Renal Cell Cancer: What Can We Learn from Pre-Operative Studies?

Abstract

Renal cell carcinoma (RCC) affects approximately 60,000 people in Europe and in the United States each year (Ferlay et al., 2007; Jemal et al., 2010), and is associated with high rates of morbidity and mortality. The incidence of RCC is rising, perhaps because of the widespread use of abdominal imaging, resulting in an increased detection of small renal masses, and surgical intervention for these (Hollingsworth et al., 2006; Falebita et al., 2009). Surgery remains an integral part of the management of RCC, and is the only curative treatment in patients with disease confined to the kidney and its regional vasculature and lymph nodes. However, about 30% of patients are diagnosed with metastatic renal cell carcinoma (mRCC) at presentation (Motzer et al., 1996) and a similar proportion will later develop metastases (Leibovich et al., 2003). Until 2007, a combination of cytoreductive nephrectomy (CN) and immunotherapy, usually interferon-α, was considered to be the standard of care for those patients presenting with mRCC deemed fit enough, although cytokine therapy was associated with modest benefits and much toxicity (Coppin et al., 2005). The basis for nephrectomy in the context of metastatic disease was provided by two similar prospective trials which randomized patients to CN plus interferon or interferon alone. Combined analysis of the two trials demonstrated a median survival of 13.6 months for surgery plus interferon, and 7.8 months for interferon alone (HR = 0.69, 95% CI = 0.55–0.87, p = 0.002; Flanigan et al., 2004). The simplest rationale for why CN might improve survival in mRCC is a reduction in overall tumor burden, thus delaying time to a lethal burden of disease; other theories include a decrease in the amount of tumor shedding and systemic signaling from the primary renal mass, effective palliation of pain, bleeding and paraneoplastic syndromes, and removal of a source of significant immunosuppression. The latter was proposed on the basis of reports of spontaneous regression in mRCC, which occurs very rarely, but this phenomenon was also observed in series when surgery was not performed (Russo and O'Brien, 2008). Despite the evidence for a combined modality approach to mRCC in the cytokine era, these agents did not improve clinical outcomes when studied in the adjuvant setting (Pizzocaro et al., 2001; Messing et al., 2003; Atzpodien et al., 2005), and were not tested as neoadjuvant treatment due to their side effects and the very limited response rates observed in the primary tumors.