- Email: [email protected]
Outcome After Liver Transplantation in Patients With Cirrhosis and Hepatocellular Carcinoma
Outcome After Liver Transplantation in Patients With Cirrhosis and Hepatocellular Carcinoma M. Rossi, M. Merli, Q. Lai, F. Gentili, G. Mennini, A. Bussotti, F. Pugliese, F. Della Pietra, L. Poli, G. Novelli, M. Giusto, S. Ginanni Corradini, M. Iappelli, A. Onetti Muda, U. Di Tondo, F. Gossetti, A.F. Attili, and P.B. Berloco ABSTRACT Hepatocellular carcinoma (HCC) is considered an optimal indication for liver transplantation (LT) because it may eliminate both the tumor and the underlying liver disease. The present study sought to compare cumulative survival, rate of HCC recurrence, and causes of death among patients with cirrhosis and HCC before and after the adoption of more restrictive criteria (Milan selection criteria) at the time of patient listing. Among 226 adult patients who received an elective liver transplantation between 1999 and 2005, 58 (27%) had a diagnosis of HCC at the time. The 38 patients who underwent transplantation for HCC in the period 1989 to 1998 were considered the “historical group.” After LT (mean follow-up, 34 ⫹ 28 months), the cumulative survival rate was better among HCC versus non-HCC recipients (93% vs 71% at 1 year and 81% vs 67% at 3 years, respectively; P ⬍ .046), although the difference tended to attenuate after 5 years (66% vs 67%, respectively). Tumor recurrence (evaluated in patients surviving at least 3 months after LT) was observed in 10/31 in the historical group versus 4/53 among those who underwent transplantation after 1999. Among the causes of death, recurrence represented 50% in the old series and 23% in patients who underwent transplantation after 1999. Cumulative survival significantly improved among HCC patients who underwent transplantation after 1999 (93% vs 66% at 1 year and 81% vs 50% at 3 years; P ⬍ .00001). The 58 patients who underwent transplantation with a diagnosis of cirrhosis and concomitant HCC after 1999 showed even better survival than patients who underwent transplantation for end-stage liver disease without malignancy.
H
EPATOCELLULAR carcinoma (HCC) is considered an optimal indication for liver transplantation (LT) because it may eliminate both the tumor and the underlying liver disease.1,2 Initial results showed that the outcomes of patients with advanced HCC were frequently compromised by rapid tumor recurrences. As a consequence, more restrictive selection criteria have been proposed. According to the Milan criteria,3 patients with a solitary tumor ⱕ5 cm or 3 or fewer lesions, none ⬎3 cm, in the absence of macroscopic vascular invasion and extrahepatic spreading, are the most appropriate candidates for LT. These criteria are based on pretransplantation evaluation of tumor dimension; however, due to inaccuracy of imaging techniques, a variable degree of understaging has been reported.4 The present study sought to compare cumulative survivals, rates of HCC recurrence, and causes of death among patients with cirrhosis and HCC before and
after the adoption of the more restrictive list criteria (Milan selection criteria). PATIENTS AND METHODS After 1999, we adopted the Milan criteria for the eligibility for LT of patients with cirrhosis and HCC.4 According to our allocation policy, no specific priority was attributed to patients with a diagFrom the II Gastroenterologia (M.M., F.G., M.G., S.G.C., A.F.A.), Divisione di Chirurgia Generale Trapianti d’Organo (M.R., Q.L., G.M., A.B., F.D.P., L.P., G.N., M.I., F.G., P.B.B.), Dipartimento di Anestesia e Rianimazione (F.P.), and Dipartimento di Anatomia Patologica (A.O.M., U.D.T.), Università “La Sapienza,” Rome, Italy. Address reprint requests to M. Rossi, Transplant Department, II Clinica Chirurgica, Policlinico Umberto I, Viale del Policlinico 155, Rome 00161, Italy. E-mail: [email protected]
© 2007 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/07/$–see front matter doi:10.1016/j.transproceed.2007.05.083
Transplantation Proceedings, 39, 1895–1897 (2007)
1895
1896 nosis of HCC. Between 1999 and 2005, 226 adult patients received an elective LT, including 58 (27%) with a diagnosis of HCC at the time of transplantation. Thirty-eight patients who underwent transplantation for HCC in the period 1989 to 1998 were considered the “historical group.” Preoperative tumor diagnosis was based on histological findings when biopsy was available or imaging studies. Extrahepatic involvement and macrovascular invasion were always excluded. Ultrasonography, computed tomography (CT), and/or magnetic resonance imaging were used to define tumor dimension and number before LT. We calculated the total tumor diameter for patients with multiple lesions as the sum of the maximal diameter of each nodule. The explanted liver was always examined. During followup, tumor recurrence was monitored with standard surveillance based on periodic liver ultrasonography, ␣-fetoprotein determination, and total body CT. The results are expressed as mean values ⫾ SD. The differences between the groups were analysed using Student t test or the 2 test. The Kaplan-Meier method with log-rank analysis was used to calculate survival probabilities among various groups of patients.
