Expanding HCC criteria for liver transplant: The urgent need for prospective, robust data

Hepatocellular carcinoma (HCC) is a major health problem worldwide.1 In the West, 30–40% of HCC cases are detected at early stages and treated with intention to cure, a figure that reaches 60% of the cases in Japan.1 Surgical resection, liver transplantation, and percutaneous ablation are considered curative therapies by published guidelines of HCC management.2, 3 CLT, cadaveric liver transplantation; HCC, hepatocellular carcinoma; RCT, randomized controlled trial; UCSF, University of California, San Francisco. Cadaveric liver transplantation (CLT) is an excellent treatment approach for HCC in well-selected candidates.4-6 The so-called Milan criteria of selection of patients—1 nodule ≤5 cm in diameter, or 2–3 nodules, all <3 cm in diameter, and without macroscopic vascular invasion—has been shown to provide excellent survival rates above 70% at 5 years with an acceptably low (approximately 10%) likelihood of recurrence.4 These criteria have been accepted by European and United States guidelines of HCC management as a result of robust validations by several groups.2, 3, 5-7 The current dilemma in the HCC transplant community is whether some patients with tumors exceeding these criteria can be cured by transplantation.8 The decision to accept these so-called expanded criteria as standard of care would have enormous clinical and economical implications worldwide. How does the scientific community decide the standard of care for a given subgroup of cancer patients? Generally, standard of care is defined as the treatment that has proven to provide consistent benefits for the patients receiving the intervention. Theoretically, the benefits of treatments should be assessed through a randomized controlled trial (RCT) or meta-analysis, whereas other sources of evidence, such as nonrandomized clinical trials or observational studies, are considered less robust. Case series and retrospective studies represent the poorest sources of evidence. Medical interventions have been tested within 80 published RCTs in HCC,9, 10 in contrast with lung, breast, and colorectal cancer, for which thousands of RCTs are available. The results of these RCTs have provided evidence of benefit in few interventions: radiofrequency ablation over ethanol injection in the local control of the disease of small HCC; chemoembolization over best supportive care in terms of survival for patients with intermediate HCC; and lack of survival advantages of systemic treatments in advanced HCC.1, 9, 10 In this context, what is the evidence-based role of transplantation for HCC, and, specifically, what selection criteria should be applied? Surgical treatments are accepted as the standard of care for early tumors because they provide survival rates consistently better than their untreated counterparts (5-year survival rates of 40–70% vs. <20%).1-6 Resection of single tumors in patients with well-preserved liver function lead to remarkable outcomes (5-year survival exceeds 50–60%).6 Similarly, the Milan criteria are considered the gold standard for selection of the best HCC candidates for CLT after numerous external validations of the seminal proposal.4 It should be kept in mind that during the 1980s, the poor outcomes (5-year survival <40%) related to the wide selection of advanced tumors made researchers question the indication of CLT for HCC in some programs.11, 12 It was the analysis of patients with minute or incidental asymptomatic tumors discovered at the time of transplantation who showed the same outcome as patients with nonmalignant disease.13 Afterward, a landmark study by Mazzaferro et al.4 proposed to restrict the selection following the Milan criteria, which have been confirmed as consistent by several other groups among more than 1,000 patients.5, 7, 14, 15 Nowadays, the United Network for Organ Sharing accepts this definition to give priority to HCC patients enlisted for liver transplantation. Thus, the Milan criteria are undoubtedly accepted as the standard of care. In this context, what is the rationale behind expanding the Milan indications? From the evidence-based perspective, no single, large, well-designed prospective cohort study has been reported to consistently challenge the Milan criteria. Despite of this unquestionable fact, the transplant community faces a complex dual situation. On one hand, some investigators promote further restriction of the selection criteria to prevent dropouts and/or recurrences after the procedure. This strategy is based on the fact that the shortage of donors has led to large waiting times distorting the outcomes when analyzed according to intention-to-treat.5, 16, 17 Our paper pointing out the concept of dropout rate and intention-to-treat survival is now widely accepted, and data is reported following these principles.5 We know that the actuarial 1-year dropout rate in patients within Milan criteria may range between 15–30%, and that the application of this concept has decreased 10–15% the actuarial 5-year survival in leading transplant centers.6 On the contrary, despite the clear donor constraints, an increasing number of studies propose that the expansion of the conventional criteria may not adversely impact patient survival.17-21 It can be acknowledged that a subgroup of patients beyond Milan criteria may present acceptable outcomes. The main concern is that we are unable