- Email: [email protected]
Computed Tomography Before and After Transarterial Chemoembolization in Patients With Hepatocellular Carcinoma Undergoing Liver Transplantation: Initial Results
Value of 18-FDG-Positron Emission Tomography/Computed Tomography Before and After Transarterial Chemoembolization in Patients With Hepatocellular Carcinoma Undergoing Liver Transplantation: Initial Results P. Cascales Campos, P. Ramirez, R. Gonzalez, B. Febrero, J.A. Pons, M. Miras, F. Sanchez Bueno, R. Robles, and P. Parrilla ABSTRACT Introduction. Liver transplantation is the treatment of choice for various types of end-stage liver disease and the most appropriate alternative for the treatment of hepatocellular carcinoma (HCC)-associated liver cirrhosis. The aim of this study was to describe our initial experience with the use of 18-FDG positron emission tomography (PET)/computed tomography CT before and after transarterial chemoembolization (TACE) in HCC patients undergoing liver transplantation, seeking to predict the percentage of tumor necrosis achieved by TACE procedures. Patients and Methods. From January 2007 through December 2009, 39 patients with HCC and liver cirrhosis were included in our liver transplantation program. We selected the 6 subjects who underwent 18-fluorodeoxyglucose PET/CT (18-FDG PET/CT) pre- and post-TACE. Results. The median SUV (standarized uptake value) in the lesions studied were 4 (range, 2.79 – 6.95) before TACE with a median post-TACE SUV of 0 (range, 0 – 4). Among patients whose post-TACE SUV decreased to ⬍3, the percentage of necrosis after studying the hepatectomy was ⬎80%. Conclusion. Performance of an 18-FDG PET/CT before and after TACE and comparison of SUV in patients with HCC awaiting liver transplantation provided valuable information regarding the effectiveness of TACE. RTHOTOPIC liver transplantation (OLT) is the treatment of choice for various types of end-stage liver disease and the most appropriate alternative for the treatment of hepatocellular carcinoma (HCC)-associated liver cirrhosis.1 Knowledge of the natural history of diseases among transplantation candidates and improvements in their management have increased the number of patients who can benefit from transplantation. However, despite the annual increase in the number of OLTs in our country, the waiting list time remains the same or has even increased.2– 4 A long time spent on the waiting list by following conventional indications may lead to worse liver function and a general deterioration in the patient’s condition. In the case of oncologic indications, a prolonged period on the list may lead to disease progression with subsequent exclusion from the waiting list. One of the main concerns of transplantation groups when determining indications for HCC patients is the risk of
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tumor and disease progression while awaiting a transplantable organ, factors that can exclude a patient from the waiting list. Therapies such as transarterial chemoembolization (TACE) are employed in patients who show a good performance status while awaiting an OLT.5– 8 Multiphasic contrast-enhanced computed tomography (CT) has become the standard imaging technique for patients with HCC. It has been considered to be the most reliable method to assess the efficacy of TACE. 18- FDG
From the Departments of Surgery (P.C.C., P.R., R.G., B.F., F.S.B., R.R., P.P.) and Hepatology (J.A.P., M.M.), Liver Transplant Unit, Virgen de la Arrixaca University Hospital, Murcia, Spain. Address reprint requests to Pedro Antonio Cascales Campos, Calle Dr Fleming N° 12 3° E, La Alberca, Murcia, Spain. E-mail: [email protected]
© 2011 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/–see front matter doi:10.1016/j.transproceed.2011.05.023
Transplantation Proceedings, 43, 2213–2215 (2011)
2213
2214
CASCALES CAMPOS, RAMIREZ, GONZALEZ ET AL
positron emission tomography (PET) is of limited use in the diagnosis of primary HCCs; its reported sensitivity in 50%–55%.9 –13 The aim of this study was to describe an initial experience with the use of 18- FDG PET/CT before and after TACE for HCC patients undergoing OLT, seeking to predict the percentage of tumor necrosis obtained with TACE procedures. PATIENTS AND METHODS From January 2007 through December 2009, 39 patients with HCC and liver cirrhosis were included in our liver transplantation program. All patients who were enrolled for OLT met the Milan criteria, namely, a single tumor ⱕ5 cm or no more than 3 nodules with the greatest not exceeding 3 cm. Before OLT TACE was used to treat HCC in 21 candidates. TACE procedures were performed with tumor embolization using drug-eluting beads containing adriamycin after arteriography identified the major arterial branches of the tumor. For this study we selected six patients who underwent 18-FDG PET/CT pre- and post-TACE. The results regarding the value of tracer uptake in the lesion (SUV) before and after TACE correlated with the percentage of necrosis found in the analysis of the recipient’s liver after transplantation.
