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Liver Transplantation for Hepatocellular Carcinoma
Review Article
LIVER TRANSPLANTATION FOR HEPATOCELLULAR CARCINOMA Chirag J Desai Chief Consultant & Program Director, Department of GI, HPB, Liver Transplant Surgery, Apollo Hospitals International Limited, Ahmedabad, India. Primary tumours of the liver represent one of the most common malignancies worldwide. The annual international incidence of the disease is some 1 million cases, with a male to female ratio of approximately 4:1. Hepatocellular carcinoma (HCC) accounts for 90% of all primary liver malignancy. It usually occurs on a background of chronic liver disease and in particular viral cirrhosis. HCC therefore is a major cause of death in high endemic areas of hepatitis B Virus(HBV) and Hepatitis C virus(HCV) infection. HCC is frequently multiple and its hypervascularity increases its propensity for hematogenous spread. The screening of high risk group helps detection of HCC early. The surgical resection and local ablation techniques are routinely used for the local control. However recurrence of the tumour is common due to persistence of underlying predisposing liver condition. Hence liver transplant looks a logical alternative but has its own limitations like recurrence, availability of graft and its cost. Early treatment of HBV & HCV may help prevent the development of HCC itself. The survival of the patients with cirrhosis depends on tumour stage as well as extent of liver damage. Key words: Hepatocellular carcinoma, Liver transplantation.
VARIOUS TREATMENT OPTIONS FOR HCC Radical Treatment •
Surgical resection
•
Liver Transplantation (CLT/LDLT)
•
Percutaneous Ablation
ethanol
injection/Radiofrequency
Selection criteria for transplant in HCC
Palliative Treatment •
Transarterial embolization/Chemoembolization.
•
Transarterial embolization-percutaneous treatments
•
Hormonal treatments/ Immunotherapy
•
Antiproliferative agents
whenever possible. Hepatic reserve is the one of the major determinants of liver resection. When compared with resection, transplantation restores liver function and has the advantage of removing tissue with an oncogenic potential. To obtain the optimal benefit from the limited number of organs available, strict selection criteria has been developed to offer liver grafts to patients with the highest likelihood of survival after transplantation.
In 1996 Mazzaferro et al showed that when strict criteria were applied, transplantation of patients with early HCC has resulted in excellent results with 4-year survival rate of 75%. This led to the development of Milan criteria from a retrospective analysis of 48 patients. This survival rate was achieved in patients with solitary tumor of less than 5 cm and those who have up to 3 tumor nodules each of which is smaller than 3 cm without vascular invasion or extra hepatic metastasis. With the achievement of good results the Milan criterion was expanded (Fig. 1).
Symptomatic Treatment
Rationale for Transplant for HCC HCC is the most common primary liver cancer and most patients with HCC also suffer from coexisting cirrhosis. Liver transplantation is obviously the most attractive therapeutic option for HCC because it removes detectable and undetectable tumour nodules together with all the preneoplastic lesions that are present in the cirrhotic liver. It simultaneously treats the underlying cirrhosis and prevents postoperative and distant complications associated with portal hypertension and liver failure. For the treatment of patients without cirrhosis, resection should be considered 377
Yao, et al. proposed UCSF criteria (solitary tumor smaller than 6.5 cm or 3 of fewer nodules with the largest lesion smaller than 4.5 cm or total tumor diameter less than 8.5 cm without vascular invasion). In this study the expansion of Milan criteria did not have adverse impact on survival. On the other hand, this approach reduced the availability of cadaveric grafts for patients with other liver diseases. The Barcelona Clinic Liver Cancer Group has proposed Apollo Medicine, Vol. 5, No. 4, December 2008
Review Article
expanding the Milan criteria to single tumor of 7 cm or less, or 5 tumors of 3 cm or less, in patients who showed a partial response to any treatment lasting for more than 6 months. With the expansion of listing criteria, liver transplantation could be performed in more advanced cancer patients but this lead in turn to poor survival rates. All patient selection criteria rely on radiological imaging to assess intrahepatic disease and exclude extra hepatic spread. It may be possible to improve patient selection by increasing the sensitivity of imaging studies and detection of micometastasis.
pattern predicted by their tumour status at the time of transplantation (i.e., after local ablative therapy) or if they follow the course indicated by tumour parameters present before such treatment. The studies have shown that the extent of response to TACE (30 % decrease in the sum of the largest diameter of tumor nodules) and the sustained response to TACE can serve effectively as a selection criterion for OLT, irrespective of tumor size and number. However this needs to be confirmed in randomised control trials.