RESULTS Comparison Between Patients Who Underwent Transplantation With or Without HCC After the Introduction of Milan Criteria
Patients with a diagnosis of HCC were more often males (81% vs 68%; P ⬍ .04), of older mean age (56 ⫾ 7 vs 50 ⫾ 11; P ⬍ .0001), Child Pugh Class A (22% vs 2%; P ⬍ .001), but not a significantly different MELD score. Mean donor age was similar (P ⫽ .17) in patients with versus without tumor diagnosis before LT. After LT (mean follow-up, 34 ⫾ 28 months), cumulative survival was better among HCC versus non-HCC recipients (93% vs 71% at 1 year and 81% vs 67% at 3 years, respectively; P ⬍ .046), although the difference tended to attenuate after 5 years (66% vs 67%, respectively). Comparison Between Patients Who Underwent Transplantation With HCC Before and After the Introduction of Milan Criteria
Patients who underwent transplantation with HCC before 1999 were similar for age (53 ⫾ 9 years) and prevalence of Child Pugh Class A (33%). The lesion was multifocal in 60% and the mean cumulative tumor diameter was ⬎8 cm in 26/38 patients (88%). Due to the lack of selective criteria for the admission to LT, HCC was outside the Milan criteria in 59% of patients. Among patients who underwent transplantation after 1999, the mean number of lesions was 1.9 ⫹ 1.5 (range, 1–7), including 54% who presented with multifocal lesions. The mean cumulative tumor diameter was ⬎8 cm in only 3 cases. Due to understaging, 5 patients did not meet the Milan criteria at the time of transplantation. Tumor recurrence (evaluated in patients surviving at least 3 months after LT) was 10/31 in the historical group versus 4/53 among those who underwent transplantation after 1999. The cases of death due to recurrence were 50% in the old series and 23% in patients who underwent
ROSSI, MERLI, LAI ET AL
Fig 1. Cumulative survival in cirrhotic patients with HCC who underwent LT before and after 1999. P ⫽ .000013.
transplantation after 1999. Cumulative survival significantly improved in HCC patients who underwent transplantation after 1999 (93% vs 66% at 1 year and 81% vs 50% at 3 years, respectively; P ⬍ .00001; Fig 1).
DISCUSSION
Due to the lower survival rate among patients with advanced HCC and to the shortage of liver donors, more restrictive criteria have been proposed for admission of HCC patients to transplantation programs.3 More recently it is debated whether these criteria could be expanded and the consequences for the waiting list, for dropout rates, for patient survival, and for the rate of tumor recurrence.5–7 In a previous report, we observed that a cumulative tumor size ⬎8 cm was the only variable showing an independent contribution to patient mortality.8 Tumor differentiation and microvascular invasion were also powerful predictors of HCC recurrence9; however, these parameters are not always available before LT. In our experience the introduction of the Milan criteria3 to select patients with HCC has been efficacious to improve survival. Surprisingly, the 58 patients who underwent transplantation with a diagnosis of cirrhosis and concomitant HCC after 1999 showed even better survival than patients who underwent transplantation for end-stage liver disease without malignancy. Our policy for organ allocation did not grant specific priority to HCC patients; however, these patients were more likely to be considered for LT before the development of severe liver impairment (22% underwent transplantation as Child Pugh Class A). Another factor contributing to the improved survival was the low rate of HCC recurrence in this selected population. A few patients (10%) underwent transplantation while exceeding the Milan criteria due to imaging understaging; 2 of these patients had a cumulative tumor diameter ⬎8 cm: 1 died due to early surgical complications and another had a tumor
CIRRHOSIS AND HCC
recurrence at 4 months after LT, confirming our previous observation.8 REFERENCES 1. Befeler AS, Di Risceglie AM: Hepatocellular carcinoma: diagnosis and treatment. Gastroenterology 122:1609, 2002 2. Bruix J, Sherman M: Management of hepatocellular carcinoma. Hepatology 42:1208, 2005 3. Mazzaferro V, Regalia E, Doci R, et al: Liver transplantation for the treatment of small hepatocellular carcinoma in patients with cirrhosis. N Engl J Med 334:693, 1996 4. Libbrecht L, Bielen D, Verslype C, et al: Focal lesions in cirrhotic explant livers: pathological evaluation and accuracy of pretransplantation imaging examinations. Liver Transpl 8:749, 2002
