Liver transplantation for hepatocellular carcinoma

Abstract

The outcome analyses for hepatocellular carcinoma (HCC) after liver transplantation (LT) were almost always assessed from the time of transplant, and not from the time of listing i.e. intention-to-treat (ITT) analysis. Based on the data from our center, if waitlist dropout was considered, the survival rates of the ITT-deceased donor liver transplantation (ITT-DDLT) patients were inferior to the ITT-living donor liver transplantation (ITT-LDLT). Bridging therapy is used to prevent tumor progression and dropout, and these include locoregional therapies such as transarterial chemoembolization (TACE) and high intensity focused ultrasound (HIFU). Despite this, tumor progression does occur, and hence novel and highly potent bridging therapies are needed. One such therapy, stereotactic body radiation therapy (SBRT), allows a precise delivery of high dose radiation to the tumor, while sparing the surrounding tissues. This thesis reviewed the current status of HCC for LT, the use of bridging therapies, the outcomes of HCC candidates using an ITT approach and the development of SBRT as a novel bridging therapy. To determine the outcome of HCC patients in transplant using an ITT approach, 375 HCC candidates from 1995-2014 were included in a retrospective study. The 5-year ITT-overall survival was significantly higher in the ITT-LDLT group (75.9% vs. 40.8%, P <0.001). The dropout rate in the ITT-DDLT group was 57%, with the majority as a result of tumor progression despite conventional bridging therapy. To explore the possibility of a novel bridging therapy, another retrospective study of 49 non-resectable HCC patients who underwent TACE followed by SBRT (TACE+SBRT) were propensity matched to 98 patients who had TACE. The 1- & 3-year progression-free survival rates were better than TACE alone (n=98) (32.5% vs. 21.4% and 15.1% vs. 5.1%, P=0.012). Based on data from these studies, a prospective study was commenced in 2015 to investigate the role of SBRT as bridging therapy. Forty patients were prospectively enrolled to SBRT and were compared to a retrospective cohort of 110 patients who underwent TACE or HIFU. Tumor control at 1-year was superior after SBRT (91.7% vs. 43.5% in TACE vs. 33.3% in HIFU, P=0.02). The cumulative incidence of dropout at 1- & 3-year was lower after SBRT (16% & 24.6%) than TACE (28.8% & 45.8%, P=0.045) and HIFU (33.3% & 45.1%, P=0.044). Pathological complete response (pCR) was more frequent after SBRT (52% vs. 25% in TACE vs. 17.9% in HIFU, P=0.024). A follow-up analysis showed that pCR, when compared to non-pCR patients had better 5-year overall (94.7% vs. 72%, P=0.017) and recurrence-free survival (90.2% vs. 71.1%, P=0.029). The risk of recurrence was 1/25 (4%) in the pCR and 9/60 (15%) in the non-pCR group. pCR was the only significant predictor for post-LT survival and recurrence. Our data showed that there was an indisputable need to prevent tumor progression for waitlist candidates. SBRT was safe and was more effective than other locoregional treatments. The benefits of SBRT extended to the post-transplant period, with a higher chance of pCR leading to improved survival. Therefore, SBRT should be utilized as an alternative to conventional bridging therapies, and should be further explored in downstaging and intermediate HCC.