Downside of transplant in HCC Organ shortage, higher dropout rate from waiting list and cost are downsides of transplantation for the treatment of HCC. Less favorable results in cases with larger tumours render these attempts to a controversial issue. Living Donor LT (LDLT) vs. Deceased Donor LT (DDLT) About 50% of HCC patients who are initially candidates for liver transplantation will become ineligible, if the median waiting period exceeds 1 year. As a result of tumor progression during the waiting period, LDLT gained popularity to transplant HCC patients in a better clinical condition without a long waiting time. LDLT has graft dedicated to the particular patient and does not deprive other patients from limited number of cadaver grafts. Although controversial, it may be claimed that LDLT can be performed in patients with HCC that exceeds the Milan criteria as 3-year survival rate of greater than 50 has been showed in some studies. In two studies it was shown that LDLT is superior to DDLT for patients with HCC meeting Milan criteria, when waiting times for organs from deceased donors exceed six months. The UNOS point system for priority scoring of liver transplant recipients now includes additional points for patients with HCC. This allows patients with early-stage disease to receive a priority score that leads to rapid transplantation. Now, even patients who are resection candidates can be treated with transplantation.
Fig 1. HCC-Liver transplantation-selection criteria
Fig 2. Liver transplantation for HCC
Treatment while on the waiting list Despite the availability of LDLT tumor progression (Fig. 2) is still a major concern and strategies (Fig.3) like chemoembolisation and radiofrequency ablation to reduce tumor growth during waiting period have shown promising results. What remains unclear, however, is whether this translates into prolonged survival after transplantation. Furthermore, it is not known whether patients who have had their tumours treated preoperatively follow the recurrence Apollo Medicine, Vol. 5, No. 4, December 2008
378
Fig 3. Liver transplantation for HCC
Review Article
Results of transplant for HCC
CONCLUSION
The controversy over appropriate management of patients with HCC will remain until more data on the longterm results for transplantation of patients with early-stage disease are reported. To date, it is known that survival for early-stage disease treated with resection is 50% to 75%, whereas with transplantation it is reportedly higher than 70%. Longer-term intention-to-treat studies will be necessary to define the better treatment.
Liver transplantation is certainly an established treatment option for patients with cirrhosis and HCC especially in early stages. A lot needs to be done to derive more refined selection criteria, treatment strategy while on waiting list and philosophy for organ allocation.
379
Apollo Medicine, Vol. 5, No. 4, December 2008
LIVER TRANSPLANTATION FOR HEPATOCELLULAR CARCINOMA Chirag J Desai Chief Consultant & Program Director, Department of GI, HPB, Liver Transplant Surgery, Apollo Hospitals International Limited, Ahmedabad, India. Primary tumours of the liver represent one of the most common malignancies worldwide. The annual international incidence of the disease is some 1 million cases, with a male to female ratio of approximately 4:1. Hepatocellular carcinoma (HCC) accounts for 90% of all primary liver malignancy. It usually occurs on a background of chronic liver disease and in particular viral cirrhosis. HCC therefore is a major cause of death in high endemic areas of hepatitis B Virus(HBV) and Hepatitis C virus(HCV) infection. HCC is frequently multiple and its hypervascularity increases its propensity for hematogenous spread. The screening of high risk group helps detection of HCC early. The surgical resection and local ablation techniques are routinely used for the local control. However recurrence of the tumour is common due to persistence of underlying predisposing liver condition. Hence liver transplant looks a logical alternative but has its own limitations like recurrence, availability of graft and its cost. Early treatment of HBV & HCV may help prevent the development of HCC itself. The survival of the patients with cirrhosis depends on tumour stage as well as extent of liver damage. Key words: Hepatocellular carcinoma, Liver transplantation.
VARIOUS TREATMENT OPTIONS FOR HCC Radical Treatment •
Surgical resection
•
Liver Transplantation (CLT/LDLT)
•
Percutaneous Ablation
ethanol
injection/Radiofrequency
Selection criteria for transplant in HCC
Palliative Treatment •
Transarterial embolization/Chemoembolization.
•
Transarterial embolization-percutaneous treatments
•
Hormonal treatments/ Immunotherapy
•
Antiproliferative agents
whenever possible. Hepatic reserve is the one of the major determinants of liver resection. When compared with resection, transplantation restores liver function and has the advantage of removing tissue with an oncogenic potential. To obtain the optimal benefit from the limited number of organs available, strict selection criteria has been developed to offer liver grafts to patients with the highest likelihood of survival after transplantation.
