This article is a review of Evolving Role of Novel Targeted Agents in Renal Cell Carcinoma.
In this issue of ONCOLOGY, Hutson and Figlin have done a fine job of summarizing areas of recent interest in the management of advanced renal carcinoma (RCC). They clearly show that targeted and rational approaches to the therapy of this disease, predicated on an improved understanding of its underlying biology, have led to the current state of increasing treatment success. As they note, a panoply of therapeutic agents are available, mostly focused on the mechanisms that broker the role of the tumor's vascular investment, but also reflecting the promiscuous molecular connections and relationships of genes that interact with VHL, tyrosine kinase inhibitors, mTOR, and so forth.[1-3] We are even beginning to understand some of the genetic aberrations in VHL that are associated with an increased chance of success.
The situation for patients with RCC is the most promising it has been for the past half-century. What a pity that Dr. Pieter DeMulder, an outstanding Dutch contributor to the field, succumbed to this aggressive disease before he was able to see the full gains of the work by the superb clinical research teams in genitourinary oncology.
So how do we now move forward? We are in the curious situation that we have 20 years of published "negative" results from Ron Bukowski, Bob Figlin, and Bob Motzer, who have become legendary for their commitment to stringent, high-quality research to overcome this disease. The fact that they have spent large parts of their careers honestly reporting an absence of progress gives them great credibility today when they document real progress. The promise that they have each seen in the current set of angiogenesis-active and tyrosine-kinase-inhibiting agents is believable. Another unique feature in this field is that we have a functioning, effective, and highly useful "old boy" network, including these fine researchers and their international collaborators, such as Escudier, Eisen, and others. These researchers are well positioned to identify the most exciting agents, and to develop highly effective collaborative relationships that will allow our patients to receive the maximum benefit as quickly as possible.
The way forward will be to execute well-crafted, statistically valid randomized clinical trials that will address some of the following topics:
• What is the "best agent"?
• What is the "best sequence"?
• Is multiagent superior to single-agent therapy?
• Does sequence matter?
• Is there a "best agent" and does it matter in this context?
• What are the mechanisms that underly success?
• What are the mechanisms that underly failure?
1. Motzer RJ, Rini BI, Bukowski RM, et al: Sunitinib in patients with metastatic renal cell carcinoma. JAMA 295:2516-2524, 2006.
2. Motzer RJ, Hutson TE, Tomczak P, et al: Phase III randomized trial of sunitinib malate (SU11248) versus interferon-alfa as first-line systemic therapy for patients with metastatic renal cell carcinoma. N Engl J Med 356:115-124, 2007.
3. Escudier B, Eisen T, Stadler WM, et al: Treatment Approaches in Renal cancer Global Evaulation Trial (TARGETs): A randomized, double-blind, placebo-controlled phase III trial of sorafenib, an oral multi-kinase inhibitor in advanced renal cell carcinoma. N Engl J Med 356:125-134, 2007.
4. Choueiri TK, Vaziri SA, Rini BI, et al: Use of Von-Hippel Lindau (VHL) mutation status to predict objective response to vascular endothelial growth factor (VEGF)—targeted therapy in metastatic renal cell carcinoma (RCC) (abstract 5012). J Clin Oncol 25(18S):238s, 2007.
5. Raghavan D: An essay on rearranging the deck chairs: What's wrong with the cancer trials system? Clin Cancer Res 12:1949-1950, 2006.