RESULTS
Six patients who underwent an 18-FDG PET/CT before and after TACE included 3 with hepatitis C virus (HCV)related cirrhosis, one of them with HCV and alcohol 2 with alcoholic cirrhosis, 1 with hepatitis B virus (HBV)-related cirrhosis. The median patient age was 64 years (range, 34 –72), with a median time on the waiting list for OLT of 113 days (range, 60 –123). All patients underwent a single TACE procedure with drug-eluting beads (adiramycin). The PET data reporting percentage of tumor necrosis after OLT are shown in Table 1. The median SUV before TACE was 4 (range, 2.79 – 6.95), with a median post-TACE SUV of 0% (range, 0 – 4). Among patients whose post-TACE SUV decreased to ⬍3, ⬎80% necrosis was observed upon study of a hepatectomy sample. DISCUSSION
HCC is now the leading cause of death among patients with liver cirrhosis. The diagnosis should be established in the early stages of the disease, while curative therapies are still possible. Programs for early detection of HCC among cirrhotic patients include alpha-fetoprotein (AFP) levels
and regular monitoring of ultrasounds. Currently the best therapeutic option for cirrhotic patients is OLT. However, the increase in patients on the waiting list has led to strategies to minimize the impact of disease progression. Currently, TACE is the most widely used method to control HCC among patients awaiting OLT. TACE initially treats and controls not only liver lesions seen on conventional imaging examinations (ultrasound, CT, and magnetic resonance imaging [MRI]), but also occult lesions that cannot be identified using conventional imaging techniques. After TACE in patients with HCC, is difficult to assess the degree of residual activity. Dynamic CT is the most reliable tool to assess the efficacy of TACE. On CT, necrotic areas appears unenhanced while viable tumors appear enhanced; nevertheless, no correlation between tumor size reduction and histopathologic necrosis rate have been described in resected specimens.9 18-FDG PET/CT is a promising diagnostic test to evaluate patients awaiting OLT who undergo TACE. When conventional examinations are normal, 18-FDG PET/CT is a valuable imaging tool for patients who show increasing AFP levels after HCC treatment. An 18-FDG PET/CT whole-body scan also provides an important, valuable imaging study to detect extrahepatic metastasis.14 Whereas normal cells contain a relative abundance of glucose-6phosphatase and lower levels of hexokinase, tumor cells tend to have increased hexokinase levels but little, if any, glucose-6-phosphatase activity.15 This difference in metabolism results in an increased accumulation of 18-FDG in tumors. It potentially allows differentiation of normal versus tumor tissue on PET scans. Despite this limitation, 18FDG PET/CT imaging remains a useful tool in the diagnosis and treatment of HCC. 18-FDG PET/CT scans in HCC patients before OLT can help transplantation physicians to detect extrahepatic metastases. In our study, one determination of 18-FDG PET/CT was not sufficient to predict the degree of tumor necrosis after TACE. However, there was a good correlation between the SUV obtained by 18-FDG PET/CT during the post-TACE period in relation to the values of SUV obtained in 18-FDG PET/CT during the pre-TACE period. So, when the value of SUV in 18-FDG PET/CT post-TACE was ⬍3, especially if the SUV pre-TACE was ⬎3, we observed a high degree (⬎80%) of tumor necrosis after OLT. Nevertheless, the
Table 1. Clinical Data, PET Results, and % Tumor Necrosis After OLT Patients
1 2 3 4 5 6
Age (y)
72 72 34 64 66 54
Cirrhosis Etiology
HCV⫹ HCV⫹ HBV⫹ Alcohol Alcohol Alcohol and HCV⫹
Waiting List (d)
No. of Nodules in TACE
PET Pre-TACE (SUV)
PET Post-TACE (SUV)
HCC Size (mm)
Necrosis After OLT (%)
77 60 110 123 113 119
1 1 3 1 1 3
2.79 4 6.95 5.8 3.95 6.65
⬍2.5 0 4 0 0 0
12 35 5/5/20 50 45 39/27/5
100 80 50 90 95 100
VALUE OF 18-FDG-PET/CT
