ARTICLE IN PRESS JID: YDLD [m5G;June 24, 2023;12:7] Digestive and Liver Disease xxx (xxxx) xxx Contents lists available at ScienceDirect Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld Meta-Analysis Efficacy of different maintenance strategies for RAS wild-type colorectal cancer: A network meta-analysis Fausto Petrelli a,∗ , Sara Cherri b , Michele Ghidini c , Gianluca Tomasello c , Antonio Ghidini d , Alberto Zaniboni b a Oncology Unit, ASST Bergamo Ovest, Treviglio (BG), Italy b Oncology Unit, Fondazione Poliambulanza, Brescia, Italy c Oncology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy d Oncology Unit, casa di cura Igea, Milano, Italy a r t i c l e i n f o Article history: Received 3 April 2023 Accepted 6 June 2023 Available online xxx Keywords: Colorectal cancer RAS wild-type Maintenance therapy Network meta-analysis a b s t r a c t Introduction: In metastatic RAS wild-type colorectal cancer (CRC), induction combination chemotherapy doublets (CT) with an anti-EGFR agent are considered the primary treatment. We performed a network meta-analysis (NMA) to compare the relative efficacy of different maintenance treatments for advanced RAS wild-type CRC. Materials and Methods: PubMed, EMBASE and Cochrane, from database inception until December 2021 were used. Randomized clinical trials enrolling adults with advanced RAS wild-type CRC and providing overall survival (OS) and/or progression-free survival (PFS) data PRISMA guidelines for NMA were fol- lowed. Between-group comparisons were estimated using hazard ratios (HRs) with 95% credible intervals (95% CrIs). Agents were ranked using surface under the cumulative ranking (SUCRA) probabilities. Results: A total of 7 randomized phase 2 trials were included (for a total of 1286 patients). Compared to depotentiation treatments, continuous CT + anti-EGFR was not significantly superior to other mainte- nance regimens for OS and was ranked as the best option for NMA (SUCRA p-score=0.69). Conversely, in the PFS analysis, single-agent fluoropyrimidines + anti-EGFR was ranked as the best treatment (SUCRA p-score=0.60). Conclusions: Maintaining chemotherapy doublet + anti-EGFR until progression appears to be the best first-line strategy in terms of OS for advanced unresectable RAS wild-type mCRC treatment. However, fluoropyrimidines single-agent + cetuximab or panitumumab represent a reasonable choice regarding PFS. © 2023 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. 1. Introduction Treatment of metastatic colorectal cancer (CRC) consists of a chemotherapy (CT) regimen plus or minus biological agents ac- cording to the molecular profile, the intention to seek a cure, pa- tient age, and comorbidities. Usually, in patients whose disease is not resectable after conversion CT, continuation of CT upon dis- ease progression or intolerable toxicity is the standard of care, al- though a clear OS compared to maintenance alone was not ob- served. Otherwise, many patients with CRC treated with first-line schedules require a treatment break for toxicity or due to per- sonal choice/physician preference, and a maintenance strategy may impact tolerability and improve treatment acceptance. Oxaliplatin- ∗ Corresponding author: Fausto Petrelli: Oncology Unit, Medical Sciences Depart- ment, ASST Bergamo Ovest, Piazzale Ospedale 1, 24047, Treviglio (BG), Italy. E-mail address: faupe@libero.it (F. Petrelli). containing regimens, in particular, may cause cumulative neurotox- icity, and patients’ withdrawal from therapy due to toxic effects may frequently occur, so that only few patients continue CT upon progression of disease. When used with anti-angiogenetic drugs (e.g., bevacizumab), a fluoropyrimidine in combination with bevacizumab is the primary maintenance choice because it does not compromise the control of disease. In fact, in patients treated with combinations of CT plus bevacizumab, the continuation of CT until progression of the disease showed no significant benefit in terms of overall survival (OS). Conversely, maintenance therapies, including a fluoropyrimi- dine ± bevacizumab, prolonged progression-free survival (PFS) and are preferred with respect to observation [1–3]. In patients who lack mutations in RAS oncogenes, a combi- nation of FOLFOX or FOLFIRI plus cetuximab or panitumumab is the cornerstone of treatment in the first-line setting. Although up- front treatment usually continues until progression or unaccept- https://doi.org/10.1016/j.dld.2023.06.008 1590-8658/© 2023 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Please cite this article as: F. Petrelli, S. Cherri, M. Ghidini et al., Efficacy of different maintenance strategies for RAS wild-type colorectal cancer: A network meta-analysis, Digestive and Liver Disease, https://doi.org/10.1016/j.dld.2023.06.008