Immunosuppression protocols for emerging oncological indications in liver transplantation: A systematic review and pooled analysis.

The evolving field of liver transplant (LT) oncology calls for tailored immunosuppression protocols to minimize the risk of tumor recurrence. We systematically reviewed the available evidence from inception to May 2023 regarding immunosuppression protocols used in patients undergoing LT for cholangiocarcinoma, neuroendocrine tumors (NET), hepatic-endothelial hemangioendothelioma, and colorectal liver metastases (CRLM) to identify common practices and to evaluate their association with oncological outcomes. Studies not involving humans, case reports, and short case series (ie, n < 10) were excluded. Among 3374 screened references, we included 117 studies involving 6797 patients distributed as follows: cholangiocarcinoma (58.1%), NETs (18.8%), hepatic-endothelial hemangioendothelioma (7.7%), CRLM (6.8%), mixed neoplasms (6.8%), or others (1.7%). Only 41% of the studies disclosed details of the immunosuppression protocol, and 20.8% of studies provided drug trough concentrations during follow-up. The immunosuppression protocols described were heterogeneous and broadly mirrored routine practices for nontumoral indications. The only exception was CRLM, where tacrolimus minimization-or even withdrawal-in combination with inhibitors of the mammalian target of rapamycin (mTORi) were consistently reported. None of the studies evaluated the relationship between the immunosuppression protocol and oncological outcomes. In conclusion, based on low-quality and indirect scientific evidence, patients with tumoral indications for LT should receive the lowest tacrolimus level tolerated under close surveillance. The combination with mTORi titrated to achieve the top therapeutic range of trough concentrations could allow complete tacrolimus withdrawal. This approach may be particularly useful in patients with cholangiocarcinoma and CRLM, in whom tumor recurrence is the main cause of death. We propose a tool for reporting immunosuppression protocols, which could be implemented in future transplant oncology studies.