Novel strategy of sirolimus plus thymalfasin and huaier granule on tumor recurrence of hepatocellular carcinoma beyond the UCSF criteria following liver transplantation: A single center experience

Abstract

Although liver transplantation (LT) lengthens the survival time of patients with hepatocellular carcinoma (HCC), LT patients exhibit a high recurrence rate; particularly those that had advanced HCC associated with the tumor biological characteristics and long-term application of immunosuppressants. A consensus on optimal prophylaxis and treatment for recurrent HCC following LT does not currently exist. The present study retrospectively analyzed data from 36 non-University of California at San Francisco criteria-eligible patients with advanced HCC who underwent LT, and then treated them with sirolimus (SRL)-based therapy with thymalfasin and huaier granules (SRL+, n=18), or with tacrolimus-based therapy (controls; n=18). The SRL+ group had significantly longer recurrence times (P=0.008) and survival times (P<0.0001) (OS, 1-year: 100%, 3-year: 94.4%, 5-year: 77.8%; DFS, 1-year: 88.9%, 3-year: 55.6%, 5-year: 50.0%). Furthermore, compared with pre-LT values and the control group, the SRL+ group had significantly lower serum α-fetoprotein (AFP) levels (both P<0.0001) and percentage of Forkhead box P3 (FoxP3)⁺ Treg lymphocytes (P<0.001) during the first year. In the SRL+ group, FoxP3⁺/cluster of differentiation (CD)8⁺ Treg lymphocyte percentages decreased significantly following LT (P<0.001); however, CD8⁺/CD3⁺ T-cells significantly increased (P<0.001). Levels of serum AFP and FoxP3⁺ Treg cells increased when tumors relapsed, and decreased to near-normal when relapse foci were cured or stabilized. SRL+ therapy may decrease AFP and Treg levels, while increasing CD8⁺ T cells, indicating an associated mechanism among them. In conclusion, SRL+ therapy appears to be safe and effective in preventing HCC recurrence following LT with no significant adverse events, and warrants further investigation.

Keywords: University of California at San Francisco criteria; advanced; hepatocellular carcinoma; liver transplantation; sirolimus; tumor recurrence.

Figure 1.

Lung metastases and relapse foci (red arrows) in relapsed treatment-group patients.

Figure 2.

Liver computed tomography scan results for the lung-relapse patients in the treatment group.

Figure 3.

Serum AFP and recurrence times for the treated (SRL+) and control groups, prior to and following LT. (A) Serum AFP changes in SRL+ and control groups at pre-LT and post-LT. (B) Serum AFP changes of non-recurrent cases following SRL+ therapy after LT. (C) Tumor recurrence times in SRL+ and control groups. (D) Serum AFP changes for recurrent cases following SRL+ therapy. Treatment gr., SRL+ group; control gr., control group; AFP, α-fetoprotein; SRL, sirolimus; SRL+, SRL combined with Zadaxin and huaier granules; LT, liver transplantation; NS, not significant.

Figure 4.

Changes in Treg and Foxp3+ Treg percentages, pre-LT and post-LT. (A) Pre-LT Treg and Foxp3⁺ Treg percentages of lymphocytes (Treg, 15%; Foxp3⁺ Treg, 1.21%). (B) Percentages of Treg and Foxp3⁺ Treg in lymphocytes at 1 year post-LT (Treg, 5.9%; Foxp3⁺ Treg, 0.63%). FoxP3, Forkhead box P3; LT, liver transplantation; FITC, fluorescein isothiocyanate; PE, phycoerythrin; CD, cluster of differentiation; SSC, side scatter height; FSC, forward scatter height; APC, allophycocyanin.

Figure 5.

Changes in Foxp3⁺ and Treg percentages of lymphocytes, and serum AFP levels in recurrent patients (A) prior to and (B) following therapy. AFP, α-fetoprotein; FoxP3, Forkhead box P3; APC, allophycocyanin.

Figure 6.

Survival rates of the patients with hepatocellular carcinoma following liver transplantation in the treated and control groups (P<0.001).