In an Italian phase IIb/III study reported in The Lancet Oncology, Mazzaferro et al found evidence that liver transplantation after tumor downstaging was associated with improved event-free and overall survival in patients with hepatocellular carcinoma. The study was closed early due to changes in organ allocation policy during the course of the trial.

Study Details

The multicenter trial included a total of 45 patients who had undergone tumor downstaging (median duration = 6 months) with locoregional, surgical, or systemic therapies according to multidisciplinary decision. They were randomly assigned between March 2011 and March 2015 to receive liver transplantation (n = 23) or nontransplantation therapies (n = 22). Patients had to have disease beyond the Milan criteria for transplantation eligibility, absence of macrovascular invasion or extrahepatic spread, 5-year estimated post-transplantation survival of at least 50%, and good liver function (Child-Pugh A-B7). The control group received sequences of locoregional and systemic treatment at tumor progression. The primary endpoints were event-free survival for the phase IIB portion of the trial, and overall survival for the phase III portion on intent-to-treat analysis.

After patient enrollment had begun, an Italian national program for expansion of the donor pool—including donation after cardiac death and revision of transplantation priorities for hepatocellular carcinoma— was implemented progressively. These developments forced the trial monitoring committee to recommend study closure on March 31, 2015.

Treatment Outcomes

At data cutoff in July 2019, median follow-up was 71 months. Event-free survival at 5 years was 76.8% (95% confidence interval [CI] = 60.8%–96.9%) in the transplantation group vs 18.3% (95% CI = 7.1%–47.0%) in the control group (hazard ratio [HR] = 0.20, 95% CI = 0.07–0.57, P = .003). Median event-free survival was not reached vs 13 months (95% CI = 12–27 months).

Overall survival at 5 years was 77.5% (95% CI = 61.9%–97.1%) in the transplantation group vs 31.2% (16.6%–58.5%) in the control group (HR = 0.32, 95% CI = 0.11–0.92, P = .035). Median survival was not reached vs 30.5 months (95% CI = 18.5–41.5 months).

Adverse Events

The most commonly reported grade 3 or 4 serious adverse events were hepatitis C virus recurrence in three patients (13%) and acute transplant rejection in two patients (9%) in the transplantation group, and postembolization syndrome in two patients (9%) in the control group. Treatment-related deaths occurred in two patients in the transplantation group (8%)—due to myocardial infarction and multiorgan failure, respectively—and in two patients in the control group (9%), due to liver decompensation in both.

The investigators concluded, “Although results must be interpreted with caution owing to the early closing of the trial, after effective and sustained downstaging of eligible hepatocellular carcinomas beyond the Milan criteria, liver transplantation improved tumor event-free survival and overall survival compared with nontransplantation therapies. Postdownstaging tumor response could contribute to the expansion of hepatocellular carcinoma transplantation criteria.”

Vincenzo Mazzaferro, MD, of the University of Milan and Fondazione IRCCS Istituto Nazionale Tumori di Milano, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by the Italian Ministry of Health. For full disclosures of the study authors, visit thelancet.com.