Systemic Therapy in Renal Cell Carcinoma: Advancing Paradigms
Renal cell carcinoma (RCC) had historically been regarded as a disease that was refractory to therapy once surgical options had been exhausted.
The 21st century has seen an explosion in the development of agents for renal-cell carcinoma (RCC), a malignancy previously considered refractory to systemic therapy beyond cytokine therapy. At this time, there are six US Food and Drug Administration (FDA)-approved agents available. In addition, there was a recent favorable review by the FDA’s Oncologic Drugs Advisory Committee of a next-generation vascular endothelial growth factor receptor (VEGFR) inhibitor, axitinib (Inlyta); other agents are in advanced testing. Moreover, while VEGF- and mammalian target of rapamycin (mTOR)-targeted therapies have become the mainstay of RCC treatment, other new molecular targets and therapeutic approaches are being developed. The availability of active agents also brings opportunities for additional clinical maneuvers, such as neoadjuvant and adjuvant therapy, as well as a need for decisions on combinatorial therapeutics in the advanced disease setting. Together, these developments and the issues they raise pose important challenges for oncologists and cancer biologists, given the limited number of patients and resources available for studies and the urgent clinical needs of the patients and families affected by RCC.
Introduction
Renal cell carcinoma (RCC) had historically been regarded as a disease that was refractory to therapy once surgical options had been exhausted. It is recognized that early intervention with nephrectomy results in excellent long-term survival. In 2005, the US Food and Drug Administration (FDA) approved the first small molecule therapy for kidney cancer, sorafenib (Nexavar). Five other approvals have followed. The introduction of these agents, which have inhibitory activity against the family of vascular endothelial growth factor receptors (VEGFRs) or the mammalian target of rapamycin (mTOR), has shifted treatment paradigms for advanced disease. Prior to this, only interferon (IFN)-alfa and interleukin (IL)-2 were used, both of which have always been viewed as highly toxic therapies with a small chance of long-term benefit. Despite the advances, however, none of the newer therapies have yielded a long-term solution for patients. Even today, the majority of patients present with locally advanced or metastatic disease, and the 5-year survival is on the order of 10% to 50%.[1] More than 60,000 new cases of RCC were expected to be diagnosed in 2011, with more than 13,000 deaths expected in the same year.[2]
This article will review the recent advances that form the current framework of therapy for RCC, as well as summarize key areas of progress and innovation in the evolving treatment paradigms for this disease.
Current Guidelines for Management of Advanced RCC
The current guidelines from the National Comprehensive Cancer Network (NCCN) continue to identify nephrectomy as an important initial consideration even in the setting of metastatic disease.[3] The current recommendations call for removal of the kidney and/or oligometastatic sites of disease prior to initiation of systemic therapy when possible. For patients with clear-cell carcinoma, there are a number of approved agents, including sunitinib (Sutent), temsirolimus (Torisel), everolimus (Affinitor), bevacizumab (Avastin; used with IFN-alfa), pazopanib (Votrient), high-dose IL-2 (Proleukin), and sorafenib (Nexavar). Despite the availability of these treatment options, clinical trials are an important consideration even in patients with untreated metastatic disease. All of the above agents have demonstrated some activity in the second-line setting. Most have shown activity in the first-line setting with the exception of everolimus, for which phase III clinical data are in the second-line setting (after progression on a tyrosine kinase inhibitor [TKI]).[4] The questions that remain unanswered by the current guidelines are: (1) what the rationales are for selecting one agent over another in the first- and/or second-line setting; (2) what role signal transduction inhibitors play in the perioperative setting; (3) what role nephrectomy plays in metastatic disease; and (4) what combinations or sequences of these therapies are effective in patients.
Signal Transduction Inhibitors
TABLE 1
Approved Systemic Agents for Renal Cell Carcinoma (RCC)