In this study, we prospectively observed the outcome of HCC patients selected and treated before LT according to our policy. The study pays particular attention to those exceeding the Milan criteria because such patients are normally not considered for LT at the majority of centers (20). This is consequently not a randomized controlled trial comparing 2 treatment groups, it is an observational study designed to ascertain the outcome of our strategy. We chose to report our results separately for patients exceeding or meeting the Milan criteria merely for descriptive purposes. In fact, our aim was to demonstrate that applying our selection and treatment protocol enables patients failing to meet the MILAN criteria to be transplanted successfully without any negative fallout on MILAN IN patients.
Since the prognosis for HCC patients enrolled for LT depends not only on the criteria adopted for listing and delisting, but also on adjuvant treatment strategies and time on the waiting list (1,20), we discussed these 3 issues separately.
The selection criteria issue
The risk of a tumor-related death before and after LT is higher in unselected patients with large and multi-nodular tumors (28), but a careful extension of the inclusion and dropout criteria has been shown to determine similar, or even fewer dropouts from the waiting list than the Milan criteria without increasing the probability of post-LT recurrence (12,21,29).
As previously reported (22,23), of the HCC patients referred to our Institution for transplantation, only those with aggressive tumor features (poor differentiation at percutaneous biopsy, macroscopic vascular invasion or extrahepatic spread) are denied the chance of a transplant, irrespective of nodule size and number. This particular listing/delisting policy enabled us to include a sizable group of patients exceeding the Milan criteria in the present analysis.
In several reports in which nodule size and number were used as dropout criteria, most patients were still alive after their removal from the waiting list as at the latest follow-up (10–13), whereas in our study the majority of patients delisted due to tumor progression died within 2 months of their exclusion (Table 4). This suggests that our policy carries a low risk of rejecting patients with a good prognosis and a potential for curative LT, whereas a dropout policy based on macro-morphological parameters alone seems likely to rule out patients whose HCC has a more heterogeneous biological behavior.
On the other hand, keeping MILAN OUT patients on the waiting list did not increase the tumor progression rate prior to LT. The overall probability of patients dropping out was less than 10% at 1 year (Figure 3A), considerably lower than the 20–50% reported by centers using nodule size and number as dropout criteria (10–13,20). Our policy is therefore associated with a low dropout probability, but it carries the intrinsic risk of arriving at LT with more advanced tumors, with a potentially greater chance of post-LT recurrence and death. No post-LT recurrences have been detected so far, however, and—after a median follow-up of 21.4 months (range 3–75)—the 5-year intention-to-treat survival of the study group was 73% (95% CI: 61, 85), better than the one described in other recent series (10–13,15). In particular, our MILAN OUT patients had a very low post-LT mortality (Table 4), and their intention-to-treat survival did not differ significantly from the situation in MILAN IN patients (Figure 4B).
Our strategy was further tested by stratifying MILAN OUT patients according to the UCSF criteria (Table 6), which revealed a poor capacity for discrimination in terms of dropout and intention-to-treat survival probabilities (Figure 6).
It has to be said, however, that the relatively short post-LT median follow-up carries the risk of underestimating tumor recurrence in our study. Since the majority of aggressive HCC recurrences occur in the first 2 years (30), the total absence of such events in the present study nonetheless points to a low risk of post-LT tumor recurrence for patients exceeding the Milan criteria and listed according to our policy.
The histological analysis of the tumors in patients who underwent LT (Table 5) further supports our previous considerations. Although MILAN OUT patients included a significantly higher proportion of tumors exceeding the Milan criteria, at histological assessment the group actually had a similar proportion of tumors with microscopic vascular invasion and poorly differentiated type. It is important to emphasize, moreover, that the proportion of such aggressive features in both groups was far lower than was recently reported by Pawlik et al. in patients with both small and large tumors (31). This suggests that, even allowing for the risk of false negatives, pre-LT biopsy in association with an aggressive treatment schedule, may reduce the number of poorly-differentiated tumors undergoing LT. Since tumor grade and vascular invasion have proved the most important predictors of post-LT recurrence (5), the low proportion of such aggressive features at the time of LT is, in itself, an important result of any selection and treatment strategy. Moreover, as previously shown (22), such a strategy has probably indirectly set a limit more for the size rather than for the number of nodules and this could explain the characteristics of our population that in many cases only slightly overcomes the UCSF criteria (Tables 5 and 6). Notably, no cases of tumor seeding were observed after percutaneous biopsy, nor of any other major complications.
