Cytoreductive Nephrectomy for Metastatic Renal Cell Carcinoma: A Review of the Historical Literature and Its Role in the Era of Targeted Molecular Therapy

Renal cell carcinoma presents with metastatic disease in approximately 30% cases. While surgical intervention remains the standard of care for organ confined disease, its role is limited in the management of metastatic disease. Over the last decade, cytoreductive nephrectomy prior to immunotherapy has demonstrated significant improvement in overall survival for appropriately selected patients. This review summarizes the evidence for the role of cytoreductive nephrectomy in combination with immunotherapy and discusses its potential role in the current era of targeted molecular therapy. 1. Introduction Renal cell carcinoma (RCC) accounts for approximately 5% of epithelial cancers worldwide [1] with clear cell RCC representing 85% of these cancers [2]. 30% of patients with RCC are found to have metastatic disease on staging investigations and roughly one-third of patients with organ confined disease undergoing nephrectomy eventually develop metastases [3]. Metastatic RCC (mRCC) is known to have a poor outcome with 2-year median survival rate of only 10–20% [4]. Historically, cytokine based immunotherapies have remained the mainstay of treatment for mRCC [5, 6], until more recently that has been replaced by targeted molecular therapies [7]. Radical nephrectomy as a treatment option in mRCC, (sometimes called debulking or cytoreductive nephrectomy (CRN)) is often indicated as part of an integrated management strategy. It has been previously described in historical series [8], but it was widely accepted as an effective form of treatment in combination with postoperative immunotherapy after the results of 2 prospective randomized trials were published [9, 10]. Previously, nephrectomy had been performed in mRCC patients largely as a palliative measure for control of pain, haemorrhage, paraneoplastic syndromes, and symptoms related to compression of adjacent viscera. It has been reported that nephrectomy performed for these palliative measures can result in spontaneous regression of metastases in up to 4% of cases [11]. Though the exact mechanism of these regression remains unknown, possible explanation could be that nephrectomy might remove a source of tumour-promoting growth factors or immunosuppressive cytokines [12]. 2. The Historical Series There was some evidence in historical series that patients treated with immunotherapy respond better if they have previously undergone nephrectomy. Walther et al. [8] studied 93 patients with the clinical diagnosis of mRCC and manifestations of paraneoplastic syndromes who underwent removal of the primary tumor, as well