1897 5. Yao FY: Selection criteria for liver transplantation in patients with hepatocellular carcinoma: beyond tumor size and number? Liver Transpl 12:1189, 2006 6. Decaens T, Roudot-Thoraval F, Handi-Bresson S, et al: Impact of UCSF criteria according to pre- and post-OLT tumor features: analysis of 479 patients listed for HCC with short waiting time. Liver Transpl 12:1761, 2006 7. Llovet JM: Expanding HCC criteria for liver transplant: the urgent need for prospective, robust data. Liver Transpl 12:1741, 2006 8. Merli M, Nicolini G, Gentili F, et al: Predictive factors of outcome after liver transplantation in pazients with cirrhosis and hepatocellular carcinoma. Transplant Proc 37:2535, 2005 9. Jonas S, Bechstein WO, Steinmuller T, et al: Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis. Hepatology 33:1080, 2001
H
EPATOCELLULAR carcinoma (HCC) is considered an optimal indication for liver transplantation (LT) because it may eliminate both the tumor and the underlying liver disease.1,2 Initial results showed that the outcomes of patients with advanced HCC were frequently compromised by rapid tumor recurrences. As a consequence, more restrictive selection criteria have been proposed. According to the Milan criteria,3 patients with a solitary tumor ⱕ5 cm or 3 or fewer lesions, none ⬎3 cm, in the absence of macroscopic vascular invasion and extrahepatic spreading, are the most appropriate candidates for LT. These criteria are based on pretransplantation evaluation of tumor dimension; however, due to inaccuracy of imaging techniques, a variable degree of understaging has been reported.4 The present study sought to compare cumulative survivals, rates of HCC recurrence, and causes of death among patients with cirrhosis and HCC before and
after the adoption of the more restrictive list criteria (Milan selection criteria). PATIENTS AND METHODS After 1999, we adopted the Milan criteria for the eligibility for LT of patients with cirrhosis and HCC.4 According to our allocation policy, no specific priority was attributed to patients with a diagFrom the II Gastroenterologia (M.M., F.G., M.G., S.G.C., A.F.A.), Divisione di Chirurgia Generale Trapianti d’Organo (M.R., Q.L., G.M., A.B., F.D.P., L.P., G.N., M.I., F.G., P.B.B.), Dipartimento di Anestesia e Rianimazione (F.P.), and Dipartimento di Anatomia Patologica (A.O.M., U.D.T.), Università “La Sapienza,” Rome, Italy. Address reprint requests to M. Rossi, Transplant Department, II Clinica Chirurgica, Policlinico Umberto I, Viale del Policlinico 155, Rome 00161, Italy. E-mail: [email protected]
© 2007 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/07/$–see front matter doi:10.1016/j.transproceed.2007.05.083
Transplantation Proceedings, 39, 1895–1897 (2007)
1895
1896 nosis of HCC. Between 1999 and 2005, 226 adult patients received an elective LT, including 58 (27%) with a diagnosis of HCC at the time of transplantation. Thirty-eight patients who underwent transplantation for HCC in the period 1989 to 1998 were considered the “historical group.” Preoperative tumor diagnosis was based on histological findings when biopsy was available or imaging studies. Extrahepatic involvement and macrovascular invasion were always excluded. Ultrasonography, computed tomography (CT), and/or magnetic resonance imaging were used to define tumor dimension and number before LT. We calculated the total tumor diameter for patients with multiple lesions as the sum of the maximal diameter of each nodule. The explanted liver was always examined. During followup, tumor recurrence was monitored with standard surveillance based on periodic liver ultrasonography, ␣-fetoprotein determination, and total body CT. The results are expressed as mean values ⫾ SD. The differences between the groups were analysed using Student t test or the 2 test. The Kaplan-Meier method with log-rank analysis was used to calculate survival probabilities among various groups of patients.
