Postinterventional Tumor Necrosis Predicts Recurrence-Free Long-Term Survival in Liver Transplant Patients with Advanced Hepatocellular Carcinoma on Clinical Staging

Abstract

Background: There is some evidence that a subset of patients with advanced HCC on clinical staging may, nonetheless, benefit from liver transplantation. The role of pretransplant interventional bridging treatment (IBT) for identifying adequate liver transplant candidates with HCC beyond the Milan criteria is still undefined. The aim of this trial was, therefore, to evaluate the value of IBT induced tumor necrosis on recurrence-free long-term survival in liver transplant patients with advanced HCC. Furthermore, we aimed at identifying pretransplant available clinical parameters that may predict histopathological response to IBT, and thereby, be useful for selecting adequate liver transplant candidates. Patients and methods: A total of 93 patients with HCC were included in this trial. 18F-FDG positron emission tomography (PET) has been performed in all of them pre-LT, classifying patients in PET− (no increased FDG tumor uptake on PET) and PET + (increased FDG tumor uptake on PET). If being eligible, patients underwent pretransplant IBT by transarterial chemoembolization (TACE) or radiofrequency ablation (RFA). Clinical response to IBT was assessed by repeat CT scans (RECIST criteria). Macromorphologic tumor staging was based on CT/MRI. Explant livers were histopathologically examined to determine variables of macromorphology, vascular and lymphatic invasion invasion, grading and grade of post-IBT tumor necrosis. Patients with a 50%-100% tumor necrosis were defined to be histological responders, while tumor necrosis rate < 50% indicated histological non-response to IBT. The impact of clinical and histopathologic parameters on clinical outcome was evaluated in uni- and multivariate analysis. Results: Current overall follow-up is ranging between 5 and 162 months posttransplantation (mean: 64.3 ± 44.2 months). Finally, 59 liver transplant patients (63.4%) have received IBT, predominantly TACE. Overall, 21 patients developed tumor recurrence post-LT (22.6%), 11 patients in the IBT-group (18.6%) and 10 patients in the non-IBT-population (29.4%). Histologic responders had a significantly better recurrence-free survival rate after 5 years than histologic non-responders (96% versus 21%; P < 0,001). Histologic response to IBT resulted in a 5-year recurrence-free survival of 80% in Milan Out patients, which was comparable to Milan In recipients (87%), but significantly better than in histologically non-responding Milan Out recipients (0%; P < 0,001). In multivariate analysis, histologic response to IBT was identified as the only independent predictor of recurrence-free long-term survival (hazard ratio 53.3; P < 0.001). In multivariate logistic regression, pretransplant PET- status was assessed as the only independent clinical parameter predicting histologic response to IBT (odds ratio 12.4; P < 0.001). Conclusion: Data of our trial indicate that liver transplant patients with HCC should undergo pretransplant IBT, if being eligible, aiming at extended tumor necrosis. Patients with advanced HCC on clinical staging may, thereby, achieve excellent recurrence-free lomg-term survival. Pretransplant PET evaluation is useful for identifying those patients that may undergo successful IBT. This could be useful for a reasonable extension of liver transplant criteria.