Contents lists available at ScienceDirect Critical Reviews in Oncology / Hematology journal homepage: www.elsevier.com/locate/critrevonc The best strategy for RAS wild-type metastatic colorectal cancer patients in first-line treatment: A classic and Bayesian meta-analysis Domenico Ciliberto a,1 , Nicoletta Staropoli a,1 , Francesca Caglioti a , Silvia Chiellino a , Antonella Ierardi a , Rossana Ingargiola a , Cirino Botta b , Mariamena Arbitrio c , Pierpaolo Correale d , Pierfrancesco Tassone b , Pierosandro Tagliaferri a, ⁎ a Medical Oncology, Translational Medical Oncology Units, Department of Experimental and Clinical Medicine, Magna Græcia University, Campus Salvatore Venuta, Catanzaro, Italy b Translational Medical Oncology Units, Department of Experimental and Clinical Medicine, Magna Græcia University, Campus Salvatore Venuta, Catanzaro, Italy c ISN-CNR, Roccelletta di Borgia, Catanzaro, Italy d Medical Oncology Unit, Azienda Ospedaliera “Bianchi Melacrino Morelli”, Reggio Calabria; Italy, Italy ARTICLE INFO Keywords: Metastatic colorectal cancer RAS wild-type Systemic chemotherapy Sidedness Meta-analysis ABSTRACT Background: At present, there is uncertainty on the best systemic treatment in first-line setting for RAS wild-type (WT) metastatic colorectal cancer (mCRC) patients. Indeed, several chemotherapy and biologics combinations showed an improvement on survival. We performed a systematic review with a pair-wise and bayesan meta- analysis to rank the best strategy for these patients. Methods: A systematic literature search through March 2017 was performed to evaluate the association between several treatment combinations and overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and toxicity rate (TR) in RAS WT mCRC patients. Data were extracted from studies and pooled using the random-effect model for pair-wise meta-analyses and bayesan model for network meta-analysis (NMA). Results: Eight studies with a total of 2518 individuals were included in the meta-analyses. Pooled analyses for subgroups stratified by type of schedule and tumor location demonstrated that anti-EGFR + doublet had the best OS when compared to doublet ± bevacizumab (0.767; 95%CI, 0.695–0.846; P < 0.0001). This benefit is limited to LSCC when compared to a doublet-based schedule and doublet + bevacizumab (HRs, 0.692; 95%CI, 0.596–0.804; P < 0.001; 0.706; 95%CI, 0.584–0.854; P < 0.001; respectively). No significant differences are detected in PFS, whereas the cetuximab-based regimens showed the highest ORR and TR. In NMA our ranking showed the best performance for FOLFOX + panitumumab. Conclusions: Our study indicates that FOLFOX + panitumumab has the major probability to provide an im- provement of survival with a good safety profile in patients with RAS WT mCRC with an added value from selection based on sidedness. 1. Background In the last 20 years, the mainstay chemotherapy in the management of metastatic colorectal cancer (mCRC) was represented by 5-fluor- ouracil and folinic acid (5FU/FA) with the addition of oxaliplatin and/ or irinotecan (Meyerhardt and Mayer, 2005; Tournigand et al., 2004). Several trials investigated the use of the targeted therapy in mCRC, providing evidence of benefit on all endpoints either with anti-angio- genetic and in selected patients with anti-EGFR agents for improving survival, potentially with a “continuum to care” strategy (Ciliberto et al., 2012; Goldberg et al., 2007; Kirstein et al., 2014). In the most recent studies, median overall survival (OS) of mCRC increased to almost 30 months with a significant improvement pro- duced by wider treatment experience and better understanding of tumor biology (Rossi et al., 2014). In fact, OS advantage reflects the availability of a correct diagnosis and a clear definition of treatment goal (conversion versus “palliative” CT) (Kopetz et al., 2009). Particu- larly, the achievement of long-term survival is strongly dependent on patient access to all anticancer drugs available in this setting (Grothey et al., 2004; Hubbard and Grothey, 2014). Furthermore, while bio- markers of response to anti-VEGF agents have not yet been identified, mutations in KRAS and NRAS genes (exons 2–4), are predictive of https://doi.org/10.1016/j.critrevonc.2018.03.003 Received 22 January 2018; Received in revised form 3 March 2018; Accepted 5 March 2018 ⁎ Corresponding author at: Medical Oncology Unit, Department of Experimental and Clinical Medicine, Magna Græcia University, 88100 Catanzaro, Italy. 1 C.D. and S.N. contributed equally to this work. E-mail address: tagliaferri@unicz.it (P. Tagliaferri). Critical Reviews in Oncology / Hematology 125 (2018) 69–77 1040-8428/ © 2018 Elsevier B.V. All rights reserved. T