In 1996 Mazzaferro et al showed that when strict criteria were applied, transplantation of patients with early HCC has resulted in excellent results with 4-year survival rate of 75%. This led to the development of Milan criteria from a retrospective analysis of 48 patients. This survival rate was achieved in patients with solitary tumor of less than 5 cm and those who have up to 3 tumor nodules each of which is smaller than 3 cm without vascular invasion or extra hepatic metastasis. With the achievement of good results the Milan criterion was expanded (Fig. 1).
Symptomatic Treatment
Rationale for Transplant for HCC HCC is the most common primary liver cancer and most patients with HCC also suffer from coexisting cirrhosis. Liver transplantation is obviously the most attractive therapeutic option for HCC because it removes detectable and undetectable tumour nodules together with all the preneoplastic lesions that are present in the cirrhotic liver. It simultaneously treats the underlying cirrhosis and prevents postoperative and distant complications associated with portal hypertension and liver failure. For the treatment of patients without cirrhosis, resection should be considered 377
Yao, et al. proposed UCSF criteria (solitary tumor smaller than 6.5 cm or 3 of fewer nodules with the largest lesion smaller than 4.5 cm or total tumor diameter less than 8.5 cm without vascular invasion). In this study the expansion of Milan criteria did not have adverse impact on survival. On the other hand, this approach reduced the availability of cadaveric grafts for patients with other liver diseases. The Barcelona Clinic Liver Cancer Group has proposed Apollo Medicine, Vol. 5, No. 4, December 2008
Review Article
expanding the Milan criteria to single tumor of 7 cm or less, or 5 tumors of 3 cm or less, in patients who showed a partial response to any treatment lasting for more than 6 months. With the expansion of listing criteria, liver transplantation could be performed in more advanced cancer patients but this lead in turn to poor survival rates. All patient selection criteria rely on radiological imaging to assess intrahepatic disease and exclude extra hepatic spread. It may be possible to improve patient selection by increasing the sensitivity of imaging studies and detection of micometastasis.
pattern predicted by their tumour status at the time of transplantation (i.e., after local ablative therapy) or if they follow the course indicated by tumour parameters present before such treatment. The studies have shown that the extent of response to TACE (30 % decrease in the sum of the largest diameter of tumor nodules) and the sustained response to TACE can serve effectively as a selection criterion for OLT, irrespective of tumor size and number. However this needs to be confirmed in randomised control trials.
Downside of transplant in HCC Organ shortage, higher dropout rate from waiting list and cost are downsides of transplantation for the treatment of HCC. Less favorable results in cases with larger tumours render these attempts to a controversial issue. Living Donor LT (LDLT) vs. Deceased Donor LT (DDLT) About 50% of HCC patients who are initially candidates for liver transplantation will become ineligible, if the median waiting period exceeds 1 year. As a result of tumor progression during the waiting period, LDLT gained popularity to transplant HCC patients in a better clinical condition without a long waiting time. LDLT has graft dedicated to the particular patient and does not deprive other patients from limited number of cadaver grafts. Although controversial, it may be claimed that LDLT can be performed in patients with HCC that exceeds the Milan criteria as 3-year survival rate of greater than 50 has been showed in some studies. In two studies it was shown that LDLT is superior to DDLT for patients with HCC meeting Milan criteria, when waiting times for organs from deceased donors exceed six months. The UNOS point system for priority scoring of liver transplant recipients now includes additional points for patients with HCC. This allows patients with early-stage disease to receive a priority score that leads to rapid transplantation. Now, even patients who are resection candidates can be treated with transplantation.
Fig 1. HCC-Liver transplantation-selection criteria
Fig 2. Liver transplantation for HCC
Treatment while on the waiting list Despite the availability of LDLT tumor progression (Fig. 2) is still a major concern and strategies (Fig.3) like chemoembolisation and radiofrequency ablation to reduce tumor growth during waiting period have shown promising results. What remains unclear, however, is whether this translates into prolonged survival after transplantation. Furthermore, it is not known whether patients who have had their tumours treated preoperatively follow the recurrence Apollo Medicine, Vol. 5, No. 4, December 2008
378
Fig 3. Liver transplantation for HCC
Review Article
Results of transplant for HCC
CONCLUSION
The controversy over appropriate management of patients with HCC will remain until more data on the longterm results for transplantation of patients with early-stage disease are reported. To date, it is known that survival for early-stage disease treated with resection is 50% to 75%, whereas with transplantation it is reportedly higher than 70%. Longer-term intention-to-treat studies will be necessary to define the better treatment.
Liver transplantation is certainly an established treatment option for patients with cirrhosis and HCC especially in early stages. A lot needs to be done to derive more refined selection criteria, treatment strategy while on waiting list and philosophy for organ allocation.
379
Apollo Medicine, Vol. 5, No. 4, December 2008