Transplantation for Hepatocellular Carcinoma

Transplantation for Hepatocellular Carcinoma and Cholangiocarcinoma CME
B. Daniel Campos, MD; Jean F. Botha, MD

Authors and Disclosures

CME Released: 04/30/2009; Valid for credit through 04/30/2010 Print This
Email this

Abstract and Transplantation for Hepatocellular Carcinoma

Pretransplant Treatment of HCC

Cholangiocarcinoma and Transplantation

References
Abstract
Hepatocellular carcinoma (HCC) and cholangiocarcinoma represent more than 95% of primary hepatic malignancies in adults. The incidence of both seems to be rising. Any form of cirrhosis and primary sclerosing cholangitis represent independent risk factors for the development of HCC and cholangiocarcinoma, respectively. The surgical treatment of these malignancies has evolved significantly in the past decade, and liver transplantation (LT) has revolutionized the prognosis of these conditions. Provided both malignancies are diagnosed early in their natural history, LT offers a greater than 75% chance of survival at 4 years. This is a remarkable improvement in the treatment of primary hepatic malignancies and compares favorably with any other form of treatment, including partial liver resection. The application of specific pretransplantation staging criteria, along with the addition of neoadjuvant chemoradiation therapy for cholangiocarcinoma, has made these results possible. The development of living donor LT further expands the treatment horizon for both diseases. It also lessens the impact of the scarcity of available deceased donor organs available for transplantation. The future challenge is to better characterize biologic staging/prognostic indicators that could expand the understanding and success in treating both malignancies.
Transplantation for Hepatocellular Carcinoma
In the past 2 decades, hepatocellular carcinoma (HCC) has shown a steady rise in incidence.[1] HCC is currently the fifth most common malignancy and the third leading cause of cancer-related death worldwide. It represents the most common primary malignancy in the liver, and arises in a background of cirrhosis in approximately 95% of cases in America and 60% in Asia.[2,3] Hepatitis B and C infections and cirrhosis per se are the most important risk factors. At diagnosis, more than 80% of patients present with multicentric HCC, advanced liver disease, or other comorbidities.[4] Liver transplantation (LT) remains the best available form of treatment for HCC in patients with cirrhosis, including Child-Turcotte-Pugh class A.[5] The successful use of LT in the treatment of HCC requires appropriate patient selection and is limited by the shortage of available organs and the progression of the underlying liver disease while awaiting transplantation.
Transplantation Criteria for HCC
Early experience with LT for HCC was discouraged by high recurrence rates and 5-year survival rates less than 40%.[6] The recognition that patients with small tumors had survival rates after LT equivalent to those after transplantation for other benign liver diseases made LT the gold standard in the treatment of HCC in patients with cirrhosis. This critical observation was pioneered by Mazzaferro et al.[7] in Milan in 1996. In a randomized controlled study, this group showed that restricting LT to patients diagnosed with a single tumor less than 5 cm in diameter or 2 to 3 tumors less than 3 cm in diameter by radiologic standards before transplantation resulted in a 4-year overall survival of 75%, recurrence-free survival of 92%, and overall recurrence rate of 8%.[7] Those results have been reproduced by other groups worldwide.[8,9] In the United States, the so-called Milan criteria has been adopted by the United Network for Organ Sharing (UNOS) for the allocation of organs.
Organ Allocation for HCC
Organ allocation for LT in the Unites States is based in the model of end-stage liver disease (MELD). Essentially the MELD is a numeric score based on bilirubin, creatinine, and international normalized ratio.[10] The MELD score has been extensively validated as a reliable measure of mortality risk in patients with end-stage liver disease. It is a disease-severity index useful to determine organ allocation priorities.[10,11] Nearly half of patients with HCC listed for LT will drop off the waiting list at 2 years because of complications concerning their end-stage liver disease, including death or progression of malignancy. To decrease these high dropout rates, the Organ Procurement and Transplantation Network of the United States has adjusted the MELD scores of patients with HCC who meet the Milan criteria at regular intervals. In a modified staging for HCC, only patients with a single tumor of 2 to 5 cm or 3 lesions and each less than 3 cm, are given priority listing for LT. This slight priority for allocating organs compensates for the risk for tumor progression and dropout.
