Liver allocation for patients with hepatocellular carcinoma

There is nothing more difficult to take in hand nor perilous to conduct or more uncertain in its success than the introduction of a new order of things because the innovator has for enemies all those who have done well under the old conditions and lukewarm defenders in those who may do well under the new. — Niccolo Machiavelli (1469-1527)

Doctors are often accused, rarely as a compliment, of playing God, that is, deciding who will live and who will die. In the field of liver transplantation, in which there is a shortfall between the number of people whose lives can be saved by a transplant and the number of usable liver grafts from deceased donors, doctors do have to make life and death decisions. For transplantation, there are 2 processes: selection (who gets on the waiting list) and allocation (who on the waiting list receives the donated graft). It is right that the basis on which the decisions are made, both for selection and for allocation, is transparent, evidence-based where possible, and supported by clear, agreed, and generally accepted principles. Although all stakeholders should be involved in formulating these principles, for practical reasons, if for no other reason, these principles need to be applied by the clinician who will, of course, remain accountable, through the courts if necessary, for their decisions. Organs from deceased donors are considered a national resource; therefore, their use should be equitable and fair.

AFP, alpha-fetoprotein; HCC, hepatocellular carcinoma; MELD, Model for End-Stage Liver Disease; OPTN, Organ Procurement and Transplantation Network.

Much has been written about the fundamental aims of any selection and allocation process, but whatever process is in place, guidelines need to be developed, agreed, and, of course, followed, and compliance must be audited. There are drawbacks to any protocol-driven approach: guidelines are just that and cannot cover every eventuality, so there needs to be a flexible system that allows for the tailoring of the system to suit the individual needs of the patient without disadvantaging others who are competing for the life-saving organ. Guidelines need to reviewed and modified if necessary to reflect not only changes in supply and demand but also changes in medical practice; furthermore, guidelines must not inhibit or discourage innovation or encourage excessive risk-averse practice.

One example of the difficulties in trying to reconcile these conflicting and competing demands is liver transplantation for those with liver cell cancer [hepatocellular carcinoma (HCC)]. One decade ago, the situation was easy: survival in the absence of transplantation was bleak, and there were few effective alternative therapies. The Milan criteria, derived from the experience of a relatively small number of patients, were rapidly adopted and provided clear parameters even though we know from studies reporting outcomes of patients grafted “outside the Milan criteria” that these guidelines were not always followed. It is widely accepted that the size and number of tumors are poor surrogates for the likelihood of the transplant “curing” the patient, but serological, molecular, or histological biomarkers are not yet sufficiently established to form a robust basis for treatment decisions. Now, imaging techniques have improved, and surveillance programs have been widely introduced so HCCs are being detected earlier at a stage at which effective treatment is feasible; clinicians have available a wide variety of therapies for treating and even curing the cancer (resection, effective locoregional therapies, effective chemotherapy, and, of course, transplantation). Newer immunosuppressive agents may further reduce the risk of recurrence. The treatment of the associated cirrhosis has also been improved. However, although there are many series looking at outcomes after different therapies, there are very few suitably powered, recent prospective randomized trials comparing different treatments; the extrapolation of outcomes from patients who were offered transplants to those who have not been considered suitable candidates may lead to misleading conclusions. Trials comparing treatment regimens in this situation are difficult to organize because the treatments may be complementary rather than alternatives. When trials include transplantation, it is important that outcomes from intention to treat are also considered. Thus, recommendations for the management of patients with HCC are often made more on the basis of prejudice than evidence.

In this rapidly evolving environment, the major US players in the field of liver transplantation convened a conference to address the use of liver transplantation for patients with HCC; the conclusions and recommendations are presented elsewhere in this issue. Some of their recommendations are summarized in Table 1.

Table 1. Summary of Some of the Main Recommendations

Abbreviations: AFP, alpha-fetoprotein; HCC, hepatocellular carcinoma; MELD, Model for End-Stage Liver Disease; OPTN, Organ Procurement and Transplantation Network.

1. Use a standardized histological reporting system for HCC.

2. Develop a standardized approach to processing explants.

3. Develop a standardized approach to imaging and reporting HCC.

4. Develop a new OPTN classification of liver tumors.

5. No change should be made in the current national policy for criteria for HCC listing or priority scoring.

6. Encourage regional agreements to explore expanding the Milan criteria.

7. Enhance reporting of tumor recurrence.

8. Locoregional therapies and resection should be encouraged while patients are awaiting transplantation (this depends on the individual circumstances).

9. Recurrence more than 2 years after resection for a tumor of any stage should be considered a de novo tumor, and if it is appropriate, replacement should be considered.

10. If recurrence occurs within 2 years of resection, the patient should be considered eligible for replacement.

11. There should be a minimum observational period of 3 months after tumor downsizing before transplantation can be considered.

