- Email: [email protected]
Long-Term Outcome of Liver Transplantation as Treatment Modality in Patients With Hepatocellular Carcinoma in Cirrhosis: A Single-Center Experience
Long-Term Outcome of Liver Transplantation as Treatment Modality in Patients With Hepatocellular Carcinoma in Cirrhosis: A Single-Center Experience V. Müller, T. Förtsch, M. Gündel, R.S. Croner, M. Langheinrich, S. Yedibela, C. Lohmüller, M. Küffner, W. Hohenberger, and A. Perrakis ABSTRACT Background. Hepatocellular carcinoma (HCC) is among the most frequent malignant diseases worldwide. In the vast majority of cases, it is associated with liver cirrhosis. Liver transplantation (OLT) is potentially the gold standard treatment for patients suffering HCC in cirrhosis, because of synchronous eradication of HCC and of the underlying hepatic disease. The aim of this study was to evaluate long-term outcomes of OLT in HCC patients. Material and Methods. Between January 2000 and December 2011, 43 patients who were diagnosed with HCC in liver cirrhosis and underwent OLT in our department, were identified from a prospective database. All patients received their grafts from deceased donors. We analyzed demographic data, laboratory values, number and size of lesions, primary liver disease, diagnostic methods, bridging therapy modalities, and postoperative outcomes, including complications, recurrences, and their treatment. Results. Patient follow-up as of January 2012 or to death ranged from 0 to 138 months (median, 59; mean, 63). None of the patients were lost to follow-up. The gender bias was 85%:15% (male:female) and the median age, 57.8 years (range, 44 – 69). The most common underlying diseases for cirrhosis and HCC were alcoholic (n ⫽ 12) and hepatitis C (n ⫽ 16). Thirty-one subjects underwent bridging therapy through transarterial chemoembolization (TACE), and/or radiofrequency ablation. All patients underwent OLT within the Milan criteria according to the preoperative evaluation and histopathologic examination of the explanted liver. Twenty-one of them suffered postoperative complications (48.8%). HCC recurrence, which occurred in 5 (10.4%), was treated by surgery (n ⫽ 3), systemic chemotherapy with sorafenib (n ⫽ 1), or TACE (n ⫽ 1). Conclusions. OLT for HCC in cirrhosis, displays a relatively high complication rate. It shows good survivals with and low recurrence. PIDEMIOLOGIC DATA from the United States, Asia, and Europe have shown that hepatocellular carcinoma (HCC) has displayed increasing incidence and mortality rates over recent years. Furthermore, HCC is the leading cause of mortality among patients with liver cirrhosis. There is a widely accepted association of the disease with hepatitis B and C viruses.1–10 Liver transplantation (OLT) has become widely accepted as the optimal treatment for patients with chronic liver disease and HCC within the Milan criteria, because this approach can eliminate the tumor and cure the underlying liver disease.1 After introduction of these eligibility criteria, patient survival has substantially improved in recent years1–5 to
E
70% with ⬍10% recurrences.2,3,11–15 However, the shortage of liver grafts and the relatively high HCC recurrence rate greatly limit the application of OLT. In addition, the 20%–30% of dropout rate from waiting lists is due in large
From the Department of Surgery (V.M., T.F., M.G., R.S.C., M.L., S.Y., C.L., W.H., A.P.) and the Institute of Radiology (M.K.), University of Erlangen-Nuremberg, Erlangen, Germany. V.M. and T.F. contributed equally to this work. Address reprint requests to Aristotelis Perrakis, MD, Department of Surgery, University of Erlangen-Nuremberg Krankenhausstr.12, D-91054 Erlangen, Germany. E-mail: aristotelis. [email protected]
