Locoregional therapy as a bridge to liver transplantation for hepatocellular carcinoma within Milan criteria: from a transplant oncology viewpoint

AbstractSince the Milan criteria were accepted as the gold standard, liver transplantation has been widely performed as a curative treatment for early-stage hepatocellular carcinoma (HCC). The outcome of liver transplantation in early-stage HCC is excellent; however, the Milan criteria are strict, and therefore, only limited numbers of patients can benefit from liver transplantation. Many HCC patients are diagnosed at an advanced stage, which falls outside the Milan criteria, so it has been proposed over the last two decades that liver transplant surgeons should perform liver transplantation in locally advanced HCC, when presenting without recurrence. Several trials exploring the upper limits of liver transplantation have been performed, and extensive research on tumor biology has enabled the expansion of liver transplant indication for HCC. Simultaneously, locoregional therapy for advanced HCC was found to be an effective procedure when used to distinguish potentially transplantable patients. This treatment approach, known as a downstaging strategy, has been developed over the last two decades and became an essential treatment option for locally advanced HCC. In this article, the current strategies of liver transplantation for the treatment of locally advanced HCC are reviewed.

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Impact of Pretransplant Bridging Locoregional Therapy for Patients With Hepatocellular Carcinoma Within Milan Criteria Undergoing Liver Transplantation

Annals of Surgery ◽

10.1097/sla.0000000000002381 ◽

2017 ◽

Vol 266 (3) ◽

pp. 525-535 ◽

Cited By ~ 50

Author(s):

Vatche G. Agopian ◽

Michael P. Harlander-Locke ◽

Richard M. Ruiz ◽

Goran B. Klintmalm ◽

Srinath Senguttuvan ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Transplantation ◽

Locoregional Therapy ◽

Milan Criteria

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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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Effectiveness of Locoregional Therapy Before Living Donor Liver Transplantation in Patients With Hepatocellular Carcinoma Who Meet the Milan Criteria

Transplantation Proceedings ◽

10.1016/j.transproceed.2012.01.067 ◽

2012 ◽

Vol 44 (2) ◽

pp. 403-408 ◽

Cited By ~ 10

Author(s):

J.M. Kim ◽

C.H.D. Kwon ◽

J.-W. Joh ◽

M.S. Choi ◽

J.H. Lee ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Transplantation ◽

Living Donor ◽

Living Donor Liver Transplantation ◽

Locoregional Therapy ◽

Milan Criteria ◽

Donor Liver ◽

Donor Liver Transplantation

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Oncological feasibility of liver transplantation for hepatocellular carcinoma

Annaly khirurgicheskoy gepatologii = Annals of HPB surgery ◽

10.16931/1995-5464.2020277-85 ◽

2020 ◽

Vol 25 (2) ◽

pp. 77-85

Author(s):

D. Ju. Efimov ◽

A. E. Shcherba ◽

S. V. Korotkov ◽

O. O. Rummo

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Transplantation ◽

San Francisco ◽

Intermediate Stage ◽

Waiting List ◽

University Of California ◽

Locoregional Therapy ◽

Milan Criteria ◽

Serological Response ◽

One Year

Aim. To evaluate the effectiveness of the liver transplantation in patients with hepatocellular carcinoma and cirrhosis according to morphological (Milan criteria) and oncological criteria.Materials and methods. A retrospective cohort study of 105 recipients with hepatocellular carcinoma who underwent liver transplantation from 2008 to 2019 was performed. The patients were divided into 3 groups. In the 1st group, transplantation was performed according to the Milan criteria (“Milan”), in the 2nd group – to recipients that did not meet the Milan and University of California San Francisco (UCSF) criteria (“extra-UCSF”), in the 3rd group – to the recipients meeting the Barcelona Clinic Liver Cancer criteria B (Intermediate stage), subjected to locoregional therapy and assessment of radiological and serological response (“Lerut”). The frequency of progression in the waiting list, the frequency of tumor recurrence after transplantation, hospital mortality, the frequency of arterial and biliary complications, and cancer-associated mortality were studied.Results. The highest rate of hepatocellular carcinoma progression on the waiting list was observed in the “extra University of California San Francisco” group of patients (36% versus 11% (p = 0.03) and 15% (p = 0.1) in the “Milan” and “Lerut” groups, respectively). The worst cancer-associated mortality rates were found in the extraUniversity of California San Francisco group. The one-year, three-year and five-year overall survival rate in the groups were 87.5%; 80.1% and 70.3% for the Milan group; 78.6%; 62.9% and 62.9% for the extra-University of California San Francisco group and 96.4%; 86.4% and 78.7% for the Lerut group, respectively.Conclusion. The oncological prognosis for patients with hepatocellular carcinoma is formed increasingly on the basis of the biological characteristics of the tumor. The use of locoregional therapy for hepatocellular carcinoma combines a therapeutic component that allows for better survival and stratification, which allows patients with an unfavorable prognosis to be selected and to allow patients beyond the accepted criteria to expect transplantation.

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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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