Gastroenterology
Volume 134, Issue 5 , Pages 1612-1614, May 2008

Liver Transplantation for Hepatocellular Carcinoma: Who Benefits and Who Is Harmed?

  • Michael Volk
    • ,
  • Jorge A. Marrero

      Affiliations

    • Corresponding Author InformationAddress requests for reprints to: Jorge A. Marrero, MD, MS, Division of Gastroenterology, 3912 Taubman Center SPC 5362, Ann Arbor, MI 48109.

Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan

Article Outline

 

See “Liver transplantation for hepatocellular carcinoma: impact of the MELD allocation system and predictors of survival” by Ioannou GN, Perkins JD, Carithers RL on page 1342.

Hepatocellular carcinoma (HCC) is the 5th most common cancer worldwide.1 In appropriately selected patients with HCC, orthotopic liver transplantation (OLT) has been shown to be an excellent treatment and it is the only therapy that simultaneously treats the cancer and the underlying liver disease. In the early experience of liver transplantation for HCC, the outcomes were often dismal largely owing to transplant of recipients with advanced tumors resulting in high rates of tumor recurrence and poor survival.2 In a seminal study by Mazzaferro et al,3 an overall 4-year survival of 85% among 35 patients transplanted with HCC was reported for liver recipients with either a solitary tumor ≤5 cm or with ≤3 tumors each ≤3 cm, now commonly referred to as the “Milan criteria.” Subsequent to these findings, the United Network for Organ Sharing (UNOS) in the United States adopted these criteria to determine priority for transplanting patients with HCC. In 2002, UNOS adopted the Model for End-stage Liver Disease (MELD) system for the allocation of deceased donor livers. Patients with HCC within Milan criteria are given priority by assigning a higher exception MELD score, currently 22 points to liver candidates with stage II HCC.

The majority of the data on OLT for HCC have been derived from single-center studies. The 5-year survival rates of patients within Milan criteria have ranged from 47 to 62% when withdrawals from the waiting list are included, and between 61% and 74% when withdrawals from the waiting list are excluded.4 Some centers report 5-year survivals of >50% with expanding the Milan criteria,5, 6, 7 raising the question of whether patients with larger tumors should be transplanted. It is impractical and perhaps even unethical to perform a randomized controlled trial of OLT for HCC and, thus, large, multicenter case series are needed to refine the estimates of posttransplant outcomes.

In this issue Gastroenterology, Ioannou et al8 provide the largest study of outcomes after liver transplantation for HCC in the United States, and evaluate the impact of the MELD allocation system. They analyzed the UNOS database on January 10, 2007, of transplant recipients and created 2 cohorts: Cohort 1 consisted of patients >18 years of age who underwent their first liver transplantation between February 27, 2002, and January 10, 2007; cohort 2 consisted of patients >18 years of age that underwent their first liver transplant between April 23, 1997, and February 26, 2007. They showed that in cohort 1 5,045 patients (26% of all transplants) underwent liver transplantation for HCC. Of these, 4,453 (88% of patients transplanted for HCC) had a MELD exception with 4,258 (96%) meeting Milan criteria; 592 had no exception, presumably owing to exceeding the Milan criteria or having a high laboratory MELD, which made the exception unnecessary. For those in cohort 2, only 731 (4.6% of all transplants) were transplanted for HCC.

When cohort 1 was evaluated, the survival of the HCC-no-exception group was worse than those without HCC. However, those with HCC that had a MELD exception had only a marginally worse survival than patients without HCC (hazard ratio [HR], 1.09; 95% confidence interval [CI], 1.0–1.2). The authors then evaluated the posttransplant survival according to tumor size and tumor number, and nicely showed that the overall survival and adjusted survival (MELD score, underlying liver disease, age, gender, race/ethnicity, body mass index, and donor age, gender, race/ethnicity) was worse with increasing tumor size, especially for tumors >3 cm in diameter. In the adjusted model for patients that meet Milan criteria, MELD score >20 (HR, 1.87; 95% CI, 1.3–2.6), alpha-fetoprotein (AFP) ≥455 ng/ml (HR, 2.2; 95% CI, 1.6–3.1) and African American race (HR, 1.57; 95% CI, 1.2–2.1) were poor predictors of posttransplant survival. The combination of AFP ≥455 ng/ml and MELD ≥20 increased the risk of death 2-fold.

The 6-fold increase in the proportion of transplanted patients with HCC from the pre-MELD era to the post-MELD era is striking, consistent with clinical experience, and likely multifactorial. The incidence of HCC has increased over the last 10 years, which has lead to increased awareness of this tumor.9 During the first few years of the MELD system, patients with HCC were given even higher priority than they have now, and those with stage 1 HCC were also given MELD exceptions. As these policies have been modified, the number of transplanted patients with HCC has decreased somewhat.10 Although the authors do not adjust for these temporal trends, it is likely that implementation of the MELD allocation system was partly responsible for the increased proportion of patients transplanted with HCC. This increase in the number of patients transplanted likely has contributed to increased awareness by physicians caring for patients with HCC and promoting surveillance.

One of the surprising findings in this study is that MELD score was a significant predictor of posttransplant survival in patients with and without HCC. There have been several studies that have indicated that MELD score is a poor overall predictor of posttransplant survival in patients with cirrhosis but without HCC11; therefore, in patients with HCC the MELD score should not be expected to be an important predictor of posttransplant survival. One possible explanation for this observation is the lack of control for regional variability. It is well known that there are significant UNOS regional variations with regard to donor availability, length of the transplant waiting list, and median MELD scores at the time of transplantation. As shown in Figure 1, there is a significant amount of variability according to UNOS region with regard to the number of patients transplanted for HCC since 1997 (based on UNOS STAR file, obtained December 30, 2007). It is likely that UNOS regions are a confounder to the relationship of high MELD score and the decrease in survival for patients with HCC. The confounding effect is likely due to the increasing waiting times in regions with decreased organ availability leading to patients being transplanted with higher laboratory MELD scores or higher exception priority points, which in turn leads to unidentified tumor progression and poorer outcomes. In fact, a recent evaluation of the UNOS database indicated that the overall accuracy of radiologic staging of only 44%, and the authors observed an unexplained variation and inaccuracies with pre-OLT staging that were deemed unacceptable.12

  • View full-size image.
  • Figure 1. 