Expanding Transplantation Criteria for HCC
The Barcelona group,[12] the University of California at San Francisco (UCSF) group,[13] and others have presented proposals for expansion of the Milan criteria. None of these proposals are backed by rigorous prospective randomized data and their application has been debated.[14,15] The most common and studied proposal is the UCSF expanded criteria, which allows transplantation of patients with 1 tumor of 6.5 cm or 3 or fewer tumors smaller than 4.5 cm, with the sum of the diameter of these tumors to less than 8 cm without compromising patient survival.[13]
Multiple other studies have reproduced the UCSF results.[16,17] The largest retrospective review of patients with HCC treated with LT published by the University of California at Los Angeles validated the UCSF expanded criteria. In this report, patients meeting Milan criteria had similar 5-year posttransplant survival compared with those meeting UCSF criteria based on preoperative imaging and explant pathology.[18] Most patients within the UCSF criteria are within the Milan criteria. This modest expansion of the Milan criteria does not seem to negatively impact posttransplant survival, although it only translates into a net increase of less than 10% to the potential recipient pool over conventional transplant criteria. However, the true impact on the remainder of the waiting list is unknown and the broader application of expanded criteria is not yet accepted.
Pretransplant Treatment of HCC
Most transplant programs are reluctant to observe cirrhotic patients with HCC while they await transplantation because of the latent risk for disease progression and dropout. Pretransplant neoadjuvant therapy in the form of radiofrequency ablation (RFA), transarterial chemoembolization (TACE), or percutaneous ethanol injection is often recommended for this subset of patients. Theoretically, neoadjuvant therapy has 3 potential benefits: 1) to downsize existing tumors that are beyond Milan criteria, thus expanding the transplantability of some patients, 2) halt disease progression preventing dropout while on the transplant list, and 3) potentially provide a survival benefit after transplant. Single-center studies have documented advantages for pretransplantation TACE[19,20] or RFA[21] in minimizing waiting-list dropout rates.
In 2006, an evidence-based review of all the available literature to that date concluded that TACE as a bridge to LT does not improve long-term survival nor decreases dropout rates on the waiting list.[22] More recently, however, Freeman et al.[23] showed a survival benefit after transplantation for patients undergoing pretransplant locoregional therapy.
Downstaging HCC
Early in the experience with TACE before LT, Majno et al.[19] found a benefit in disease-free survival for patients who responded to TACE (50% reduction on size) compared with those who did not. Effectively downstaging tumors that are beyond the Milan criteria is emerging as a viable alternative to simply expanding the transplantation criteria. A review of the UNOS database involving 1377 histology reports from explanted livers indicates that pretransplantation ablation treatment resulted in markedly more cases being downstaged than those in which no ablation was given, with TACE being more effective than RFA.[24]
The USCF group recently reported excellent outcomes after LT in a strictly selected group of patients beyond the Milan criteria who were primarily downstaged with laparoscopic RFA or TACE. Tumor downstaging was successful in 70.5% of the patients. Survival rates at 1 and 4 years were 96.2% and 92.1%, respectively. No patient had HCC recurrence after a median follow-up of 25 months. Treatment failed in 29.5% mainly because of tumor progression.[25] The authors infer that successful downstaging dissects-out those tumors with a more aggressive biologic behavior based on their progression despite treatment.[25,26] After these most recent reports, pretransplantation neoadjuvant treatments remain an option for downstaging HCC tumors despite the absence of randomized data.[24]
Salvage Transplantation