most important limitation of this study was the limited number of patients. In conclusion, performance of an 18-FDG PET/CT before and after TACE with comparison of SUV values among patients with HCC awaiting OLT provided valuable information regarding the effectiveness of TACE. REFERENCES 1. Yao FY, Hirose R, LaBerge JM, et al: A prospective study on downstaging of hepatocellular carcinoma prior to liver transplantation. Liver Transpl 11:1505, 2005 2. Yao FY, Kerlan RK Jr, Hirose R, et al: Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: an intention-to-treat analysis. Hepatology 48:819, 2008 3. Otto G, Herber S, Heise M, et al: Response to transarterial chemoembolization as a biological selection criterion for liver transplantation in hepatocellular carcinoma. Liver Transpl 12:1260, 2006 4. Pompili M, Mirante VG, Rondinara G, et al: Percutaneous ablation procedures in cirrhotic patients with hepatocellular carcinoma submitted to liver transplantation: assessment of efficacy at explant analysis and of safety for tumour recurrence. Liver Transpl 11:1117, 2005 5. Yao FY: Liver transplantation for hepatocelular carcinoma: beyond the Milan criteria. Am J Transplant 8:1982, 2008 6. Adam R, McMaster P, O’Grady JG, et al: Evolution of liver transplantation in Europe: report of the European Liver Trans-
2215 plant Registry. European Liver Transplant Association. Liver Transpl 9:1231, 2003 7. Qiu J, Ozawa M, Terasaki PI: Liver transplantation in the United States. Clin Transpl 17:28, 2005 8. Cascales Campos PA, Romero PR, Gonzalez R, et al: Improving the waiting list by using 75-year-old donors for recipients with hepatocellular carcinoma. Transplant Proc 42:627, 2010 9. Takayasu K, Arii S, Matsuo N, et al: Comparison of CT findings with resected specimens after chemoembolization with iodized oil for hepatocellular carcinoma. AJR 175:699, 2000 10. Guan YS, Sun L, Zhou XP, et al: Hepatocellular carcinoma treated with interventional procedures: CT and MRI follow-up. World J Gastroenterol 10:3543, 2004 11. Strauss LG, Conti PS: The applications of PET in clinical oncology. J Nucl Med 32:623, 1991 12. Okazumi S, Isono K, Enomoto K, et al: Evaluation of liver tumors using fluorine-18-fluorodeoxyglucose PET: characterization of tumour and assessment of effect of treatment. J Nucl Med 33:333, 1992 13. Khan MA, Combs CS, Brunt EM, et al: Positron emission tomography scanning in the evaluation of hepatocellular carcinoma. J Hepatol 32:792, 2000 14. Chen YK, Hsieh DS, Liao CS, et al: Utility of FDG-PET for investigating unexplained serum AFP elevation in patients with suspected hepatocellular carcinoma recurrence. Anticancer Res 25:4719, 2005 15. Böhm B, Voth M, Geoghegan J, et al: Impact of positron emission tomography on strategy in liver resection for primary and secondary liver tumors. J Cancer Res Clin Oncol 130:266, 2004
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tumor and disease progression while awaiting a transplantable organ, factors that can exclude a patient from the waiting list. Therapies such as transarterial chemoembolization (TACE) are employed in patients who show a good performance status while awaiting an OLT.5– 8 Multiphasic contrast-enhanced computed tomography (CT) has become the standard imaging technique for patients with HCC. It has been considered to be the most reliable method to assess the efficacy of TACE. 18- FDG
From the Departments of Surgery (P.C.C., P.R., R.G., B.F., F.S.B., R.R., P.P.) and Hepatology (J.A.P., M.M.), Liver Transplant Unit, Virgen de la Arrixaca University Hospital, Murcia, Spain. Address reprint requests to Pedro Antonio Cascales Campos, Calle Dr Fleming N° 12 3° E, La Alberca, Murcia, Spain. E-mail: [email protected]
© 2011 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/–see front matter doi:10.1016/j.transproceed.2011.05.023
Transplantation Proceedings, 43, 2213–2215 (2011)
2213
2214
CASCALES CAMPOS, RAMIREZ, GONZALEZ ET AL
