Platinum Priority – Collaborative Review – Kidney Cancer Editorial by XXX on pp. x–y of this issue A Systematic Review of Sequencing and Combinations of Systemic Therapy in Metastatic Renal Cancer Laurence Albiges a, *, Toni Choueiri b , Bernard Escudier a , Matthew Galsky c , Dan George d , Fabian Hofmann e , Thomas Lam f , Robert Motzer g , Peter Mulders h , Camillo Porta i , Thomas Powles j , Cora Sternberg k , Axel Bex l a Institut Gustave Roussy, Villejuif, France; b Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; c The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; d Duke University Medical Center, Durham, NC, USA; e Department of Urology, Sunderby Hospital, Sunderby, Sweden; f Academic Urology Unit, University of Aberdeen, Aberdeen, UK; g Memorial Sloan-Kettering Cancer Center, New York, NY, USA; h Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands; i Medical Oncology, IRCCS San Matteo University Hospital Foundation, Pavia, Italy; j Barts Cancer Institute, London, UK; k Department of Medical Oncology, San Camillo and Forlanini Hospitals Padiglione Flajani, Rome, Italy; l Division of Surgical Oncology, Department of Urology, The Netherlands Cancer Institute, Amsterdam, The Netherlands E U R O P E A N U R O L O G Y X X X ( 2 0 1 4 ) X X X – X X X ava ilable at www.sciencedirect.com journa l homepage: www.europea nurology.com Article info Article history: Accepted April 13, 2014 Keywords: Renal cell carcinoma Tyrosine kinase inhibitor Sequence of systemic therapies Combination of systemic therapies Abstract Context: The introduction of novel molecular-targeted agents has revolutionised the man- agement of patients with metastatic renal cell carcinoma (mRCC). However, uncertainties remain over sequential or simultaneous combination therapies. Objective: To systematically review relevant literature comparing the clinical effectiveness and harms of different sequencing and combinations of systemic targeted therapies for mRCC. Evidence acquisition: Relevant databases (including Medline, Cochrane Library, trial regis- tries, and conference proceedings) were searched (January 2000 to September 2013) including only randomised controlled trials (RCTs). Risk of bias assessment was performed. A qualitative and quantitative synthesis of the evidence was presented. Evidence synthesis: The literature search identified 5149 articles. A total of 24 studies reporting on 9589 patients were eligible for inclusion; data from four studies were included for meta-analysis. There were generally low risks of bias across studies; however, clinical and methodological heterogeneity prevented pooling of data for most studies. Overall, the data showed several targeted therapies were associated with an improvement in progression-free survival in patients with mRCC. There were limited data from RCTs regarding the issue of sequencing; studies on combination therapies have been hampered by difficulties with tolerability and safety. Conclusions: Although the role of vascular endothelial growth factor/vascular endothelial growth factor receptor targeting therapies and mammalian target of rapamycin inhibition in the management of mRCC is now established, limited reliable data are available regarding sequencing and combination therapies. Although data from retrospective cohort studies suggest a potential benefit for sequencing systemic therapies, significant uncertainties remain. Presently, mRCC systemic treatment should follow international guidelines (such as the European Society for Medical Oncology, National Comprehensive Cancer Network, and European Association of Urology) for patients fit to receive several lines of systemic therapies. Patient summary: We thoroughly examined the literature on the benefits and harms of combining drugs for the treatment of kidney cancer that has spread and on the sequence in which the drugs should be given. # 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Institut Gustave Roussy, 114 rue Edouard Vaillant, Villejuif 94805, France. E-mail address: laurence.albiges@gustaveroussy.fr (L. Albiges). EURURO-5622; No. of Pages 11 Please cite this article in press as: Albiges L, et al. A Systematic Review of Sequencing and Combinations of Systemic Therapy in Metastatic Renal Cancer. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.04.006 http://dx.doi.org/10.1016/j.eururo.2014.04.006 0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.