What Is the Impact of Mammalian Target of Rapamycin Inhibitors on Hepatocellular Carcinoma Recurrence After Liver Transplantation.

Abstract

We read with great interest the article by Lee et al1 regarding the pooled data from 2 randomized trials evaluating the 24 mo safety and efficacy of mammalian target of rapamycin inhibitor (mTORi) everolimus with reduced tacrolimus (EVR with reduced tacrolimus, n = 387) versus standard tacrolimus (n = 385) regimen after liver transplantation (LT). Interestingly, the authors found that the recurrence of hepatocellular carcinoma (HCC) was numerically lower, although not statistically significant, in patients transplanted beyond Milan with EVR with reduced tacrolimus than in patients with standard tacrolimus (5.9% versus 23.1%; P = 0.215), whereas no difference was found in those within Milan criteria (2.9% versus 2.1%; P = 1.0). The authors mentioned that these findings were similar to our meta-analysis,2 but in fact, in our study,2 we had found that the rate of HCC recurrence was significantly lower in LT recipients under mTORi than in those under calcineurin inhibitors (CNIs; tacrolimus or cyclosporine), but only in those with pre-LT HCC within Milan criteria (mTORi: 3.8% versus CNIs: 9.2%; P = 0.03); comparatively, the rate of HCC recurrence was similar among patients transplanted for HCC outside Milan criteria (mTORi: 29.5% versus CNIs: 29.2%; P = 1.0). Indeed, our findings were confirmed in the SiLVER randomized trial,3 in which sirolimus (another mTORi) showed a benefit only in low-risk LT recipients (ie, those with HCC within Milan criteria pretransplant). Although Lee et al1 did not provide any explanation, these discordance results could not be attributed to different anti neoplastic properties between sirolimus and EVR. (In fact, in our meta-analysis, HCC recurrence was significantly more frequently observed in patients who received sirolimus than in those who received EVR [10.5% versus 4.1%; P = 0.02]). The absence of any clear benefit from EVR administration regarding HCC recurrence might be attributed to the relatively low rates of HCC recurrence in both groups under the mTORi and the mTORi-free regimens at 24 mo (3.3% and 6.3%, respectively).1 Interestingly, in the SiLVER study,3 the recurrence-free survival at 24 mo was 83% in the group under mTORi and 77% in the mTORi-free group, which was possibly related to the lower proportion of patients with HCC within Milan criteria, compared with the study by Lee et al1 (eg, in the group under mTORi: 65.1% versus 82.9%, respectively). Nevertheless, longer follow-up would be useful in the study by Lee et al1 to overcome this limitation, as in the SiLVER study,3 recurrence-free survival benefit was evident in the first 3 to 5 y, especially in low-risk patients. Finally, it would be useful to provide the trough levels of CNIs, particularly during the first month after LT,4 as well as the trough levels of mTORi in those with and without HCC recurrence, as we recently showed that the recipients with mean trough levels of EVR ≥6 ng/mL at 7 to 12 mo post-LT, compared with those with EVR <6 ng/mL, had decreased HCC recurrence rates (log-rank: 2.3; P = 0.007).5