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Page 12 of 19 Kornberg et al. Hepatoma Res 2018;4:60 I http://dx.doi.org/10.20517/2394-5079.2018.86

Table 7. Immunosuppressive approaches to reduce the oncological risk after LT
Reference n Immunosuppressive approach Impact on tumor-specific outcome
Vivarelli et al. [140] 70 Reduced CsA exposure Mean CsA exposure was 278.3 ± 86.4 ng/mL in patients with, and
(≤ 189.6 ng/mL) 169.9 ± 33.3 ng/mL in those without HCC recurrence. Reduced CsA
exposure was identified as the only independent predictor of HCC
recurrence (P < 0.001)
Vivarelli et al. [141] 130 Reduced CNI exposure Apart from tumor grading, MVI and AFP level, exposure to CNI was
(CsA ≤ 220 ng/mL; Tac ≤ 10 ng/mL) identified as the only independent predictor of HCC relapse (HR =
4.01; 95%CI 1.33-12.09; P = 0.014)
Rodriguez-Peralvarez et al. [142] 219 Reduced CNI exposure Apart from tumor nodule diameter, micro- and macrovascular
(CsA ≤ 300 ng/mL; Tac ≤ 10 ng/mL) invasion, exposure to CNI was identified as independent predictor of
HCC relapse (HR = 2.82; 95%CI 1.4-5.8; P = 0.005). Reduced CNI
exposure resulted in a significantly better RFS in MC Out patients
(P = 0.004), whereas there was a trend of improved tumor-specific
outcome in Milan Out patients (P = 0.09)
Liang et al. [149] 2950 SRL-based IS SRL-based regimens led to improved overall survival at 1 (OR = 4.53;
95%CI 2.31-8.89), 3 (OR = 1.97; 95%CI 1.29-3.00) and 5 years
(OR=2.47; 95%CI 0.21-0.83) post-LT. In addition, HCC recurrence
rate was significantly decreased (OR = 0.42; 95%CI 0.21-0.83)
Menon et al. [150] 474 SRL-based IS SRL-based IS resulted in lower recurrence rate (OR = 0.3; 95%CI
0.16-0.55; P < 0.001), lower recurrence-related mortality (OR = 0.29;
95%CI 0.20-0.70; P = 0.005) and lower overall mortality (OR = 0.35;
95%CI 0.20-0.61; P < 0.001) compared to CNI-based IS
Cholongitas et al. [151] 3666 mTORi-based IS HCC recurrence rate was significantly lower in mTORi-based IS (8%)
compared to CNI-based protocol (13.8%; P < 0.001)
Zhang et al. [152] 7695 SRL-based IS SRL-based IS prolonged 1-year (OR = 2.44; 95%CI 1.66-3.59), 3-year
(OR = 1.67; 95% CI 1.08-2.58) and 5-year (OR = 1.68; 95%CI 1.21-
2.33) OS compared to the control group. SRL resulted in lower HCC
recurrence rates (OR = 1.68; 95%CI 0.37-0.98), lower recurrence-
related mortality (OR = 0.58; 95%CI 0.42-0.81) and lower overall
mortality (OR = 0.62; 95% CI 0.44-0.89) compared to SRL-free
regimens
CI: confidence interval; CNI: calcineurin inhibitor; CsA: cyclosprin A; HCC: hepatocellular carcinoma; IS: immunosuppression; mTORi: mammalian
target of rapamycin inhibitor; OR: odds ratio; SRL: sirolimus; Tac: tacrolimus

independent predictor of favourable cancer-specific outcome. Stratified according the pathologic MC, reduced
CNI exposure resulted in a significantly better RFS in Milan In patients, whereas there was a clear trend of
[142]
improved RFS in Milan Out patients (P = 0.09), respectively ; and (2) the protective effect of sirolimus (SRL)
based immunosuppression is still inconclusive.

The use of mammalian target of rapamycine inhibitors (mTORis), such as rapamycine (SRL) and everolimus
(EVL) provide anti-cancer effects by inhibiting the PI3K/AKt/mTOR pathway beyond its immunosuppressive
capabilities [143,144] . Therefore, many hopes had been placed in this immunosuppressant in recent years
for reducing the risk of post-LT HCC recurrence without affecting the immunological outcome [145-148] .
Several systematic reviews and meta-analyses in the past suggested a significant benefit of SRL in HCC LT
[152]
patients [149-151] [Table 7]. Just recently, Zhang et al. presented data on an updated meta-analysis including
the largest number of patients (n = 7695) from a total of 11 studies. The authors reported that patients treated
with SRL demonstrated lower recurrence rates, lower recurrence-related mortality and lower overall mortality
compared to SRL-free regimens. Whether advanced HCC patients were particularly benefiting from SRL was,
however, not adequately assessed. The only prospective, randomized, multicenter, open-label study recently
[153]
finalized, however, did not find a significant improvement of OS and RFS beyond 5 years .

Currently, several approaches to achieve recipient tolerance by IS weaning protocols in order to reduce long-
term CNI-induced complications, such as hyperlipidemia, cardiovascular events, renal dysfunction and
de-novo carcinoma are under consideration [154-157] . About 25% of liver transplant patients were reported to
be suitable for complete IS withdrawal without increasing the risk of patient and graft loss. Probably, the
application of non-invasive biomarkers predicting “operational tolerance” might permit significant reduction