The treatment strategy issue
A second constitutive feature of this prospective study was the adoption of a pre-determined treatment schedule (Figure 1) applied to all patients to aggressively control tumor growth before LT. Several studies in recent years (14–18) have shown the utility of locoregional therapies in containing tumor progression before LT, and the recent guidelines of the American Association for the Study of the Liver (20) have recommended the use of such therapies if the expected waiting time is longer than 6 months. The role of locoregional therapies has been largely evaluated only in HCC patients meeting the Milan criteria (14–19), whereas the present study reports clinical data on such treatments in patients exceeding the criteria too. The overall number of procedures per patient, their complexity and multimodality were significantly higher in MILAN OUT group (Table 2). Since response to adjuvant therapy was the main criterion for deciding on any further treatment, irrespective of nodule size and number, such an asymmetrical distribution in the 2 groups was due mainly to a predictably higher rate of good responses in the MILAN IN than in the MILAN OUT group. Given the priority for LT assigned in our policy for patients a progressive disease, this fact probably also explains the trend toward shorter waiting times for the MILAN OUT than for MILAN IN group in our study. All these considerations might be indicative of a policy that is excessively unbalanced in favor of MILAN OUT patients, but the low probability of dropouts in the MILAN IN group, with better survival figures than those reported in other recent publications (11–13,15–17) demonstrated that this subgroup of patients was not damaged by our policy. Despite our aggressive pre-LT treatment strategy, complete necrosis was found in only a minority of our patients, with a similar distribution in the 2 groups (Table 5). We did see extensive tumor necrosis in most patients, however, which reduced the overall neoplastic burden. It is impossible to say whether this tumor reduction might have been responsible for the small proportion of aggressive features (e.g. vascular invasion and poorly differentiated type) that we encountered. The absence of a control group given no such treatment prevents us from drawing any definitive conclusions on the prognostic effect of pre-LT adjuvant therapy, though it was probably extremely important in achieving our results. As recently suggested by Yao et al. (17), in fact, such a positive effect is probably greater for patients exceeding than for those meeting the Milan criteria.
The time before LT issue
It has been amply demonstrated (10–13) that a long waiting time increases the risk of tumor growth before LT, but the time to LT may paradoxically become an indirect selection tool, since an adequate follow-up period and response to adjuvant therapy are often fundamental to the identification of tumors with a worse biology and higher risk of post-LT recurrence (20). Our relatively long median waiting time for HCC patients (Table 3, Figure 2) probably had a positive synergic interaction with our treatment algorithm (Figure 1) and inclusion-dropout policy in selecting less aggressive HCC cases for LT. In this line, some criticism with regard to the extremely short waiting times reported for HCC patients in the UNOS–MELD area emerged in recent studies (20,32,33).
In conclusion, we prospectively showed that, in patients failing to meet the Milan criteria, excluding only tumors found poorly differentiated at percutaneous biopsy and cases of macroscopic vascular invasion or extrahepatic spread, and adopting an aggressive multimodal adjuvant protocol was associated with a low dropout probability before LT and excellent intention-to-treat survival figures, comparable with those obtained for patients meeting said selection criteria. In terms of effective tumor bulk, such a policy apparently seems to represent only a gentle tilt beyond UCSF criteria, but this result is obtained completely readdressing the critical issue of patient selection for LT from tumor size and number to tumor grade and response to therapy used as biological selection criteria.