Liver transplantation in hepatocellular carcinoma after tumour downstaging (XXL): a randomised, controlled, phase 2b/3 trial

Abstract

Background. Liver transplantation cures hepatocellular carcinoma (HCC) if within conventional selection criteria. Expanded criteria are elusive. Loco-regional treatments pursue tumor downstaging from outside Milan criteria to within criteria. No trial investigated HCC-downstaging strategy to expand transplant eligibility. Methods. This multi-center trial aimed at comparing successfully downstaged HCC followed by transplantation vs. non-transplant therapies. Eligible patients had good liver function (Child-Pugh A-B7), HCC beyond Milan, 5-year estimated post-transplant survival ≥50%, no macrovascular or extrahepatic spread. Only partial-complete responses according to modified-RECIST were randomized 1:1 after 3 months observation period, during which sorafenib was allowed. Co-endpoints were survival and timeto-tumor event. We used Kaplan-Meier method, log-rank test, Cox regression for intention-to-treat analysis. Survival benefit was the difference between groups mean survival time. Organ allocation policy changed over time and limited patients' accrual to 4 years. After 4 additional years conditional power calculation estimated the probability that the final results would be statistically significant in the remaining study, given the data observed. ClinicalTrials.gov NCT01387503. Findings. 74 patients were enrolled between March 2011 to March 2015: 29 dropped-out pre-randomization. Downstaging median duration was 6 months (1-17). Success-rate was 73%. Progression during observation was 17%. 45 patients were randomized: 23 transplanted vs. 22 controls. Median followup was 71 months (IQR 60-85). 5-year overall survival was 77.5% (95%CI 61.9-97.1%) in transplants vs. 31.2% (95%CI: 16.6-58.5%) in controls (Cox hazard ratio [HR] 0.22, 95%CI: 0.08-0.61; p=0.004). 5-year tumor eventfree survival was 76.8 (95%CI: 60.8-96.9%) vs. 18.3% (95%CI: 7.1-47.0%) in controls (HR: 0.14, 95%CI: 0.05-0.38; p<0001). 5-year survival-benefit favored transplantation by 14.5 months (95%CI: 3.6-25.3; p=0.009). The trial retained a conditional power of 98.6%. Interpretation. After effective and sustained downstaging of eligible HCCs beyond Milan criteria, liver transplantation is superior to nontransplant therapies. Post-downstaging tumor response should contribute to HCC transplant criteria expansion. Funding. Italian Ministry of Health

Validation of novel Japanese indication criteria and biomarkers among living donor liver transplantation recipients with hepatocellular carcinoma - a single center retrospective study

“…As the developments and advances in imaging modalities, anti-viral treatments, and immunosuppression regimens might have changed practice in the management of LT considerably over the last two decades, it seems mandatory to validate the criteria in the recent cohort or in the prospective study. Although the usefulness of tumor downstaging before LT has been reported recently [43] , unfortunately there was no case of intentional downstaging in the present cohort. In Japan, where the indication of LT for HCC is restricted to those with decompensated cirrhosis by the national insurance system, HCC patients with compensated cirrhosis are usually recommended for locoregional treatments and will be referred for LT when they develop decompensated cirrhosis not amenable to locoregional treatments.…”

The Revolution in Indication for Liver Transplantation: Will Liver Metastatic Disease Overcome the End-Stage Liver Disease in the Next Future?

“…Living donation alone or combined with two-stage hepatectomy could be other feasible options for these recipients and results from the ongoing trial are awaited. As in the HCC setting [48,49], the optimization of patients' selection will be essential to ensure transplant benefit and achieve adequate outcomes in terms of both patient's OS and DFS. A multi-disciplinary transplant oncology team with specialized surgeons, oncologists, hepatologists and radiologists would be essential to guarantee the correct work-up and risk stratification for these patients.…”

Recent developments and ongoing trials in transplant oncology

“…Liver transplantation doubled the 5-year overall survival at 77% compared to 31.2% in the control group without LT, thus providing prospective evidence for the safety of LT after downstaging for selected patients. 28 Another crucial point is a sufficient time interval between downstaging and LT, aptly coined the "ablate and wait" strategy. 29 This is done to exclude patients with undetected, microscopic intra-or extrahepatic spread already present at the time of the first LRT.…”

“…Most recently, Mazzaferro et al published the results of a randomized controlled trial comparing LT to non‐transplantation therapies for successfully downstaged patients. Liver transplantation doubled the 5‐year overall survival at 77% compared to 31.2% in the control group without LT, thus providing prospective evidence for the safety of LT after downstaging for selected patients 28 . Another crucial point is a sufficient time interval between downstaging and LT, aptly coined the “ablate and wait” strategy 29 .…”