The Role of Liver Transplantation in the Management of HCC
The Role of Liver Transplantation in the Management of HCC
Background Hepatocellular carcinoma (HCC) is a major cause of morbidity and mortality worldwide. Liver transplantation offers a potential cure for this otherwise devastating disease. The selection of the most appropriate candidates is paramount in an era of graft shortage.
Aim To review systematically the role of liver transplantation in the management of HCC in current clinical practice.
Methods An electronic literature search using PUBMED (1980–2010) was performed. Search terms included HCC, hepatoma, liver cancer, and liver transplantation.
Results Liver transplantation is a highly successful treatment for HCC, in patients within Milan criteria (MC), defined as a solitary tumour ≤50 mm in diameter or ≤3 tumours ≤30 mm in diameter in the absence of extra-hepatic or vascular spread. Other eligibility criteria for liver transplantation are also used in clinical practice, such as the University of California, San Francisco criteria, with outcomes comparable to MC. Loco-regional therapies have a role in the bridging treatment of HCC by minimising wait-list drop-out secondary to tumour progression. Beyond MC, encouraging results have been demonstrated for patients with down-staged tumours. Post-liver transplantation, there is no evidence to support a specific immunosuppressive regimen. In the context of an insufficient cadaveric donor pool to meet demand, the role of adult living donation may be increasingly important.
Conclusions Liver transplantation offers a curative therapy for selected patients with HCC. The optimisation of eligibility criteria is paramount to ensure that maximum benefit is accrued. Although wait-list therapies have been incorporated into clinical practice, additional high quality data are required to support this strategy.
The majority of cases of hepatocellular carcinoma (HCC) arise on a background of cirrhosis. This in itself complicates management as hepatocellular dysfunction and/or portal hypertension can limit the tolerability of 'classical' cancer treatments such as resection or systemic cytotoxic chemotherapy. However, in selected patients, liver transplantation (LT) enables resection of the tumour with the widest possible surgical margin as well as treating the underlying cirrhosis, the latter strategy reducing the risk of subsequent de novo HCC formation.
Early experiences of LT as a treatment for HCC were associated with poor outcomes, reflecting the fact that the selected patients had advanced disease. However, patients in whom HCC was diagnosed on the basis of explant pathology alone were demonstrated to have a survival rate comparable to patients without malignancy, thereby indicating that LT might still be an appropriate treatment for early HCC. This was supported by Mazzaferro in a seminal paper, whereby 4-year survival of 75% was demonstrated in 48 patients with either one tumour ≤50 mm in diameter or ≤3 tumours each with diameter ≤30 mm, and with no vascular invasion evident on imaging or extra-hepatic disease. Survival rates in those selected were similar to patients transplanted for non-malignant liver disease. These aforementioned criteria have since been referred to as the 'Milan criteria' (MC), and have been widely adopted into clinical practice, including integration into the Union for International Cancer Control (UICC) TMN and United Network for Organ Sharing (UNOS) staging systems for HCC (Table 1), as well as providing a benchmark for other eligibility criteria.
LT continues to be associated with significant morbidity and mortality despite improvements in surgical technique and immunosuppressive regimens. Furthermore, unlike other forms of oncological surgery, LT requires a donor organ. In view of this, utility and fairness need to be considered in relation to allocation for both donor and recipient. For this reason, the application of strict eligibility criteria, such as MC has evolved as an important aspect of current clinical practice. This theoretically ensures that LT is offered to patients with HCC who are most likely to gain the greatest benefit, whilst not disadvantaging patients requiring LT for non-oncological indications.
Whilst the importance of eligibility criteria for LT is clear cut, the optimisation of these criteria as well as the management of patients already listed for LT remains a source of debate. In this article, we systematically review the role of LT in the management of HCC arising in the cirrhotic liver including the expansion of eligibility criteria beyond MC, the role of neo-adjuvant or adjuvant therapies (such as bridging therapy and down-staging), and organ allocation strategies. HCC surveillance, diagnostic strategies, and the management of patients not eligible for LT will not be discussed, although these topics have recently reviewed in this journal. Furthermore, the potential role of LT in the management of other liver tumours, such as cholangiocarcinoma, haemangioendothelioma, and neuro-endocrine tumours is beyond the scope of this article and therefore not discussed.
