  Citation: Gazzaniga, G.; Villa, F.; Tosi, F.; Pizzutilo, E.G.; Colla, S.; D’Onghia, S.; Di Sanza, G.; Fornasier, G.; Gringeri, M.; Lucatelli, M.V.; et al. Pneumatosis Intestinalis Induced by Anticancer Treatment: A Systematic Review. Cancers 2022, 14, 1666. https://doi.org/10.3390/ cancers14071666 Academic Editor: Brigitte Bauvois Received: 15 February 2022 Accepted: 22 March 2022 Published: 25 March 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). cancers Systematic Review Pneumatosis Intestinalis Induced by Anticancer Treatment: A Systematic Review Gianluca Gazzaniga 1,† , Federica Villa 2,3,† , Federica Tosi 3 , Elio Gregory Pizzutilo 2,3 , Stefano Colla 1 , Stefano D’Onghia 1 , Giusy Di Sanza 1 , Giulia Fornasier 1 , Michele Gringeri 1 , Maria Victoria Lucatelli 1 , Giulia Mosini 1 , Arianna Pani 2,4 , Salvatore Siena 2,3 , Francesco Scaglione 2,4,‡ and Andrea Sartore-Bianchi 2,3, * ,‡ 1 Department of Medical Biotechnology and Translational Medicine, Postgraduate School of Clinical Pharmacology and Toxicology, Università degli Studi di Milano, 20122 Milan, Italy; gianluca.gazzaniga@unimi.it (G.G.); stefano.colla@unimi.it (S.C.); stefano.donghia@unimi.it (S.D.); giusy.disanza@unimi.it (G.D.S.); giulia.fornasier@unimi.it (G.F.); michele.gringeri@unimi.it (M.G.); mariavictoria.lucatelli@unimi.it (M.V.L.); giulia.mosini@unimi.it (G.M.) 2 Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, 20122 Milan, Italy; federica.villa@ospedaleniguarda.it (F.V.); elio.pizzutilo@unimi.it (E.G.P.); arianna.pani@ospedaleniguarda.it (A.P.); salvatore.siena@unimi.it (S.S.); francesco.scaglione@unimi.it (F.S.) 3 Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, 20162 Milan, Italy; federica.tosi@ospedaleniguarda.it 4 Department of Chemical-Clinical and Microbiological Analyses, Grande Ospedale Metropolitano Niguarda, 20162 Milan, Italy * Correspondence: andrea.sartorebianchi@unimi.it; Tel.: +39-0264442291 † These authors contribute equally to this work. ‡ These authors contribute equally to this work. Simple Summary: Anticancer treatments commonly cause adverse events (AE). Among others, pneumatosis intestinalis (PI) is reported to be infrequent, though it can lead to severe consequences. The aim of our systematic review was to investigate the concurrency of PI and oncological therapy exposure; moreover, we defined the characteristics of patients and the primarily involved tumor types. We analyzed 88 different episodes of PI. The median time of onset was 6 weeks and oncological patients with respiratory system cancers and those treated with targeted therapies appeared be at higher risk. Symptoms were frequently mild to absent; nevertheless, life-threatening complica- tions were reported. Therefore, this AE, although uncommon, should be considered in the case of specific symptoms. Potential pharmacological mechanisms of anticancer drugs in inducing PI are also discussed. Abstract: Pneumatosis intestinalis (PI) is a rare condition due to the presence of gas within the bowel wall; it is mainly caused by endoscopic procedures, infections and other gastrointestinal diseases. Oncological therapies have been reported to be a cause of PI as well, but their role is not clearly defined. This systematic review investigates the concurrency of PI and antitumor therapy in cancer patients, considering both solid tumors and onco-hematological ones. We performed a literature review of PubMed, Embase and the Web of Science up to September 2021 according to the PRISMA guidelines. A total of 62 papers reporting 88 different episodes were included. PI was mainly reported with targeted therapies (sunitinib and bevacizumab above all) within the first 12 weeks of treatment. This adverse event mostly occurred in the metastatic setting, but in 10 cases, it also occurred also in the neoadjuvant and adjuvant setting. PI was mostly localized in the large intestine, being fatal in 11 cases, while in the remaining cases, symptoms were usually mild, or even absent. A significant risk of PI reoccurrence after drug reintroduction was also reported (6/18 patients), with no fatal outcomes. Potential pharmacological mechanisms underlying PI pathogenesis are also discussed. In conclusion, although uncommonly, PI can occur during oncological therapies and may lead to life-threatening complications; therefore, consideration of its occurrence among other adverse events is warranted in the presence of clinical suspicion. Cancers 2022, 14, 1666. https://doi.org/10.3390/cancers14071666 https://www.mdpi.com/journal/cancers