Selection of patients with hepatocellular carcinoma before liver transplantation: need to combine alpha-fetoprotein with morphology?

Christian Toso, Gilles Mentha and Pietro Majno

Geneva, Switzerland

Selection of patients with hepatocellular carcinoma before liver transplantation: need to combine alpha-fetoprotein with morphology?

Christian Toso, Gilles Mentha and Pietro Majno

Geneva, Switzerland

Liver transplantation is the best treatment for selected patients with unresectable hepatocellular carcinoma (HCC). While candidate selection has been historically based on the restrictive Milan criteria, allowing transplantation for patients with single HCC ≤5 cm or ≤3 HCCs each ≤3 cm, much evidence now promotes the transplantation of patients with more advanced HCCs, with or without previous downstaging.[1-4]It remains however to define how far this expansion should go.

In this regard, new criteria should fulfil several requirements. They should keep good intent-totreat survival rates from the time of listing and stable post-transplant survivals. This should be achieved by comparing patients within the Milan criteria to those beyond the Milan criteria, but within the newly proposed criteria. Ideally, the new criteria should be validated externally in independent patient populations. Finally, they should allow repeated and easy assessment while the patient is on the waiting list.

The group at the University of California, San Francisco (UCSF), was the first to propose expanded criteria, allowing for transplantation of patients with a single HCC ≤6.5 cm or ≤3 HCCs each ≤4.5 cm and with a cumulative diameter ≤8 cm.[1]While validated by other investigators, the UCSF criteria have failed to gain unanimous recognition, at least in part because they include a strict (and low) limit of HCC number, while this variable is only a weak predictor of outcome. Many groups have subsequently explored the possibility of an expansion of the Milan criteria.[5]Among them, the group in Hangzhou, China, was the most ambitious, allowing transplantation of patients with a total tumor diameter ≤8 cm or a total tumor diameter >8 cm, but with pathological gradeior II and alpha fetoprotein (AFP) ≤400 ng/ml.[6]This strategy is of interest as it does not include any tumor number restriction and takes AFP into account. In addition, good outcomes were maintained (70.7% overall and 62.4% tumor-free survival at five years for patients within the Hangzhou criteria), despite a majority of patients transplanted beyond the Milan criteria (63%).[6]The validation of this score appears important, however, as the patient population in Hangzhou was almost exclusively made up of patients with hepatitis B virus, and similar results may be more difficult to achieve in centers with higher prevalence of hepatitis C virus infection.

One of the main advantages of the Hangzhou score is its lack of cut-off in the number of HCCs, while the backbone of many previous scores is a combination of HCC size and number. We introduced the concept of the total tumor volume (TTV ≤115 cm3), which provides post-transplant survival rates similar to those achieved by patients within the Milan criteria, despite the inclusion of more patients, in two independent studies.[7,8]The advantages of the TTV are the lack of strict cut-off in the number of HCCs (a poor predictor of outcome) and the improved radiological accuracy, linked to the fact that larger HCCs, which can be better characterized by radiology, have more weight in the score, due to r3in the (4/3)πr3formula.

Beside morphology, biological markers like AFP are extremely powerful in predicting post-transplant outcome.[8,9]While they reflect the aggressiveness of the HCC (including grade and micro-vascular invasion),they are not linked to tumor size. As a consequence, TTV and AFP behave independently, and only a combination of both variables can accurately select patients for transplantation. Based on the observation that both large and aggressive HCCs are associated with an increased risk of post-transplant recurrence, the combination of TTV ≤115 cm3and AFP ≤400 ng/ml was introduced. With this score, post-transplant survivals similar to those with the Milan criteria are found in the Scientific Registry of Transplant Recipients, a large US transplant registry (71% survival at three years for patients within Milan vs. 65% for patients beyond Milan but within TTV/AFP,P=0.25). Of note, the use of PIVKA-II, another biological marker, could also be considered. However, it does not appear to have a clear advantage over AFP, which we favour as it is more widely available.

Overall, several points appear important in the selection of candidates with HCC for liver transplantation:

1) The Milan criteria are too restrictive, excluding from transplantation patients with good expected outcomes, thus leading to unfair discrimination and ethical concerns. They must be expanded.

2) HCC number is a weak predictor of posttransplant survival compared to size. Scores without a strict cut-off in HCC number should be favored. As a consequence, the Milan and UCSF criteria are not ideal for patient selection.

3) Scores in which small tumors have minimal weight should be favored. This allows for a more accurate pre-transplant radiological staging. TTV confers this advantage thanks to r3in (4/3)πr3.

4) A new score should be based both on morphological and biological (AFP) criteria in order to exclude patients with advanced and/or aggressive HCCs. In our view, this is a key point.

Overall, an expansion of pre-transplant selection is required, but should be performed within reasonable limits. An expansion will only be justified if the overall results of liver transplantation for HCC are maintained, thus not harming candidates with a non-HCC diagnosis. With the amount of work performed on the topic so far, we favor a pre-transplant patient selection based on a combination of total tumor volume (TTV ≤115 cm3) and AFP (≤400 ng/ml).

Funding:None.

Ethical approval:Not needed.

Contributors:TC wrote the editorial. MG and MP critically reviewed the manuscript. TC is the guarantor.

Competing interest:No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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2 Yao FY, Kerlan RK Jr, Hirose R, Davern TJ 3rd, Bass NM, Feng S, et al. Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: an intention-to-treat analysis. Hepatology 2008;48:819-827.

3 Ravaioli M, Grazi GL, Piscaglia F, Trevisani F, Cescon M, Ercolani G, et al. Liver transplantation for hepatocellular carcinoma: results of down-staging in patients initially outside the Milan selection criteria. Am J Transplant 2008;8: 2547-2557.

4 Mazzaferro V, Llovet JM, Miceli R, Bhoori S, Schiavo M, Mariani L, et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol 2009;10:35-43.

5 Toso C, Kneteman NM, James Shapiro AM, Bigam DL. The estimated number of patients with hepatocellular carcinoma selected for liver transplantation using expanded selection criteria. Transpl Int 2009;22:869-875.

6 Zheng SS, Xu X, Wu J, Chen J, Wang WL, Zhang M, et al. Liver transplantation for hepatocellular carcinoma: Hangzhou experiences. Transplantation 2008;85:1726-1732.

7 Toso C, Trotter J, Wei A, Bigam DL, Shah S, Lancaster J, et al. Total tumor volume predicts risk of recurrence following liver transplantation in patients with hepatocellular carcinoma. Liver Transpl 2008;14:1107-1115.

8 Toso C, Asthana S, Bigam DL, Shapiro AM, Kneteman NM. Reassessing selection criteria prior to liver transplantation for hepatocellular carcinoma utilizing the Scientific Registry of Transplant Recipients database. Hepatology 2009;49:832-838.

9 Xu X, Ke QH, Shao ZX, Wu J, Chen J, Zhou L, et al. The value of serum alpha-fetoprotein in predicting tumor recurrence after liver transplantation for hepatocellular carcinoma. Dig Dis Sci 2009;54:385-388.

June 25, 2010

Accepted after revision August 28, 2010

Author Affiliations: Abdominal and Transplant Surgery, University Hospitals of Geneva, Geneva, Switzerland (Toso C, Mentha G and Majno P)

Christian Toso, MD, PhD, Abdominal and Transplant Surgery, Department of Surgery, H?pitaux Universitaires de Genève, rue Gabrielle-Perret-Gentil 4, 1211 Genève 14, Switzerland (Tel: +41-22-37227693; Fax: +41-22-3727707; Email: christian.toso@hcuge.ch)

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