) or inhibition of the mTOR pathway with intravenous CCI-779 are under investigation. Preliminary clinical results with all these compounds are promising, and the results of ongoing first-line phase III studies will become available in the next years.

Pretreatment with Interferon-a2a Modulates Perioperative Immunodysfunction in Patients with Renal Cell Carcinoma

“…Others have shown that IFN may increase IL-10 [26], which was possibly prevented by our maintenance dose. For the treatment of metastatic RCC, the tyrosine kinase inhibitors sorafenib and sunitinib are currently changing the therapeutic paradigm [7,27] and have led to a decrease in the use of IL-2 and IFN-α, the cytokines that have been the mainstay of therapy for 2 decades. Several studies are currently evaluating the combination of tyrosine kinase inhibitors with IFN-α, Gottlob et al [28] presented data of 40 patients with metastatic RCC treated with sorafenib and IFN-α.…”

Do the Results of the New Trials Change the Standard Treatment of Metastatic Renal Cell Cancer?

“…The overall response rate was 13.9 vs. 2.2% for controls with a 1-year survival of 53 vs. 43% and a median survival improvement of 3.8 months (p = 0.007). IL-2-based therapy gives similar survival rates [1]. In summary, these data indicate a small survival advantage for IFN-α.…”

“…In a recent review, we discussed the targeted approaches in advanced clear cell carcinoma [1]. Since that publication, the data form 3 randomized studies have been presented at several international symposia.…”

Managing Side Effects of Angiogenesis Inhibitors in Renal Cell Carcinoma

“…These new agents are small molecule inhibitors of the vascular endothelial growth factor receptor (VEGFR) and related receptors which have been proven effective in clinical trials. 2 compounds have been approved for the treatment of advanced or metastatic RCC in Europe in 2006, sunitinib and sorafenib [4]. Both compounds target VEGFR 2 and 3, and platelet-derived growth factor (PDGF) receptor β, c-KIT and FLT-3, but nevertheless differ distinctively in their profile: sunitinib also inhibits VEGFR 1, PDGFR α, RET, and CSF 1R, whereas sorafenib has been shown to block the activity of RAF kinases, which has been considered a molecular target for tumor therapies in different malignancies [5,6].…”