12. There should be a uniform protocol for monitoring patients after downsizing.

13. A continuous HCC priority score should be developed that reflects not only the parenchymal disease (MELD score) but also tumor growth characteristics.

14. Those with a MELD score < 15 and HCC should have a given score of 15 for the first 3 months; thereafter, the MELD/HCC score should be recalculated every 3 months.

15. Allocation points should be based on the calculated MELD score plus AFP < 500 ng/mL, a tumor within the Milan criteria, and the time within the Milan criteria (including downsized tumors).

The first 2 working parties focused on agreeing to common approaches to the imaging and histological classification of liver cell cancers: clearly, this would be beneficial not only by supporting optimal practice but also by allowing meaningful comparisons between centers and allowing solid conclusions to be drawn. Of course, there will be some degree of subjectivity in aspects of these measurements, but, as the authors recognize, this is not a valid reason to halt progress. Implementation may require some additional resources, but these should be found. The establishment of a national biorepository for liver cell cancers will allow more rapid evaluation of genetic markers.

The third group focused on the possible expansion of the Milan criteria to allow transplantation. The conclusions appear paradoxical: there should be no change to the current national policy, but there should be encouragement of regional agreements to explore expanding the Milan criteria. These local agreements should be encouraged: only by pushing at the boundaries will we gain knowledge and improve management. Maintaining the status quo with the Milan criteria is useful only because we do not have better predictors of outcome. Of course, clinicians need to define the outcome that they seek: is this graft survival, patient survival, or tumor-free survival? Should the criteria be developed so that the graft outcome of the recipient with cancer is the same as that of the patient without cancer? This approach seems very reasonable but is simplistic. Are outcomes assessed as crude survival at any one period after transplantation? Long-term outcomes of those receiving grafts for primary biliary cirrhosis are better than long-term outcomes of those receiving grafts for hepatitis C virus infection, and no change in allocation is suggested to ensure that patients in the 2 groups have similar outcomes. Furthermore, is outcome to be considered at 1, 5, or 20 years? The selection of different outcome periods will alter the selection criteria. Others have tried to look at transplant benefit: this may prove to be the ultimate goal, but the statistical models are not yet available for such a scheme. The need to give additional points to those with cancer to ensure that they have a probability of receiving a graft or dying without one similar to that of those without cancer is a result of the central allocation system: in the United Kingdom, in which at present livers are allocated to the center rather than the recipient, there is no advantage or disadvantage for those with cancers.

Better reporting of tumor recurrence data, as proposed by the working parties, is also welcomed, but this suggests that clinicians should monitor recipients for recurrence. If so, how should this be done, and unless the treatment will be changed, is it in the interest of the patient that there should be surveillance for asymptomatic tumors?

The fourth group considered the role of locoregional therapies and made recommendations based on such evidence as is available. It still seems unclear whether such therapies will help on their own or provide a time frame in which to evaluate the natural history of the cancer. Nonetheless, the recommendations are clear and unambiguous: time will tell whether these recommendations are correct. The fifth group considered downstaging (although sometimes only downsizing is actually achieved). As discussed previously, it is unlikely that the size and number of tumors reflect more than a marker for tumor biology, and this really justifies their recommendation that a minimum period of 3 months after downsizing should be required and, of course, that resection cannot be considered downsizing or downstaging.

The final group reviewed organ allocation principles. The criteria for the allocation system are clearly identified, and few would take exception to them. The expertise of the participants and the availability of a huge database allow for a rational approach to the process. Of course, there are the usual criticisms relating to the application of a score to all recipients that does not take into account individual variation, external factors that might affect the components of the score, potential gaming by patients or clinicians to manipulate the score artificially, and so forth. These criticisms are possibly valid but no longer relevant. There is flexibility in the system. The decision to take an allocated liver is still with the clinician, who has to balance the risks and benefits of using a given graft with the risks of extending the wait; variations between regions in which the availability of organs and the case mix of recipients are different will allow for the development of the allocation system. Lessons learned from living donor transplants, for which different considerations apply, will also inform the management.

This approach taken by the groups is to be warmly welcomed outside and within the United States, and it is very much to be hoped that this report will not be the final word but the first in a series refining the role of liver transplantation in the management of patients with liver cancer. The advent of more robust markers to define the natural history of tumors, the introduction of newer agents to treat tumors, and the better use of immunosuppression to slow the natural history of recurrent disease will mean that these considerations may well become of little more than historical interest in a few years. Meanwhile, these recommendations remain a valuable step in optimizing the management of the waiting lists. Two factors would mean that all the work by these groups would be wasted: not implementing these recommendations and not reconvening in 1 or 2 years to reevaluate and modify the recommendations.

As the participants will have recognized, the main questions for liver transplant clinicians are primarily not what the indications for liver transplantation are in those with HCC but rather what the best pathway is for management, when replacement should be considered, and how the needs of the patient with HCC should be balanced against those with other liver diseases that affect either the quality or quantity of life.