The Milan criteria are considered a universal standard for the selection of HCC patients for OLT. The debate regarding the feasibility of transplanting a patient beyond the Milan criteria has not been resolved thus far. Although the relapse rate is higher, OLT remains the only possible curative treatment for these patients. The prevention of disease recurrence is extremely important in these patients. Zhang et al.  evaluated the efficacy of post-OLT adjuvant chemotherapy with FOLFOX regimen to patients beyond the Milan criteria, and concluded that adjuvant FOLFOX could not prevent tumor recurrence but may improve the survival. One of the major concerns for this study, however, was the possibility that the cytotoxic agents used could damage the transplanted livers, rendering sorafenib as a potential solution for reducing the possibility of tumor recurrence. However, there are only a few studies that have examined this issue. Similarly, a phase 3 placebo-controlled randomized trial is currently ongoing for evaluating whether sorafenib can be an effective adjuvant therapy for HCC patients after tumor resection or local ablation (STORM trial). The results of this study would be available in the near future, which can possibly establish the rationale of adjuvant sorafenib therapy after OLT in HCC patients beyond the Milan criteria.
Although prospective and randomized-control studies regarding the role of adjuvant sorafenib on post-OLT HCC patients beyond Milan criteria remain unavailable, there is a retrospective study conducted by Saab et al.  suggesting that sorafenib has the potential benefit to extend both DSF and OS in high-risk HCC patients after OLT. In this study, the DFS and OS at 1 year is 85.7% and 87.5%, respectively. Although there is no significant statistical analysis in Saab's cohort, this study provides initial but important evidence that adjuvant sorafenib could be effective for patients receiving OLT for HCC for better DFS and OS. Results from our study further demonstrated that patients receiving adjuvant sorafenib had significantly better DFS than those who did not. Our preliminary data showed that DFS rates in patients with or without adjuvant sorafenib were 100% and 37.5% (p = 0.034) at 6 months, 66.7% and 9.4% (p = 0.026) at 12 months, and 66.7% and 0.0% (p = 0.011) at 18 months, respectively. To our knowledge, this is the first report showing statistical significance for survival benefits in post OLT HCC patients who are beyond Milan criteria.
The second aim of our study was to investigate the role of palliative sorafenib in post-OLT patients with relapsed HCC. One of the first studies regarding this issue was conducted by Kim et al. , involving 9 patients who received sorafenib after OLT for HCC recurrence. Survival benefits were not discussed in this study because the purpose of the study was to evaluate drug safety and feasibility, and 6 of the 9 patients required dose reduction due to side effects. A study conducted by Yoon et al.  further surveyed the survival benefits by sorafenib in this setting. Thirteen patients within the Milan criteria were retrospectively reviewed, showing that the median progression-free survival and OS was 2.9 months and 5.4 months, respectively. Yoon et al. therefore suggested that sorafenib could be a feasible treatment for recurrence HCC in patients with OLT. In our study, because all the patients in the palliative group had their disease in progression at the first follow up after initiating the treatment, progression-free survival could not be obtained in our analyses. Although no statistical significance was observed, a trend toward superior OS was noted for the patients in this group as compared to those in the control group. Variations in tumor recurrence location in the palliative and control groups could possibly explain why OS did not reach statistical significance in this analysis.
It has been demonstrated that TACE can prolong survival in patients with unresectable HCC . In our cohort, only 33.3% (2/6) patients in the palliative group experienced recurrence over liver parenchyma, indicating that TACE could not have improved survival in the remaining 4 patients. In the control group, however, except 1 patient who died of HCV reactivation, recurrence over the liver occurred in 3 of 5 patients (60%). All of these 3 patients had received TACE for their liver recurrence. This variation suggested that a larger portion of the patients in the control group could possibly benefit from TACE. Our speculation can be partially supported by a study conducted by Tan et al. , who demonstrated that in patients with HCC recurrence after OLT, the median OS for patients undergoing TACE with sorafenib and TACE alone was 14 and 6 months, respectively (p = 0.005). Patients who receive TACE with sorafenib thus had a better median OS than those who received sorafenib alone. Performing TACE in patients with recurrent HCC after OLT would thus further enhance the treatment efficacy of palliative sorafenib therapy.
Was superior DFS by adjuvant sorafenib able to result in superior OS? Our results showed that the answer to this question was positive. Our data showed that patients in the adjuvant group had better OS than those in the palliative and control groups at 24-month follow up (p = 0.031). This result supported the study by Saab et al., that adjuvant sorafenib could significantly improve both DFS and OS in post-OLT HCC patients beyond the Milan criteria.
However, the retrospective nature and the small size of our cohort were the major limitations of our study. In addition, all patients in the adjuvant group were at BCLC stage A or B, while most of patients in the palliative and control groups were at C and D (p = 0.011). These findings suggested that the low recurrence rate in the adjuvant group could be partially because of the better BCLC stage, instead of sorafenib alone. Further, a heterogeneous dose of sorafenib raised a new issue: the most optimal dose, either in the adjuvant or palliative setting, for HCC patients after OLT needs to be examined.
In summary, our preliminary data showed that adjuvant sorafenib improved both DFS and OS in HCC patients beyond the Milan criteria after OLT. Palliative sorafenib could possibly prolong OS in post-OLT patients with disease progression. Performing TACE in these patients for liver recurrence might further provide survival benefits. Prospective and randomized control studies with larger cohorts are urgently warranted to answer these questions.