Squaring the circle of selection and allocation in liver transplantation for HCC: An adaptive approach

Potential conflict of interest: Dr. Mazzaferro is on the speakers' bureau for Bayer and BTG. This study was supported in part by the Italian Association for Cancer Research, INT‐Milan, and the Italian Ministry of Health. Training for details produces tunnel vision, and men of broader perspective are required for useful application of scientific progress. Michael Shimkin Nearly every day, the issue of liver transplantation (LT) for hepatocellular carcinoma (HCC) is debated worldwide during rounds, publications, meetings, and—more importantly—in front of patients with liver cancer who are seeking their doctors' advice, often after the digital information media have left them and their families empty‐handed. Physicians have realized how their certainties can weaken and can strongly differ, regardless of whether the prediction of post‐LT outcome is applied to large populations or to single individuals with liver cancer. In addition, liver‐dedicated physicians with nontransplantation expertise may find themselves puzzled when dealing with the existing restrictions on the distribution of the scarce resource of donated organs.1 Allocation rules are in fact continuously released based on adjustments adopted within the transplantation community to maximize patient benefit—defined as an improvement in quantum of life in each patient independent of tumor stage—while avoiding harm to other patients who are waiting for a liver graft. Putting this into practice, the mission of doing justice in transplantation is attempted either through application of the utility principle (i.e., when organs are allocated to patients who have the best post‐LT predicted survival) or in adherence to the mandate to care for the “sickest patient first.”4 In transplantation candidates with HCC, the main obstacle to a smooth organ allocation is the lack of instruments able to determine, with sufficient detail, exactly how sick a patient is, how specific a given tumor presentation is, and how likely the tumor response to various treatments will be. Scores modulated on HCC characteristics have been proposed,4 but the estimation of the risk of pretransplantation dropout or posttransplantation benefit remains suboptimal. What is missing to fully accomplish the “nearly impossible mission” to frame the complex scenario of LT for HCC is the ability to capture, in a weighty manner, the evolution of a given cancer in relation to treatment, as this could be the main driver to predict posttransplantation outcome in patients who have cirrhosis with HCC, similarly to what the Model for End‐Stage Liver Disease (MELD) system does in noncancer candidates. Notably, the lack of precise prognostication tools for transplantation candidates with HCC has been repeatedly reported as causing detrimental effects for non‐HCC patients, who may be disfavored by unbalances in points systems that oversupply cancer patients.4 Looking at the magnitude of the information presented on LT for HCC and at its diffuse interpretation, any further attempt to create new prognostication scores seems inadequate unless a precise description of the objective granularity of tumor presentation and of its spectrum of responses to different treatment options is taken into account. Also, as modern discussions on LT in HCC move into the broaden concept of a medicine made of economic, social and ethical components, a more accountable description of the tumor conditions could be instrumental to move the scale of priorities into a more realistic and treatment‐oriented approach to HCC. Priority in organ allocation and patient selection are crucial factors that are difficult to merge because they have endpoints that are inherently far from one another. Optimization of a given resource in the case of organ allocation and maximization of outcomes when patient selection is targeted are in fact the driving forces that tend to split LT for HCC apart. Yet the attempt to reconcile these postulates is often referred to as an effort to “square the circle.” In this article, the impossible task to square the closed circle of patient selection and graft allocation in LT for HCC is approached as it would be during a math class, solving this same problem by multiplying the square of the radius (r2) by π: an irrational number (i.e., a number that never ends) used to approximate a solution that otherwise would be to the infinitum. To do this, a comprehensive assessment of HCCs examined for transplantation is proposed. In the proposed model, tumor presentation and response to therapy are used as a “π”: a sort of rectifying factor to be used within the challenging contexts of listing and prioritization, with the aim of improving their mutual efficiency in optimizing patient outcome and resource allocation in the field of LT for HCC. Background: The Fruits of Long Endeavors The likelihood of patient survival after transplantation remains an essential criterion when deciding on LT for HCC and represents the most important factor for indicating such a demanding therapeutic option.1 About two decades ago, the Milan criteria defined the benchmark for achieving the best post‐LT survival in HCC.11 Since then, these restricted criteria (single nodule ≤5 cm or multiple [≤3] nodules ≤3 cm in size) have become the best predictor of excellent post‐LT outcome and cost‐effective transplantation. This result strongly influenced staging systems for HCC, guidelines, recommedations, and allocation policies for deceased donor liver grafts.12 Starting with the University of California San Francisco (UCSF) criteria (single nodule ≤6.5 cm; 2 to 3 lesions each ≤5 cm or 4 to 5 lesions each ≤3 cm, with the maximum sum of diameters ≤8 cm in all cases)15 multiple other metrics have been established over time in an attempt to predict the results of LT for HCC.16 Most of these metrics have shown the same good survival results achieved when restricted indications were met, even though subsequent observations revealed a progressively increased rate of cancer recurrence in tumors transplanted beyond conventional limits. Clearly, the expanded criteria mechanism built on pure morphologic