Treatment selection for patients with metastatic renal cell carcinoma

The availability of approved agents with distinct mechanisms of action has encouraged investigations to identify optimal treatment strategies for specific patients and specific tumor features. Study of tumors from patients treated with interleukin-2 (IL-2) has suggested that response was unlikely in patients with tumors with papillary features or low carbonic anhydrase IX (CAIX) expression. A model combining histologic features and CAIX expression separated patients into 2 groups of roughly equal size, with 96% of the responding patients being in the favorable prognostic group. Additional studies have begun to identify molecular features that might predict response to IL-2 therapy. In contrast, clinical trial data suggest that temsirolimus was relatively more active than interferon in patients with tumors containing non-clear cell features. Furthermore, pathologic examination showed no correlation of response with CAIX expression, but an apparent association with high expression of either phospho-AKT or phospho-S6, proteins either upstream or downstream of mammalian target of rapamycin. Preliminary investigations of tumor specimens from patients receiving vascular endothelial growth factor-targeted therapy suggested that high hypoxia-inducible factor expression might predict response. In addition, response appeared more likely in tumors with mutated or methylated VHL genes; however, substantial antitumor activity was still observed in patients with VHL wild-type tumors, particularly in patients treated with either sunitinib or axitinib, rather than bevacizumab or sorafenib. Although these data provide some guidance in treatment selection, considerably more research is needed to identify and validate selection models for particular treatment approaches, and to enable rational and optimal utilization of the available treatment options.