Liver Transplantation for Hepatocellular Carcinoma

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was subsequently validated by other groups.6,7 The Milan criteria are now used worldwide to identify patients with HCC who have good prognosis after liver transplantation. The major criteria include a single tumor ≤ 5 cm, or up to 3 nodules ≤ 3 cm each, and with no macrovascular invasion. Liver transplantation offers the advantage that the malignancy is resected, and it is the only therapy addressing metachronous risk by elim- inating the parenchymal liver disease that leads to HCC. Disadvantages of liver transplantation include a high perioperative risk, a life-long need for immunosuppres- sants, the side effects of those drugs, including those on tumor behavior following liver transplantation, and a large donor/recipient disparity.
Wait List and Allocation Issues Patients initially meeting the Milan criteria could become ineligible due to tumor progression. This is particularly significant in regions of the United States where waiting times for liver transplantation are long. Pretransplant therapies are therefore utilized in an
Liver Transplantation for Hepatocellular Carcinoma Angel E. Alsina, MD, FACS
Background: The treatment of hepatocellular carcinoma (HCC) is challenging, but transplantation of the liver has emerged as one of the options in the therapeutic armamentarium against this disease. Methods: This article reviews the changing criteria for patient eligibility for liver transplantation for HCC and presents an initial evaluation of institutional treatment outcomes for this treatment modality. A method for evaluating prognosis is also described. Results: Patients are considered for liver transplantation if they meet the Milan criteria for eligibility or a UCSF-attributed expansion of these criteria that includes the “rule of 7,” whereby the sum of the size of the largest nodule plus the total number of nodules cannot exceed 7. Preliminary institutional experience suggests a tumor recurrence rate of 11% in 91 patients with HCC who received liver transplants between 1996 and 2008. Conclusions: Liver transplantation offers an opportunity for long-term survival in patients with HCC and chronic cirrhosis whose tumor cannot be resected. Criteria for patient selection for this modality of treatment continue to be upgraded and refined.
From the Departments of Surgery, Liver Transplantation, and Hepa- tobiliary Surgery at LifeLink HealthCare Institute, Liver Transplan- tation at Tampa General Hospital, Tampa, Florida.
Submitted June 15, 2009; accepted February 24, 2010.
Address correspondence to Angel E. Alsina, MD, FACS, Department of Surgery, LifeLink HealthCare Institute, 409 Bayshore Boulevard, Tampa, FL 33606. E-mail: [email protected]
No significant relationship exists between the author and the com- panies/organizations whose products or services may be referenced in this article.
Introduction Hepatocellular carcinoma (HCC) is the fifth most com- mon cancer worldwide.1 Patients with hepatitis C and alcohol-related cirrhosis comprise the majority of cases of HCC in the United States,2 where the incidence is increasing. However, hepatitis B is the single most com- mon cause worldwide.3 Liver transplantation emerged in the 1990s as a viable approach to treating HCC, fol- lowing poor results in the 1980s.4 A landmark study from the Milan group reported survival at 4 years of 85%, with a recurrence rate of 8%.5 This experience
Autumn Olive Fruit_13646. Photograph courtesy of Henry Domke, MD. www.henrydomke.com
Liver transplantation can provide
long-term survival for well-selected
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attempt to reduce dropouts from the waiting list and to reduce recurrence rates following liver transplantation. These treatments include ablative therapies; radiofre- quency ablation and transarterial chemoembolization are both widely utilized as a “bridge” to liver transplan- tation. The concept of tumor resection as a bridge is not practiced. Patients who have had a tumor resection have no priority for liver transplantation unless a recur- rence arises. A patient who has a recurrence after tumor resection, has poor liver function, and meets the criteria for liver transplantation, however, could benefit from liver transplantation.