© 2013 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/–see front matter http://dx.doi.org/10.1016/j.transproceed.2013.01.035
Transplantation Proceedings, 45, 1957–1960 (2013)
1957
MU¨LLER, FÖRTSCH, GU¨NDEL ET AL
1958
part to tumor progression during the extended period awaiting OLT.7 Therefore, there is a need to control the disease during the waiting period. This problem has been addressed with several locoregional modalities: Radiofrequency ablation (RFA), transarterial chemoembolization (TACE), or liver resection in stable patients,16 with early cirrhosis free of its complications or of impaired liver function.3,14 –20 The largest experience is with TACE and RFA.3,14,18 –20 Two prospective studies have shown survival after liver transplantation to be similar when patients with large tumor burdens are successfully treated by downstaging versus subjects who initially met the criteria for transplantation.3,14 As far as the diagnostic methods are concerned, recent reports suggest that either dynamic triple phase computed tomography (CT) or magnetic resonance imaging (MRI), including unenhanced, arterial, portal venous, and delayed phases, provide improved sensitivity and specificity compared with standard techniques of the past.2–21 Contrastenhanced ultrasonography seems also to have an important value in the diagnostic algorithm for HCC. Pathologic features in the explanted liver that have prognostic value for staging HCC include tumor size and number of nodules, satellite lesions, vascular invasion (macroscopic or microscopic), and lymph node metastases.1– 6,13–15,21–25 The aim of this study was to evaluate the long-term outcomes of OLT among HCC patients, including postoperative outcomes, survival, recurrence rates, evaluation of bridging therapy before OLT, and treatment modalities for recurrences.
PATIENTS AND METHODS We identified 43 patients diagnosed with HCC in liver cirrhosis who underwent OLT in our department between January 2000 and December 2011 using a prospective database. All patients received their grafts from deceased donors. All subjects were initially treated with tacrolimus starting 36 hours after transplantation (0.1 mg/kg twice daily) and methylprednisolone (500 mg) in the anhepatic phase. In addition, basiliximab (Simulect, 20 mg) was infused during the anhepatic phase followed by a second administration (20 mg) at 4 days thereafter. Mycophenolate mofetil (500 mg twice daily, intravenous or orally) was administered starting on postoperative day 5. An acute rejection episode was diagnosed based on histopathologic examination after liver biopsy according to BANFF criteria. All recipients received broad-spectrum antimicrobial prophylaxis, consisting of antibacterial, antiviral, and antimycotic agents, using piperacillin–tazobactam for 7 days, as well as acyclovir and anidulafungin/posaconazole. Selective digestive decontamination consisted of oral amphotericin B (200 mg) 3 times daily until postoperative day 21. Furthermore, high-risk recipients of a cytomegalovirus-positive donor grafts received pre-emptive antiviral treatment with gancyclovir/valgancyclovir adjusted to renal function for a 6-week course. We analyzed demographic data, number and size of the lesions, primary liver disease, diagnostic methods, bridging therapy, and postoperative outcomes, including complications, recurrence rates, and treatments of recurrence.
Statistical Analysis The statistical analysis was performed using (SPSS for Windows version 20.0 (SPSS Inc., Chicago, Ill) and Excel 2007 (Microsoft, Redmond, Wash) for Student’s t-test. P ⱕ .05 was considered significant.
