Renal Cell Carcinoma
August 10th, 2008 | by admin |UroToday.com - Metastatic renal cell carcinoma was once considered to be a disease without significant therapeutic leads. Intravenous administration of interleukin-2 was until recently the only FDA approved treatment for metastatic renal cell carcinoma. Interleukin-2 at best results in durable complete responses in less than 10% of patients.
Considerable toxicity is encountered with this regimen, including fluid retention, renal insufficiency, and hypotension. An alternative standard of care, subcutaneously administered interferon-alpha, produces fewer durable responses with side effects including fatigue, depression, and cytopenia. There was clearly an unmet medical need for more effective and less toxic treatments for metastatic renal cell carcinoma.
A better understanding of the molecular changes responsible for the development of renal cell carcinoma has lead to a new therapeutic target: angiogenesis. The identification of the deletion or silencing of the Von Hippel Landau protein in and its role in the control of angiogenesis through HIF (Hypoxia Inducible Factor has led to clinical trials which evaluate drugs targeted to this pathway.
There are 3 ligands and receptors of the VEGF class, homo and heterodimerization can lead to different biological effects including hemangiogenesis, angiogenesis, and lymphangiogenesis. Of the 3 ligands in the VEGF class, the one most important to cancer cell angiogenesis is VEGF A. This ligand binds to the VEGF-2 receptor. There are multiple ways in which this target can be inhibited. Antibodies can prevent the binding of the VEGF-A ligand to the receptor. Drugs which work by this mechanism include bevacuzimab. The signal cascade of the VEGF a receptor can be blocked by tyrosine kinase inhibitors. Two drugs in this class include sorafanib and sunitinib.
Motzer et al evaluated the multitargeted receptor kinase receptor inhibitor sunitinib in patients with metastatic clear cell carcinoma. Both sunitinib targets the kinase activity of the both vascular endothelial growth factor receptor B and platelet derived growth factor A total of 750 patients were randomized to receive sunitinib 50 mg orally daily for 4 weeks with a 2 week break, or interferon, starting at 3 MU TIW.
The primary endpoint of his study was progression free survival, with secondary endpoints including overall survival response rate and toxicity.. Stratification factors included serum LDH, ECOG performance status, as well as presence or absence of a nephrectomy. The majority of the patients entered in this study were good to intermediate risk. When evaluated by a central review, 31% of patients treated with sunitinib and 6% of patients treated with interferon demonstrated a response.
The median progression free survival utilizing the results from this independent review was 11 months vs 5 months. This treatment effect was observed for all MSKCC risk factors including prior nephrectomy, ECOG performance status, LDH, hemoglobin and corrected calcium. Significant differences in toxicities included neutropenia (11/1) and lymphopenia in the interferon arm. Fatigue was also greater in the interferon arm. Grade 3 or 4 diarrhea (5%), hypertension (8%), and hand-foot syndrome (5%) were at a significantly higher rate in the sunitinib arm than the interferon arm. Using the functional assessment of cancer therapy-general (FACT-G) score, quality of life parameters were also significantly better in the sunitinib arm compared to the interferon arm.
The median overall survival has yet to be reached for both groups. An update of this data presented at ASCO 2008 demonstrated a superior survival for sunitinib when compared to interferon alpha.The PTEN/AKT pathway controls a variety of cellular functions, including angiogenesis, cell proliferation, gluconeogesis and apoptosis. One of the downstream elements of PTEN pathway is mTOR which acts as a sensor for metabolism. mTOR can control protein synthesis, be considered as a master switch for metabolism, proteins involved in transcription, translation and cell cycle control. Hudes et al studied CCI 779, an inhibitor of the final common pathway of ATK, mTor, in a 3 armed randomized trial where this drug was compared to interferon or the combination of CCI 779 and interferon. In contrast to the Motzer study, where patients were predominately good or intermediate risk, patients were required at entry to have 3 or more poor risk features as defined by the Motzer criteria. Patients received interferon 3 times per week, escalating to a total dose of 18 MU. TEMS 25 mg IV weekly, and Temsr combined with interferon at 6 MU. As expected the primary side effect of interferon was asthenia, with 27% of patients demonstrating grade 3 or 4 toxicity. The overall improvement in median survival of the single agent was 3.6 months, an an improved time to progression 1.8 months. Other mTOR inhibitors demonstrated promise in metastatic renal cell carcinoma. RAD001 demonstrated an improved survival compared to best supportive care in patients who failed a previous tyrosine kinase inhibitor.
Presented by: Daniel P. Petrylak, MD, at the Masters in Urology Meeting - July 31, 2008 - August 2, 2008, Elbow Beach Resort, Bermuda
UroToday - the only urology website with original content written by global urology key opinion leaders actively engaged in clinical practice.
To access the latest urology news releases from UroToday, go to:www.urotoday.com
Copyright © 2008 - UroToday
Stumble it!
