Neil Osterweil

November 19, 2014

BOSTON — Downstaging patients with hepatocellular carcinoma before liver transplantation leads to excellent 5-year recurrence-free and overall survival rates, findings from a multicenter study suggest.

Treating lesions with local-regional therapy allowed 119 of 187 patients with hepatocellular carcinoma to become eligible for liver transplant, and 80% of transplanted patients lived at least 5 years after surgery, said Neil Mehta, MD, from the University of California at San Francisco (UCSF).

"Successful downstaging to the Milan criteria was achieved in nearly two thirds of our patients," he reported here at The Liver Meeting 2014.

The Milan criteria are considered by many clinicians to be the gold standard for selecting patients with cirrhosis and hepatocellular carcinoma for transplantation. According to the criteria, patients with one lesion no larger than 5 cm or two or three lesions no larger than 3 cm can be considered for transplantation.

To be eligible for priority listing for liver transplant in the United States, patients must meet the conventional stage T2 criteria of one lesion 2 to 5 cm in diameter with no vascular invasion, or multiple tumors that are not larger than 5 cm.

With local-regional therapy, either radiofrequency ablation of tumors or transcatheter arterial chemoembolization, some of these patients can meet the Milan criteria.

Dr Mehta and colleagues looked at outcomes at three transplant centers. All follow the downstaging protocol developed at UCSF.

The UCSF criteria are one lesion 5 to 8 cm; two or three lesions, each 5 cm or less, with a total lesion diameter no more than 8 cm; four or five lesions, each 3 cm or less, with a total tumor diameter no more than 8 cm; and no evidence of vascular invasion on imaging.

After downstaging, there is a 3-month waiting period before patients can undergo liver transplantation. Patients with acute hepatic decompensation after downstaging must still meet the criteria before they can be put on the transplant list.

The researchers reviewed data on 187 consecutive adults with hepatocellular carcinoma who underwent downstaging from 2002 to 2012. They used cumulative risk analysis to determine probabilities and identify significant predictors of recurrence and of dropping off the transplant list.

Cancer Caused by Hepatitis C

The primary cause of hepatocellular carcinoma was hepatitis C in 106 patients, hepatitis B in 46, and other in 35.

Of the 187 patients, 68 (36.4%) dropped off the transplant list a median of 7.4 months after initial downstaging attempts.

On univariate analysis, compared with a class A Child-Pugh score, a class C score was a predictor of dropout (hazard ratio [HR], 2.2; P = .04), as was a class B score (HR, 1.9; P = .02). A pretreatment level of alpha-fetoprotein above 100 ng/dL was also predictive of dropout.

On multivariate analysis, class B and C Child-Pugh scores remained significant predictors, but alpha-fetoprotein level did not.

In the study cohort, 119 patients went on to the transplant list. At the most recent follow-up, 106 had received an organ from a deceased donor, three had undergone a living-donor transplant, and 10 were waiting for a deceased-donor organ to become available. The median time from the initial downstaging procedure to transplantation was 12.6 months.

The group at UCSF has really pioneered the approach. Dr Gregory Gores

Of the explanted organs, 35% had complete tumor necrosis, 46% had tumors that met the Milan criteria, 17% had tumors that did not meet the Milan criteria (stages T3 or T4a), 1% had macrovascular invasion, and 1% had lymph node invasion.

In an intention-to-treat analysis, Kaplan-Meier survival at 1 year was 84%; at a median follow-up of 4.2 years, it was 54%.

For all patients who went on to transplantation, however, 1-year survival was 95% and 5-year survival was 80%.

Hepatocellular carcinoma recurred in 12 (11%) of the 109 patients who underwent transplantation. Median time to recurrence was 19.1 months after surgery. The probability of recurrence-free survival was 95% at 1 year and 87% at 5 years.

On multivariate analysis that controlled for age, sex, race and ethnicity, cause of liver disease, type and number of local-regional therapies received, pathologic stage, and tumor grade, predictors of recurrence were an alpha-fetoprotein level above 500 ng/dL (HR, 8.4; P = .003) and microvascular invasion (HR, 7.3; P = .02).

There were no differences between centers for any of the outcomes. "These results support broader application of this downstaging protocol," Dr Mehta said.

"Downstaging has been around a long time, and the group at UCSF has really pioneered the approach," said Gregory Gores, MD, from the Mayo Clinic in Rochester, Minnesota.

Some of the good results reported by Dr Mehta's team can be attributed to patient selection. They are choosing patients for downstaging on the basis of relatively favorable tumor characteristics and responses to the local-regional therapy, he told Medscape Medical News.

"What they're saying is that with the two-part selection process, the patients who get through that funnel and get beyond the transplant will do well," he said.

The study was supported by the member institutions, Dr Mehta and Dr Gores have disclosed no relevant financial relationships.

The Liver Meeting 2014: American Association for the Study of Liver Diseases (AASLD): Abstract 111. Presented November 10, 2014.


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