Optimal Liver Allocation for Hepatocellular Carcinoma: Hurry up AND wait, but which one when?

Authors


Abstract

Waiting longer for a liver transplant does not improve the outlook for patients with hepatocellular carcinoma, and patients within Milan criteria who are awaiting transplant should be prioritized proportionally to their likelihood of drop-out without a mandatory waiting period. See brief communication by Bittermann et al on page 1657.

Hepatocellular carcinoma (HCC) is the second-leading cause of cancer death worldwide, with GLOBOCAN 2012 estimating that 95% of the 782 000 annual cases die of the disease. The natural history of untreated HCC is known; with median survival for patients within Milan criteria (BCLC class A) approximately 36 months, and for BCLC B 16 months [1], we can expect half of a typical transplant-eligible patient cohort to progress to ineligibility over 20 months. Against this back-drop, the hypothesis of Bittermann et al [2] in this issue that “longer waiting time would be associated with a lower risk of developing unfavorable tumor characteristics” seems absurd indeed. Where else in the world of cancer but in liver transplantation for HCC is early (T1) cancer left to progress untreated, and definitive treatment systematically delayed? Using newly available data from the United Network for Organ Sharing (UNOS) Liver Recipient Explant Pathology Worksheet, the authors could not confirm their hypothesis; they in fact demonstrated no significant change for better or worse in tumor characteristics over time. Locoregional treatment was employed in most patients even with short waiting time, and in over 95% of those waiting >9 months. The issue of waiting list drop-out was not the focus of the manuscript, but based on the data provided in table S1 [2], 15.1% of patients listed nationwide with automatic T2 priority for HCC (698/4633) dropped out with a median national waiting time for transplanted patients in their study between 3 and 6 months, not an insignificant number.

The “test of time” has been proposed as a surrogate assessment of tumor biology [3]. The “ablate and wait” approach may well be valid when down-staging patients with locally advanced tumors that carry high risk of occult extrahepatic spread. It has a considerably weaker rationale, however, when applied to patients within Milan criteria who have repeatedly been shown to have excellent posttransplant survival; the ability to maintain an HCC within Milan criteria hinges on a number of factors other than tumor biology. The risk of progression to beyond Milan in these patients depends on how close they are to the limit to start with: patients with two to three tumors or with single tumors >3 cm are at higher risk than those with single tumors ≤3 cm [4]. While response (or lack thereof) to locoregional treatment may to an extent be a function of tumor biology, it is also related to technical factors such as, for example, the location of a tumor within the liver, as well as to expertise of the treating physician. The ability to carry out effective tumor treatment is limited by the functional reserve of the underlying liver; in patients with high natural Model for End-Stage Liver Disease (MELD), optimal locoregional treatment may not be safe to give.

The limited availability of donor organs means that tough choices must be made, and not everyone can receive. The current system, however, by preferentially directing organs to the patients who are least likely to drop-out, actually minimizes the benefit of transplantation: a patient with a successfully ablated solitary tumor <3 cm and normal alpha-fetoprotein, whose likelihood of drop-out is under 2% [4], has close to a 50% likelihood of surviving 5 years without a transplant, even if he or she is in Child's class B [5]. While 10-year survival may be lower, transplant remains an option if recurrence appears, and with the survival of patients with high natural MELD scores with whom these patients compete measured in months, is a consideration we can ill-afford.

The data of Bittermann et al [2] do not support the imposition of mandatory waiting time for patients listed with HCC meeting Milan criteria. Waiting is part of the transplant game, but similar to transplant candidates without HCC, priority needs to be proportional to the risk of drop-out. These data further strengthen the rationale for a dynamic, continuous priority score for HCC patients incorporating natural MELD, tumor-related factors and response to treatment such as was proposed in the report of the 2009 national conference on liver allocation in patients with HCC [6] and is currently under debate at UNOS. Under such a system patients within Milan criteria but with high risk of drop-out could be transplanted expeditiously while those at low risk could forgo transplant for the time being to the benefit of all patients awaiting transplant, both with and without HCC.

Disclosure

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

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