    The number of liver transplantations from 1997 to 2006 for Hepatocellular Carcinoma according to United Network of Organ Sharing regions. Region 1 = Maine, Eastern Vermont, New Hampshire, Connecticut, Massachusetts, and Rhode Island. Region 2 = Delaware, District of Columbia, Maryland, New Jersey, Pennsylvania, and West Virginia. Region 3 = Florida, Georgia, Alabama, Mississippi, Louisiana, Arkansas, and Puerto Rico. Region 4 = Texas, Oklahoma. Region 5= Arizona, California, Nevada, New Mexico, and Utah. Region 6 = Alaska, Hawaii, Idaho, Montana, Oregon, and Washington. Region 7 = Illinois, Minnesota, North Dakota, South Dakota, and Wisconsin. Region 8 = Colorado, Iowa, Kansas, Missouri, Nebraska, and Wyoming. Region 9 = New York and Western Vermont. Region 10 = Indiana, Ohio, and Michigan. Region 11 = Kentucky, North Carolina, South Carolina, Tennessee, and Virginia.

One important aspect of this study is that an elevated AFP, in this study ≥455 ng/ml, was an important predictor of poor survival. Even though AFP is not an optimal test for screening cirrhosis for HCC, it provides important prognostic information in patients with HCC. It has been shown to be an important predictor of recurrence after resection or transplantation for patients with HCC.13, 14 Therefore, when considering transplantation of patients with HCC and an AFP >455 ng/ml, careful attention should be given to whether there is more tumor burden than indicated in the imaging tests, and perhaps a waiting period of 3–6 months before transplantation may be the best option to select patients with favorable tumor biology. This approach of waiting has been utilized in patients who exceed Milan criteria and are treated to try to reduce the tumor burden to proceed with transplant, that is, downstaging. A study of 30 patients who exceeded Milan criteria was treated with the intent of downstaging the HCC, a median follow-up of 6 months elapsed from treatment to liver transplantation.15 This resulted in a 2-year survival of 82%. Current ongoing research on molecular tools that predict clinical behavior in HCC may improve our ability to better determine who benefits from OLT.

The study by Ioannou et al provides important information about the survival of patients with HCC after transplantation. The question still remains, however, if these patients receive enough benefit to justify the harm caused to other patients by the use of scarce organs. We created a novel Markov model to evaluate the harm and benefits of transplantation for HCC.16 Our model showed that the amount of harm caused to other patients on the waiting list was sensitive to the distribution of MELD scores >20 on the waiting list, which is a function of geographic variation. Controlling for these regional differences is critical when assessing the benefits and harms of liver transplantation for HCC.

The benefit of transplantation for patients with HCC depends not only on posttransplant survival, but also on the available treatment alternatives. For patients with tumor <2 cm in size, recent data have shown that radiofrequency ablation leads to 5-year survival rates of 55%17 and had similar results to surgical resection18 in patients with Child class A cirrhosis. Therefore, for these patients radiofrequency ablation or resection should be the treatment of choice depending on location, performance status of the patient, and degree of portal hypertension. Given the scarcity of organ donors, we need to select patients who not only will do well with transplantation, but who will do poorly without it.

Should we transplant those who exceed Milan criteria? The single-center case series have reported mixed results, but some patients have clearly benefited. The study by Ioannou et al clearly shows that increasing tumor size leads to a worse outcome. In our recent model, we showed that transplanting those who exceed the Milan criteria increases the risk of another patient dying on the waiting list by 44%, with the risk being the highest among those without HCC and MELD scores >20.16 We showed that expanding the Milan criteria would require a 5-year posttransplant survival of 61% to outweigh the harm caused to other patients on the waiting list. On sensitivity analysis, there was significant UNOS regional variability for the 5-year posttransplant survival needed to counterbalance this harm. For example, in the region with the least severe organ shortage (Region 3), a 5-year survival of 25% was acceptable for transplanting patients exceeding the Milan criteria, but in the regions of organ shortage (Regions 1, 5, 7 and 9) a 5-year survival of 72% was required to justify the harm caused to others. A pilot demonstration project in regions with least organ shortage may be reasonable to determine the feasibility of transplanting those who exceed the Milan criteria. However, at this time a widespread policy of transplanting those who exceed Milan criteria is not supported by the data and may to lead to unjustifiable harm to others waiting for a transplant.

In summary, the study by Ioannou et al was well done and is the largest study ever reported on patients undergoing OLT for HCC. It shows that those with high AFP and larger tumor burden have a worse overall survival. Whether MELD score >20 is a clinically important prognostic factor remains to be seen, but more studies accounting for regional variations are needed.

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References 

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PII: S0016-5085(08)00536-2

doi:10.1053/j.gastro.2008.03.042

Refers to article:

  • Editorial Accompanies Article Liver Transplantation for Hepatocellular Carcinoma: Impact of the MELD Allocation System and Predictors of Survival , 14 February 2008

    George N. Ioannou, James D. Perkins, Robert L. Carithers
    Gastroenterology May 2008 (Vol. 134, Issue 5, Pages 1342-1351)

Gastroenterology
Volume 134, Issue 5 , Pages 1612-1614, May 2008

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