Advances in the treatment of colorectal liver metastases

Adenocarcinoma of the colon and rectum are the third most common cancer worldwide and the second cause of cancer-related mortality. About half of these patients will develop colorectal liver metastases (CRLM) during the course of their disease. Currently, surgical resection of CRLM provides the only curative treatment for this disease. Unfortunately, liver metastases are resectable in only 1 in 5 of patients at diagnosis. Systemic therapies are therefore of major importance in the treatment of patients with colorectal liver metastases. Unfortunately, there has been little evolution in the available cytotoxic chemotherapies and, where targeted immunotherapy appears to be successful in other cancer types, we see that immunotherapy has little effect on colorectal cancers and CRLM. The aim of this research is twofold: first of all to better understand the tumor biology of colorectal liver metastases so that new and more efficient systemic therapies could be developed. On the other hand, we need to optimize the surgical treatment of colorectal liver metastases to save as much functional parenchyma as possible during a surgical procedure and, in addition, the interventions are also accompanied by the lowest possible morbidity and mortality to promote recovery after surgery. This project will consist of 2 main parts. The first is a translational research chapter in which we will try to better map tumor biology, the cell types present in CRLM and their mutual interaction. Based on previous research, we hypothesized that cytotoxic chemotherapy is necessary to trigger an immune response against CRLM through T-cell activation. A second hypothesis is that the macrophages present in CRLM, which will clear up dead cells after cell death by cytotoxic chemotherapy, can inhibit the immune response of the T cells. If these hypotheses can be confirmed, this may provide an explanation why current immunotherapies do not work in CRLM and offer us useful targets for the development of new immune based (combination) therapies. Samples from 10 chemo-naive patients and 10 patients pre-treated with cytotoxic chemotherapy will be collected from patients undergoing surgical resection of CRLM. Molecular analyzes at the individual cell level (single cell RNA sequencing, Bulk TCR, Bulk RNA sequencing and Whole exome sequencing) will provide an in-depth profile of tumor biology, the immune cells present in CRLM and their mutual interactions. In this way, we will try to demonstrate changes in T cells and macrophages after chemotherapy to test our hypotheses. The second part of the research project consists of 3 clinical projects where we will assess the impact and our personal experience of using parenchyma sparing and minimally invasive surgical techniques (local ablation therapy - LAT, laparoscopy, robot-assisted surgery) for the treatment of CRLM. In a first project, we will identify prognostic factors for survival and recurrence rates after thermal ablation of colorectal liver metastases in a retrospective monocentric cohort study (321 consecutive patients). As a second project, we aim to study the results of open and laparoscopic liver resections between 2010 and 2017 to determine predictors for serious complications and survival. The clinical, surgical, pathological and oncological outcomes of robotic-assisted liver resections will be prospectively studied in a third project over the course of 2 years and we will also document the learning curve and cost analysis of the use of this new technology. A third and last project will conduct a prospective studie to evaluate the impact op pre-operative 3d visualisation of the liver on short term outcomes for liver resection for colorectal liver metastasis.