RESULTS
Patient follow-up as of January 2012 or to time of death ranged from 0 to 138 months (median, 59; mean, 63). No patient was lost to follow-up. The gender bias was 85%:15% (male:female), the median age was 57.8 years (range, 44 – 69). The most common underlying diseases for cirrhosis and HCC were alcoholic (n ⫽ 12) and hepatitis C (n ⫽ 16). The Child-Turcotte-Pugh classification showed A (n ⫽ 16), B (n ⫽ 15), and C (n ⫽ 12). Thirty-one patients underwent bridging therapy through TACE and/or RFA. Nineteen patients underwent only TACE, 5 only RFA, and 7 TACE and RFA. Four stable patients with CHILD A cirrhosis had undergone liver resection owing to HCC before OLT. Eleven patients had a unifocal and 33, multifocal HCC. All patients underwent OLT within the Milan criteria according to the preoperative evaluation and histopathologic examination of the explanted liver. All patients underwent diagnostic examinations using spiral triple phase CT and MRI of the liver. Furthermore, 20 underwent contrast-enhanced ultrasonography as a further diagnostic tool to detect HCC or as follow-up after bridging therapy. Twenty-one patients suffered postoperative complications (48.8%). Their Dindo-Clavien classes (26) were grade I (n ⫽ 6), grade II (n ⫽ 9), grade III (n ⫽ 3), and grade IV (n ⫽ 3). Five patients underwent retransplantation because of primary non-function. All patients underwent systematic follow up after OLT consisting of an ultrasound examination of the abdomen (AUS) and/or MRI (every 6 months for the first 36 months after OLT) and monitoring of alpha fetoprotein (AFP). The immunsuppressive regimen included tacrolimus (n ⫽ 33), cyclosporine (n ⫽ 7) or sirolimus (n ⫽ 2). After HCC recurrence, the patients (n ⫽ 5) were switched to mammalian target of rapamycin (mTOR) inhibitors sirolimus (n ⫽ 4) or everolimus (n ⫽ 1). Recurrence of HCC occurred in 5 patients (10.4%): Three were extrahepatic and 2 an intrahepatic HCC recurrence. The median time of recurrence was 20 months (range, 3– 40) Treatment modalities were surgery (n ⫽ 3), systemic chemotherapy with sorafenib (n ⫽ 1), or TACE (n ⫽ 1). Overall, the 1 year survival rate among recurrencefree patients was 70.4% (Fig 1). DISCUSSION
The incidence and the mortality rates of HCC have increased over the last 15 years.2,4 –12 Viral and nonviral factors, such as diabetes mellitus type II and nutritive toxic parameters, play important etiologic roles. Hepatitis B and C induced liver cirrhosis are the most common parameters for the development of HCC.2–12 The option of OLT has
LONG-TERM OUTCOMES WITH HCC IN CIRRHOSIS
Fig 1. Survival rates in HCC patients after OLT without recurrence.
become the main therapy for early-stage HCC in cirrhosis, offering in most cases a definite cure with good survival and recurrence-free rates.1–5,8 –10,14,15 The main concern after liver transplantation for HCC is the (8%–20%) risk of tumor recurrence.3,15,21 It is usually observed within the first 2 years after liver transplantation and is associated with a median survival of about 1 year from the time of diagnosis.3,15,21 We registered a 10.4% disease recurrence, most of which had an extrahepatic manifestation. The adoption of routine imaging and AFP monitoring has led to the early detection of recurrence, with the possibility of cure by ablation or surgical intervention.3,13,15,21 However, there are no standard guidelines for follow-up. A limitation of the use of extensive imaging examinations (CT or MRI) is their high cost to detect HCC recurrence. Most high-volume centers have limited their application to every 6 –12 months for the first 3–5 years after liver transplantation or to the presence of abnormal AFP concentrations. We performed an extensive follow-up through AUS and/or MRI every 6 months in the first 3 years after OLT with monitoring of AFP. Furthermore, there is a debate whether mTOR inhibitors have significant value for immunosuppression in HCC patients after liver transplantation.22,23 Immunsuppressive regimens based on mTOR show antiproliferative properties in experimental models. These immunsuppressive regimens, offer both prophylaxis against acute or chronic rejection and tumor recurrence.3,22,23 However, this hypothesis has not been confirmed in large, randomized, controlled trials (RCT). Furthermore no RCTs have shown that lowering immunosuppression reduces the risk of HCC recurrence after liver transplantation. Our