Most agree that the best surgical treatment strategy for small HCC in patients with preserved liver function (Child-Turcotte-Pugh class A) remains LT. Some authors believe that small, resectable HCCs with preserved hepatic function should undergo liver resection as first-line treatment, reserving transplantation for HCC recurrence (salvage transplantation). This approach is a reasonable option for saving organs and sparing some patients the burdens and risks associated with transplantation and immunosuppression. However, it appears to result in higher recurrence and decreased survival compared with primary LT.[27,28] On average, only 1 of 5 patients who undergo liver resection for HCC will receive a "salvage" liver transplant, as reported by the transplantability rates of the groups in Spain, Italy, and France (16.2%, 21.2%, and 25%, respectively).[29]
Living Donor LT
LT is limited by a shortage of deceased donor liver grafts, particularly in Asia, where the rate of deceased donors is negligible. To overcome this shortage, living donor liver transplantation (LDLT) was developed with favorable preliminary results since its success in a child in 1989 in Brisbane and an adult by the Shinsyu group in 1993. Recent advances in LDLT using a right lobe graft have overcome the need for size matching between recipient and donor. The benefits of living donation and transplantation for HCC are clear in terms of eliminating the waiting-list time and its multiple implications. LDLT has been increasingly used to treat hepatic tumors worldwide in recent years, and is currently the most effective alternative to deceased donor LT to overcome the problem of organ shortage.
The indications for LDLT are not clearly outlined. Most groups agree that if a patient with HCC meets conventional Milan criteria and cannot undergo liver resection because of poor liver function, and a cadaveric graft is not available within 6 months, LDLT may be selected.[30] The multicenter adult-to-adult LDLT study reported a statistically significant higher HCC recurrence rate after LDLT versus deceased donor LT.[31,32] Another Asian group reported similar recurrence rates.[33] More studies are needed to better define the role of living-related LT for HCC. In terms of survival after LDLT for HCC, a group from Japan reports a 3-year survival of 60% for patients beyond the Milan criteria compared with 78% for patients meeting the Milan criteria. The mortality of donor hepatectomy ranges from 0.25% to 1%, with an overall morbidity of 12% to 21%.[31,34]
HCC Biology
Several factors have been identified as markers of more aggressive disease: vascular invasion, poor differentiation, lack of fibrous capsule, large tumor size, and elevated serum levels of AFP. After transplantation, AFP level, histologic grade, tumor size, lymphovascular invasion, and bilobar distribution were found to be independent risk factors for HCC recurrence.[35] These variables have been associated with poor outcome in multiple studies.[36–38] Current transplant criteria is statistically effective in predicting good outcomes based on the size and number of tumors. Nevertheless, it is a mere representation of the true biologic behavior of HCC. Anecdotal evidence exists of large tumors of indolent nature and low recurrence potential, and of the exact opposite. The challenges for the upcoming decade will be to identify better markers of HCC biologic behavior and to implement those into new staging and transplantation criteria. Understanding the biology of HCC will ultimately allow patients to be better selected for transplantation and pretransplantation treatments.
Cholangiocarcinoma and Transplantation
An anatomic definition of cholangiocarcinomas is necessary before discussing the role of transplantation in its management. Cholangiocarcinomas are divided into intrahepatic and extrahepatic. In the most current data, LT is applied to unresectable extrahepatic cholangiocarcinomas. Specifically, tumors arising high in the biliary tract above the cystic duct, in the territory of the confluence of the bile duct. These tumors have been historically referred as hilar or perihilar cholangiocarcinomas or, if right at the confluence, Klatskin tumors. They represent approximately two thirds of all cholangiocarcinomas. Traditionally, resecting extrahepatic cholangiocarcinomas is advisable when feasible. The Bismuth-Corlette[39] classification is a useful tool in determining respectability, which is usually achievable in types I, II, and III. A type IV tumor, involving both sides of the confluence, is best resected by total hepatectomy and could be considered a clear indication for LT[40] (Figure 1).