positron emission tomography (PET) is of limited use in the diagnosis of primary HCCs; its reported sensitivity in 50%–55%.9 –13 The aim of this study was to describe an initial experience with the use of 18- FDG PET/CT before and after TACE for HCC patients undergoing OLT, seeking to predict the percentage of tumor necrosis obtained with TACE procedures. PATIENTS AND METHODS From January 2007 through December 2009, 39 patients with HCC and liver cirrhosis were included in our liver transplantation program. All patients who were enrolled for OLT met the Milan criteria, namely, a single tumor ⱕ5 cm or no more than 3 nodules with the greatest not exceeding 3 cm. Before OLT TACE was used to treat HCC in 21 candidates. TACE procedures were performed with tumor embolization using drug-eluting beads containing adriamycin after arteriography identified the major arterial branches of the tumor. For this study we selected six patients who underwent 18-FDG PET/CT pre- and post-TACE. The results regarding the value of tracer uptake in the lesion (SUV) before and after TACE correlated with the percentage of necrosis found in the analysis of the recipient’s liver after transplantation.
RESULTS
Six patients who underwent an 18-FDG PET/CT before and after TACE included 3 with hepatitis C virus (HCV)related cirrhosis, one of them with HCV and alcohol 2 with alcoholic cirrhosis, 1 with hepatitis B virus (HBV)-related cirrhosis. The median patient age was 64 years (range, 34 –72), with a median time on the waiting list for OLT of 113 days (range, 60 –123). All patients underwent a single TACE procedure with drug-eluting beads (adiramycin). The PET data reporting percentage of tumor necrosis after OLT are shown in Table 1. The median SUV before TACE was 4 (range, 2.79 – 6.95), with a median post-TACE SUV of 0% (range, 0 – 4). Among patients whose post-TACE SUV decreased to ⬍3, ⬎80% necrosis was observed upon study of a hepatectomy sample. DISCUSSION
HCC is now the leading cause of death among patients with liver cirrhosis. The diagnosis should be established in the early stages of the disease, while curative therapies are still possible. Programs for early detection of HCC among cirrhotic patients include alpha-fetoprotein (AFP) levels
and regular monitoring of ultrasounds. Currently the best therapeutic option for cirrhotic patients is OLT. However, the increase in patients on the waiting list has led to strategies to minimize the impact of disease progression. Currently, TACE is the most widely used method to control HCC among patients awaiting OLT. TACE initially treats and controls not only liver lesions seen on conventional imaging examinations (ultrasound, CT, and magnetic resonance imaging [MRI]), but also occult lesions that cannot be identified using conventional imaging techniques. After TACE in patients with HCC, is difficult to assess the degree of residual activity. Dynamic CT is the most reliable tool to assess the efficacy of TACE. On CT, necrotic areas appears unenhanced while viable tumors appear enhanced; nevertheless, no correlation between tumor size reduction and histopathologic necrosis rate have been described in resected specimens.9 18-FDG PET/CT is a promising diagnostic test to evaluate patients awaiting OLT who undergo TACE. When conventional examinations are normal, 18-FDG PET/CT is a valuable imaging tool for patients who show increasing AFP levels after HCC treatment. An 18-FDG PET/CT whole-body scan also provides an important, valuable imaging study to detect extrahepatic metastasis.14 Whereas normal cells contain a relative abundance of glucose-6phosphatase and lower levels of hexokinase, tumor cells tend to have increased hexokinase levels but little, if any, glucose-6-phosphatase activity.15 This difference in metabolism results in an increased accumulation of 18-FDG in tumors. It potentially allows differentiation of normal versus tumor tissue on PET scans. Despite this limitation, 18FDG PET/CT imaging remains a useful tool