Lecture : Resection remains the optimal treatment of liver metastases from colorectal cancer (LMCR) as the only one able to achieve long-term survival and a possibility of cure. However only 10-15% of patients are initially resectable and up front suitable for surgery. Despite the tremendous progress in the efficacy of chemotherapy, the prognosis of patients with unresectable liver metastases from colorectal cancer (LMCR) remains poor, with anecdotal long-term survivors. Accordingly, tumor shrinkage to induce resectability has become a main objective of the treatment strategy, since complete resection when tumor downsizing is obtained by chemotherapy, offers a 33% 5-year survival. When resectability could not be achieved, no other therapeutic option than palliative chemotherapy could be offered, with a dismal prognosis even when the disease is limited to the liver, responding well to chemotherapy, and there is no chance of long term survival. In this situation, liver transplantation (LT) is an attractive option that may offer a curative approach to patients with liver-limited disease. The results obtained up to the nineties in 50 patients transplanted in european centers, however demonstrated a 5-year survival of only 18% (1). These poor results lead to consider LMCR as a relative contraindication to LT. However, many arguments currently suggest that these results could be significantly improved : - Better expertise in LT procedure : the analysis of European experience through ELTR shows that almost 50% of deaths were related to non-tumoral causes, in a period when LT was still in a learning curve process. As survival post-LT for all indications has improved by 30% in the last 20 year-period (2) owing to the better expertise in operative and perioperative management of transplanted patients, we can logically expect also an improvement of the results of LT for LMCR especially through a reduction of non-tumoral causes of patient death - Progress in Imaging: the important progress in imaging techniques has made that optimized CT and PET-CT could now detect extrahepatic tumor with better accuracy, avoiding inappropriate indications of LT for LMCR considered in the past as liver-only disease, while having yet misdiagnosed extrahepatic tumor. - Improved efficacy of Chemotherapy: by contrast to the situation in the eighties when only 5 Fu was available with a 20% response rate, the dramatic progress accomplished by chemotherapy and targeted therapy in recent years for the treatment of metastatic colorectal cancer currently offers response rates close to 80%, allowing downsizing of liver metastases or at least stabilization of the metastatic disease. Accordingly, it becomes possible to avoid surgery or LT in a context of tumor progression, a situation well known adversely affect the outcome of operated patients (3) - Change in Immunosuppression: Traditional immunosuppressive protocols, containing drugs without antiproliferative properties targeting micro metastases post transplant, might accelerate the malignant disease. The immunosuppressive drug, sirolimus has shown a significant anti angiogeneic effect in addition to a direct inhibitory effect on tumour growth and proliferation by blocking the intracellular pathway complex mTOR (4). Everolimus have emerged with the same advantage. Therefore, immunosuppressive therapy could now be tailored to decrease the risk of tumor recurrence through the use of m-Tor inhibitors (Sirolimus, Everolimus…). - Better Knowledge of the prognostic factors of LMCR. We have learnt more in recent years about the factors involved in the outcome of patients with LMCR especially in the “oncosurge” management of these patients rate post-LT, in the need to control the disease before surgery, in the critical value of the 1st line chemotherapy, in the emergence of some predictive or prognostic tools of molecular biology (K-Ras, N-Ras, B-Raf…) Therefore, we have proposed to revisit the indication of LT for LMCR with the hypothesis that a 5-year survival of at least 50% could be achieved , improving significantly the outcome of these patients conventionally treated by palliative chemotherapy with a survival expectancy of less than 10% at 5 years. This was obtained in a preliminary study (5) and validated in a Norwegian pilot study reporting a 60% estimated survival at 5 years (6) as well as in a retrospective study showing 50% 5-year survival in 12 patiens from 4 european centers (7). However, in the former study, median follow up was limited (27 months), no attention was paid of pre-transplant chemotherapy, adjuvant chemotherapy was not given after liver transplantation and the disease free survival (DFS) in this preliminary study has still been poor with 19/21 patients who recurred after LT. For this reason we prompt a randomized trial comparing chemotherapy (expected survival: 10% at 10 years) to chemotherapy and LT (expected survival: ≥ 50% at 5 years) . This trial is still in progress with 74 included patients out of 90 designed for the study. The new anticipated insights will be: 1- To validate LT as a recognized treatment option in very well selected patients suffering from confirmed unresectable liver metastases from colorectal cancer 2- To base the selection process not only on a surgical consideration but on a multidisciplinary decision involving medical oncologists, radiologists, pathologists and surgeons 3- To reach a 5-year survival of at least 50% by restricting the candidates to patients younger than 65 yrs, with metastases responding to ≤ 3 lines of chemotherapy while remaining unresectable (as confirmed by an independent steering committee), with non mutated BRAF, CEA/ CA19-9 levels < 100 ng/ml and a previous high standard carcinological resection of the primary. Finally to combine routinely LT with perioperative chemotherapy 4- To precise the real survival benefit provided by this approach compared to modern chemotherapy treatment in a constantly evolving field of progress. References: 1. Hoti E, Adam R. Liver transplantation for primary and metastatic liver cancers. Transplant international, 2008;21(12):1107-17. Epub 2008/08/21. 2. Adam R, Lucidi V, Karam V. Liver transplantation in Europe: is there a room for improvement? Journal of hepatology. 2005;42(1):33-40. Epub 2005/01/05. 3. Adam R, Pascal G, Castaing D, Azoulay D, Delvart V, Paule B, et al. Tumor progression while on chemotherapy: a contraindication to liver resection for multiple colorectal metastases? Ann Surg. 2004; 240(6):1052-61; discussion 61-4. Epub 2004/12/01. 4. Chan S, Scheulen ME, Johnston S, Mross K, Cardoso F, Dittrich C, et al. Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J Clin Onc, 2005;23(23):5314-22. Epub 5. Foss A, Adam R, Dueland S. Liver transplantation for colorectal liver metastases: revisiting the concept. Transplant Int . 2010;23(7):679-85. Epub 2010/05/19. 6. Hagness M, Foss A, Line PD, Scholz T, Jorgensen PF, Fosby B, et al. Liver transplantation for nonresectable liver metastases from colorectal cancer. Ann Surg. 2013;257(5):800-6. Epub 2013/01/31. 7. Toso C, Pinto Marques H, Andres A, Castro Sousa F, Adam R, Kalil A, Clavien PA, Furtado E, Barroso E and Bismuth H. Liver transplantation for colorectal liver metastasis: Survival without recurrence can be achieved. Liver Transpl. 2017, 23(8): 1073-1076.