Abstract and Introduction
Abstract
Background Hepatocellular carcinoma (HCC) is a major cause of morbidity and mortality worldwide. Liver transplantation offers a potential cure for this otherwise devastating disease. The selection of the most appropriate candidates is paramount in an era of graft shortage.
Aim To review systematically the role of liver transplantation in the management of HCC in current clinical practice.
Methods An electronic literature search using PUBMED (1980–2010) was performed. Search terms included HCC, hepatoma, liver cancer, and liver transplantation.
Results Liver transplantation is a highly successful treatment for HCC, in patients within Milan criteria (MC), defined as a solitary tumour ≤50 mm in diameter or ≤3 tumours ≤30 mm in diameter in the absence of extra-hepatic or vascular spread. Other eligibility criteria for liver transplantation are also used in clinical practice, such as the University of California, San Francisco criteria, with outcomes comparable to MC. Loco-regional therapies have a role in the bridging treatment of HCC by minimising wait-list drop-out secondary to tumour progression. Beyond MC, encouraging results have been demonstrated for patients with down-staged tumours. Post-liver transplantation, there is no evidence to support a specific immunosuppressive regimen. In the context of an insufficient cadaveric donor pool to meet demand, the role of adult living donation may be increasingly important.
Conclusions Liver transplantation offers a curative therapy for selected patients with HCC. The optimisation of eligibility criteria is paramount to ensure that maximum benefit is accrued. Although wait-list therapies have been incorporated into clinical practice, additional high quality data are required to support this strategy.
Introduction
The majority of cases of hepatocellular carcinoma (HCC) arise on a background of cirrhosis. This in itself complicates management as hepatocellular dysfunction and/or portal hypertension can limit the tolerability of 'classical' cancer treatments such as resection or systemic cytotoxic chemotherapy. However, in selected patients, liver transplantation (LT) enables resection of the tumour with the widest possible surgical margin as well as treating the underlying cirrhosis, the latter strategy reducing the risk of subsequent de novo HCC formation.
Early experiences of LT as a treatment for HCC were associated with poor outcomes, reflecting the fact that the selected patients had advanced disease. However, patients in whom HCC was diagnosed on the basis of explant pathology alone were demonstrated to have a survival rate comparable to patients without malignancy, thereby indicating that LT might still be an appropriate treatment for early HCC. This was supported by Mazzaferro in a seminal paper, whereby 4-year survival of 75% was demonstrated in 48 patients with either one tumour ≤50 mm in diameter or ≤3 tumours each with diameter ≤30 mm, and with no vascular invasion evident on imaging or extra-hepatic disease. Survival rates in those selected were similar to patients transplanted for non-malignant liver disease. These aforementioned criteria have since been referred to as the 'Milan criteria' (MC), and have been widely adopted into clinical practice, including integration into the Union for International Cancer Control (UICC) TMN and United Network for Organ Sharing (UNOS) staging systems for HCC (Table 1), as well as providing a benchmark for other eligibility criteria.
LT continues to be associated with significant morbidity and mortality despite improvements in surgical technique and immunosuppressive regimens. Furthermore, unlike other forms of oncological surgery, LT requires a donor organ. In view of this, utility and fairness need to be considered in relation to allocation for both donor and recipient. For this reason, the application of strict eligibility criteria, such as MC has evolved as an important aspect of current clinical practice. This theoretically ensures that LT is offered to patients with HCC who are most likely to gain the greatest benefit, whilst not disadvantaging patients requiring LT for non-oncological indications.
Whilst the importance of eligibility criteria for LT is clear cut, the optimisation of these criteria as well as the management of patients already listed for LT remains a source of debate. In this article, we systematically review the role of LT in the management of HCC arising in the cirrhotic liver including the expansion of eligibility criteria beyond MC, the role of neo-adjuvant or adjuvant therapies (such as bridging therapy and down-staging), and organ allocation strategies. HCC surveillance, diagnostic strategies, and the management of patients not eligible for LT will not be discussed, although these topics have recently reviewed in this journal. Furthermore, the potential role of LT in the management of other liver tumours, such as cholangiocarcinoma, haemangioendothelioma, and neuro-endocrine tumours is beyond the scope of this article and therefore not discussed.