tumor indexes (i.e., largest diameter and number of tumor nodules) did not help in defining which patients with cirrhosis and HCC beyond the Milan criteria should be offered LT first, but did unravel the negative prognostic influence of biological and pathological features rarely observed in patients meeting conventional criteria (such as high alpha‐fetoprotein [AFP] serum level, presence of microvascular invasion, and poorly differentiated [G3] tumors).4 Conventional selection criteria have persisted, however, in guidelines and organ procurement organization policies, while the “transplantable HCC” category (i.e., curable with transplantation only) has been enriched over time, with cases at worse prognosis (i.e., T3 stage according to the United Network for Organ Sharing [UNOS] system) defined as transplantable on the basis of local dynamics of the waiting list that did not prejudice other noncancer recipients with a better prognosis.17 It is conceivable that 25%‐40% of the current HCC patients listed for LT belong to such a T3 subgroup receiving exception points and presumably some form of tumor downstaging.4 The introduction of direct antiviral agents in daily practice19 will further increase organ availability for patients with HCC in the near future, as a significant number of patients with decompensated cancer‐free hepatitis C virus (HCV) cirrhosis will likely be inactivated and delisted within 1 year just by the introduction of second‐generation direct antiviral agents. In a recent multicenter European study, it was estimated that 33% and 25% of HCV cancer‐free listed cirrhosis will be inactivated or delisted, respectively.20 In parallel, the practice of downstaging tumors in patients who were originally thought to be ineligible for transplantation21 will increase the number of borderline HCC cases presented to liver transplantation boards for decision. Emboldened by its own success, transplantation for HCC—a neglected indication just 20 years ago—is likely to become the leading indication for liver replacement in the near future. The Inverse Perspective of Case Selection: From Tumor Presentation to Response to Therapy Tumor subclasses correlating with diverse molecular assays and clinicopathologic behavior have been discovered progressively,22 with gene signatures also playing a role in the prognostication of LT patients beyond the Milan criteria.24 However, the extreme molecular heterogeneity of HCC still represents a significant limitation to the full introduction of precision medicine in patients within the transplantation landscape.23 Despite the absence of reliable biomarkers or genetic alterations influencing clinical decisions, a different kind of individualized medicine has progressively gained credit from multidisciplinary tumor board discussions in which all tumor and individual characteristics of each patient are weighed by different specialties and routed to variegated therapeutic alternatives. Perhaps the less known but most relevant result of this approach is the inverse perspective that has emerged in centers with a large referral of HCC patients regardless of their indication for transplantation. In practice, rather than considering up front patients with HCC as being eligible for LT according to disease presentation, most patients with HCC remain within the spectrum of eligibility for LT—the exclusions determined only by macrovascular invasion, extrahepatic spread, comorbidities, and age beyond limits—and are assigned to different forms of combined therapy that, if sufficiently effective within a certain time, may allow liver transplantation listing. A flexible approach aimed at merging tumor stage and results of treatment is going to be adopted in a large European region25 and is based on the observations that post‐LT survival outcomes in HCC beyond Milan criteria with objective and sustained response to pre‐LT therapy are not significantly different compared with those patients who meet conventional criteria at presentation.17 In order to avoid the risks of uncontrolled expansion of HCC criteria, such an “inverse selection approach” based on response to therapy requires a few restrictions: All suitable patients with cirrhosis who have treatable HCC by nontransplantation means should be treated, regardless of whether LT is in their therapeutic future. The best available option (i.e., monotherapy or combination therapy) should be determined after thorough multidisciplinary discussion. A minimal observation period after the conclusion of a given (combination) treatment is mandatory, because time is a surrogate of tumor aggressiveness and therefore an additional factor in the selection process.17 Time as a covariate is also required to assess tumor response and evolutionary All information on tumor should be and the this and of serum over time, as as during or should be The minimal survival for patients LT this conditions should be increased from the conventional of at 5 years to or In doing the benefit in HCC beyond conventional criteria could be to of posttransplantation while avoiding any harm to patients who remain on waiting on these and other a of patients with HCC who are eligible for and curable with transplantation could be attempted within a comprehensive frame able to the large of tumor and in a the granularity of responses to 1 a scale of HCC disease that is to of organ allocation by means of points systems determined according to and transplantable tumors will be defined the or expanded criteria with the donor rate in each allocation the of patients and the of the waiting and allocation for HCC within the spectrum of LT of and allocation within the for HCC in LT eligibility and are not determined up but they into after the best available therapy has been on application rules are given in of within from patients with HCC (i.e., disease by or to patients conventional criteria tumors either at or as recurrence years from a as on rather than patients in transplantable criteria are still at or after or response to downstaging be as the are patients who have achieved a response (i.e., a treatment or patients with cancer recurrence years from a and tumor staging still to a transplantable The main what can be an approach