in the diagnosis and treatment of HCC. 18-FDG PET/CT scans in HCC patients before OLT can help transplantation physicians to detect extrahepatic metastases. In our study, one determination of 18-FDG PET/CT was not sufficient to predict the degree of tumor necrosis after TACE. However, there was a good correlation between the SUV obtained by 18-FDG PET/CT during the post-TACE period in relation to the values of SUV obtained in 18-FDG PET/CT during the pre-TACE period. So, when the value of SUV in 18-FDG PET/CT post-TACE was ⬍3, especially if the SUV pre-TACE was ⬎3, we observed a high degree (⬎80%) of tumor necrosis after OLT. Nevertheless, the
Table 1. Clinical Data, PET Results, and % Tumor Necrosis After OLT Patients
1 2 3 4 5 6
Age (y)
72 72 34 64 66 54
Cirrhosis Etiology
HCV⫹ HCV⫹ HBV⫹ Alcohol Alcohol Alcohol and HCV⫹
Waiting List (d)
No. of Nodules in TACE
PET Pre-TACE (SUV)
PET Post-TACE (SUV)
HCC Size (mm)
Necrosis After OLT (%)
77 60 110 123 113 119
1 1 3 1 1 3
2.79 4 6.95 5.8 3.95 6.65
⬍2.5 0 4 0 0 0
12 35 5/5/20 50 45 39/27/5
100 80 50 90 95 100
VALUE OF 18-FDG-PET/CT
most important limitation of this study was the limited number of patients. In conclusion, performance of an 18-FDG PET/CT before and after TACE with comparison of SUV values among patients with HCC awaiting OLT provided valuable information regarding the effectiveness of TACE. REFERENCES 1. Yao FY, Hirose R, LaBerge JM, et al: A prospective study on downstaging of hepatocellular carcinoma prior to liver transplantation. Liver Transpl 11:1505, 2005 2. Yao FY, Kerlan RK Jr, Hirose R, et al: Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: an intention-to-treat analysis. Hepatology 48:819, 2008 3. Otto G, Herber S, Heise M, et al: Response to transarterial chemoembolization as a biological selection criterion for liver transplantation in hepatocellular carcinoma. Liver Transpl 12:1260, 2006 4. Pompili M, Mirante VG, Rondinara G, et al: Percutaneous ablation procedures in cirrhotic patients with hepatocellular carcinoma submitted to liver transplantation: assessment of efficacy at explant analysis and of safety for tumour recurrence. Liver Transpl 11:1117, 2005 5. Yao FY: Liver transplantation for hepatocelular carcinoma: beyond the Milan criteria. Am J Transplant 8:1982, 2008 6. Adam R, McMaster P, O’Grady JG, et al: Evolution of liver transplantation in Europe: report of the European Liver Trans-
2215 plant Registry. European Liver Transplant Association. Liver Transpl 9:1231, 2003 7. Qiu J, Ozawa M, Terasaki PI: Liver transplantation in the United States. Clin Transpl 17:28, 2005 8. Cascales Campos PA, Romero PR, Gonzalez R, et al: Improving the waiting list by using 75-year-old donors for recipients with hepatocellular carcinoma. Transplant Proc 42:627, 2010 9. Takayasu K, Arii S, Matsuo N, et al: Comparison of CT findings with resected specimens after chemoembolization with iodized oil for hepatocellular carcinoma. AJR 175:699, 2000 10. Guan YS, Sun L, Zhou XP, et al: Hepatocellular carcinoma treated with interventional procedures: CT and MRI follow-up. World J Gastroenterol 10:3543, 2004 11. Strauss LG, Conti PS: The applications of PET in clinical oncology. J Nucl Med 32:623, 1991 12. Okazumi S, Isono K, Enomoto K, et al: Evaluation of liver tumors using fluorine-18-fluorodeoxyglucose PET: characterization of tumour and assessment of effect of treatment. J Nucl Med 33:333, 1992 13. Khan MA, Combs CS, Brunt EM, et al: Positron emission tomography scanning in the evaluation of hepatocellular carcinoma. J Hepatol 32:792, 2000 14. Chen YK, Hsieh DS, Liao CS, et al: Utility of FDG-PET for investigating unexplained serum AFP elevation in patients with suspected hepatocellular carcinoma recurrence. Anticancer Res 25:4719, 2005 15. Böhm B, Voth M, Geoghegan J, et al: Impact of positron emission tomography on strategy in liver resection for primary and secondary liver tumors. J Cancer Res Clin Oncol 130:266, 2004