Four-year follow-up data from one of the largest single-institution datasets in the United States show that the Model of Recurrence After Liver Transplant (MORAL) score for hepatocellular carcinoma is highly predictive of recurrence-free survival and can accurately identify patients who should not undergo liver transplant with a living donor.
The simple test, which measures neutrophil-lymphocyte ratio (NLR), alpha-fetoprotein (AFP) level, and tumor size, was superior to the Milan criteria — the decades-old gold standard for assessing recurrence risk and transplant eligibility, says a research team led by Karim J. Halazun, MD, of the Division of Liver Transplantation and Hepatobiliary Surgery at Weill Cornell Medical College, New York City.
The MORAL score predicted recurrence both before transplant (pre-MORAL score) and after transplant (post-MORAL score), with c-statistics of 0.82 and 0.87, compared with 0.63 for the Milan criteria. A combination of the two scores produced a “combo-MORAL” score with a c-statistic of 0.91, the researchers report in the March issue of Annals of Surgery.
“The best utility for the transplant community is when we add this [MORAL score] to Milan,” Dr Halazun commented in an email to Medscape Medical News. He said that the the Milan criteria have made a “huge impact on the liver transplant landscape in the US and worldwide,” but pointed out that Milan criteria are based on radiologic findings, whereas the MORAL score objectively measures indices of tumor biology associated with risk for recurrence.
Patients with a high pre-MORAL score and tumors with aggressive biology should be excluded from transplant or given intensive therapy followed by observation “to either alter tumor biology or allow it to declare itself,” the researchers emphasize.
Conversely, a low pre-MORAL score is associated with a 5-year recurrence-free survival rate of almost 100%, effectively eliminating “the likelihood of tumor recurrence,” they say.
“The risk-stratified MORAL score provides the most accurate risk stratification model to date for tumor recurrence in patients with HCC [hepatocellular carcinoma] undergoing liver transplant,” the researchers say.
Although the MORAL score, as a stand-alone score, appears to be highly predictive of recurrence-free survival, when the researchers used it as an adjunct to the Milan criteria, they identified a subgroup of patients at higher risk for disease recurrence than had previously been thought.
“If validated by external groups, this score can act as an adjunct to the Milan criteria, allowing for a more objective identification of tumors with aggressive biology and aid in the selection and management of patients with HCC to undergo liver transplantation,” Dr Halazun and colleagues say.
The team is currently working with groups in the United Stats and Europe to validate their MORAL score, Dr Halazun told Medscape Medical News. “We should have these results within the next year or so.”
For their analysis, the team analyzed follow-up data from 339 adults who underwent liver transplant for hepatocellular carcinoma at Columbia University Medical Center between January 2001 and December 2012. They found that patients with high or very-high MORAL scores fared just as poorly, irrespective of whether risk stratification fell inside or outside Milan criteria. For this group, the 5-year recurrence-free survival was less than 50%, the researchers report.
Conversely, patients with low-risk MORAL scores outside the Milan criteria (T3 tumors) did “extremely well,” with 5-year recurrence-free survival of almost 80%. “The addition of NLR and AFP to Milan may therefore allow us to identify higher risk patients for recurrence in what is traditionally perceived to be the lowest risk group,” they say.
The analysis also identified three independent preoperative predictors of worse recurrence-free survival: an NLR ≥ 5 (hazard ratio [HR], 6.2); AFP > 200 (HR, 3.8); and tumor size greater than 3 cm (HR, 3.2; all P < .0001).
Results show that the 5-year recurrence-free survival for patients with the highest pre-MORAL score (13 points for all three risk factors) was 17.9% compared to 98.6% for the group with the lowest pre-MORAL score (0 points with none of the risk factors; P < .0001).
The post-MORAL score was constructed using what the researchers observed to be four independent predictors of worse recurrence-free survival. These included grade 4 disease (HR, 5.6; P < .0001; ); vascular invasion (HR, 2.0; P = .019); tumor size greater than 3 cm (HR, 3.2; P < .0001,); and a score higher than 3 (HR, 1.8; P = .048).
“The post-MORAL score can aid in this process [of risk stratification] by again identifying very-high risk patients whose 5-year recurrence-free survival rate is 22%,” the researchers say. This rate is equivalent to that seen in patients with aggressive cholangiocarcinoma or pancreatic adenocarcinoma after surgery, they add.
Patients can be given a more precise long-term prognosis, and the post-MORAL score can also be used to identify high-risk groups for targeted adjuvant therapies following orthotopic liver transplant, the researchers say. “Such therapies are not routinely used post transplant for HCC [hepatocellular carcinoma], even in the highest risk patients,” they point out.
Combining AFP and tumor size with NLR has “vastly improved” the utility of the biomarker, Dr Halazun said, noting that other groups have since modified the MORAL score using variables such as PIVKA, a marker of subclinical vitamin K deficiency.
Still, the researchers are standing behind their MORAL score, which they say is the only one to use the NLR. “We believe our original score including the NLR provides a more useful risk stratification of patients with HCC and has a broader application to recipients of any type of grafts.”
When Medscape Medical News asked whether the older Milan criteria, which are based on radiologic findings, should be replaced with an objective measure of tumor biology, such as the MORAL score, Dr Halazun answered: “I don’t believe that these criteria should be entirely replaced…. Instead, my feeling, based on our research and that of others, is that adjuncts to the Milan criteria that move us away from simple size and number indices and provide true reflections of tumor biology are required, and MORAL may represent as one of these adjuncts.”
Other scores are highly predictive of recurrence, Dr Halazun acknowledged. But whether it’s MORAL, PIVKA II, or some other index of tumor biology, more accurate measures of tumor biology are needed to better stratify risk when selecting patients with hepatocelluar carcinoma for liver transplant, he said. “It’s clear that continued research in the area is required.”
Although the researchers did not include patient survival in their analysis, tumor recurrence is associated with poor prognosis, Dr Halazun noted. “We believe that recurrence of hepatocellular carcinoma after liver transplantation constitutes failure, as organs to transplant these patients are scarce. As such, eliminating recurrence will greatly improve survival.”
The authors have disclosed no relevant financial relationships.
Ann Surg. 2017;265:557-564. Abstract
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