Complications of Treatment A contemporary update on rates and management of toxicities of targeted therapies for metastatic renal cell carcinoma Ahmed Alasker a,d,1 , Malek Meskawi a,⇑,1 , Maxine Sun a , Salima Ismail a,d , Nawar Hanna a,d , Jens Hansen a,c , Zhe Tian a , Marco Bianchi a,b , Paul Perrotte d , Pierre I. Karakiewicz a,d a Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Center, Montreal, Canada b Department of Urology, Urological Research Institute, Vita-Salute San Raffaele University, Milan, Italy c Martini-Clinic, Prostate Cancer Center Eppendorf-Hamburg, Hamburg, Germany d Department of Urology, University of Montreal, Montreal, Canada article info Article history: Received 28 June 2012 Received in revised form 3 December 2012 Accepted 7 December 2012 Keywords: Side effects Targeted therapy Renal cell carcinoma Adverse events abstract Background: To provide an updated review of adverse events associated with sunitinib, pazopanib, bevacizumab, temsirolimus, axitinib, everolimus and sorafenib and their management. Materials and methods: We performed a PubMed and Cochrane-based review of side effects associated with the seven agents including product monographs to provide an outline of treatment measures aiming to reduce their toxicities. Subject and outcome of interest, design type, sample size, pertinence and qual- ity, and detail of reporting were the indicators of manuscript quality. Results: All targeted therapies cause adverse events. Most adverse events may be prevented or tested before they escalate to severe levels. Conclusion: Prevention, early recognition, and prompt management of side effects are of key importance and avoid unnecessary dose reductions, which may undermine treatment efficacy. Ó 2012 Elsevier Ltd. All rights reserved. Introduction A paradigm shift occurred in the management of metastatic re- nal cell carcinoma (mRCC) with the advent of novel biological agents targeting vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways. The advent of these agents prompted a considerable improvement in progres- sion-free survival (PFS) and overall survival (OS) of mRCC patients in recent years. This was contingent upon the use, efficacy and tol- erability of several sequential targeted therapies (TTs). 1–13 Of those, four agents (sunitinib, bevacizumab, temsirolimus and paz- opanib) demonstrated efficacy in first-line therapy. 1–8 Three other agents (sorafenib, axitinib and everolimus) showed efficacy in sec- ond or subsequent treatment lines. 9–13 However, toxicity and suboptimal tolerability of some agents may undermine their benefits. In consequence, early identification, prevention and/or treatment of toxicities are crucial to maximize their efficacy. Based on these considerations, we provide an exhaustive and comprehensive assessment of toxicities that may be expected with each of these agents. Additionally, we provide an outline of toxicity management to ensure tolerability and the attainment of maximal efficacy. Materials and methods We performed a systematic English language literature review using the keywords ‘‘bevacizumab,’’ ‘‘sorafenib,’’ ‘‘sunitinib,’’ ‘‘temsirolimus,’’ ‘‘everolimus,’’ ‘‘pazopanib,’’ ‘‘axitinib’’, ‘‘toxicity,’’ ‘‘adverse effects,’’ and ‘‘side effects’’ within the PubMed and Cochrane. The search was limited to English literature, humans, and persons aged 18 years and older. Subject and outcome of inter- est, design type, sample size, pertinence and quality, and detail of reporting were the indicators of manuscript quality. Due to avail- ability of only one phase III trial for each of addressed molecules, except for bevacizumab and sorafenib with more than one phase III trial available, all phase III data were included in the current manuscript. 1–13 Moreover, individual patient data were not consid- ered. As a result, strict adherence to the Oxman criteria, 14 which is based on a Overview Quality Assessment Questionnaire (OQAQ) of 0305-7372/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ctrv.2012.12.006 ⇑ Corresponding author. Address: Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Center (CHUM), 264 Boul. Rene-Levesque East, Suite 228, Montreal QC, Canada H2X 1P1. Tel.: +1 514 890 8000x35336; fax: +1 514 227 5103. E-mail addresses: ahmed.alasker@umontreal.ca (A. Alasker), malek.meskawi@ gmail.com (M. Meskawi), maxine.sun@gmail.com (M. Sun), ismail.salima@gmail. com (S. Ismail), nawarhanna10@gmail.com (N. Hanna), jenshansen81@gmail.com (J. Hansen), zhe.tian24@gmail.com (Z. Tian), bianchihsr@gmail.com (M. Bianchi), paul.perrotte@umontreal.ca (P. Perrotte), pierre.karakiewicz@umontreal.ca (P.I. Karakiewicz). 1 These authors contributed equally to this work. Cancer Treatment Reviews 39 (2013) 388–401 Contents lists available at SciVerse ScienceDirect Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv