Targeted therapy for advanced renal cell cancer (RCC): a Cochrane systematic review of published randomised trials

OBJECTIVE To estimate the effects of drugs with molecular targets on patients with advanced renal cell cancer (RCC). PATIENTS AND METHODS MEDLINE, EMBASE, and the Cochrane Collaboration Library were systematically searched on-line through to June 2011 to identify eligible randomised trials. We also searched abstract reports from major oncology and urology meetings. We included randomised trials that tested a targeted agent and reported at least one outcome by allocation on an intent-to-treat basis. Completeness of ascertainment and risk of bias were assessed. Our primary outcome was progression-free survival (PFS). RESULTS In all, 28 studies met our inclusion criteria and 10 were placebo-controlled. Two studies were too small to assess, and five early studies used nonspecific anti-angiogenic agents with poor activity. In all, 15 studies, in 5587 patients, tested anti-vascular epithelial growth factor (VEGF) agents: bevacizumab (BEV), sorafenib, sunitinib, pazopanib, tivozanib, or axitinib. Three studies, in 1147 patients, tested the mammalian target of rapamycin (mTOR) inhibitors, temsirolimus or everolimus. Two studies included epidermal growth factor receptor (EGFR) inhibitors, and one tested the combination of temsirolimus plus BEV. In treatment-naive patients with mostly good-moderate prognostic risk, in separate trials oral sunitinib (one trial) and intravenous BEV plus subcutaneousinterferon-alpha (two trials) improved PFS compared with the previous standard of care interferon-alpha within randomised phase III trials. Sorafenib did not improve PFS over interferon-alpha in the first-line setting and the addition of cytokines did not improve sorafenib efficacy. In poor-risk patients, the mTOR inhibitor temsirolimus improved PFS and overall survival (OS). The studies of other VEGF inhibitors have used placebo controls no longer appropriate in this setting, although pazopanib is an approved option. Several trials examined agents in the second-line setting. After cytokine therapy, sorafenib (one study) and pazopanib (one study) prolonged PFS over placebo. A preliminary report of the investigational VEGF receptorinhibitor axitinib gave superior PFS to sorafenib after either prior cytokine or prior sunitinib treatment. After cancer progression <= 6 months of sunitinib and/or sorafenib therapy, everolimusprolonged PFS. OS was marginally improved in several studies. A more substantial effect on OS may have been diluted by crossover from control therapy to the investigational arm and/or by other anti-angiogenic agents after trial closure. Patient-reported outcomes were considered unreliable in trials without 'blinding'. A clear cell RCC (ccRCC) component was required for most trials, and information for non-ccRCCs is consequently limited CONCLUSIONS Agents targeting VEGF and mTOR pathways improve PFS in both first-line and second-line settings. These treatments rarely yield complete responses and thus are not curative. No placebo-controlled trial has reported a health-related quality of life benefit.