Beyond the milan criteria: Is it the right time?

We thank Dr. Audet and colleagues for their interest and comments regarding our study of a new proposal for criteria for orthotopic liver transplantation (OLT) in patients with cirrhosis and hepatocellular carcinoma (HCC). Having adopted the criteria proposed by Zheng et al., the authors presented their experience with transplanting HCC patients. An analysis of 196 patients showed that the 5-year overall survival rate was similar between patients who had tumors within the Milan criteria (MC) and patients who had tumors beyond the MC: 77% versus 74%. On the other hand, the risk of tumor recurrence was higher among those patients in whom the explant pathology demonstrated tumors beyond the MC (P 0.04). Moreover, the authors pointed out the importance of considering the detection of circulating cancer cells prior to OLT in an attempt to identify those patients who have a high risk of recurrence, instead of using radiological and/or pathological features of HCC. Despite being an interesting approach, it requires further studies for validation. Several alternatives for expanding the MC have recently been proposed (Table 1). Whatever criteria are adopted, there are important aspects that should be considered. From an epidemiological point of view, the robustness of the data of the studies already developed in that setting deserves a critical analysis. Many of the proposals for expanding the MC are based on tumor pathology. Despite advances in radiological assessment over time, it is well known that preoperative imaging underestimates HCCs in about 20% of cases. In addition, some studies have reported worse survival and higher recurrence rates in those cases in which the radiological evaluation underestimated tumor stage. Therefore, the extrapolation of the histopathological data to the preoperative scenario might be misleading, and the possibility of expanding the MC should be validated on the basis of a radiological evaluation. Few studies have evaluated the expansion of the MC using the intention-to-treat principle, and in such studies, contradictory results have been described. Because of the progressive time on the waiting list with an associated higher risk of dropout, analyses based on the intention-to-treat principle are appropriate. It has been suggested that expansion of the MC would lead to a higher rate of dropout from the waiting list. In fact, this phenomenon has already been observed in patients who had tumors within the MC. Those cases with a single lesion 3 cm or up to 3 lesions had a much greater risk of dropout than those with a single lesion 3 cm. Rather than interpreting that these are worse candidates for OLT by virtue of their greater risk of dropout, we should direct future efforts toward improving their access to timely OLT. In other words, the comparison of the groups within and beyond the MC could be validated, even if only transplanted patients are analyzed. Another relevant topic surrounding this matter was recently pointed out by Volk et al. When OLT is considered an appropriate treatment, it should not be offered to a group of patients with worse prognosis than other groups, given the shortage of organs for this procedure worldwide. Although the expansion of the MC may achieve 5-year survival rates higher than 50%, this may not be sufficient data because of the possible lower survival in comparison with patients within the MC or without HCCs. It has been demonstrated that a higher threshold of 61% at 5-year survival is needed to justify expansion of the MC, at least in the United States. This is a relevant contribution to the discussion surrounding this problem that requires further debate. Standard of care can be defined as a treatment that has been thoroughly validated to provide consistent benefits to those patients who receive such intervention. Therefore, it demands an appropriate recommendation on the basis of the level of evidence. In the topic presented, meta-analysis needs a homogeneous inclusion of the studies concerning design (prospective/retrospective), tumor assessment (radiology/pathology), and criteria (within the MC/the same expanded criteria proposal). Thus, when we consider the studies described in Table 1, it is clear that meta-analysis cannot yet be considered. Furthermore, randomized controlled trials are not appropriate, given the fact that all patients require the same therapy. Therefore, a high-quality trial in this area would need to consider cohorts with the following endpoints and design: