Tumor Burden Limits Liver Transplant Feasibility for HCC

Researchers have uncovered an upper limit in tumor burden after which there is a lower probability of successfully downstaging patients with hepatocellular carcinoma (HCC) for liver transplantation, according to findings presented at the 2016 AASLD Liver Meeting.

In the small prospective study, tumor burden was negatively predictive of successful downstaging for patients with HCC (HR, 0.87; P <.05). Overall, patients with a sum of number of tumors plus largest tumor diameter of 8 had a 68% probability of being downstaged to within Milan criteria at 1 year compared to those with a tumor burden of 14 who had only a 38% probability at 1 year.

“Using this metric of tumor burden, the sum of the number of lesions plus the diameter of the largest tumor, we can see that the greater the tumor burden, the lower the rate of successful downstaging,” said lead investigator Jasmine Rassiwala, MD, MPH, from the University of California, San Francisco (UCSF). “Our results suggest that there does exist an upper limit in tumor burden beyond which successful downstaging to a goal of liver transplant becomes unrealistic.”

Liver transplantation is one of only a few curative therapies for HCC, warranting studies to enhance its use. Eligibility for transplant has traditionally been based on Milan criteria. For patients who do not meet these criteria, the UCSF Down Staging (UCSF-DS) protocol has proven that HCC patients who achieved successful downstaging to Milan criteria had similar outcomes after liver transplant compared to those with HCC initially within Milan criteria (Hepatology 2015; 61:1968-1977).

Downstaging can facilitate liver transplantation for patients outside of Milan criteria. The benefits of downstaging include decreased tumor burden and time to identify those with less aggressive tumor biology. However, downstaging and post-liver transplant outcomes for patients with tumor burden initially exceeding the UCSF-SD’s criteria (>8cm without metastatic evidence or lymphovascular invasion per imaging) is not well known.

To explore these outcomes further, UCSF conducted a prospective cohort study that included 74 patients with HCC enrolled from 2005-2015 with tumor burden beyond UCSF-SD criteria. These patients were defined as “all-comers” did not have evidence of extrahepatic spread or vascular invasion. Outcomes in all-comers were compared with 133 patients that met UCSF-SD criteria who were enrolled over the same period of time.

Those within the all-comer and UCSF-DS groups were similar except there were significantly fewer Asian (18% vs 36%) and more Hispanic patients (24% vs 11%) in the all-comer group compared with the UCSF-DS group, respectively. A diagnosis of hepatitis C virus was more predominant (68% vs 53%) and there were fewer rates of hepatitis B virus (16% vs 29%) and alcoholism (11% vs 17%) in the all-comers group compared with the UCSF-DS group, respectively. Overall, patients in the all-comers group had greater tumor burden than those in the UCSF-DS group (12 cm versus 6.3 cm median tumor diameter).

All comer patients underwent downstaging and were placed on the liver transplant list if they remained within Milan for 6 months versus UCSF-SD’s criteria, which is 3 months. Downstaging was attempted using locoregional therapy (LRT).

At 12 months, 62% of patient in the all-comer group were successfully downstaged compared with 89% of those in the UCSF-SD group. At 24 months, 75% of all-comer patients were downstaged compared with 93% in the UCSF-DS group. Those with a tumor burden of 10, had a 57% probability of being downstage at 1-year. Those with a tumor burden of 12 had a 47% probability of downstaging.

The median time to downstaging was 3.1 months. Of those who were successfully downstaged, 9 (12%) underwent orthotopic liver transplantation in a median time of 7.4 months from downstaging. Seven patients who were downstaged are still awaiting transplant.

At 12 months, 54% of the all-comer patients had dropped out compared with 25% of UCSF-DS patients. At 36 months, the incidence of dropout in the all-comer group was 80% compared with 36% in the UCSF-DS group. The most common reason for dropout in both groups was HCC progression.

Similar results were found in the post-liver transplant 5-year survival rates. At 5-years, 50% of patients in the all-comers group remained alive compared with 79% in UCSF-DS group (P = .51). Post-liver transplant 5-year recurrence-free survival was 40% in the all-comers group versus 86% in UCSF-DS arm (P = .008).

“Though this was not a significant difference, significance in this study was largely limited by the only few events within the all-comers cohort,” said Rassiwala. “For reference, 5-year post transplant survival in T2 group within Milan is 81%. UCSF criteria was 75.2%.”

In the intent-to-treat population, the 5-year survival in the all-comers cohort was 21%, which was significantly lower than the survival rate of 56% in the UCSF-DS cohort, Rassiwala noted. The traditional survival rate in the Milan T2 group at 5 years is 63%.

Overall, there was no significant difference in the time from LRT initiation to death between the groups. The median was 13 months in the all comers group and 16.5 months in the UCSF-DS group (P = .125).

“All-comers have inferior outcomes following downstaging compared to the UCSF-DS group,” Rassiwala concluded. “Future studies are needed to further evaluate prognostic factors to define a subgroup beyond the UCSF-DS criteria who may still achieve acceptable outcomes after downstaging.”

Rassiwala R, Mehta N, Dodge JL, et al. Are There Upper Limits in Tumor Burden for Successful Down-staging of Hepatocellular Carcinoma to Liver Transplant? Analysis of the “All-comers” Down-staging Protocol. AASLD Liver Meeting; Boston, Massachusetts, November 11-15, 2016. Abstract 137.

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In the 9 patients who receive a transplant in the all-comers group, 3 had experienced a recurrence. The median time to recurrence was 21.4 months. The recurrence rate in the UCSF-DS group was 7.5% (5 of 64).