Since 2001, the transplant regulatory body in the United States — the United Network for Organ Sharing (UNOS)8 — has assigned an automatic Model End-stage Liver Disease (MELD) score to patients with HCC meet- ing the Milan criteria, based on the high mortality of these patients prior to transplant and the improved results following liver transplantation. Thus, HCC has become a prioritized condition under the MELD liver allocation system. Among the 104 liver transplantations performed in 2008 at our center, approximately 18% were for HCC. A patient with a MELD score of 22 in our center and in the southeastern part of the United States will have a mean waiting time to liver transplantation of only 3 months. Thus, the likelihood of dropout from the waiting list is low, and the likelihood of liver trans- plantation is high. This could translate to less vascular invasion, reduced recurrence following liver transplan- tation, and better outcomes. However, this has not been proven. Methods to expand the pool of donors for patients with HCC include the use of split liver transplantation, living donor liver transplantation, and expanded criteria of high-risk donors, including those with hepatitis C.9
Tumor Resection vs Liver Transplantation Less than 15% of patients with HCC are candidates for resection. Although hepatic resection is widely avail- able, it should be offered early and should be limited to patients without portal hypertension in order to avoid postoperative hepatic failure. Five-year survival rates of 40% to 50% have been reported, but high recurrence rates of 40% to 70% represent the main cause of death.10 It has been hypothesized that increased hepa- tocyte regeneration after resection might enhance hepatocarcinogenesis in the remnant.11 However, a more accepted theory is that recurrences are usually the result of multicentric carcinogenesis or intrahepat- ic recurrence via the systemic circulation.12
Salvage Liver Transplantation Following Resection This concept could be utilized at the time of tumor recurrence. Studies from Asia indicate that 80% of patients at the time of recurrence could be eligible for
liver transplantation.13 However, this refers to patients with hepatitis B and also with the use of living donors, both rare events in the United States. The data are not reproducible in our large hepatitis C population with HCC, where tumor recurrence exceeds the Milan crite- ria in 60% of patients following resection.14 Therefore, in a cirrhotic patient with hepatitis C, resection may represent a loss of opportunity for cure since only a limited number of patients can subsequently undergo transplantation. If the tumor meets liver transplanta- tion criteria, this approach should be considered. This is not to imply that cirrhotic patients with hepatitis C should never have a tumor resection. Resection and transplant patients differ in many aspects, including tumor stage, liver function, comorbidities, and psy- chosocial status. These two management modalities have not been compared directly.
Expansion of HCC Criteria A dilemma arises since some patients exceeding the Milan criteria have the potential for cure by liver trans- plantation. These patients are currently ineligible for liver transplantation, except in 2 of the 11 geographic regions in the United States, as defined by UNOS. Inves- tigators at the University of California at San Francisco have proposed the UCSF criteria that consists of 1 lesion ≤ 6.5 cm, or 3 lesions with the largest lesion ≤ 4.5 cm and the total tumor burden ≤ 8 cm.15,16 Downstag- ing protocols at many institutions, including our own, have been implemented (Table). Furthermore, UNOS Region 3 (southeastern United States) has approved a downstaging protocol that includes prioritizing these patients by assigning them a MELD score of 22.
Table. — Institutional Downstaging Protocol for Hepatocellular Carcinoma
Criteria for Inclusion 1. Single tumor ≤ 6.5 cm 2. Total tumor burden ≤ 8 cm 3. No vascular invasion
Criteria for Successful Downstaging 1. Decrease in tumor size and number to meet United Network
for Organ Sharing (UNOS) T2 criteria or 2. Complete tumor necrosis without contrast enhancement
to suggest residual tumor, equal to obliteration of tumor irrespective of tumor size
Criteria for Treatment Failure 1. Dropout due to tumor progression 2. Vascular invasion 3. Extrahepatic or lymphatic metastases
Criteria Prior to Placement on Waiting List Once Downstaged (Time-Out Period)
Once criteria for downstaging are met, a minimum of 3 months of follow-up is required before the patient is listed for liver transplantation along with new imaging that meets the criteria for successful downstaging
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The Metroticket Project The Metroticket project was introduced at the Interna- tional Liver Transplant Society (ILTS) meeting in 2005 as a Web-based survey.17 In an attempt to gather a suf- ficient number of patients to allow for robust statistical analysis, the project collected data on more than 1,000 patients who exceeded the Milan criteria and received transplants. The Metroticket project has been endorsed by the European Liver and Intestine Transplant Associa- tion (ELITA) and the ILTS. The result of the project is the Metroticket calculator,18 which can be used to pre- dict 5-year survival based on a patient’s morphological and biological characteristics (size of the total nodules, size of the largest nodule, and vascular invasion if avail- able). The calculator also places a patient on the “HCC weather forecast chart”: the blue zone indicates good survival (a 5-year survival rate of 50%), and the red zone indicates poor prognosis (a 5-year survival rate of < 50%, which is considered unacceptable in liver trans- plantation for HCC). The Metroticket predicts survival beyond the Milan criteria, the upper limit of liver trans- plantation being the “rule of 7” where the size of the largest nodule and the total number of nodules cannot exceed 7.
