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Cumulative exposure to tacrolimus and incidence of cancer after liver transplantation.

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.

SUBMITTER: Rodriguez-Peralvarez M

PROVIDER: S-EPMC9315045 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Cumulative exposure to tacrolimus and incidence of cancer after liver transplantation.

Rodríguez-Perálvarez Manuel M Colmenero Jordi J González Antonio A Gastaca Mikel M Curell Anna A Caballero-Marcos Aránzazu A Sánchez-Martínez Ana A Di Maira Tommaso T Herrero José Ignacio JI Almohalla Carolina C Lorente Sara S Cuadrado-Lavín Antonio A Pascual Sonia S López-Garrido María Ángeles MÁ González-Grande Rocío R Gómez-Orellana Antonio A Alejandre Rafael R Zamora-Olaya Javier J Bernal-Bellido Carmen C

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 20220331 6

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, ...[more]

PMID: 35286761

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Project description:BackgroundThe initial dose of tacrolimus after liver transplantation (LT) is critical for rapidly achieving the steady state of the drug concentration, minimizing the potential adverse reactions and warranting long-term patient prognosis. We aimed to develop and validate a genotype-guided model for determining personalized initial dose of tacrolimus.MethodsBy combining pharmacokinetic modeling, pharmacogenomic analysis and multiple statistical methods, we developed a genotype-guided model to predict individualized tacrolimus initial dose after LT in the discovery (n = 150) and validation cohorts (n = 97) respectively. This model was further validated in a prospective, randomized and single-blind clinical trial from August, 2021 to February, 2022 (n = 40, ChiCTR2100050288).FindingsOur model included donor's and recipient's genotypes, recipient's weight and total bilirubin, which achieved an area under the curve of receiver operating characteristic curve (AUC of ROC) of 0.88 and 0.79 in the discovery and validation cohorts, respectively. We found that patients who were given tacrolimus within the recommended concentration range (RCR) (4-10 ng/mL), the new-onset metabolic syndromes are lower, especially for new-onset diabetes (p = 0.043). In the clinical trial, compared to those in experience-based (EB) group, patients in the model-based (MB) group were more likely to achieving the RCR (75% vs 40%, p = 0.025) with a more variable individualized dose (0.023-0.096 mg/kg/day vs 0.045-0.057 mg/kg/day). Moreover, significantly fewer medication adjustments were required for the MB group than the EB group (2.75 ± 2.01 vs 6.05 ± 3.35, p = 0.001).InterpretationOur genotype-based model significantly improved the initial dosing accuracy of tacrolimus and reduced the number of medication adjustments, which are critical for improving the prognosis of LT patients.FundingNational Natural Science Foundation of China, Shanghai three-year action plan, National Science and Technology Major Project of China.

Project description:Everolimus-facilitated reduced-exposure tacrolimus (EVR + rTAC) at 30 days after liver transplantation (LT) has shown advantages in renal preservation. This study evaluated the effects of early initiation of EVR + rTAC in de novo LT recipients (LTRs). In HEPHAISTOS (NCT01551212, EudraCT 2011-003118-17), a 12-month, multicenter, controlled study, LTRs were randomly assigned at 7 to 21 days after LT to receive EVR + rTAC or standard-exposure tacrolimus (sTAC) with steroids. The primary objective was to demonstrate superior renal function (assessed by estimated glomerular filtration rate [eGFR]) with EVR + rTAC versus sTAC at month 12 in the full analysis set (FAS). Other assessments at month 12 included the evaluation of renal function in compliance set and on-treatment (OT) patients, efficacy (composite endpoint of graft loss, death, or treated biopsy-proven acute rejection [tBPAR] and individual components) in FAS, and safety. In total, 333 patients (EVR + rTAC, 169; sTAC, 164) were included in the FAS. A high proportion of patients was nonadherent in maintaining tacrolimus trough levels (EVR + rTAC, 36.1%; sTAC, 34.7%). At month 12, the adjusted least square mean eGFR was numerically higher with EVR + rTAC versus sTAC (76.2 versus 72.1 mL/minute/1.73 m2 , difference: 4.1 mL/minute/1.73 m2 ; P = 0.097). A significant difference of 8.3 mL/minute/1.73 m2 (P = 0.03) favoring EVR + rTAC was noted in the compliance set. Incidence of composite efficacy endpoint (7.7% versus 7.9%) and tBPAR (7.1% versus 5.5%) at month 12 as well as incidence of treatment-emergent adverse events (AEs) and serious AEs were comparable between groups. A lower proportion of patients discontinued EVR + rTAC than sTAC treatment (27.2% versus 34.1%). Early use of everolimus in combination with rTAC showed comparable efficacy, safety, and well-preserved renal function versus sTAC therapy at month 12. Of note, renal function was significantly enhanced in the compliance set.

Project description:BackgroundIndividual environmental exposures are associated with cancer development; however, environmental exposures occur simultaneously. The Environmental Quality Index (EQI) is a county-level measure of cumulative environmental exposures that occur in 5 domains.MethodsThe EQI was linked to county-level annual age-adjusted cancer incidence rates from the Surveillance, Epidemiology, and End Results (SEER) Program state cancer profiles. All-site cancer and the top 3 site-specific cancers for male and female subjects were considered. Incident rate differences (IRDs; annual rate difference per 100,000 persons) and 95% confidence intervals (CIs) were estimated using fixed-slope, random intercept multilevel linear regression models. Associations were assessed with domain-specific indices and analyses were stratified by rural/urban status.ResultsComparing the highest quintile/poorest environmental quality with the lowest quintile/best environmental quality for overall EQI, all-site county-level cancer incidence rate was positively associated with poor environmental quality overall (IRD, 38.55; 95% CI, 29.57-47.53) and for male (IRD, 32.60; 95% CI, 16.28-48.91) and female (IRD, 30.34; 95% CI, 20.47-40.21) subjects, indicating a potential increase in cancer incidence with decreasing environmental quality. Rural/urban stratified models demonstrated positive associations comparing the highest with the lowest quintiles for all strata, except the thinly populated/rural stratum and in the metropolitan/urbanized stratum. Prostate and breast cancer demonstrated the strongest positive associations with poor environmental quality.ConclusionWe observed strong positive associations between the EQI and all-site cancer incidence rates, and associations differed by rural/urban status and environmental domain. Research focusing on single environmental exposures in cancer development may not address the broader environmental context in which cancers develop, and future research should address cumulative environmental exposures. Cancer 2017;123:2901-8. © 2017 American Cancer Society.

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Cumulative exposure to tacrolimus and incidence of cancer after liver transplantation.

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Cumulative exposure to tacrolimus and incidence of cancer after liver transplantation.

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