Figure 1.
Bismuth-Corlette classification of hilar cholangiocarcinoma.[54]
Cholangiocarcinoma is the second most common primary hepatic malignancy. It arises in the background of primary sclerosing cholangitis (PSC) in 7% to 40% of patients. Diagnosis in the setting of PSC is challenging because of the difficult clinical and pathologic distinction between benign versus malignant strictures of the biliary tree. Cholangiocarcinoma is a highly aggressive malignancy with grim prognosis, not surprisingly, less than 20% of patients with hilar cholangiocarcinoma are amenable to a potentially curative resection. Those who undergo resection have a 5-year survival ranging from 11% to 40%.[41–43]
Early Experience LT
The results of LT for cholangiocarcinoma have been historically discouraging and much inferior to the results of transplantation for HCC or other benign liver conditions. The European transplant registry reported a 0% survival at 5 years in 1987.[44] One decade later, a series of patients with cholangiocarcinoma treated with LT at the University of Pittsburg reported a 5-year survival of 36.2%.[45] The London Kings College reported a 5-year survival of 10%,[46] and the Humbolt University in Germany reported a 5-year survival of 38% after LT combined with partial pancreatectomy.[47]These cumulative data of poor results prompted many centers to consider cholangiocarcinoma a contraindication for transplantation in the 1990s.
Neoadjuvant Therapy and Transplantation
In the present decade, the addition of neoadjuvant chemoradiation therapy in the treatment of cholangiocarcinoma has significantly improved the outcome. In 2002, the authors' group at the University of Nebraska reported a 5-year survival of 45% with the use of chemoradiation and LT.[48] In 2005, the Mayo Clinic group published an unprecedented report in the treatment of cholangiocarcinoma. A total of 38 patients underwent rigorous pretransplantation evaluation and neoadjuvant chemoradiation. This approach yielded a 5-year survival of 82%, which is not different from the results of LT for early HCC or other benign conditions. The 5-year recurrence rate reported was 12%. The intention-to-treat analysis of this group was 58% at 5 years, which compares favorably with any other form of treatment for this disease.[49]
These remarkable results are a reflection of a highly meticulous pretransplantation evaluation and exclusion criteria. Almost 50% of patients were excluded from transplantation during evaluation. Diagnosis was based in intraluminal brush cytology/biopsy or a carbohydrate antigen (CA) 19.9 greater than 100 ng/mL in the setting of a radiographic malignant stricture or biliary aneuploidy shown with digital image analysis and fluorescent in-situ hybridization. Staging studies included standard imaging plus endoscopic ultrasound with fine needle aspiration of any suspicious lymph nodes. The neoadjuvant chemoradiation protocol was based on combination cycles of external beam radiotherapy and 5-fluorouacil (5-FU) followed by intraluminal Iridium brachytherapy followed by infusional 5-FU. At the end of this protocol, an exploratory laparotomy with biopsies was performed on all patients. Of the patients who completed neoadjuvant chemoradiation and reached operative staging, 23% were excluded because of intraoperative findings that precluded transplantation.[49]A detailed algorithm of this protocol is presented in

Mayo Clinic protocol for neoadjuvant therapy for cholangiocarcinoma prior to liver transplantation.[47,49] Abbreviations: PSC, primary sclerosing cholangitis; 5-FU, 5-fluorouacil; CA, carbohydrate antigen; CBC, common bile duct; DIA, digital image analysis; EBRT, external beam radiation therapy; FISH, fluorescent in-situ hybridization; FNA, fine needle aspiration; GDA, gastroduodenal artery; HA, hepatic artery; IV, intravenously; LT, liver transplantation.

Mayo Clinic protocol for neoadjuvant therapy for cholangiocarcinoma prior to liver transplantation.[47,49] Abbreviations: PSC, primary sclerosing cholangitis; 5-FU, 5-fluorouacil; CA, carbohydrate antigen; CBC, common bile duct; DIA, digital image analysis; EBRT, external beam radiation therapy; FISH, fluorescent in-situ hybridization; FNA, fine needle aspiration; GDA, gastroduodenal artery; HA, hepatic artery; IV, intravenously; LT, liver transplantation.
Despite these remarkable results some controversy exists. The pathologic examination of 16 of the 38 explants in the Mayo study contained no identifiable tumor; 7 of these patients did not have a diagnosis using cytology before transplantation. This finding could indicate the efficacy of the neoadjuvant chemoradiotherapy protocol or may create concern regarding incorrect diagnoses in those patients. However, the exclusion of these 7 patients from the analysis did not seem to significantly affect the 5-year survival. Some experts have also argued the need for a staging laparotomy. Whether laparoscopic techniques, laparoscopic ultrasound, PET, or other forms of imaging could replace the staging laparotomy proposed by the Rochester group remains speculative. The widespread application of their protocol awaits validation by other centers.
Resection and Transplantation
Based on most current results, a comparison between surgical resection and transplantation would be fundamentally inaccurate because the protocol of neoadjuvant therapy followed by transplantation is only applicable to patients with unresectable hilar cholangiocarcinoma. Historically, an average of only 50% of patients undergoing exploration with the intent of surgical resection are suitable for a potentially curative resection. Memorial Sloan-Kettering Cancer Center reported a 5-year survival of 39% for patients treated with liver resection.[43] Neuhaus et al.,[51] proposed extended resection, including right trisegmentectomy and portal vein resection, reporting a 5-year survival of 72%. However, limited functional hepatic reserve limits this approach. The Mayo Clinic group reported their results with liver resections as treatment for cholangiocarcinoma. Survival at 1, 3, and 5 years was 87%, 53%, and 18%, respectively, regardless of the presence of a node-negative R0 resection. Overall cumulative data of surgical resection as treatment of cholangiocarcinoma show persistent poor results. No reports exist of neoadjuvant therapy before resection as treatment for cholangiocarcinoma. As of today, patients with unresectable hilar cholangiocarcinoma enrolled in a protocol of neoadjuvant therapy followed by transplantation have a better chance of survival.
Complications of Neoadjuvant Therapy
Limitations to this approach include chemoradiation hepatotoxicity. Major hepatic resections may not be safe after this approach. LT is naturally not affected by the neoadjuvant chemotherapy in terms of posttransplant synthetic liver function. However, a recent report from the group at the Mayo Clinic has reported an unusually high incidence of vascular complications. Vascular complications developed in 40% of patients, and were equally distributed between arterial and venous. An adjustment on the surgical technique for arterial reconstruction was introduced early in the experience of diseased donor LT.[52]
Risk Factors for Recurrence and Allocation
A retrospective analysis of 65 patients who developed recurrences identified older age, pretransplant elevated CA 19.9, larger tumors, prior cholecystectomy, residual tumor greater than 2 cm at explants, and perineural invasion as risk factors for recurrence. Complete absence of viable tumor at explant did not predict the lack of recurrence. PSC was not associated with a difference in outcome.[53] None of these factors are considered as criteria for inclusion or exclusion to transplant protocols nor for organ allocation.
The allocation of organs for patients with cholangiocarcinoma is based on the MELD score. No priority or exception is given unless an individual written petition is presented to the regional UNOS review board. Based on historical data and the new era of chemoradiation therapy before LT for cholangiocarcinoma, the MELD Exception Group recommended a standardized MELD exception across all regions for patients with early unresectable hiliar cholangiocarcinoma enrolled in an approved protocol of neoadjuvant therapy with strict inclusion and exclusion criteria.[54]
LDLT is an emerging viable option for the treatment of this disease. It overcomes the potential waiting list time and the limited supply of deceased donated organs. The introduction of neoadjuvant chemoradiation therapy has improved outcomes significantly. A rigorous pretransplant evaluation seems critical to reproduce comparable outcomes.

Disclaimer

The material presented here does not necessarily reflect the views of MedscapeCME or companies that support educational programming on cme.medscape.com. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity.

J Natl Compr Canc Netw. 2009;7(4):409-417. © 2009 JNCCN