Liver Transplantation for the Treatment of Hepatocellular Carcinoma

Liver Transplantation for HCC

The early experience with liver transplantation for large HCCs was marred by a high tumor recurrence rate both in the liver and in extrahepatic locations. However, proper patient selection based on pre-transplant imaging has rendered liver transplantation the most effective long-term therapy for small HCCs, and it has become the standard of care in patients who meet the Milan criteria.

The Milan criteria

In 1996, Mazzaferro et al published a series of 60 patients with small HCCs (1 lesion < 5 cm or 3 lesions < 3 cm each on pre-transplant imaging). These data showed that the 5-year survival was > 70%, with a recurrence rate of < 15%.[39] Since 2002, the Milan criteria have been accepted in the United States by the United Network for Organ Sharing (UNOS) and other parties as the standard by which liver transplantation should be offered. Because donor livers are allocated according to the modified end-stage liver disease (MELD) scoring system, patients with HCC meeting the Milan criteria are granted a MELD “exception" of 22 points, which increases their likelihood of receiving a donor liver. If they do not receive a transplant within 3 months, such patients qualify for a further increase in MELD score—to 25. Use of this liver allocation system in the United States has made liver transplantation a commonly used treatment for HCCs that meet the Milan criteria.

Survival after orthotopic liver transplantation (OLT) for patients with TNM stage II disease has been shown to be excellent, with 5-year survival ranging from 60% to 80%. Importantly, with the addition of the MELD exception, the number of transplants for HCC has grown from 8.8% prior to 2002 to 22% in 2009. The disease-free survival (DFS) in patients undergoing transplantation is far better than the DFS in those undergoing partial resection (which is only 20% after 10 years).[40] Lastly, recent multi-institutional data have shown that partial hepatectomy in patients with portal hypertension stratified by platelet count is associated with a 75% morbidity rate.[41] Therefore, in patients with HCC in the setting of chronic liver disease, the intervention that is most successful at improving both the quality and length of life is OLT; it must be borne in mind, however, that not all patients will pass the rigorous medical, social, and financial screening necessary to receive an OLT.

Use of other criteria for liver transplantation

Soon after the Milan criteria were accepted as the means for determining which patients should be offered liver transplants, aggressive OLT centers began extending the criteria and performing transplants in patients with higher-stage disease. Their rationale was that 13 of the 48 patients in the Milan paper had had disease beyond stage II disease.[39] The 4-year outcomes in the subset of patients with more advanced disease were worse than those in patients with disease that met the Milan criteria. Interestingly, however, the University of California San Francisco (UCSF) has been able to expand the Milan criteria to include a single lesion < 6.5 cm or 1 to 3 HCCs each < 4.5 cm, with a total tumor size < 8 cm (Figure 2). The 1-year survival in the patients who met these UCSF criteria was shown to be 90%, with a 5-year survival of 75%. Therefore, in very select patients, OLT can be offered to patients with stage III disease.[40,42,43]

The University of Toronto has shown that in tumors as large as 10 cm, OLT can be performed successfully, with acceptable 5-year survival. The Toronto criteria employ a protocol biopsy for tumors that do not meet the Milan criteria, and in those patients with well differentiated or moderately differentiated tumors, transplant—along with aggressive bridging therapy—is offered. Factors associated with a worse outcome in this cohort were AFP level > 400 ng/mL, the number of nodules, and total tumor diameter. However, using multivariate analysis, only AFP level > 400 ng/mL had a significant impact on DFS, with a RR of 2.3, compared with patients whose tumors met the Milan criteria. The overall 5-year survival was 72%, with a DFS of 68%. There was no difference between the two groups in 5-year survival (72% vs 70%, P = .63) or in DFS (70% vs 66%, P = .25).[43] This study challenges the current dogma that tumor size and number affect overall survival (OS); however, to date the Milan criteria remain the standard of care in most UNOS regions.

Local-regional bridge therapy

The above data, and the recognition that local therapy was effective at treating small HCCs, led the transplant community to adopt a policy of down-staging HCCs so that they would meet the Milan criteria. Multiple single-center studies have been performed showing the efficacy of either transarterial chemoembolization (TACE) with doxorubicin(Drug information on doxorubicin) beads (deb-TACE) or radiofrequency ablation.[3,40,44] The choice of local therapy is usually based on center-specific expertise. The AHPBA supports the use of Deb-TACE as the preferred method of treating patients with unresectable HCC or as a bridge to transplant.[40] In a recent report, pre-transplant TACE was used effectively to downstage 18 of 76 patients (23.6%) with otherwise unresectable or non-transplantable stage III/IV disease. This led to transplant in 17 out of 18 patients, with a DFS and OS of 94% at 19.6 months of follow-up.[40] Therefore, most transplant centers support the use of neoadjuvant deb-TACE to downstage patients into the Milan criteria. Built into these protocols is a mandatory waiting period of 3 to 6 months, during which time patients are observed to ensure that disease does not progress. Patients with stable hepatic-only disease, without evidence of progression for 3 to 6 months, should be considered for OLT.[40]

