More accurate prediction of recurrence risk may expand liver transplantation to previously ineligible HCC patients

Compared with currently accepted hepatocellular carcinoma (HCC) selection tools, a new tool that incorporates a dynamic α-fetoprotein response (AFR-R)—the New York/California (NYCA) score—predicted recurrence-free survival (RFS) better at five years. Researchers of a retrospective, international analysis concluded that this tool may expand the option of liver transplantation to patients who would otherwise be denied a potential cure.

In a cohort of 2,236 patients undergoing liver transplantation for HCC at eight centers in the US, Canada and Europe, the five-year cumulative incidence of recurrence in NYCA risk categories was 9.5% for low-risk patients with an NYCA score of 0 to 2; 20.5% for acceptable-risk patients with an NYCA score of 3 to 6; and 40.5% for high-risk patients with an NYCA score of 7 or more (all P<0.001), Karim Halazun, MD, of Weill Cornell Medicine, New York City, and colleagues reported in JAMA Surgery.

Compared with the Milan Criteria (MC)—another HCC selection tool—the NYCA score also predicted RFS at a center-specific level where 83.1% of patients who did not meet the MC would be recategorized into NYCA low and acceptable-risk groups with a 5-year RFS risk in excess of 75% and a five-year overall survival (OS) in excess of 70%, investigators added. Similarly, 69.2% of patients who did not meet the French-AFP HCC selection criteria would be recategorized into NYCA low and acceptable-risk groups, as would 76.1% of patients who did not meet the Metroticket 2.0 HCC selection tool criteria.

As the authors pointed out, recurrence after transplant is considered terminal, and thus, they chose recurrence as the study end point.

“α-[f]etoprotein levels are known to predict response to locoregional therapy, waitlist outcomes, postresection outcomes, and liver transplant outcomes. The degree of increase, absolute cut-off levels, and their application to liver transplant selection have, however, been a source of controversy,” wrote Halazun and colleagues.

“This study externally validates the only HCC selection tool to incorporate AFP-R, the NYCA score, on a large, heterogeneous cohort of patients from Europe and North America and underscores the importance of incorporating the AFP-R metric into selection of patients for liver transplant,” they concluded.

Adults undergoing liver transplantation for HCC between Jan. 1, 2001 and Dec. 31, 2013 at four North American and four European centers were analyzed. Almost 81% of the cohort were men, with a mean age of 58.3 years. Hepatitis C prevailed as the dominant diagnosis in North America (60.1%), whereas in Europe, alcohol-related liver disease was the most common diagnosis (37.2%; P<0.001).

Researchers recorded first AFP at diagnosis, maximum AFP at any point, and the final or immediate pretransplant AFP, and found that the difference between the maximum and final pre-liver transplant AFP levels—when categorized into low, acceptable, and high-risk groups—predicted RFS and overall survival (OS).

“[W]e observed a progressive increase in recurrence risk with an increasing NYCA score, with the high-risk group having more than a 5-times increased recurrence risk compared with the low-risk group and more than 2 times the recurrence risk of the acceptable-risk group,” wrote Halazun and colleagues.

They also performed a sensitivity analysis to explore the validity of the NYCA score only in patients on the wait list for more than six months—the current situation for most candidates for a liver transplant in the U.S.—and found that the NYCA remained valid in this subgroup of patients who had an almost identical cumulative risk for recurrence in all three NYCA risk categories as did the overall cohort.

After controlling for hepatitis C and age (the only two other factors that significantly affected OS), NYCA score also independently predicted OS, where OS among patients in the NYCA acceptable-risk category was 35% worse (HR: 1.35; 95% CI 1.14-1.60; P=0.001) compared with those in the NYCA low-risk group and over 2.3-times worse (HR: 2.36; 95% CI, 1.81-3.10; P<0.001) for those in the NYCA high-risk group again compared to the low-risk group.

“The superiority of including AFP-R into selection criteria is not limited to improved RFS or OS; it also allows for inclusion of patients who would have been excluded by both the MC and the F-AFP,” the authors explained.

“Reclassification of 83% of patients who did not meet MC and 69% of patients who did not meet F-AFP into the acceptable or low-risk NYCA groups in this study… underlies the importance of moving away from dichotomous single AFP nonkinetic scores,” they emphasized.

Commenting on the study, Chirag Desai, MD and A. Sidney Barritt IV, MD, both from the University of North Carolina School of Medicine in Chapel Hill, North Carolina, noted that certain limitations should be taken into consideration in interpreting the current analysis.

First, all patients in the current study received a transplant.

“These patients were deemed to have appropriate tumor biologic factors; thus, there is substantial selection bias inherent in the study population,” the editorialists wrote.

In addition, the authors provided no data on patients who did not undergo liver transplantation or for those who may have had either a favorable or unfavorable AFP-R. They also included patients who underwent transplantation between 2001 and 2013, during which time, liver graft allocation changed to a different system and exception points for HCC varied widely, Desai and Barritt noted.

“In addition, there were many differences in pretransplant treatment strategies, listing criteria, waiting time and other transplant-related practices in this cohort,” the editorialists observed. “[A]nd the predictive value of AFP-R may be different in patients with longer wait times, thus raising the temporal relevance of this validation cohort,” they added.

Perhaps most importantly, expansion of HCC criteria may not improve transplant priority for all potential candidates, although it may do so in countries where living donor liver transplants are more readily available.

Other study limitations include its retrospective, multicenter design.

“In summary, this study advances our knowledge regarding the predictive ability of AFP-R,” Desai and Barritt acknowledged. “[H]owever, universal adaptation for deceased donor graft allocation still needs prospective validation,” they stressed.

  1. Novel HCC selection tool that incorporates a dynamic rather than a static α-fetoprotein response predicted recurrence-free survival at five years better than currently accepted HCC selection tools.

  2. More accurate prediction of recurrence risk for HCC patients may expand liver transplantation to those currently deemed ineligible for transplantation by alternative HCC selection tools.

Pam Harrison, Contributing Writer, BreakingMED™

Halazun had no conflicts of interest to declare.

Neither Desai nor Barritt had any conflicts of interest to disclose.

Cat ID: 636

Topic ID: 630,636,636,730,192,925