HCC is one of the most common cancers worldwide with the incidence rising over the last 20 years.[22] Since the Milan criteria has been widely accepted, LT has gradually become a superior way to LR or other locoregional treatments for HCC patients who met the criteria, because it enabled the widest possible resection margins and completely removes the diseased liver at risk of developing HCC.23 However, the debate regarding the feasibility of transplantation for patients beyond the Milan criteria has not been resolved thus far, since the recurrence rate was reported rising in varying degrees.[6, 10, 11] However, LT remains the only possible curative treatment for these patients who was considered to be at high risk of recurrence after transplantation.
In addition, some other factors have been identified as high risk factors for HCC recurrence after transplantation. It was widely proved that macrovascular and microvascular invasion, high AFP level before LT, as well as poor tumor differentiation are the most important factors affecting HCC recurrence.[6, 24] AFP and tumor differentiation as an important index were involved in Hangzhou standard, as well as the latest AFP model and Up-to-Seven criteria Metroticket V2.0.[9, 25] Besides, some other researchers proposed that MVI is also one of the important factors influencing HCC recurrence after LT through Cox regression analysis.[4, 26] Li et al demonstrated in their study that exceeding Milan criteria, macrovascular invasion, liver capsule invasion and satellite lesions were significant different between the patients with and without HCC recurrence after LT by univariate analysis, implying they were high risk factors for HCC recurrence.[27] Based on these reports and the experience in our center, we adopted the above-mentioned high-risk factors for recurrence in our study.
Before lenvatinib, sorafenib was the first and only one molecule-targeted drug approved for HCC treatment, so several studies have been carried out to evaluate the effect of sorafenib on preventing from the HCC recurrence of patients after LT. A retrospective study from Satapathy and his colleagues showed that preemptive treatment with sorafenib in OLT recipients with high-risk features in explant did not improve HCC recurrence-free or overall survival.[28] Shetty et al demonstrated decreased overall rate of HCC recurrence rate and prolonged 1-year disease free survival of patients by adjuvant sorafenib after LT, concluding that adjuvant use of sorafenib could decreases risk of HCC recurrence in high-risk LT recipients.[29] In a multicenter phase I trial of adjuvant sorafenib in 14 LT recipients with high-risk HCC, one patient (7.1%) died and four (28.5%) recurred over a median follow-up of 953 days, implying a potentially promising effect of post-transplant sorafenib on recurrence-free survival.[5] Another study demonstrated the safety and potential benefit of sorafenib in reducing the incidence of HCC recurrence and in extending disease-free and overall survival for high-risk liver transplant recipients.[13] In a case control study, the disease-free survival at 6 months, 12 months and 18 months and the overall survival rate at 24 months for patients with adjuvant sorafenib were increased significantly.[14] Accordingly, there is no certain conclusion about the adjuvant use of sorafenib in patients with high-risk HCC after transplantation.
Lenvatinib is a noval oral multi-kinase inhibitor that targets VEGF receptors 1–3, FGF receptors 1–4, PDGF receptor α, RET, and KIT. In 2018, lenvatinib was proved to be non-inferior to sorafenib in overall survival in untreated advanced HCC in the randomized phase III trial, in which the patients with HBV-related HCC in lenvatinib group had a superior PFS and OS to the patients in sorafenib gourp.[15] Therefore,we conducted this retrospective study. As far as we know, this is the first report to describe the potential role of lenvatinib as adjuvant therapy in reducing HCC recurrence after liver transplant for high-risk patients.
Since lenvatinib was just approved for HCC treatment in March, 2018 in Japan, which is the first country in the world approving lenvatinib for HCC treatment and a number of studies revealed that postoperative recurrence of HCC often occured in early stage after LT[14], this study involved twenty-three high-risk HCC patients who underwent LT in recent two years. Although lenvatinib only being SFDA-approved for advanced HCC in September 2018, before that, two patients who took lenvatinib purchased the drugs from abroad themselves and one of them relapsed after administration of lenvatinib for 7 months. Within our cohorts, there was a significant longer DFS in lenvatinib group, which inferred a certain benefit of adjuvant lenvatinib on prolonging the DFS of HBV-related high-risk HCC patients after LT. Although no significant statistical difference was observed in recurrence rate between two groups, this study provides initial but important evidence that adjuvant lenvatinib could be effective for decreasing HCC recurrence of high-risk patients following transplantation. We found extrahepatic recurrences, especially in the lung, were the more common in early postoperative days, which was observed in the former study.[27] In lenvatinib group, one of three recurrent patients who experienced intrahepatic multiple recurrence received TACE and replacement of anlotinib, another target drug. Another patient with lung metastasis had pulmonary surgery and anlotinib instead as well. The third patient suffering from multiple recurrences continued to oral lenvatinib without dose change and lived for 14 months after recurrence. In control group, four recurrent patients started oral lenvatinib when diagnosis of HCC recurrence except for one patient who was found HCC metastasis in his left adrenal gland underwent resection of left adrenal gland. All patients in both groups survival so far, resulting in no significant difference in OS. To sum up the efficacy, adjuvant lenvatinib had a potential role in increasing the DFS and decreasing the recurrence rate for high-risk HBV-related HCC patients following LT.
In terms of lenvatinib safety, total incidence of AEs in our study was 92.9% (13/14), similar with the previous trials, as all 46 patients experienced at least one AE in phase II trial and 94%of subjects had varying degrees of AEs.[15, 17] However, in our cohorts, the incidence of Grade 3 AEs was 28.5% (4/14) with no AEs beyond Grade 3, obviously lower than the rate of 48% in phase II trial and 57% in phase III trial.[15, 17] This may be resulted from the small number of cases in this study, the better basic physical condition of the patients who could went through LT, and the elimination of the patients’ underlying liver diseases by LT. Besides, in both of this study and previous trials, the most common AE was hypertension with similar incidence(64.3% vs 76.1% vs 42%). In our cohorts, treatment-related AEs led to lenvatinib drug interruption in one patient (7.1%), dose reduction in 6 patients (42.9%), and drug withdrawal in 3 patients (21.4%), lower than those in phase III trial. It inferred that patients after LT might behaved a superior tolerance to lenvatinib.
As a special group, the interaction between any additional medication and the immunosuppressants should be considered for the LT recipients, so the dose and blood concentration change of FK506 was detected in the study to evaluate whether lenvatinib would influence the FK506 usage. Since the patients in lenvatinib group began lenvatinib administration about 1 month after surgery, we compared the dose and blood concentration of FK506 during the first six months after LT between the two groups, founding no significant difference. The results suggested no obvious influence of lenvatinib on the use of CNI immunosuppressants of the LT recipients.
In conclusion, this preliminary study demonstrates a potential benefit of adjuvant lenvatinib on prolonging the disease-free survival and reducing the recurrence of high-risk patients with HBV-related HCC following liver transplantation with an acceptable drug safety and patient tolerance. Limitations of this study include its retrospective analysis, and only one center experience, small number of patients involved as a result of strict selection criteria. Therefore, a prospective and randomized study with large sample should be encouraged.