1959
series did not show such a phenomenon despite a calcineurin inhibitor-based immunsuppressive regimen; we switched only 2 patients to an mTOR at 6 months after OLT. Furthermore, we switched immunsuppression to mTOR for all patients suffering an HCC recurrence. In case of a recurrence we successfully used locoregional therapy, including liver resection, RFA, or TACE, for limited disease.15,21 Sorafenib has been used with limited side effects, sometimes in conjunction with mTOR inhibitors. It may be considered when systemic as opposed to locoregional treatment is warranted.24 It is recommended that HCC recurrence after liver transplantation to be treated by surgery for resectable intrahepatic or extrahepatic manifestations or by locoregional therapy and systemic therapy with chemotherapeutic agents such as sorafenib for unresectable or multiple lesions in the liver or in presence of systemic disease with multiple metastatic lesions.3,24 A liver retransplantation in cases of HCC recurrence is not recommended. Among our series, HCC recurrence was diagnosed at a median of 20 months; treatment was multimodal: surgery, chemotherapy with sorafenib or TACE. Two patients with limited tumor recurrences, who underwent surgery, remained free of disease upon follow-up. In conclusion, we have shown that long-term survival after HCC is possible with low HCC recurrence rates. An important role of have bridging therapeutical modalities (RFA, TACE) in the pre-OLT phase for downstaging offers the possibility of stable disease in the waiting time. Systematic follow-up after OLT through imaging (AUS, MRI) and AFP monitoring is of great importance. Whether mTOR offers relevant advantages for HCC-free survival and overall survival after OLT is still an open matter.
REFERENCES 1. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334:693– 699. 2. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology. 2001;33:1394 –1403. 3. Clavien PA, Lesurtel M, Bossuyt PM, et al; for OLT for HCC Consensus Group. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol. 2012;13:e11– e22. 4. Sangiovanni A, Del Ninno E, Fasani P, et al. Increased survival of cirrhotic patients with a hepatocellular carcinoma detected during surveillance. Gastroenterology. 2004;126: 1005–1014. 5. Deuffic S, Poynard T, Buffat L, et al. Trends in primary liver cancer. Lancet. 1998;351:214 –215. 6. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med. 1999;340:745–750. 7. Nagai H, Matsui T, Kanayama M, et al. Multimodal therapy for liver cirrhosis patients with advanced hepatocellular carcinoma. Cancer Chemother Pharmacol. 2011;68:139 –145. 8. Kudo M, Chung H, Osaki Y. Prognostic staging system for hepatocellular carcinoma (CLIP score): its value and limitations, and a proposal for a new staging system, the Japan Integrated Staging Score (JIS score). J Gastroenterol. 2003;38:207–215.
1960 9. Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis. 1999; 19:329 –338. 10. A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators. Hepatology. 1998;28:751–755. 11. Bilimoria MM, Lauwers GY, Doherty DA, et al. Underlying liver disease, not tumor factors, predicts long-term survival after resection of hepatocellular carcinoma. Arch Surg. 2001;136: 528 –535. 12. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208 –1236. 13. Vibert E, Azoulay D, Hoti E, et al. Progression of alphafetoprotein before liver transplantation for hepatocellular carcinoma in cirrhotic patients: a critical factor. Am J Transplant. 2010;10:129 –137. 14. Ravaioli M, Grazi GL, Piscaglia F, et al. Liver transplantation for hepatocellular carcinoma: results of down-staging in patients initially outside the Milan selection criteria. Am J Transplant. 2008;8:2547–2557. 15. Parfitt JR, Marotta P, Alghamdi M, et al. Recurrent hepatocellular carcinoma after transplantation: use of a pathological score on explanted livers to predict recurrence. Liver Transpl. 2007;13:543–551. 16. Lang H, Sotiropoulos GC, Domland M, et al. Liver resection for hepatocellular carcinoma in noncirrhotic liver without underlying viral hepatitis. Br J Surg. 2005;92:198 –202. 17. Mergental H, Porte RJ. Liver transplantation for unresectable hepatocellular carcinoma in patients without liver cirrhosis. Transpl Int. 2010;23:662– 667. 18. Lesurtel M, Mullhaupt B, Pestalozzi BC, et al. Transarterial chemoembolization as a bridge to liver transplantation for hepa-
