Improving predictive performance of selection criteria for liver transplantation with hepatocellular carcinoma: combining morphological and biomarker criteria

Liver transplantation (LTx) has become well established internationally as the best treatment option for patients with small unresectable hepatocellular carcinomas (HCC). Our impact and effectiveness in utilizing LTx in the treatment of HCC has been limited mainly by donor availability and by our (in)ability to select the appropriate candidates. This has included both errors of omission (where candidates that may have expected a reasonable long-term survival were ruled out for transplant) and commission (where patients with advanced and/or aggressive tumors have been transplanted only to experience early recurrence and short survival). Initial problems with near open candidacy for HCC in the 1980’s led to poor outcomes (1) and a veritable moratorium that was reversed largely by Mazzaferro’s report of excellent outcomes in a population with tumors tightly selected by size and number (2). Low rates of tumor recurrence, thanks to tight selection with Milan criteria, in a patient group that usually has a low natural MELD (model for end-stage liver disease) score provides excellent survivals, but is now recognized to exclude from transplant candidacy a significant number of patients that might expect more than satisfactory survivals after LTx for more advanced HCC.

A series of important papers have been published reporting good post-transplant results in patient groups that were characterized by an expansion of the morphological criteria of tumor size and number in the Milan criteria (3-6). Perhaps not surprisingly, as in other areas of oncology, the impact of both tumor staging and grading (degree of differentiation) have become increasingly apparent over time. The importance of markers of aggressive tumor biology in predicting higher rates of tumor recurrence and poor survival have included such factors as microvascular invasion (7), tumor grade on explant pathology (8), as well as serum biomarkers such as alpha-fetoprotein (AFP) (3), des-gamma-carboxy prothrombin (DCP/PIVKA II) (9,10), and lens culinaris agglutinin A-reactive fraction of AFP (AFP-L3) (11). Ease of assay on serum and widespread availability have allowed extensive evaluation and increasing application of AFP in this role. Information that is only available from post-transplant pathology logically cannot be used for candidate selection and the potential morbidity of pre-transplant biopsy has discouraged broad adoption of other such histologically based biological markers.

Our analysis of factors associated with patient survival after LTx for HCC in the scientific registry of transplant recipients was the first to report that morphological factors [represented by total tumor volume (TTV) of <115 cm³] and biomarkers (represented by AFP <400 ng/mL) were independent predictors of outcome and that a combination of both outperformed Milan and UCSF (University of California, San Francisco) criteria (12). Our initial report has been supported and extended by the recently published outcomes of a prospective multicenter study on the application of the composite TTV/AFP selection criteria for LTx with HCC. Overall HCC recurrence rate in a consecutive series of 166 patients transplanted in three centers in Canada and Switzerland was 5.4% (9 of 166), including 6 of 134 patients (4.5%) within Milan by morphological assessment and 3 of 32 (9.4%) beyond Milan (13). Recurrence-free survival at 4 years did not differ between the two groups (86.1%±3.5% vs. 83.4%±3.8%, P=0.932). In 2012, Duvoux et al. first reported their findings from prospective study of a large series of LTx patients from France where a model including AFP improved the performance of the Milan criteria for both prediction of tumor recurrence and improved survival (14). A multicenter cohort study from Latin America recently provided additional support for the combining of AFP with morphological criteria in the AFP model (15).

Of interest, an analysis of results from UCSF with 211 consecutive patients within Milan criteria led to the suggestion that inclusion of an AFP cutoff of 1,000 ng/mL in the selection criteria could lead to reduction of HCC recurrence and improved 5-year disease-free survival after LTx (16).

The report by Notarpaolo et al. in J Hepatol (17) provides further support for a composite selection criteria from retrospective analysis of an independent patient population in Italy where viral hepatitis represented the underlying pathology to HCC in >80% of patients. Combining morphological and biomarker factors again outperformed Milan criteria in prediction of recurrence rate and patient survival. AFP was found to be a surrogate for both tumor differentiation and microvascular invasion in explant pathology evaluation. As predicted by the AFP model, high AFP correlated with increased recurrence rates and reduced survivals.

Where do we see the current state of selection criteria for LTx in patients with HCC? An increasing body of literature supports the addition of AFP as a biomarker to improve prediction of established morphological criteria. Such composite criteria are now established as national criteria in France and Canada. Many questions remain. What impact might such changes have on other LTx candidates on the waitlist, including non-tumor patients and HCC patients within Milan? The expansion of candidacy with broadened morphological criteria whether TTV or UCSF-like appears to be about 30%, an impact that is tempered by an approximate 10% reduction secondary to application of AFP limits (17,18). While a 20% increase in candidacy will be expected to lengthen wait-times for all, it seems unfair to consider continuing to deny candidacy to such expanded HCC patients where multiple programs from several countries on three continents have now demonstrated 5-year survival numbers above 70%.

Do we see advantages of one system or another that would support further adoption? The AFP model could be simplified for bedside application by distilling it to its essence—what are the situations where factors yield a score >2:

• Largest tumor diameter >6 cm;
• AFP > 1,000 ng/mL;
• Any 2 of: tumor >3 cm, >3 tumors, AFP> 100 ng/mL.

Will the AFP model achieve better outcomes from subtle differences in patients with mid-range risk of both tumor size/number and AFP, where the TTV/AFP criteria utilizes two hard endpoints? Or do the ranges involved prove a disadvantage? Does utilization of TTV as a better representation of the mass of cancer (akin to AFP level) provide more accurate prediction of recurrence risk that a one-dimensional assessment by diameter? Is the increased impact of large tumors on volume and the parallel improvement in radiological prediction with TTV more important than additional numbers of small tumors in the AFP model? Consider 2 patients:

• Three tumors of 3 cm (TTV, 42.4 cm³) and an AFP of 975 ng/mL;
• Four tumors of 1 cm (TTV, 2.1 cm³) and an AFP of 110 ng/mL.

The first patient qualifies under the AFP model (and the updated UCSF model), but not under the TTV/AFP. The second patient is excluded under AFP model (and UCSF), but remains a candidate with TTV/AFP. With 20-fold greater tumor mass and 9-fold higher AFP, it would seem the first patient has a substantially higher risk for recurrence.

We are in agreement with the summary from Notarpaolo et al. (17): Only by analysis of additional and larger well-structured prospective series will we be able to provide the data to allow accurate ongoing refinement of our HCC candidate selection criteria.

Acknowledgements

Funding: Norman Kneteman is Supported by CHA Chair in transplantation research; Christian Toso has also support for the most recent paper “Dynamic Volume Assessment of Hepatocellular Carcinoma in Rat Livers Using a Clinical 3T MRI and Novel Segmentation”.

Footnote

Provenance and Peer Review: This article was commissioned and reviewed by the Section Editor Dr. Ying Peng (Department of Gastroenterology, University-Town Hospital of Chongqing Medical University, Chongqing, China).

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/amj.2017.08.01). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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