BackgroundColorectal cancer is the 3rd most common malignancy worldwide and the 2nd leading cause of cancer-related deaths in Western countries.1 Venous drainage from the colon and rectum allows metastases to travel to the liver via the portal vein. This explains why the liver is the most common site of colorectal metastases, with approximately 50% of patientsdeveloping liver metastases. In the treatment of colorectal liver metastases (CRLM), surgical resection remains the preferred definitive therapeutic approach and offers the best long-term outcomes. Unfortunately, less than 25% of CRLM patients are eligible for resection. For patients with initially unresectable CRLM, systemic therapy can, in up to 30%, produce a tumour response that allows for resection and hence long-term disease control or even cure, albeit at the cost ofsystemic side effects. The administration of chemotherapy directly to the hepatic artery is a more selective treatment thatincreases the concentration of certain cytotoxic agents withinthe tumour while minimizing systemic side effects.2 The rationale for using the hepatic artery to deliver chemotherapy derives from the fact that liver metastases are perfused almost exclusively by the hepatic artery, whereas normal liver parenchyma receives its blood supply mainly from the portal vein.3 An important goal of this aggressive therapy in patients with initially unresectable CRLM is the conversion to resectability. The purpose of this review is to investigate the additive value of hepatic artery infusion chemotherapy (HAI) and trans-arterial chemo-embolization (TACE) over systemic chemotherapy alone in downstaging initially unresectableCRLM. HAI and TACE are both liver directed infusion chemotherapies. Research-questionIs liver directed chemotherapy (HAI and TACE) superior to systemic chemotherapy alone in downstaging patients with initially unresectable colorectal liver metastases?MethodsThe Population–Intervention–Comparator–Outcome–Study Design (PICOS) framework is used to structure the research question and to design the literature search. The population of interest is patients with unresectable CRLM; the interventions of interest are HAI and TACE; the comparator of interest is systemic chemotherapy; outcomes of interest include conversion to surgically resectable disease and tumour response (critical endpoints), disease free and overall survival(important endpoints) and adverse events and quality of life (less important endpoints). Only randomized controlled studies, comparative observational studies with multivariate analysis and/or matching will be included. If an insufficient number of studies is found non-comparative prospective phase II and III studies will be added. In order to evaluate the impact of liver directed chemotherapy (HAI and TACE) and systemic chemotherapy on downstaging CRLM, a literature search will be performed using PubMed, EMBASE and Medline. Search terms will include ‘colorectal cancer’, ‘liver metastasis’, ‘hepatic artery’ and ‘chemotherapy’.Inclusion criteria:- Publication language: English- Full text is available- Date of publication: 1st January 2000 – 8th January 2018- Study population: HumansExclusion criteria:- Studies with the wrong outcomes- Studies with the wrong therapy- Studies that evaluated chemotherapy as adjuvant after resection- Studies with the wrong primary tumour pathology- Phase I studies – Review articles References:1.) Misiakos, E., Karidis, N. and Kouraklis, G. (2011). Current treatment for colorectal liver metastases. World Journal of Gastroenterology, 17(36), p.4067.2.) Chan, D., Alzahrani, N., Morris, D. and Chua, T. (2015). Systematic review and meta-analysis of hepatic arterial infusion chemotherapy as bridging therapy for colorectal liver metastases. Surgical Oncology, 24(3), pp.162-171.3.) Kingham, T., D’Angelica, M. and Kemeny, N. (2010). Role of intra-arterial hepatic chemotherapy in the treatment of colorectal cancer metastases. Journal of Surgical Oncology, 102(8), pp.988-995.