High trough levels of everolimus combined to sorafenib improve patients survival after hepatocellular carcinoma recurrence in liver transplant recipients

Abstract

Recurrence of hepatocellular carcinoma (HCC) following liver transplantation (LT) occurs in 10%-20% of patients transplanted for HCC. The treatment of HCC recurrence after LT remains a challenge. Consecutive patients who underwent LT for HCC between 2005 and 2015 at our center were recruited. Characteristics of patients with recurrence, modalities of treatment and outcome were collected retrospectively. Patient survival was analyzed according to HCC recurrence therapeutic strategy. Among 306 transplanted patients, 43 patients (14.1%) developed recurrence with a median survival time after recurrence of 10.9 months (95%CI: 6.6À18.6). Survival of patients treated with Sorafenib (SOR) and everolimus (EVL) (n = 19) was significantly better than that of the group treated with other strategies (n = 24) (P = 0.001). Multivariable analysis demonstrated that SOR plus EVL therapy and absence of dissemination at diagnosis of recurrence were independent predictive factors of prolonged survival after recurrence. Among the patients who treated with EVL, survival of patients with controlled EVL blood trough levels ≥5 ng/ml was significantly better compared to those with EVL trough levels <5 ng/ml (P = 0.021). Combination therapy of sorafenib and everolimus was an independent predictor for better survival after HCC recurrence. Patients with controlled everolimus trough level ≥5 ng/ml might get the best survival benefit.

Immunotherapy for hepatocellular carcinoma recurrence after liver transplantation, can we harness the power of immune checkpoint inhibitors?

“…On the other hand, the everolimus-based regimen was also proved to be effective in patients with post-LT HCC recurrence. Patients who had high serum trough levels of everolimus (more than 5 ng/ml) had better survival compared to those treated with less than 5 ng/ml ( 34 ). In addition, early introduction of everolimus with reduced-CNIs is also associated with a significant renal benefit compared with CNsI-based immunosuppressive regime ( 35 ).…”

The Importance of the Immunosuppressive Regime on Hepatocellular Carcinoma Recurrence After Liver Transplantation

“…However, switching to mTORi-containing modifications or minimizing IS is the two preferred treatment approaches today. The literature reflects a tendency towards adding or switching to mTORi containing IS modification [24][25][26][27][28][29][30]. Even in a recent study emphasizing that minimizing IS provides a significant survival advantage, it is noteworthy that while the authors went for significant dose reduction in IS regimens containing CNIs, MMF, and steroids, they increased the use of mTORi instead of decreasing it after the diagnosis of recurrent HCC [26].…”

“…Thus, it would not be wrong to say that there is a general trend towards IS modification involving mTORi in the case of P-Tx-rHCC. It is understood from the literature that there is a tendency towards a modification in the form of transition to IS protocols containing mTORi [24][25][26][27][28][29][30]. Even in a recent study emphasizing that minimizing IS provides a significant survival advantage, it is noteworthy that, while the authors went for significant dose reduction in IS regimens containing CNIs, MMF, and steroids, they increased the use of mTORi instead of decreasing it after the diagnosis of recurrent HCC [26].…”

“…In the most recent study on the use of mTORi and sorafenib in P-Tx-rHCC [25], 43 patients with post-transplant recurrence were analyzed and the median post-recurrence survival of 19 patients who received a combination of sorafenib with everolimus (Eve) was 19.9 months; while using other treatments, the median survival was 6.3 months (p = 0.0006). Among the patients who were of treated with Eve, survival of patients with controlled blood trough levels of ≥ 5 ng/ ml was significantly better compared to those with Eve trough levels of < 5 ng/ml (p = 0.021).…”

Impact of very early introduction of everolimus on liver regeneration after partial liver transplantation in rats

“…The introduction of everolimus (EVR) allows less use of calcineurin inhibitors, which has led to greater preservation of renal function and reduced the risk of post‐liver transplantation (LT) recurrence of hepatocellular carcinoma 1–4 . It has been suggested that early introduction of EVR after LT is more effective than late introduction with respect to yielding these benefits 5–7 .…”