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Impact of Early Initiated Everolimus on the Recurrence of Hepatocellular Carcinoma After Liver Transplantation

Rodríguez-Perálvarez, Manuel, PhD1; Guerrero, Marta, MD1; Barrera, Lydia, MD2; Ferrín, Gustavo, PhD1; Álamo, Jose M., PhD2; Ayllón, María D., PhD1; Artacho, Gonzalo Suarez, MD2; Montero, José L., PhD1; Briceño, Javier, PhD1; Bernal, Carmen, MD2; Padillo, Javier, PhD2; Marín-Gómez, Luis M., PhD2; Pascasio, Juan M., PhD2; Poyato, Antonio, PhD1; Gómez-Bravo, Miguel A., PhD2; De la Mata, Manuel, PhD1

doi: 10.1097/TP.0000000000002270
Original Clinical Science—Liver

Background Many centers implement everolimus-based immunosuppression in liver transplant patients with hepatocellular carcinoma. We aimed to explore the potential impact of early initiated everolimus on tumor recurrence after liver transplantation.

Methods This study included 192 patients with hepatocellular carcinoma undergoing liver transplantation among who 64 individuals were prospectively enrolled (2012-2015) and received early initiated everolimus (ie, started between postoperative day 15 to 21), whereas the remaining 128 patients acted as historical controls without everolimus. Propensity score matching was performed to ensure comparability. Multivariate Cox regression and competing risks analysis were used to control for potential confounders.

Results Patients with and without everolimus were comparable in terms of number of nodules (P = 0.37), total tumor diameter (P = 0.44), Milan criteria fulfillment (P = 0.56), and histological differentiation (P = 0.61), but there were increased microvascular invasion rates in the everolimus group (26.5% vs 13.3%; P = 0.026). Tumor recurrence rates were similar with and without everolimus (10.9% vs 9.9% at 36 months respectively; P = 0.18). After controlling for microvascular invasion among other potential confounders, everolimus had no significant impact on tumor recurrence, neither in the multivariate Cox regression (relative risk = 3.23; P = 0.09), nor in the competing risks analysis for tumor recurrence-death (relative risk = 1.02; P = 0.94). Patients receiving everolimus had reduced tacrolimus trough concentrations and lower serum creatinine within the first 18 months postliver transplantation.

Conclusion Everolimus may not be universally prescribed to prevent tumor recurrence in liver transplant patients with hepatocellular carcinoma. Future randomized trials should be focused on patients with histological features of increased tumor aggressiveness, in whom the potential benefit would be higher.

The authors of this retrospective study compare the outcome of liver transplant patients with hepatocellular carcinoma (HCC) who receive everolimus or standard immunosuppression without observing significant differences of HCC recurrence rates.

1 Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain.

2 General Surgery and Transplantation, Hospital Virgen del Rocío, IBIS, Sevilla, Spain.

Received 5 January 2018. Revision received 28 April 2018.

Accepted 2 May 2018.

The authors declare no conflict of interest.

M.R.-P. and M.G. contributed equally to the present article.

The present study was supported by the Instituto de Salud Carlos III (FIS PI11-02867 and PI14/01469) and co-funded by FEDER. Additional funding was granted by the Andalusian Society for Organ Transplantation (SATOT). M.R-P is a recipient of the Physician Scientist Fellowship awarded by the European Association for the Study of the Liver (EASL). The financial sources listed above had no vested interest in the results of the study.

M.dlM. and M.R.-P. conceived the original idea and designed the study. L.B., G.F., M.D.A., G.S.-A., C.B., and J.M.P. enrolled patients and acquired the data. M.R.-P., M.G., and A.P. analyzed the data. M.R.-P. and M.G. drafted the article. J.L.M., J.B., J.P., L.M.M.-G. and M.dlM. critically revised the article for important intellectual content.

Correspondence: Manuel de la Mata, MD, PhD. Department of Hepatology and Liver Transplantation at the Reina Sofía University Hospital, Avda/ Menéndez Pidal s/n, 14004, Córdoba, Spain. (

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