Decision Analysis for Liver Transplantation Our current morphological criteria, based on the size and number of nodules, are inadequate, predicting good outcomes in patients who fulfill them but not poor outcomes in those who exceed them. Two other criteria need to be incorporated in liver transplanta- tion: pathological and biological markers. The most important pathological criteria are vascular invasion, grade, satellitosis, and α-fetoprotein (AFP). Poor histo- logical grade is detrimental to liver transplantation.19
The diameter and number of nodules in correlation with grade were predictive of vascular invasion if tumors were > 5 cm.20
Institutional Experience With HCC At our institution, patients referred for the possibility of liver transplantation are prioritized. Imaging studies and clinical data are reviewed. The American Associa- tion for the Study of Liver diseases (AASLD) guidelines for diagnosis of HCC are followed.21 Ablative tech- niques are employed early in the evaluation process as a bridge to liver transplantation or as definitive treat- ment. Candidates for tumor resectional therapy are offered surgical resection. Patients being considered for liver transplantation undergo continued evaluation during the cancer treatment process. The severity of liver disease, the etiology and comorbidities, the ability to obtain immunosuppressants, and the social support systems are examined. Final candidacy is decided by a liver transplant patient selection committee. Patients with tumors of poor grade, diffuse tumor spread,
macrovascular invasion on imaging, or microvascular or lymphatic invasion on pretransplant pathology are usu- ally not accepted for liver transplantation.
A total of 754 patients underwent liver transplanta- tion at our institution between December 1996 and June 2008, including 91 patients with the preoperative diag- nosis of HCC. The overall tumor recurrence rate was 11%. No significant difference in overall posttransplant cancer recurrence was observed between well-compensated cirrhotic patients (n = 35, 8.5%) and decompensated cirrhotic patients (n = 56, 12.5%). A third group of inci- dental HCC discovered at pathological explant represent- ed 5% of all liver transplant recipients. The recurrence rate for this group was 7.3%. Tumor recurrence in all cancer patients occurred at a median time of 13 months and was uniformly fatal. The short- and long-term sur- vival, the effects of ablative treatments, and the morbid- ity of liver transplantation are being evaluated. These data are currently unpublished.
Conclusions Liver transplantation offers an opportunity for long- term survival in HCC patients with underlying cirrhosis whose tumor cannot be resected. Resection and trans- plantation patients are dissimilar, and the two therapies have not been compared directly or in randomized tri- als. The outcome of liver transplantation in the well- compensated cirrhotic patient is not well known and is currently under study in our center.
Tumors ≤ 5 cm in diameter or 3 tumors each ≤ 3 cm and without vascular invasion are considered to be within the Milan criteria and are prioritized for trans- plant. Expansion of eligibility beyond the Milan criteria of ≤ 6.5 cm in size, or the “rule of 7,” is achieving accept- able outcomes and is now more widely accepted. A downstaging protocol at Tampa General Hospital has been developed. UNOS Region 3 (southeastern United States) has approved prioritizing successfully down- staged patients. The Metroticket calculator is a first step in prognostic tools. Additional parameters will be added in the future. Objective approaches will be need- ed for policies and prioritization when patients are being listed with UNOS on the national waiting list.
Recurrence of HCC following liver transplantation is a double failure. Multicenter clinical trials should be focused on morphological, pathological, and biological parameters to minimize failure. Transplantation for HCC is already being prioritized, but new policies are being implemented.
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