are in which should be in with 1 for and Allocation 1 The system only to and stage HCC in liver and criteria are invasion, extrahepatic and HCC in decompensated cirrhosis is determined by and 2 In any HCC in cirrhosis is as criteria are criteria (i.e., tumor and used for transplantation eligibility should be defined a at a on the dynamics of the waiting of HCC non‐HCC patients, harm to patients who remain on the waiting donor and should not be at any time during patient (i.e., up to or criteria reported should be with information tumor when and all information should be the tumor transplantation board points 3 and 4 able to transplantation eligibility even in presence of tumor conditions should be defined a as as that from to or according to increase over 3 All should be with the best available treatment according to guidelines and should be for at the of each treatment any treatment of a should into the transplantation and after therapy 4 criteria for and in HCC and after treatment should determined a and should also the of tumor and of disease should be for or 5 are not treatable to or not by (i.e., the patient should be as HCC and and should be because disease may over time on and should be at a of time at tumor presentation if points and 2 in tumor conditions (i.e., disease for a sufficient period of time 3 in case of tumor during at the of each treatment in downstaging should be as in case of response at the of to the tumor stage conventional as in case of tumor over time in patients still meeting transplantation patients in for LT listing could be only after response and if part of that in serum while patients are on the waiting list to in posttransplantation should tumor response of a transplantable tumor during treatment In patients who have a in after treatment should be at a more significant than those who do In patients in downstaging and could help in various of different patients with HCC should be approached similarly to HCC, with treatment and as listed in points HCC may be as or according to the time of whether this is years (i.e., or years (i.e., from the This different priorities because of the risk of dropout in should be listed only if the tumor transplantable criteria at the time of treatment and after which is at the time of transplantation The stage of an HCC one tumor as the sum of the HCC should be listed if meeting transplantation criteria at the time of transplantation as they could be as regardless of the stage of the HCC years to the frame of stage and priorities are with from a In the current may be transplantation applied to tumors treatment for cm lesions in for responses of and to response in tumors in to the system shown in should be in order of as of the of an additional of or extrahepatic tumor In this model, tumor A and may further treatment, in or dropout on whether the still transplantation C and the patient from transplantation (i.e., dropout from the waiting the of proposed in this the of and treatments are routed into different subclasses that current in local and resource and evolutionary conditions to treatment as as HCC tumor and objective tumor assessment with with different all these conditions a role in the current on LT for HCC and are in a system in which transplantation eligibility and are not determined up front but they into after all relevant have been and therapy has been a of a “transplantable is inherently to more specific of staging and allocation and is in with recent policies of HCC in which tumor subclasses of and have been to increase tumor staging and points in (i.e., and in the Organ and Network for liver allocation in in which criteria for and are Priority as a of Allocation may the scale of in the proposed is a concept with on which allocation principle In addition, the endpoints may be from the of pre‐LT risk to when the principle is adopted to the maximization of post‐LT outcome in case the utility is for the transplantation the survival by the survival achieved with LT by the survival with nontransplantation In addition, patients, and at large significantly influence the of as as with have been to all of these however, because within this even a in the of or in to different In the proposed concept of a of observations the of a in HCC not only as a of tumor but also as a of and The list of which each is is in 2 and Priority of HCC in the LT to Allocation Priority to HCC Priority to Priority of and tumor after treatment of HCC risk of dropout in HCC benefit on only The patient should not transplantation tumor after for transplantable HCC risk of dropout in HCC benefit on The patient was eligible for transplantation but can be on because the tumor seems to be HCC cm risk of dropout in HCC benefit in presence of nontransplantation treatments The patient should not transplantation if are other treatment options tumor after treatment of a HCC HCC should not be listed up similarly to non‐HCC in patients with scores benefit on only The patient was not eligible for transplantation and has been by other means HCC at presentation or HCC years after treatment increase of dropout risk over time for and number on of treatments This patient has the best posttransplantation survival HCC for not by (i.e., dropout time to liver is therapeutic for HCC The patient is to have good utility posttransplantation response after therapy in a transplantable tumor of selection of with increased of a therapy with therapeutic The patient is to have good utility posttransplantation eligibility after downstaging or HCC years after treatment of any HCC dropout risk over time for and number on absence of treatments should be offered in patients it is the the defining each can be through of the of transplantation that to a of a the of into the scale has to be determined at a and Allocation the the the number of adjustments not just in selection but also in rules for LT in HCC, has the current effort to transplantation for patients with HCC within a modern The is that transplantation eligibility and allocation in HCC could be prejudice to other this is likely to as will a in transplantation indication for cirrhosis and an increase in the practice of downstaging HCC. 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