Many renal cancers 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 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, Birt-Hogg-Dubé, and hereditary leiomyomatosis-renal cell cancer.
Surgical resection of localized renal cell carcinoma can be curative for lower-stage disease, but patients with advanced or metastatic disease are rarely cured by surgery alone. 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 being tested in the neoadjuvant and adjuvant settings have created some excitement.
Seven novel targeted agents approved by the Food and Drug Administration are available for patients with metastatic disease: the tyrosine kinase inhibitors sorafenib, sunitinib, pazopanib, and axitinib; mTOR inhibitors temsirolimus and everolimus; and VEGF-inhibiting monoclonal antibody bevacizumab. The role of these therapies in either the neoadjuvant or adjuvant setting is being investigated.
The Adjuvant Sorafenib or Sunitinib in Unfavorable Renal Cell Carcinoma (ASSURE; ECOG 2805) trial 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 and to demonstrate a 25 percent reduction in the hazard rate of disease-free survival events.
The EVErolimus for Renal Cancer Ensuing Surgical Therapy (EVEREST) study (SWOG 0931), similar in design to ASSURE, examines the benefit of adjuvant systemic therapy after surgical procedures in patients with intermediate high-risk or very high-risk disease. Although sorafenib, sunitinib, 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.
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 from patients with metastatic disease to the adjuvant setting.
Dr. Meng is associate professor of urology, department of urology, University of California, San Francisco, and director of the fellowship in urologic oncology.
Dr. Nelson is Fred C. Andersen Professor of Surgery and chair, division of surgery research, Mayo Clinic College of Medicine, Rochester, MN, and Program Director of the Alliance/American College of Surgeons Clinical Research Program.