MU¨LLER, FÖRTSCH, GU¨NDEL ET AL tocellular carcinoma: an evidence-based analysis. Am J Transplant. 2006;6:2644 –2650. 19. Yao FY, Kerlan RK, Hirose R, et al. Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: an intention-to-treat analysis. Hepatology. 2008;48: 819 – 827. 20. Martin AP, Goldstein RM, Dempster J, et al. Radiofrequency thermal ablation of hepatocellular carcinoma before liver transplantation-a clinical and histological examination. Clin Transplant. 2006;20:695–705. 21. Zimmerman MA, Ghobrial RM, Tong MJ, et al. Recurrence of hepatocellular carcinoma following liver transplantation: a review of preoperative and postoperative prognostic indicators. Arch Surg. 2008;143:182–188. 22. Soll C, Clavien PA. Inhibition of mammalian target of rapamycin: two goals with one shot? J Hepatol. 2011;54:182–183. 23. Toso C, Merani S, Bigam DL, et al. Sirolimus-based immunosuppression is associated with increased survival after liver transplantation for hepatocellular carcinoma. Hepatology. 2010;51: 1237–1243. 24. Soderdahl G, Backman L, Isoniemi H, et al. A prospective, randomized, multi-centre trial of systemic adjuvant chemotherapy versus no additional treatment in liver transplantation for hepatocellular carcinoma. Transpl Int. 2006;19:288 –294. 25. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359: 378 –390. 26. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240:205–213.
E
70% with ⬍10% recurrences.2,3,11–15 However, the shortage of liver grafts and the relatively high HCC recurrence rate greatly limit the application of OLT. In addition, the 20%–30% of dropout rate from waiting lists is due in large
From the Department of Surgery (V.M., T.F., M.G., R.S.C., M.L., S.Y., C.L., W.H., A.P.) and the Institute of Radiology (M.K.), University of Erlangen-Nuremberg, Erlangen, Germany. V.M. and T.F. contributed equally to this work. Address reprint requests to Aristotelis Perrakis, MD, Department of Surgery, University of Erlangen-Nuremberg Krankenhausstr.12, D-91054 Erlangen, Germany. E-mail: aristotelis. [email protected]
© 2013 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/–see front matter http://dx.doi.org/10.1016/j.transproceed.2013.01.035
Transplantation Proceedings, 45, 1957–1960 (2013)
1957
MU¨LLER, FÖRTSCH, GU¨NDEL ET AL
1958
part to tumor progression during the extended period awaiting OLT.7 Therefore, there is a need to control the disease during the waiting period. This problem has been addressed with several locoregional modalities: Radiofrequency ablation (RFA), transarterial chemoembolization (TACE), or liver resection in stable patients,16 with early cirrhosis free of its complications or of impaired liver function.3,14 –20 The largest experience is with TACE and RFA.3,14,18 –20 Two prospective studies have shown survival after liver transplantation to be similar when patients with large tumor burdens are successfully treated by downstaging versus subjects who initially met the criteria for transplantation.3,14 As far as the diagnostic methods are concerned, recent reports suggest that either dynamic triple phase computed tomography (CT) or magnetic resonance imaging (MRI), including unenhanced, arterial, portal venous, and delayed phases, provide improved sensitivity and specificity compared with standard techniques of the past.2–21 Contrastenhanced ultrasonography seems also to have an important value in the diagnostic algorithm for HCC. Pathologic features in the explanted liver that have prognostic value for staging HCC include tumor size and number of nodules, satellite lesions, vascular invasion (macroscopic or microscopic), and lymph node metastases.1– 6,13–15,21–25 The aim of this study was to evaluate the long-term outcomes of OLT among HCC patients, including postoperative outcomes, survival, recurrence rates, evaluation of bridging therapy before OLT, and treatment modalities for recurrences.
