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.

Multicenter analysis of immunosuppressive medications on the subsequent risk of malignancy in solid organ transplant recipients

“…In liver transplant recipients, cumulative exposure to tacrolimus increased the risk of cancer. 36 This finding was not unsurprising and not in opposition to our data as we did not assess cumulative exposure to tacrolimus. However, our data demonstrated a lower risk of cancer in individuals who receive tacrolimus compared to other immunosuppressive medications.…”

Recipient and Center Factors Associated With Immunosuppression Practice Beyond the First Year After Liver Transplantation and Impact on Outcomes

“…10 In addition, lower CNI exposure has also been shown to reduce post-transplant malignancy risk, which may explain why CNI monotherapy was less commonly employed in recipients with HCC in our cohort. 25,26 Given that the dominant reason for graft loss in our cohort was patient death, these reasons likely explain the improvement in graft survival found. Interestingly, similar long-term benefits of using CNI+antiM at LT hospital discharge were also observed in a prior study that did not account for regimen changes over time.…”

The Role of Immunosuppression for Recurrent Cholangiocellular Carcinoma after Liver Transplantation

“…Sirolimus has been shown to have slower HCC growth in vitro and longer disease-free survival [ 16 , 19 ]. On the other hand, a significant association was shown between cumulative CNI dose and malignancy incidence after LT, cumulative exposure to tacrolimus, and incidence of cancer after LT [ 20 ]. Recently, a significant effect of CNI reduction after diagnosis of HCC recurrence on survival was demonstrated by our group [ 21 ].…”