FIGURE 2

Comparison of the Milan Criteria and the University of California San Francisco (USCF) Criteria for Orthotopic Liver Transplantation in Patients With Hepatocellular Carcinoma (HCC

The use of local-regional therapy as a bridge to transplant has several therapeutic goals. Specifically, these are (1) to avoid HCC progression and drop-out from the waiting list; (2) to increase tumor-free survival; and (3) to downstage the disease in those patients who present with advanced disease. Currently, there are no data that pre-transplant therapy affect DFS or OS. Moreover, recent data suggest that local therapy to prevent drop-out only shows benefit in patients with wait-times greater than 240 days. On average, most large studies show a drop-out rate of approximately 2% per month regardless of treatment status.[40]

Role of liver resection

No review of liver transplantation for HCC would be complete without mentioning the role of liver resection. The use of resection as a bridge to transplant has been used with acceptable long-term results in very select series of patients who came to “salvage transplant." In Asia, this strategy is often used. However, it is not recommended that hepatic resection be used for down-staging, as will be explained below. Moreover, recent publications have shown that liver resections in the setting of thrombocytopenia are associated with significant morbidity.

Liver resection for HCC in the setting of normal liver morphology is supported and is not germane to the scope of this review. The real debate concerns those patients who have chronic liver disease and HCC. Multiple experts have stated that hepatic resection should not be entertained unless the FLR is > 40%. Liver resection is not recommended in patients with platelet counts < 100,000/μL, splenomegaly, paraesophageal varices, or other signs of clinically significant portal hypertension.[41] In patients with viral hepatitis, the removal of the tumor burden does not change the field effect caused by the rest of the cirrhotic liver, and therefore the recurrence rate in such patients exceeds 70%.[45,46] For this reason, liver transplantation offers the best long-term cure for both malignancy and underlying liver disease. Lastly, resection of the lesion, unlike local therapy, negates the UNOS exception score; patients are therefore disadvantaged from an allocation perspective if their tumor is resected.

Immunosuppression and HCC

The use of adjuvant therapy to prevent recurrence of HCC is a novel idea and one that is not universally supported by the oncology community. What is accepted is that post-OLT maintenance needs to include some sort of anti-rejection medication. If that anti-rejection medication also had anti-tumor effects, then two goals could be met with one therapy. There are no large randomized trials comparing one anti-rejection regimen to another with respect to their effect on recurrence or survival. In one recent Italian study of 69 OLT patients with HCC, cyclosporine was used exclusively and showed a lower mortality rate and lower recurrence rate in the first year in a dose-dependent fashion.[47]Multivariate analysis showed that the only independent prognostic determinant of recurrence was the blood level of cyclosporine.

The mammalian target of rapamycin (mTOR) inhibitors, sirolimus (Rapamune) and everolimus (Afinitor), are immunosuppressive agents that also have anti-tumor properties: they inhibit the clonal expansion of interleukin-2–activated T lymphocytes via blockade of mTOR. There are few studies that show the efficacy of sirolimus in OLT patients; however, in one Canadian study, 40 consecutive liver transplant patients with HCC that met either the Milan criteria (n=19) or extended criteria (n=21) received a sirolimus-based regimen. The survival rates were similar in the two groups and the recurrence rates remained low in both cohorts.[48] There is also a large registry-based trial that showed that sirolimus monotherapy was associated with improved survival after OLT for HCC. Lastly, there are two studies showing improved survival rates in patients who received sirolimus-based therapy compared with those who received conventional calcineurin-based therapy.[49,50] Therefore, in patients with poor prognostic factors on explant (eg, vascular invasion, tumors that do not meet the Milan criteria, low differentiation grade, or presence of satellite nodules), it is acceptable to use a sirolimus-based regimen at the onset.[51]

Conclusion

For patients with HCC and cirrhosis, liver transplantation offers the best long-term survival and excellent DFS. The Milan criteria transformed the landscape of what can be offered to this difficult-to-treat cohort of patients. In the future, as local-regional therapy improves or as novel anti-tumor medications become available, this modality may be able to be made available to patients whose disease does not meet the current Milan criteria while still providing them with acceptable long-term outcomes.

Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.