Citation: Famularo, S.; Milana, F.; Cimino, M.; Procopio, F.; Costa, G.; Galvanin, J.; Paoluzzi Tomada, E.; Bunino, F.M.; Palmisano, A.; Donadon, M.; et al. Hepatectomy versus Chemotherapy for Resectable Colorectal Liver Metastases in Progression after Perioperative Chemotherapy: Expanding the Boundaries of the Curative Intent. Cancers 2023, 15, 783. https:// doi.org/10.3390/cancers15030783 Academic Editors: Nikolaos Machairas, Stylianos Kykalos and Dimitrios Schizas Received: 2 December 2022 Revised: 23 January 2023 Accepted: 24 January 2023 Published: 27 January 2023 Copyright: © 2023 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 Article Hepatectomy versus Chemotherapy for Resectable Colorectal Liver Metastases in Progression after Perioperative Chemotherapy: Expanding the Boundaries of the Curative Intent Simone Famularo 1,2,† , Flavio Milana 1,2,† , Matteo Cimino 2 , Fabio Procopio 1,2 , Guido Costa 1,2 , Jacopo Galvanin 2 , Elisa Paoluzzi Tomada 1,2 , Francesca Margherita Bunino 1,2 , Angela Palmisano 2 , Matteo Donadon 1,2 and Guido Torzilli 1,2, * 1 Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy 2 Department of Hepatobiliary and General Surgery, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy * Correspondence: guido.torzilli@hunimed.eu † These authors shared the first authorship. Simple Summary: The aim of our study was to estimate the rate of overall survival (OS) in patients undergoing hepatectomy compared with those treated exclusively with chemotherapy in cases of dis- ease progression (PD) after perioperative chemotherapy for colorectal liver metastases. One hundred and five patients with PD to at least one line of chemotherapy were analyzed. Of these, 27 (25.7%) underwent hepatic resection; the rest prosecuted chemotherapy. After inverse probability weighting, the OS values at 1 and 3 years were 54.4 and 10.6% for CHT, and 97.8 and 49.3% for HEP (HR 0.256, 95%CI: 0.08–0.78, p = 0.033). When feasible, hepatic resection could offer a chance of a longer OS than the prosecution of chemotherapy only, even in the case of PD after perioperative treatment. Abstract: Disease progression (PD) at neoadjuvant chemotherapy for patients with colorectal liver metastases (CLMs) is considered a contraindication to hepatic resection. Our aim was to estimate the overall survival (OS) in patients undergoing surgery compared with those treated exclusively with chemotherapy in cases of PD. Patients from a single centre with PD were analyzed and subdivided into two groups: hepatectomy (HEP) versus chemotherapy (CHT). An Inverse Probability Weighting (IPW) was run to balance the baseline differences between the two groups. A Cox regression was carried out on identifying factors predicting mortality. From 2010 to 2020, 105 patients in PD to at least one line of chemotherapy were analyzed. Of these, 27 (25.7%) underwent hepatic resection. After a median follow-up of 30 (IQR 14–46) months, 61.9% were dead. The OS values at 1 and 3 years were 54.4 and 10.6% for CHT, and 95 and 46.8% for HEP (p < 0.001). After IPW, two balanced pseudopopulations were obtained: HEP = 85 and CHT = 103. The OS values at 1 and 3 years were 54.4 and 10.6% for CHT, and 97.8 and 49.3% for HEP (HR 0.256, 95%CI: 0.08–0.78, p = 0.033). After IPW, in the multivariate model, surgery resulted in the only protective variable (HR 0.198, 95%CI: 0.08–0.48, p = 0.0016). Our results show that hepatic resection could offer a chance of a longer OS than the prosecution of chemotherapy only in originally resectable patients. Keywords: colorectal liver metastases; liver resection; disease progression 1. Introduction Colorectal cancer (CRC) is the fourth most frequent tumor and the second most common cause of death worldwide [1]. About half of patients affected by colorectal cancer will develop metastases, with the liver representing the most common spreading site. In the case of colorectal liver metastases (CLM), hepatic resection represents the only curative option, with rates of overall survival (OS) at 5 and 10 years of 50 and 35%, respectively [2,3]. In recent decades, the introduction of modern chemotherapy combined with hepatectomy Cancers 2023, 15, 783. https://doi.org/10.3390/cancers15030783 https://www.mdpi.com/journal/cancers