The Milan criteria for the transplantation of patients with hepatocellular carcinoma (HCC) were adopted as guidelines for transplantation because they identified a population with an excellent outcome following transplantation that appeared to be equivalent to that of patients who underwent transplantation without HCC (Fig. 1).1
At that time, this seemed to be a reasonable tenet, but the general fallacy of these criteria and other criteria has become clear over time. It has not been shown that there is any particular tumor size that represents no risk of recurrence, at least among those tumors that can be detected radiologically. Furthermore, the degree of risk is not the same for all patients within the Milan criteria. Figure 2 demonstrates the concept that there is a gradation of recurrence risk that depends in part on tumor size and number.2 Although the isobars of risk are not exact, in theory, one could choose the risk that would be acceptable for posttransplant recurrence and select patients with that degree of risk; however, the risk of recurrence is never zero. A recent analysis has suggested that a 5-year posttransplant survival rate of approximately 60% would be necessary for outcomes that would justify transplantation for patients with HCC beyond the Milan criteria.3 If we accept that there is some risk of recurrence with any criteria for the transplantation of patients with HCC, the acceptable degree of difference in outcome is relative and is a matter of balancing utility and competing needs.
Although the tumor size and the number of tumors constitute the Milan criteria, they truly are only surrogate markers for the underlying tumor biology. Vascular invasion by the tumor is another marker of tumor biology. Patients with large tumors but without microvascular invasion do quite well with transplantation, but at the current time, we can know this only on a post hoc basis because the pathological finding of invasion requires analysis of the excised specimen by a pathologist.4 Other markers of outcome, such as molecular features and serum markers, have been suggested, but these have not been validated and are not yet of clinical use.
Another surrogate for tumor biology is tumor behavior over time. One approach that we have taken at the University of California San Francisco for patients with large tumors is downstaging.5 This involves radiofrequency ablation, chemoembolization, or both to control the tumor and then a requisite waiting period (Fig. 3).5 This allows for expression of the tumor biology over time as the development of extrahepatic or intrahepatic spread is observed. This paradigm results in approximately 30% of the patients being excluded from orthotopic liver transplantation (OLT) because of HCC progression, but those who make it to transplantation have an excellent outcome (Fig. 4). It is important to note that the median time between the first ablative procedure and transplantation was 8.2 months with a range of 3 to 25 months. This approach suggests that the test of time may be the surest method for selecting patients with HCC for transplantation destined to have good outcomes, at least within the size and number boundaries in our experience.
Our experience with ablative treatment and then observation suggests that patients who undergo transplantation with HCC far exceeding the Milan criteria can do quite well if time is added as a criterion for transplantation. This raises the question whether all patients with HCC should undergo such a test of time prior to transplantation. This strategy could be called “ablate and wait,” although chemoembolization is not usually defined as ablation. Our experience suggests that the original tumor(s) can be controlled with multimodality therapy and that the ultimate outcomes of transplantation are not dependent on the primary tumor but depend more on the time spent by patients waiting for transplantation. It seems logical that smaller and/or fewer tumors, though more unlikely to spread, will also benefit from a period of time if the primary tumor can be controlled. The waiting period may be able to reduce the 10% recurrence rate seen in patients within the Milan criteria who undergo transplantation.
This concept of treating patients with the response as a selection criterion for transplantation has been suggested previously.6 That study examined patients waitlisted for transplantation who met the Milan criteria de novo or who underwent downstaging to meet the Milan criteria and then were listed for transplantation. The patients whose tumors exceeded the Milan criteria but who responded to transarterial chemoembolization (TACE) were placed on the waiting list (n = 34). For 5 of these 34 patients, their disease progressed while they waited, and they did not undergo transplantation. Twenty-seven patients underwent transplantation. The median waiting time was approximately 6 months, and the median number of TACE treatments was 3. A second group of 34 patients whose tumors were initially within the Milan criteria, 6 were delisted because of tumor progression. Patients who underwent transplantation and had no progression during the waiting period (which was defined as no expansion in the size or number of lesions prior to liver transplantation) had a better 5-year recurrence-free rate than those whose tumors progressed (94.5% versus 35.4%). This finding appeared to be independent of the Milan criteria (see Fig. 5).6
Another study revealed similar results.7 In that study, patients whose tumors were within the Milan criteria and who were treated with TACE and had a complete response to therapy of the original tumor had better 5-year posttransplant survival results than patients with a devascularization response ≥ 30% or with no response (89% versus 73.4% versus 37.5%). The authors did not find that patients who exceeded the Milan criteria had a difference in survival according to the results of TACE because of the small numbers. The median waiting time for transplantation was 9 months.
A recent study examined the posttransplant outcomes of 14 patients who exceeded the Milan criteria and were successfully downstaged.8 The median time between downstaging and transplantation was 338 days. After a median posttransplant follow-up of 35 months, 2 patients developed recurrence. One recurrence was in a patient with a misdiagnosed cholangiocarcinoma.
A similar study of downstaging patients outside the Milan criteria with TACE prior to transplantation found recurrence in 1 of 17 patients who underwent transplantation with a median follow-up of 19.6 months. The median time between the first treatment and transplantation was 5.3 months.9
Another recent study demonstrated similar results in 15 patients who were downstaged, and 2 of 15 died after transplantation with a median follow-up of 24 months.10 The time prior to transplantation was 11 months.
