Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Cytoreductive nephrectomy in metastatic renal cell carcinoma Vitaly Margulis, Surena F. Matin and Christopher G. Wood Introduction In 2001, the results of the European Organization for Research and Treatment of Cancer (EORTC) Genitour- inary Group trial 30 947 and the similarly designed South- west Oncology Group (SWOG) trial 8949 documented improved overall survival for patients who underwent cytoreductive nephrectomy before systemic immu- notherapy with interferon-a (IFN-a) when compared with patients treated with immunotherapy alone [1,2]. In a combined analysis of these two trials (326 patients), Flanigan et al. [3] demonstrated a median survival duration of 13.6 months for patients who underwent cytoreductive nephrectomy and IFN-a versus 7.8 months for patients treated with IFN-a alone (P ¼ 0.002). Con- sequently, the current multidisciplinary paradigm for management of metastatic renal cell carcinoma (mRCC) has consisted of cytoreductive nephrectomy followed by systemic administration of biologic disease modifiers such as IFN-a or interleukin (IL)-2. More recently, a growing understanding of the underlying molecular biology of RCC has led to the development of several systemic therapeutic agents targeting the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (MTOR) pathways. When used as first-line and second-line therapies for mRCC, these novel agents have demonstrated previously unprecedented response rates and improvements in time to progression and survival [4  –6  ]. Impressive antitumor activity and a relatively favorable toxicity profile of these novel systemic agents balanced against improved surgical techniques and out- comes have resurrected concerns about the necessity, patient selection for and timing of cytoreductive nephrect- omy in the targeted molecular therapy era. Necessity of cytoreductive nephrectomy in the targeted molecular therapy era In the era of immunotherapy, the main benefit of cytor- eductive nephrectomy stemmed from enhanced clinical Department of Urology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA Correspondence to Christopher G. Wood, MD, FACS, Associate Professor of Urology, Department of Urology – Unit 1373, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA Tel: +1 713 563 7463; fax: +1 713 794 4824; e-mail: cgwood@mdanderson.org Current Opinion in Urology 2008, 18:474–480 Purpose of review Cytoreductive nephrectomy has an established role in management of metastatic renal cell carcinoma when performed in properly selected patients prior to administration of systemic cytokine therapy. Within the past several years, novel molecular targeted agents have not only revolutionized management of metastatic renal cell carcinoma but also created controversy regarding the necessity, patient selection for and timing of cytoreductive nephrectomy. Recent findings Benefits of targeted molecular therapeutics have largely been observed in the context of prior cytoreductive nephrectomy, and limited available evidence supports cytoreductive nephrectomy in appropriately selected patients with metastatic renal cell carcinoma who are candidates for targeted systemic therapy. Presurgical systemic therapy with targeted molecular agents is an attractive paradigm, which not only offers a rational approach to select patients who are most likely to benefit from cytoreductive nephrectomy but also allows access to treated tumor tissue to study molecular mechanisms of response and resistance. Surgical approaches increasingly utilized in patients with localized kidney cancer, such as nephron-sparing and minimally invasive techniques are similarly relevant and should be utilized, when appropriate, in patients with metastatic renal cell carcinoma. Summary Cytoreductive nephrectomy should be considered to provide a survival benefit for patients with metastatic renal cell carcinoma and should be used in patients who are candidates for systemic therapy before or after surgery. Keywords cytoreductive nephrectomy, immunotherapy, renal cell carcinoma, targeted molecular therapy Curr Opin Urol 18:474–480 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins 0963-0643 0963-0643 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins