When is liver transplantation a reasonable treatment option?

When patients with hepatocellular carcinoma (HCC) meet certain criteria for tumor size, tumor number, and metastasis, liver transplantation may be a reasonable treatment option. The allocation of available organs is based on the severity of liver disease. For patients on the transplant waiting list, local bridging therapies can be performed for tumor control: transarterial chemoembolization (TACE), radiofrequency ablation (RFA), and percutaneous ethanol injection (PEI).

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-associated death worldwide and the sixth leading cause of death in Switzerland [1]. The incidence is increasing over the long-term course. The main causes are infections with hepatitis B and C viruses (HBV, HCV) and, more recently, the epidemiological increase in non-alcoholic steatohepatitis (NASH). Untreated, HCC has an unfavorable prognosis with a 5-year survival rate of less than 10%.

The majority of patients develop HCC in the setting of cirrhosis, making optimal treatment strategies much more difficult. In the last decade, significant advances have been made in biomedical knowledge of the disease as well as its therapy. Treatment options are mainly based on surgical (resection, liver transplantation) and non-surgical interventions (interventional-radiological chemoembolization, loco-regional ablation, chemotherapy). In the case of localized and non-multifocal HCC disease, surgical tumor removal and liver transplantation are the gold standard [2,3].

Patient selection based on tumor size and prognosis

Liver transplantation appears to be the ideal HCC therapy because complete removal of the tumor-infested liver is formally equivalent to oncologic tumor removal with negative resection margins. However, in the context of donor organ shortage, liver transplantation is considered only in patients whose probability of survival is comparable to that of an organ recipient without HCC.

Originally, Bismuth’s group reported the extent of tumor involvement as a surrogate marker for tumor biology: patients with small, uni- or binodular tumors <3 cm had better survival in the case of transplantation compared with tumor resection (83% vs. 18%) [4]. Patients with diffuse HCC with more than two nodules >3 cm or portal vein thrombus had a higher recurrence rate with consecutive decreased survival. Mazzaferro et al. studied patients with cirrhosis and non-resectable HCC treated by transplantation [5]. The authors established specific criteria – the basis of the so-called Milan criteria – defined as a single tumor <5 cm or ≤3 tumors each <3 cm in diameter (Fig. 1) . Patients who met the Milan criteria showed significantly improved recurrence-free and overall survival after transplantation.

Numerous studies have reported excellent survival data in HCC patients transplanted within these criteria. This led some experts to consider the criteria too restrictive. In fact, a research group at the University of California, San Francisco (UCSF) showed that patients outside the Milan criteria also benefit significantly from transplantation. The broader UCSF criteria are defined as a single tumor ≤6.5 cm or ≤3 tumors each ≤4.5 cm and sum of total tumor diameters ≤8 cm (Fig. 1) [6].

Patients transplanted within Milan or UCSF criteria have similar survival data (80% vs. 75% 5-year survival). However, transplantation outside the UCSF criteria is associated with a 5-year survival rate well below 50% (Fig. 2) [7]. Regardless of tumor size and number, evidence of macrovascular tumor invasion implies a contraindication to liver transplantation.

Organ allocation according to severity of liver disease

Donor livers are allocated according to the severity of liver disease in the potential recipient; severity is assessed using a scoring system according to the Model for End-Stage Liver Disease (MELD) score [8]. The MELD score is suitable for assessing the probability of survival of patients on the waiting list. It takes into account liver and kidney function and is calculated from the laboratory values total bilirubin, Quick and creatinine with values from 6 – 40.

The higher the MELD score, which can range from 6 – 40, the higher the patient’s prioritization on the waiting list for an organ offer. However, because HCC patients may have compensated cirrhosis, MELD score may underestimate the true risk of death, which is why MELD exemption criteria for HCC have been established. Patients with HCC in Switzerland receive 14 MELD points at initial listing and 1.5 points more each month on the waiting list. Thus, a patient with HCC and compensated liver function who has been on the waiting list for six months has a MELD score of 23 (14 + 9).

Criteria for listing for liver transplantation

Patients with HCC are carefully evaluated before possible liver transplantation. This involves radiological assessment of tumor size and number. Extrahepatic metastasis and vascular invasion must be excluded. Histologic evidence of HCC is not mandatory: accepted HCC criteria without histologic evidence include arterial enhancement followed by portal venous washout on computed tomography (CT) or magnetic resonance imaging (MRI) if the focus is >1 cm, or evidence of tumors on angiography. In order for transplantation to be considered in all patients with HCC, assessment as non-resectable is required. Reevaluation is performed every three months by MRI or CT to rule out disease progression beyond established criteria.

Bridging therapies for patients on the waiting list

Patients with HCC on the liver transplant list are reevaluated regularly. In the case of hepatic progression of tumor disease outside of listing criteria – as determined by imaging and α-fetoprotein (AFP) – passive listing occurs in many cases and downstaging is attempted. If progression occurs despite loco-regional therapies, “delisting” from the transplant waiting list should occur. HCC patients may have a relatively low MELD score and remain on the waiting list longer, which is why the cancer may progress and thus the prognosis after liver transplantation is less favorable or even exclusion from the list.

Transplant centers with long waiting lists perform local bridging therapies for tumor control in these patients, consisting of transarterial chemoembolization (TACE), radiofrequency ablation (RFA), and percutaneous ethanol injection (PEI).

TACE is selective embolization of hepatoma arterial inflow using chemotherapeutic agents (mainly cisplatin or doxorubicin), resulting in ischemic tumor damage, combined with local chemotherapy with low systemic side effects. With this interventional method, a size reduction of the tumor from 50% to complete tumor necrosis can be achieved. TACE also reduces the waiting list drop-out rate and tumor recurrence rate after liver transplantation and results in downstaging.
In RFA, an RFA probe is placed percutaneously into the tumor, assisted by imaging, and the tumor is destroyed using high-frequency alternating electrical energy. Results have been satisfactory, with reports of a zero percent drop-out rate and 3-year survival of up to 83%.
PEI has been the least researched as a bridging therapy. By using a fine needle, PEI is theoretically less invasive and therefore less likely to cause tumor seeding. With a favorable side effect spectrum of PEI, successful results can be achieved with up to 80% tumor necrosis. However, because multiple treatments are required, the majority of PEI has been replaced by XRF.

In case of borderline tumor size and number after bridging therapy, the patient is listed inactive to elicit tumor biology by MRI, CT and AFP. If no tumor progression is observed after a three-month inactive waiting period on the list, the patient will be actively listed.

Tumor resection versus liver transplantation.

Liver transplantation is clearly superior to resection in terms of 5-year recurrence-free survival and is certainly the best therapeutic option in cirrhotic patients with small HCC. Due to the shortage of donor organs as well as the often advanced stage of disease outside the criteria, transplantation can only be offered in a selective HCC population. Therefore, resection remains the treatment of choice for cirrhotic patients with compensated liver function (Child-Pugh stage A) without portal hypertension [9].

Combination therapy of liver resection and transplantation may be considered in three different clinical scenarios:

Primary therapy with salvage transplantation for tumor recurrence (Fig. 3).
Diagnostic procedure for histopathological evaluation of the tumor with regard to vascular invasion as well as tumor satellites with consecutive adequate selection of transplant candidates.
Bridging therapy before transplantation to ensure tumor control within Milan or UCSF criteria [10].

HCC patients with noncompensated liver function (Child-Pugh B or C) and/or portal hypertension should receive primary liver transplantation if the tumor disease is within the respective accepted transplantation criteria (Fig. 3).

Live Liver Transplant

Another way to address the shortage of donor organs is the possibility of living liver donation (right or left hemi-liver) from a healthy donor, which leads to equivalent survival compared to cadaveric donation. However, the sometimes reported high donor morbidity of about 40% is not without concern.

Internationally applicable guidelines recommend living liver transplantation in HCC patients in whom the expected 5-year survival is identical to cadaveric donation transplantation. The Milan criteria are used as a guideline for patient selection. Live liver transplantation should be performed only at highly specialized centers with great experience and expertise in liver surgery and liver transplantation. If living donation occurs outside the criteria, retransplantation should not be performed using cadaveric donation in the event of graft failure (Table 1) [3].

International recommendations for liver transplantation for HCC.

In December 2010, a consensus conference with international experts was held in Zurich. The goal was to elaborate the current practice of liver transplantation for HCC and to develop internationally accepted guidelines. A total of 37 statements and recommendations were formulated. These address the areas of evaluation of liver transplant candidates, criteria for listing cirrhotic and non-cirrhotic patients, role of tumor downstaging, treatment of patients on the waiting list, value of living liver donation, and post-transplant treatment. The most important 17 recommendations (“strong statements”) are summarized in Table 1 [3].

Take-Home Messages

Liver transplantation via cadaveric or living donation is a potential therapeutic option for patients with HCC and end-stage liver disease (ESLD).
Specific criteria (Milan, UCSF) were defined for patient selection based on tumor size and number. Evidence of macrovascular tumor invasion is a contraindication to liver transplantation.
Liver dysfunction is determined by Model for End-Stage Liver Disease (MELD); however, the MELD value in HCC patients may be the same as that in healthy individuals, which is why MELD exemption criteria have been established for HCC.
Patients on the transplant waiting list benefit from bridging therapies consisting of transarterial chemoembolization (TACE), radiofrequency ablation (RFA), and percutaneous ethanol injection (PEI).

Literature:

Parkin DM, et al: Global cancer statistics 2002. CA Cancer J Clin 2005; 55(2): 74-108.
Dutkowski P, et al: Challenges to Liver Transplantation and Strategies to Improve Outcomes. Gastroenterology 2015 Feb; 148(2): 307-323.
Clavien PA, et al: Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol 2012; 13(1): e11-22.
Bismuth H, et al: Liver resection versus transplantation for hepatocellular carcinoma in cirrhotic patients. Ann Surg 1993; 218(2): 145-151.
Mazzaferro V, et al: Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996; 334(11): 693-699.
Yao FY, et al: Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 2001; 33(6): 1394-1403.
Duffy JP, et al: Liver transplantation criteria for hepatocellular carcinoma should be expanded: a 22-year experience with 467 patients at UCLA. Ann Surg 2007; 246(3): 502-509; discussion 509-511.
Malinchoc M, et al: A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology 2000; 31(4): 864-871.
Clavien PA, et al: Strategies for safer liver surgery and partial liver transplantation. N Engl J Med 2007; 356(15): 1545-1559.
Chua TC, et al: Hepatic resection for transplantable hepatocellular carcinoma for patients within Milan and UCSF criteria. Am J Clin Oncol 2012; 35(2): 141-145.
Agopian V, Petrowsky H: Liver transplantation for malignant tumors. In: Fong Y, Poon R, Tang ZY, Dupuy D, Berlin JD (eds): Hepatobiliary cancer. People’s Medical Publishing House-USA, Ltd, 2014, 293-316.