Another study that examined the success of treatment and outcome found that a reduction of the viable tumor volume greater than 90% with interventional therapy prevented tumor recurrence after liver transplantation.11
The aforementioned studies provide strong evidence that the ablate and wait strategy allows for the discrimination of patient outcomes after transplantation for HCC.
The period of time that one would want to wait after therapy is debatable but might be something on the order of 6 months according to the published literature.
The ablate and wait strategy does draw from the experience of resection and transplantation. The differences between the outcomes of transplantation and resection are related to the recurrence of disease within the remaining liver. The development of disease outside the liver due to unrecognized extrahepatic disease present at the time of transplantation or resection is most likely similar with the 2 therapies. On the basis of the resection experience, we would like to treat the tumor and wait for some period of time for the tumor to demonstrate bad biology but not enough time for other primary tumors to appear in the native liver that could complicate the outcome. Resection, with the exclusion of patients with microvascular invasion or other pathological markers of bad biology, would be another strategy for deciding if transplantation would be an alternative step, although current United Network for Organ Sharing policy prohibits transplantation in patients who are candidates for resection, and many patients may not tolerate resection.
For a patient within the Milan criteria, the ablate and wait strategy is going to be a tradeoff between the risk of a partially ablated tumor producing extrahepatic disease while the patient waits and the time necessary for the detection of extrahepatic disease that existed at the time of ablation. On a microscopic level, the tradeoff is the rate of progression from a partially treated tumor with good biology to a tumor with bad biology while the patient waits versus exposure of the extrahepatic disease that existed prior to ablation and waiting. Maddala et al.12 examined 54 patients with HCC with an average number of TACE sessions of 3 and a median time to transplantation of 211 days. Eight patients dropped off the waiting list: 2 because of non-HCC reasons and 6 because of HCC progression. Of the 6 with progression, 2 developed extrahepatic metastases, 2 developed portal vein invasion, and 2 had intrahepatic progression. Interestingly, these events all occurred within 4 months of listing. Because of the rate of growth of HCC and the short time between the events and listing, these events most likely represented expression of disease that was present at the time of ablation rather than degeneration of the ablated tumor and appearance of the progressive disease.
In a small study of 20 patients with a median number of treatments of 2 and a mean time to transplant of 343 days, Hayashi et al.13 found 7 patients with tumors within the Milan criteria who dropped off the waiting list: 2 because of non-HCC causes, 1 because of decompensation, and 5 because of increased intrahepatic disease. The time to exclusion for HCC was less than 6 months in 4 of 5 patients. No patients had developed HCC after transplantation at a mean follow-up of 2.94 years.
The aforementioned studies suggest that treated tumors do not frequently degenerate in the time between TACE and transplantation. This suggests that the treatment of patients with small tumors and then prolongation of the waiting time to transplantation are not likely to disadvantage those patients who could have undergone immediate transplantation.
Radiofrequency ablation has also been reported to produce good results in patients who subsequently undergo transplantation. Mazzaferro et al.14 reported on 50 patients who underwent a single ablation session and then waited 9.5 months on average for transplantation. Apparently, no patients dropped out while they awaited transplantation. At a median follow-up of 22 months, only 2 patients had experienced recurrence. Lu et al.15 reported 52 patients who underwent radiofrequency ablation, most frequently in isolation (the mean number of sessions was 1.46). After 12 months, 3 patients had dropped out at a mean of 11 months, with 2 patients having extrahepatic disease. Forty-one patients underwent transplantation, with no patients having experienced HCC recurrence at a mean follow-up of 15 months.
The University of California San Francisco downstaging experience with patients who have disease outside the Milan criteria demonstrates that approximately one-third of patients who are ablated will drop out because of disease progression (either extrahepatic or intrahepatic). The median time to treatment failure was 7 months, and this suggests that the manifestation is not from biological degeneration of the ablated tumors and spreading but is rather from the discovery of disease that had spread before ablative therapy.
For patients with HCC and adequate liver function who fall within the current Milan criteria, ablation of the tumors with radiofrequency or chemoembolization could increase the risk of tumor spreading, especially with tumor track seeding along the probe tracks, although this appears to be a rare occurrence. It is possible that this strategy should be applied to patients who are within the Milan criteria but have a tumor diameter greater than 3 cm or more than 1 tumor because these patients are more likely to have recurrence after transplantation.
As we consider the ablate and wait strategy for different types of patients, there are going to be patients in whom the strategy will not work. These would be patients who do not have the functional reserve to undergo ablation or to wait after ablation. We suggest that these patients undergo transplantation under the currently accepted criteria for transplantation.
This proposal is complicated by the variability of transplantation based on the geographical region. In 2007, approximately 62% of patients underwent transplantation within 3 months of receiving exception points for HCC (Fig. 6). Figure 7 demonstrates the regional differences for receiving transplants for HCC exceptions within the first 3-month period in 2007. (The more rapid transplantation rate in some regions might suggest that a higher recurrence rate exists in these regions. Unfortunately, there are no complete data on HCC recurrence available.) The more rapid transplantation rate in some geographic areas is going to create some issues if transplantation is delayed under an ablate and wait strategy. Fortunately, if the wait is 6 months long, major effects on center transplant numbers are likely to be small.