Over the past decade, significant changes have occurred in the presentation, understanding, and treatment of renal cell carcinoma. Increased imaging has led to the incidental identification of most renal masses, with a concomitant migration of tumors to a lower stage at the time of diagnosis. This, in turn, has led to the opportunity to change the surgical management of renal cancers so that many tumors can now be managed in a minimally invasive fashion with either laparoscopic or robotic-assisted surgery. Potentially of greatest importance is the elucidation of the biological basis of sporadic as well as hereditary forms of renal carcinomas.
Most renal tumors arise from loss of function of the von Hippel-Lindau (VHL) gene and resultant activation of the hypoxic response, including upregulation of hypoxia inducible factor leading to vascular endothelial growth factor induction and ultimately angiogenesis. In addition to the VHL syndrome, other hereditary forms include hereditary papillary renal carcinoma (MET gene), Birt-Hogg-Dubé (FLCN gene), and hereditary leiomyomatosis-renal cell cancer (fumarate hydratase gene).
The most revolutionary change in the management of renal cell carcinoma may be the approach and options for advanced disease. Surgical resection of localized renal cell carcinoma can be curative for lower-stage disease and remains the standard initial intervention. However, patients with advanced or metastatic disease are rarely cured through surgical procedures alone, and systemic treatments often benefit these patients. Historically, traditional chemotherapy has had poor response rates and systemic options have been focused on immunotherapy with cytokines, such as interleukin-2 and interferon alfa. Hence, new targeted agents that are routinely used for metastatic disease and being tested in the neoadjuvant and adjuvant settings have created some excitement among urologists and medical oncologists.
Improvements in the understanding of the molecular pathophysiology of renal cell carcinoma have led to the development of several novel targeted agents, with seven approved by the Food and Drug Administration (FDA) and currently available for patients with metastatic disease. These agents include the tyrosine kinase inhibitors sorafenib (approved in 2005), sunitinib (2006), pazopanib (2011), and axitinib (2012); mTOR inhibitors temsirolimus (2007) and everolimus (2009); and VEGF-inhibiting monoclonal antibody bevacizumab (2009). The role of these therapies in either the neoadjuvant or adjuvant setting remains unclear and is an active area of investigation.
The Adjuvant Sorafenib or Sunitinib in Unfavorable Renal Cell Carcinoma (ASSURE; ECOG 2805) trial completed accruing patients in September 2010. The trial, activated April 24, 2006, has enrolled 1,865 patients randomized to one year of sunitinib, sorafenib, or placebo therapy after surgical excision of the primary tumor. The current standard of care, even for patients with high-risk pathologic features, is surveillance after surgical procedures when no evidence of residual disease can be found. Thus, the study is designed to determine whether adjuvant targeted therapy improves cancer-specific survival.
Eligible patients included those having: (1) intermediate risk of relapse (≈33 percent) with pT1G3-4, pT2, or pT3aG1-2 tumor; (2) high risk of relapse (50 percent to 60 percent) with pT3aG3-4, +adrenal involvement, pT3b-c, pT4; or (3) very high risk of relapse (≈66 percent) with N+ disease. Results are expected to be available in the next few years, and the study was designed to demonstrate a 25 percent reduction in the hazard rate of disease-free survival events. The trial also included correlative science to examine items such as microvessel density and associated markers of angiogenesis; pharmacokinetics and effect of cytochrome p3A4/5, B-raf, and VEGF polymorphisms on outcome; and DNA hypermethylation of P16 and VHL.
A recently endorsed trial is the EVEolimus for Renal Cancer Ensuing Surgical Therapy (EVEREST) study (SWOG 0931). Similar in design to ASSURE, EVEREST examines the benefit of adjuvant systemic therapy after surgical procedures in patients with intermediate high-risk (pT1b G3-4; pT2 G1-4; pT3a G1-2) or very high-risk disease (pT3a G3-4; +adrenal involvement; pT3b-c; pT4; N+). Although sorafenib, sunitnib, and everolimus are all used clinically, sorafenib and sunitinib are tyrosine kinase inhibitors, whereas everolimus is an mTOR inhibitor. An estimated 1,218 patients will be randomized to either everolimus or placebo, stratified by pathologic stage, histologic subtype, and performance status. It will be interesting to see which agent(s) proves to be beneficial in the adjuvant setting, whether there are significant differences in side effect profile, and which population benefits the most.
Similar ongoing adjuvant trials include the Pfizer-sponsored S-TRAC trial (n=720) comparing sunitinib with placebo and the Medical Research Council SORCE trial (n=1,656) comparing sorafenib with placebo. Other agents are also being tested in the adjuvant setting, including pazopanib (PROTECT), as well as those that exploit the purported immunogenicity of renal cell carcinoma.
An accrued phase III trial has tested the antibody girentuximab, which binds specifically to carbonic anhydrase IX (G250 antigen) that is expressed on the cell surface of clear renal cell carcinomas. Future trials may extend the potential role of cell-based immunotherapy, such as RNA-loaded autologous dendritic cells, from patients with metastatic disease to the adjuvant setting.