PATIENTS AND METHODS We identified 43 patients diagnosed with HCC in liver cirrhosis who underwent OLT in our department between January 2000 and December 2011 using a prospective database. All patients received their grafts from deceased donors. All subjects were initially treated with tacrolimus starting 36 hours after transplantation (0.1 mg/kg twice daily) and methylprednisolone (500 mg) in the anhepatic phase. In addition, basiliximab (Simulect, 20 mg) was infused during the anhepatic phase followed by a second administration (20 mg) at 4 days thereafter. Mycophenolate mofetil (500 mg twice daily, intravenous or orally) was administered starting on postoperative day 5. An acute rejection episode was diagnosed based on histopathologic examination after liver biopsy according to BANFF criteria. All recipients received broad-spectrum antimicrobial prophylaxis, consisting of antibacterial, antiviral, and antimycotic agents, using piperacillin–tazobactam for 7 days, as well as acyclovir and anidulafungin/posaconazole. Selective digestive decontamination consisted of oral amphotericin B (200 mg) 3 times daily until postoperative day 21. Furthermore, high-risk recipients of a cytomegalovirus-positive donor grafts received pre-emptive antiviral treatment with gancyclovir/valgancyclovir adjusted to renal function for a 6-week course. We analyzed demographic data, number and size of the lesions, primary liver disease, diagnostic methods, bridging therapy, and postoperative outcomes, including complications, recurrence rates, and treatments of recurrence.
Statistical Analysis The statistical analysis was performed using (SPSS for Windows version 20.0 (SPSS Inc., Chicago, Ill) and Excel 2007 (Microsoft, Redmond, Wash) for Student’s t-test. P ⱕ .05 was considered significant.
RESULTS
Patient follow-up as of January 2012 or to time of death ranged from 0 to 138 months (median, 59; mean, 63). No patient was lost to follow-up. The gender bias was 85%:15% (male:female), the median age was 57.8 years (range, 44 – 69). The most common underlying diseases for cirrhosis and HCC were alcoholic (n ⫽ 12) and hepatitis C (n ⫽ 16). The Child-Turcotte-Pugh classification showed A (n ⫽ 16), B (n ⫽ 15), and C (n ⫽ 12). Thirty-one patients underwent bridging therapy through TACE and/or RFA. Nineteen patients underwent only TACE, 5 only RFA, and 7 TACE and RFA. Four stable patients with CHILD A cirrhosis had undergone liver resection owing to HCC before OLT. Eleven patients had a unifocal and 33, multifocal HCC. All patients underwent OLT within the Milan criteria according to the preoperative evaluation and histopathologic examination of the explanted liver. All patients underwent diagnostic examinations using spiral triple phase CT and MRI of the liver. Furthermore, 20 underwent contrast-enhanced ultrasonography as a further diagnostic tool to detect HCC or as follow-up after bridging therapy. Twenty-one patients suffered postoperative complications (48.8%). Their Dindo-Clavien classes (26) were grade I (n ⫽ 6), grade II (n ⫽ 9), grade III (n ⫽ 3), and grade IV (n ⫽ 3). Five patients underwent retransplantation because of primary non-function. All patients underwent systematic follow up after OLT consisting of an ultrasound examination of the abdomen (AUS) and/or MRI (every 6 months for the first 36 months after OLT) and monitoring of alpha fetoprotein (AFP). The immunsuppressive regimen included tacrolimus (n ⫽ 33), cyclosporine (n ⫽ 7) or sirolimus (n ⫽ 2). After HCC recurrence, the patients (n ⫽ 5) were switched to mammalian target of rapamycin (mTOR) inhibitors sirolimus (n ⫽ 4) or everolimus (n ⫽ 1). Recurrence of HCC occurred in 5 patients (10.4%): Three were extrahepatic and 2 an intrahepatic HCC recurrence. The median time of recurrence was 20 months (range, 3– 40) Treatment modalities were surgery (n ⫽ 3), systemic chemotherapy with sorafenib (n ⫽ 1), or TACE (n ⫽ 1). Overall, the 1 year survival rate among recurrencefree patients was 70.4% (Fig 1). DISCUSSION
The incidence and the mortality rates of HCC have increased over the last 15 years.2,4 –12 Viral and nonviral factors, such as diabetes mellitus type II and nutritive toxic parameters, play important etiologic roles. Hepatitis B and C induced liver cirrhosis are the most common parameters for the development of HCC.2–12 The option of OLT has
LONG-TERM OUTCOMES WITH HCC IN CIRRHOSIS
Fig 1. Survival rates in HCC patients after OLT without recurrence.
