Liver Transplantation in Patients with Hepatocellular Carcinoma beyond the Milan Criteria: A Comprehensive Review

The Milan criteria (MC) were developed more than 20 years ago and are still considered the benchmark for liver transplantation (LT) in patients with hepatocellular carcinoma (HCC). However, the strict application of MC might exclude some patients who may receive a clinical benefit of LT. Several expanded criteria have been proposed. Some of these consider pretransplant morphological and biological variables of the tumor, others consider post-LT variables such as the histology of the tumor, and others combine pre- and post-LT variables. More recently, the HCC response to locoregional treatments before transplantation emerged as a surrogate marker of the biological aggressiveness of the tumor to be used as a better selection criterion for LT in patients beyond the MC at presentation. This essential review aims to present the current data on the pretransplant selection criteria for LT in patients with HCC exceeding the MC at presentation based on morphological and histological characteristics of the tumor and to critically discuss those that have been validated in clinical practice. Moreover, the role of HCC biological markers and the tumor response to downstaging procedures as new tools for selecting patients with a tumor burden outside of the MC for LT is evaluated.

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Living donor liver transplantation for hepatocellular carcinoma beyond the Milan criteria: outcome of expanded criteria in tumor size

BMC Surgery ◽

10.1186/s12893-021-01403-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Hsin-Rou Liang ◽

Chia-En Hsieh ◽

Kuo-Hua Lin ◽

Chih-Jan Ko ◽

Yu-Ju Hung ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Transplantation ◽

Living Donor ◽

Milan Criteria ◽

Tumor Diameter ◽

Donor Liver ◽

Donor Liver Transplantation ◽

Living Donor Liver Transplant ◽

Expanded Criteria ◽

Donor Liver Transplant

Abstract Background The Milan criteria are the universal standard of liver transplantation for hepatocellular carcinoma (HCC). Numerous expanded criteria have shown outcomes as good as the Milan criteria. In Taiwan, living donor liver transplant (LDLT) accounts for the majority of transplantations due to organ shortages. Methods We retrospectively enrolled 155 patients who underwent LDLT for HCC from July 2005 to June 2017 and were followed up for at least 2 years. Patients beyond the Milan criteria (n = 78) were grouped as recurrent or nonrecurrent, and we established new expanded criteria based on these data. Results Patients beyond the Milan criteria with recurrence (n = 31) had a significantly larger maximal tumor diameter (4.13 ± 1.96 cm versus 6.10 ± 3.41 cm, p = 0.006) and total tumor diameter (7.19 ± 4.13 cm versus 10.21 ± 5.01 cm, p = 0.005). Therefore, we established expanded criteria involving maximal tumor diameter ≤ 6 cm and total tumor diameter < 10 cm. The 5-year survival rate of patients who met these criteria (n = 134) was 77.3%, and the 5-year recurrence rate was 20.5%; both showed no significant differences from those of the Milan criteria. Under the expanded criteria, the pool of eligible recipients was 35% larger than that of the Milan criteria. Conclusion Currently, patients with HCC who undergo LDLT can achieve good outcomes even when they are beyond the Milan criteria. Under the new expanded criteria, patients can achieve outcomes as good as those with the Milan criteria and more patients can benefit.

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Using Hepatocellular Carcinoma Tumor Burden Score to Stratify Prognosis after Liver Transplantation

Cancers ◽

10.3390/cancers12113372 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3372

Author(s):

Dimitrios Moris ◽

Brian I. Shaw ◽

Lisa McElroy ◽

Andrew S. Barbas

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Transplantation ◽

Continuous Variable ◽

Tumor Burden ◽

Milan Criteria ◽

Transplant Recipients ◽

Liver Transplants ◽

Free Survival ◽

Promising Tool ◽

Tumor Number

Liver transplantation (LT) remains a mainstay of treatment for hepatocellular carcinoma (HCC). Tumor factors such as size and number of tumors define eligibility for LT using the Milan criteria. The tumor burden score (TBS) incorporates both tumor number and size into a single continuous variable and has been used to differentiate prognosis among patients undergoing resection for HCC. The objective of the present study was to evaluate the ability of the TBS to predict overall and recurrence-free survival in patients undergoing LT for HCC. The Scientific Registry of Transplant Recipients (SRTR) was used to analyze all liver transplants for HCC, with initial tumor size data from 2004 to 2018. There were 12,486 patients in the study period. In the unadjusted analyses, patients with a high TBS had worse overall (p < 0.0001) and recurrence-free (p < 0.0001) survival. In the adjusted analyses, a high TBS was associated with a greater hazard ratio (HR) of death (HR = 1.21; 95%CI, [1.13–1.30]; p < 0.001) and recurrence (HR = 1.49; 95%CI [1.3–1.7]; p < 0.001). When we superimposed the TBS on the Milan criteria, we saw that a higher TBS was associated with a higher hazard of recurrence at values that were either all within (HR = 1.20; 95%CI, [1.04–1.37]; p = 0.011) or variably within (HR = 1.53; 95%CI, [1.16–2.01]; p = 0.002) the Milan criteria. In conclusion, the TBS is a promising tool in predicting outcomes in patients with HCC after LT.