to recognize them by preoperative radiological means, and more sophisticated tools at the molecular level might be required. Two fundamental concepts should be addressed when assessing any proposal of expanded indications. First, the criteria should be analyzed on the basis of radiological staging applied at time 0 of waiting time. In clinical practice, decisions are taken with preoperative radiological imaging techniques. It is well known that state-of-the-art imaging techniques underestimate HCC staging in 20–30% of cases, and thus exercises extrapolating pathological data to the preoperative scenarios are misleading.22 The most informative prospective study reported so far from Mount Sinai School of Medicine in New York included a series of 80 HCC patients exceeding Milan criteria who were receiving neoadjuvant treatment with chemoembolization and systemic doxorubicin.8 After a dropout rate of 46% (37 patients), the overall 5-year intention-to-treat survival was 25%. The study was useful to alert us about expanding the criteria to unlimited tumor size/number. Nonetheless, 5-year survival rates above 50% were achieved in patients effectively transplanted with tumors of 5-7 cm in diameter without vascular invasion.8 European studies proposed a modest expansion based on tumor size (single tumor ≤6 cm, or up to 3 tumors ≤5 cm)17 or on exclusion of patients with poor differentiation degree.20 This evidence shows that the heterogeneous group of patients with expanded criteria can be further refined. On the other hand, the main concern about expanding criteria is that relaxation of the current guidelines would further lengthen time spent on the waiting list, which may increase the withdrawal rates and decrease survival. The University of California, San Francisco (UCSF), proposed a new tumor staging classification (1 tumor ≤6.5 cm, or up to 3 tumors ≤4.5 and total tumor diameter ≤8 cm) based on a retrospective study of 70 HCC transplanted patients.19 The overall survival of the patients meeting the new criteria at 1 and 5 years was 90% and 75%, respectively, which was significantly better than survival for those outside the criteria. As noted by the authors in additional studies and other groups, though, the proportion of patients exceeding Milan criteria within UCSF criteria was small, around 5% of all enlisted.19, 23, 24 No specific data on this subgroup of patients have been prospectively assessed taking into account the intention-to-treat survival concept. This analysis is crucial and will prevent the common “dilution effect,” wherein a specific expansion of criteria is tested in a cohort of patients mostly within Milan criteria with just a few patients effectively fulfilling the expanded indication to be tested. The present study by Decaens et al. provides some insights for answering these key questions, in a case series of 479 HCC patients.25 The study deals with the scenario of an unexpectedly low dropout rate (2.5%) and short waiting times (<4 months), compared with the common 15–20% dropout rate and 6–12 month waiting times of North American and European series.4, 5, 17, 25 Nonetheless, the authors specifically tested the implications of applying the UCSF selection criteria preoperatively and postoperatively. Recurrence was higher in patients fulfilling radiological UCSF criteria prior to CLT (26%) than in patients with pathological UCSF criteria (13%), a result that highlights the importance of radiological criteria in this matter. Overall, recurrence occurred at a median of 7 months after CLT, applying UCSF criteria and 22 months after CLT, applying Milan criteria, reflecting a more aggressive neoplastic behavior. More importantly, the overall intention-to-treat 5-year survival was 45% for patients with preoperative UCSF criteria (44 patients, <10% of the series) and 60% for patients within Milan criteria. These figures may further decrease in scenarios of 2% dropout rate per month and waiting times of more than 6 months usually faced by transplantation centers. The transplant community established the rule of the 50% 5-year survival threshold for CLT, since it is a scarce resource that requires equipoise in its administration.26, 27 Outcomes below this threshold are not competitive when compared with those of patients transplanted due to end-stage liver disease. The analysis by the French group highlights for the first time the outcome implications of applying UCSF criteria preoperatively, and shows evidence for the urgent need for a large prospective study to address this issue. Expansion of criteria can be decided only with robust, solid data, and thus far it is not available. In the meantime, we can continue to apply the evidence-based cost-effective Milan criteria, if we are considering just the size and number of nodules. Eventually, molecular data can provide some insights in identifying 2 subgroups of patients who are currently unrecognized by conventional means: (1) patients within the Milan criteria, but leading either to tumor progression/dropout or with recurrence after CLT (10–20% of cases), and (2) patients exceeding Milan criteria, but presenting acceptable survival rates due to a less aggressive biological phenotype. Preliminary data assessing allelic imbalance of microsatellites showed accuracy in detecting nonrecurring tumors after CLT.25 We expect that the intense research on HCC genomics might impact patient selection in the near future.