become the main therapy for early-stage HCC in cirrhosis, offering in most cases a definite cure with good survival and recurrence-free rates.1–5,8 –10,14,15 The main concern after liver transplantation for HCC is the (8%–20%) risk of tumor recurrence.3,15,21 It is usually observed within the first 2 years after liver transplantation and is associated with a median survival of about 1 year from the time of diagnosis.3,15,21 We registered a 10.4% disease recurrence, most of which had an extrahepatic manifestation. The adoption of routine imaging and AFP monitoring has led to the early detection of recurrence, with the possibility of cure by ablation or surgical intervention.3,13,15,21 However, there are no standard guidelines for follow-up. A limitation of the use of extensive imaging examinations (CT or MRI) is their high cost to detect HCC recurrence. Most high-volume centers have limited their application to every 6 –12 months for the first 3–5 years after liver transplantation or to the presence of abnormal AFP concentrations. We performed an extensive follow-up through AUS and/or MRI every 6 months in the first 3 years after OLT with monitoring of AFP. Furthermore, there is a debate whether mTOR inhibitors have significant value for immunosuppression in HCC patients after liver transplantation.22,23 Immunsuppressive regimens based on mTOR show antiproliferative properties in experimental models. These immunsuppressive regimens, offer both prophylaxis against acute or chronic rejection and tumor recurrence.3,22,23 However, this hypothesis has not been confirmed in large, randomized, controlled trials (RCT). Furthermore no RCTs have shown that lowering immunosuppression reduces the risk of HCC recurrence after liver transplantation. Our
1959
series did not show such a phenomenon despite a calcineurin inhibitor-based immunsuppressive regimen; we switched only 2 patients to an mTOR at 6 months after OLT. Furthermore, we switched immunsuppression to mTOR for all patients suffering an HCC recurrence. In case of a recurrence we successfully used locoregional therapy, including liver resection, RFA, or TACE, for limited disease.15,21 Sorafenib has been used with limited side effects, sometimes in conjunction with mTOR inhibitors. It may be considered when systemic as opposed to locoregional treatment is warranted.24 It is recommended that HCC recurrence after liver transplantation to be treated by surgery for resectable intrahepatic or extrahepatic manifestations or by locoregional therapy and systemic therapy with chemotherapeutic agents such as sorafenib for unresectable or multiple lesions in the liver or in presence of systemic disease with multiple metastatic lesions.3,24 A liver retransplantation in cases of HCC recurrence is not recommended. Among our series, HCC recurrence was diagnosed at a median of 20 months; treatment was multimodal: surgery, chemotherapy with sorafenib or TACE. Two patients with limited tumor recurrences, who underwent surgery, remained free of disease upon follow-up. In conclusion, we have shown that long-term survival after HCC is possible with low HCC recurrence rates. An important role of have bridging therapeutical modalities (RFA, TACE) in the pre-OLT phase for downstaging offers the possibility of stable disease in the waiting time. Systematic follow-up after OLT through imaging (AUS, MRI) and AFP monitoring is of great importance. Whether mTOR offers relevant advantages for HCC-free survival and overall survival after OLT is still an open matter.