RESULTS Comparison Between Patients Who Underwent Transplantation With or Without HCC After the Introduction of Milan Criteria
Patients with a diagnosis of HCC were more often males (81% vs 68%; P ⬍ .04), of older mean age (56 ⫾ 7 vs 50 ⫾ 11; P ⬍ .0001), Child Pugh Class A (22% vs 2%; P ⬍ .001), but not a significantly different MELD score. Mean donor age was similar (P ⫽ .17) in patients with versus without tumor diagnosis before LT. After LT (mean follow-up, 34 ⫾ 28 months), cumulative survival was better among HCC versus non-HCC recipients (93% vs 71% at 1 year and 81% vs 67% at 3 years, respectively; P ⬍ .046), although the difference tended to attenuate after 5 years (66% vs 67%, respectively). Comparison Between Patients Who Underwent Transplantation With HCC Before and After the Introduction of Milan Criteria
Patients who underwent transplantation with HCC before 1999 were similar for age (53 ⫾ 9 years) and prevalence of Child Pugh Class A (33%). The lesion was multifocal in 60% and the mean cumulative tumor diameter was ⬎8 cm in 26/38 patients (88%). Due to the lack of selective criteria for the admission to LT, HCC was outside the Milan criteria in 59% of patients. Among patients who underwent transplantation after 1999, the mean number of lesions was 1.9 ⫹ 1.5 (range, 1–7), including 54% who presented with multifocal lesions. The mean cumulative tumor diameter was ⬎8 cm in only 3 cases. Due to understaging, 5 patients did not meet the Milan criteria at the time of transplantation. Tumor recurrence (evaluated in patients surviving at least 3 months after LT) was 10/31 in the historical group versus 4/53 among those who underwent transplantation after 1999. The cases of death due to recurrence were 50% in the old series and 23% in patients who underwent
ROSSI, MERLI, LAI ET AL
Fig 1. Cumulative survival in cirrhotic patients with HCC who underwent LT before and after 1999. P ⫽ .000013.
transplantation after 1999. Cumulative survival significantly improved in HCC patients who underwent transplantation after 1999 (93% vs 66% at 1 year and 81% vs 50% at 3 years, respectively; P ⬍ .00001; Fig 1).
DISCUSSION
Due to the lower survival rate among patients with advanced HCC and to the shortage of liver donors, more restrictive criteria have been proposed for admission of HCC patients to transplantation programs.3 More recently it is debated whether these criteria could be expanded and the consequences for the waiting list, for dropout rates, for patient survival, and for the rate of tumor recurrence.5–7 In a previous report, we observed that a cumulative tumor size ⬎8 cm was the only variable showing an independent contribution to patient mortality.8 Tumor differentiation and microvascular invasion were also powerful predictors of HCC recurrence9; however, these parameters are not always available before LT. In our experience the introduction of the Milan criteria3 to select patients with HCC has been efficacious to improve survival. Surprisingly, the 58 patients who underwent transplantation with a diagnosis of cirrhosis and concomitant HCC after 1999 showed even better survival than patients who underwent transplantation for end-stage liver disease without malignancy. Our policy for organ allocation did not grant specific priority to HCC patients; however, these patients were more likely to be considered for LT before the development of severe liver impairment (22% underwent transplantation as Child Pugh Class A). Another factor contributing to the improved survival was the low rate of HCC recurrence in this selected population. A few patients (10%) underwent transplantation while exceeding the Milan criteria due to imaging understaging; 2 of these patients had a cumulative tumor diameter ⬎8 cm: 1 died due to early surgical complications and another had a tumor
CIRRHOSIS AND HCC
recurrence at 4 months after LT, confirming our previous observation.8 REFERENCES 1. Befeler AS, Di Risceglie AM: Hepatocellular carcinoma: diagnosis and treatment. Gastroenterology 122:1609, 2002 2. Bruix J, Sherman M: Management of hepatocellular carcinoma. Hepatology 42:1208, 2005 3. Mazzaferro V, Regalia E, Doci R, et al: Liver transplantation for the treatment of small hepatocellular carcinoma in patients with cirrhosis. N Engl J Med 334:693, 1996 4. Libbrecht L, Bielen D, Verslype C, et al: Focal lesions in cirrhotic explant livers: pathological evaluation and accuracy of pretransplantation imaging examinations. Liver Transpl 8:749, 2002
1897 5. Yao FY: Selection criteria for liver transplantation in patients with hepatocellular carcinoma: beyond tumor size and number? Liver Transpl 12:1189, 2006 6. Decaens T, Roudot-Thoraval F, Handi-Bresson S, et al: Impact of UCSF criteria according to pre- and post-OLT tumor features: analysis of 479 patients listed for HCC with short waiting time. Liver Transpl 12:1761, 2006 7. Llovet JM: Expanding HCC criteria for liver transplant: the urgent need for prospective, robust data. Liver Transpl 12:1741, 2006 8. Merli M, Nicolini G, Gentili F, et al: Predictive factors of outcome after liver transplantation in pazients with cirrhosis and hepatocellular carcinoma. Transplant Proc 37:2535, 2005 9. Jonas S, Bechstein WO, Steinmuller T, et al: Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis. Hepatology 33:1080, 2001