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Multicenter Study
. 2022 Jun;22(6):1671-1682.
doi: 10.1111/ajt.17021. Epub 2022 Mar 31.

Cumulative exposure to tacrolimus and incidence of cancer after liver transplantation

Manuel Rodríguez-Perálvarez  1   2 , Jordi Colmenero  2   3 , Antonio González  4 , Mikel Gastaca  5 , Anna Curell  6 , Aránzazu Caballero-Marcos  2   7 , Ana Sánchez-Martínez  8 , Tommaso Di Maira  2   9 , José Ignacio Herrero  2   10 , Carolina Almohalla  11 , Sara Lorente  12 , Antonio Cuadrado-Lavín  13 , Sonia Pascual  2   14 , María Ángeles López-Garrido  15 , Rocío González-Grande  16 , Antonio Gómez-Orellana  17 , Rafael Alejandre  1 , Javier Zamora-Olaya  1 , Carmen Bernal-Bellido  18 ; Chronic immunosuppression, cancer Spanish consortium
Collaborators, Affiliations
Multicenter Study

Cumulative exposure to tacrolimus and incidence of cancer after liver transplantation

Manuel Rodríguez-Perálvarez et al. Am J Transplant. 2022 Jun.

Abstract

Cancer is the leading cause of death after liver transplantation (LT). This multicenter case-control nested study aimed to evaluate the effect of maintenance immunosuppression on post-LT malignancy. The eligible cohort included 2495 LT patients who received tacrolimus-based immunosuppression. After 13 922 person/years follow-up, 425 patients (19.7%) developed malignancy (cases) and were matched with 425 controls by propensity score based on age, gender, smoking habit, etiology of liver disease, and hepatocellular carcinoma (HCC) before LT. The independent predictors of post-LT malignancy were older age (HR = 1.06 [95% CI 1.05-1.07]; p < .001), male sex (HR = 1.50 [95% CI 1.14-1.99]), smoking habit (HR = 1.96 [95% CI 1.42-2.66]), and alcoholic liver disease (HR = 1.53 [95% CI 1.19-1.97]). In selected cases and controls (n = 850), the immunosuppression protocol was similar (p = .51). An increased cumulative exposure to tacrolimus (CET), calculated by the area under curve of trough concentrations, was the only immunosuppression-related predictor of post-LT malignancy after controlling for clinical features and baseline HCC (CET at 3 months p = .001 and CET at 12 months p = .004). This effect was consistent for de novo malignancy (after excluding HCC recurrence) and for internal neoplasms (after excluding non-melanoma skin cancer). Therefore, tacrolimus minimization, as monitored by CET, is the key to modulate immunosuppression in order to prevent cancer after LT.

Keywords: hepatocellular carcinoma; immunosuppression; malignancy; neoplasm; tacrolimus.

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Figures

FIGURE 1
FIGURE 1
Approximate equivalence between different strata of cumulative exposure to tacrolimus and target trough concentrations
FIGURE 2
FIGURE 2
Cumulative incidence of any type of cancer after liver transplantation in 2465 patients according to the number of clinical predictors (age >50 years old, male sex, alcoholic liver disease, and active smoking at waitlist inclusion). For this analysis, 30 patients who did not have reliable data of smoking history were excluded
FIGURE 3
FIGURE 3
Kaplan–Meier curves showing survival rates in 491 patients with cancer after LT according to the stage of diagnosis (A) and initial therapy (B)
FIGURE 4
FIGURE 4
Flowchart showing the study population. The eligible cohort was formed by 2495 patients who underwent liver transplantation at 16 liver transplantation institutions in Spain and received tacrolimus‐based immunosuppression within the first 12 months
FIGURE 5
FIGURE 5
Smooth splines showing the relationship between cumulative exposure to tacrolimus and risk of cancer after liver transplantation in 425 cases and 425 matched controls. The effect of cumulative exposure to tacrolimus at (A) 3 months and (B) 12 months
See this image and copyright information in PMC

References

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