REFERENCES 1. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334:693– 699. 2. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology. 2001;33:1394 –1403. 3. Clavien PA, Lesurtel M, Bossuyt PM, et al; for OLT for HCC Consensus Group. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol. 2012;13:e11– e22. 4. Sangiovanni A, Del Ninno E, Fasani P, et al. Increased survival of cirrhotic patients with a hepatocellular carcinoma detected during surveillance. Gastroenterology. 2004;126: 1005–1014. 5. Deuffic S, Poynard T, Buffat L, et al. Trends in primary liver cancer. Lancet. 1998;351:214 –215. 6. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med. 1999;340:745–750. 7. Nagai H, Matsui T, Kanayama M, et al. Multimodal therapy for liver cirrhosis patients with advanced hepatocellular carcinoma. Cancer Chemother Pharmacol. 2011;68:139 –145. 8. Kudo M, Chung H, Osaki Y. Prognostic staging system for hepatocellular carcinoma (CLIP score): its value and limitations, and a proposal for a new staging system, the Japan Integrated Staging Score (JIS score). J Gastroenterol. 2003;38:207–215.
1960 9. Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis. 1999; 19:329 –338. 10. A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators. Hepatology. 1998;28:751–755. 11. Bilimoria MM, Lauwers GY, Doherty DA, et al. Underlying liver disease, not tumor factors, predicts long-term survival after resection of hepatocellular carcinoma. Arch Surg. 2001;136: 528 –535. 12. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208 –1236. 13. Vibert E, Azoulay D, Hoti E, et al. Progression of alphafetoprotein before liver transplantation for hepatocellular carcinoma in cirrhotic patients: a critical factor. Am J Transplant. 2010;10:129 –137. 14. Ravaioli M, Grazi GL, Piscaglia F, et al. Liver transplantation for hepatocellular carcinoma: results of down-staging in patients initially outside the Milan selection criteria. Am J Transplant. 2008;8:2547–2557. 15. Parfitt JR, Marotta P, Alghamdi M, et al. Recurrent hepatocellular carcinoma after transplantation: use of a pathological score on explanted livers to predict recurrence. Liver Transpl. 2007;13:543–551. 16. Lang H, Sotiropoulos GC, Domland M, et al. Liver resection for hepatocellular carcinoma in noncirrhotic liver without underlying viral hepatitis. Br J Surg. 2005;92:198 –202. 17. Mergental H, Porte RJ. Liver transplantation for unresectable hepatocellular carcinoma in patients without liver cirrhosis. Transpl Int. 2010;23:662– 667. 18. Lesurtel M, Mullhaupt B, Pestalozzi BC, et al. Transarterial chemoembolization as a bridge to liver transplantation for hepa-
MU¨LLER, FÖRTSCH, GU¨NDEL ET AL tocellular carcinoma: an evidence-based analysis. Am J Transplant. 2006;6:2644 –2650. 19. Yao FY, Kerlan RK, Hirose R, et al. Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: an intention-to-treat analysis. Hepatology. 2008;48: 819 – 827. 20. Martin AP, Goldstein RM, Dempster J, et al. Radiofrequency thermal ablation of hepatocellular carcinoma before liver transplantation-a clinical and histological examination. Clin Transplant. 2006;20:695–705. 21. Zimmerman MA, Ghobrial RM, Tong MJ, et al. Recurrence of hepatocellular carcinoma following liver transplantation: a review of preoperative and postoperative prognostic indicators. Arch Surg. 2008;143:182–188. 22. Soll C, Clavien PA. Inhibition of mammalian target of rapamycin: two goals with one shot? J Hepatol. 2011;54:182–183. 23. Toso C, Merani S, Bigam DL, et al. Sirolimus-based immunosuppression is associated with increased survival after liver transplantation for hepatocellular carcinoma. Hepatology. 2010;51: 1237–1243. 24. Soderdahl G, Backman L, Isoniemi H, et al. A prospective, randomized, multi-centre trial of systemic adjuvant chemotherapy versus no additional treatment in liver transplantation for hepatocellular carcinoma. Transpl Int. 2006;19:288 –294. 25. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359: 378 –390. 26. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240:205–213.