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Liver Transplantation for Hepatocellular Carcinoma: How Should We Improve the Thresholds?

Cancers ◽

10.3390/cancers14020419 ◽

2022 ◽

Vol 14 (2) ◽

pp. 419

Author(s):

Tsuyoshi Shimamura ◽

Ryoichi Goto ◽

Masaaki Watanabe ◽

Norio Kawamura ◽

Yasutsugu Takada

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Transplantation ◽

Patient Selection ◽

Tumor Burden ◽

Biological Behavior ◽

Locoregional Therapy ◽

Milan Criteria ◽

Surrogate Markers ◽

Patient Selection Criteria ◽

Fdg Pet Ct

Hepatocellular carcinoma (HCC) is the third highest cause of cancer-related mortality, and liver transplantation is the ideal treatment for this disease. The Milan criteria provided the opportunity for HCC patients to undergo LT with favorable outcomes and have been the international gold standard and benchmark. With the accumulation of data, however, the Milan criteria are not regarded as too restrictive. After the implementation of the Milan criteria, many extended criteria have been proposed, which increases the limitations regarding the morphological tumor burden, and incorporates the tumor’s biological behavior using surrogate markers. The paradigm for the patient selection for LT appears to be shifting from morphologic criteria to a combination of biologic, histologic, and morphologic criteria, and to the establishment of a model for predicting post-transplant recurrence and outcomes. This review article aims to characterize the various patient selection criteria for LT, with reference to several surrogate markers for the biological behavior of HCC (e.g., AFP, PIVKA-II, NLR, 18F-FDG PET/CT, liquid biopsy), and the response to locoregional therapy. Furthermore, the allocation rules in each country and the present evidence on the role of down-staging large tumors are addressed.

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Comparative evaluation of expanded criteria for patients with hepatocellular carcinoma beyond the Milan criteria undergoing living-related donor liver transplantation

Clinical Transplantation ◽

10.1111/j.1399-0012.2011.01463.x ◽

2011 ◽

Vol 25 (5) ◽

pp. E491-E498 ◽

Cited By ~ 30

Author(s):

Ken Shirabe ◽

Akinobu Taketomi ◽

Kazutoyo Morita ◽

Yuji Soejima ◽

Hideaki Uchiyama ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Transplantation ◽

Comparative Evaluation ◽

Milan Criteria ◽

Donor Liver ◽

Donor Liver Transplantation ◽

Expanded Criteria ◽

Related Donor ◽

Living Related ◽

Living Related Donor

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Effect of conversion to sirolimus-based immunosuppression on tumor recurrence after liver transplantation for hepatocellular carcinoma beyond the Standard Milan Criteria

Academic Journal of Second Military Medical University ◽

10.3724/sp.j.1008.2012.00642 ◽

2013 ◽

Vol 32 (6) ◽

pp. 642-645 ◽

Cited By ~ 2

Author(s):

Li-kui FENG ◽

Zhi-jia NI ◽

Shao-hua SONG ◽

Feng LIN ◽

Hong FU ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Transplantation ◽

Tumor Recurrence ◽

Milan Criteria

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The Treatment Effect of Liver Transplantation versus Liver Resection for HCC: A Review and Future Perspectives

Cancers ◽

10.3390/cancers13153730 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3730

Author(s):

Berend R. Beumer ◽

Roeland F. de Wilde ◽

Herold J. Metselaar ◽

Robert A. de Man ◽

Wojciech G. Polak ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Transplantation ◽

Liver Resection ◽

Early Stage ◽

Disease Free Survival ◽

Milan Criteria ◽

Term Survival ◽

Equal Distribution ◽

Intention To Treat ◽

Treat Analysis

For patients presenting with hepatocellular carcinoma within the Milan criteria, either liver resection or liver transplantation can be performed. However, to what extent either of these treatment options is superior in terms of long-term survival is unknown. Obviously, the comparison of these treatments is complicated by several selection processes. In this article, we comprehensively review the current literature with a focus on factors accounting for selection bias. Thus far, studies that did not perform an intention-to-treat analysis conclude that liver transplantation is superior to liver resection for early-stage hepatocellular carcinoma. In contrast, studies performing an intention-to-treat analysis state that survival is comparable between both modalities. Furthermore, all studies demonstrate that disease-free survival is longer after liver transplantation compared to liver resection. With respect to the latter, implications of recurrences for survival are rarely discussed. Heterogeneous treatment effects and logical inconsistencies indicate that studies with a higher level of evidence are needed to determine if liver transplantation offers a survival benefit over liver resection. However, randomised controlled trials, as the golden standard, are believed to be infeasible. Therefore, we suggest an alternative research design from the causal inference literature. The rationale for a regression discontinuity design that exploits the natural experiment created by the widely adopted Milan criteria will be discussed. In this type of study, the analysis is focused on liver transplantation patients just within the Milan criteria and liver resection patients just outside, hereby ensuring equal distribution of confounders.

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