J Cancer Res Clin Oncol (2014) 140:341–348 DOI 10.1007/s00432-013-1576-0
ORIGINAL PAPER
Liver transplantation for hepatocellular carcinoma exceeding the Milan criteria: a single‑center experience Ping Wan · Qiang Xia · Jian‑Jun Zhang · Qi‑Gen Li · Ning Xu · Ming Zhang · Xiao‑Song Chen · Long‑Zhi Han
Received: 15 December 2013 / Accepted: 18 December 2013 / Published online: 30 December 2013 © Springer-Verlag Berlin Heidelberg 2013
Abstract Purpose To establish a prognostic prediction system for patients with hepatocellular carcinoma (HCC) exceeding Milan criteria after liver transplantation (LT). Methods A total of 130 patients undergoing LT for HCC exceeding Milan criteria were enrolled into the study. Independent predictors for relapse-free survival (RFS) were adopted to establish a grading system to predict the risk of post-LT tumor recurrence. Results Multivariate Cox analysis revealed that tumor size >10 cm [vs. ≤5 cm: relative risk (RR) = 4.214, P 400 ng/ml (vs. ≤400 ng/ml: RR = 1.657, P 6. RFS rates of patients with grade I–IV (n = 35, 46, 30 and 19) were 87.5, 57.8, 34.7 and 0 % in 1 year; and 74.4, 41.7, 14.4 and 0 % in 5 years. Both of overall survival (OS) and RFS correlated well with the risk index grade. Patients with grade I achieved comparable prognostic outcomes with the Milan group patients (n = 119) (5-year OS = 73.7 vs. 74.7 %, P = 0.748; 5-year RFS = 74.4 vs. 85.7 %, P = 0.148).
P. Wan · Q. Xia (*) · J.-J. Zhang · Q.-G. Li · N. Xu · M. Zhang · X.-S. Chen · L.-Z. Han Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, No.1630 Dongfang Road, Shanghai 200127, China e-mail: [email protected]
Conclusions The new grading system was proved to be a promising system in predicting the patient prognosis after LT for HCC exceeding Milan criteria. Keywords Liver transplantation · Hepatocellular carcinoma · Milan criteria · Survival · Recurrence · Prognosis
Introduction Hepatocellular carcinoma (HCC) is the sixth most common cancer, the third cause of cancer-related death and accounts for 7 % of all cancers worldwide (European Association for the Study of the Liver et al. 2012; Parkin et al. 2005). A significant proportion of HCC patients are accompanied by serious liver cirrhosis or liver dysfunction, and radical liver resection is limited in such patients. Liver transplantation (LT) is considered as a well-established therapeutic option in patients with unresectable HCC. In 1996, Mazzaferro et al. (1996) put forward the Milan criteria (single nodule ≤5 cm or no more than three nodules, each measuring 3 cm or less) for LT in HCC patients. However, patients’ chance of cure has been restricted by such a narrow indication. Therefore, there are still a great number of patients with HCC exceeding the Milan criteria treated with LT every year. For instance, more than half of HCC patients who underwent LT were beyond the Milan criteria in Japan (Todo et al. 2004). Although it is commonly believed that moderate expansion of the Milan criteria can obtain acceptable prognostic outcomes (Mazzaferro et al. 2009; Fan et al. 2009; Ito et al. 2007; Soejima et al. 2007; Sugawara et al. 2007; Yao et al. 2001; Zheng et al. 2008; Lee et al. 2008; Li et al. 2009), surgical morbidities and mortalities associated with LT may reduce rather than
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J Cancer Res Clin Oncol (2014) 140:341–348
improve the quality of life and survival of patients with an advanced tumor. Therefore, a predictive system was required to assist the clinician in the evaluation of the result of treatment. However, the TNM system turned out to be poorly predictive of tumor recurrence after LT or hepatic resection (Izumi et al. 1994; Marsh et al. 2000). The purpose of this study was to determine the predominant factors that might significantly affect the survival and tumor recurrence rates of patients with HCC beyond the Milan criteria. If we can define a subgroup of patients in whom LT is expected to be associated with favorable tumor-free survival, morbidities and mortalities caused by excessive surgeries can be avoided.
7 days before surgery. All the surgical procedures were performed by specialists with experience in LT technique in the Department of Liver Surgery, Ren Ji Hospital, Shanghai, China. LT was performed using standard techniques. Classic orthotopic LT was the only surgical technique for deceased donor liver transplantation (DDLT). All patients undergoing living donor liver transplantation (LDLT) were operated using right liver grafts without middle hepatic vein. Organ donations and transplantations in the study were carried out in strict accordance with the regulation of Shanghai Organ Transplant Committee and the declaration of Helsinki. All of the living organs were donated with an informed consent, and cadaveric donors involved in the study were obtained from brain death or no-heartbeating donors.
Methods
Immunosuppressive regimens
Patients
A triple-drug regimen of tacrolimus or cyclosporine (CsA) combined with methylprednisolone and/or mycophenolate mofetil (MMF) was used after LT. Immunosuppression was started during surgery with 500 mg methylprednisolone, followed by tapering from 240 to 40 mg per day over 6 days. Maintenance prednisone at an initial dose of 20 mg daily was gradually reduced every week and was withdrawn 3 months after LT. The initial dose of tacrolimus was 0.06–0.15 mg/kg per day with a target trough level of 8–10 ng/ml during the first 30 days. MMF was administered orally after LT at 0.5–0.75 g twice a day. If tacrolimus did not reach the target level, it would be replaced by CsA at 6–10 mg/kg per day. The target C0 and C2 levels for CsA were 150–200 ng/ml and 800–1,200 ng/ml, respectively.
Between January 2007 and December 2010, 270 consecutive patients with pathologically proven HCC underwent LT in the Department of Liver Surgery in Ren Ji Hospital, Shanghai, China. Twenty-one patients were excluded for the following reasons: (1) 11 patients who received preoperative down-staging treatment had complete tumor necrosis; (2) 6 patients had possible metastatic disease before LT; (3) coexistence of HCC and gallbladder carcinoma was identified in 2 patients after LT; (4) one patient underwent additional left nephrectomy for his concurrent renal carcinoma; (5) one patient underwent combined liver–kidney transplantation. Finally, 249 patients met the eligibility criteria of the study, of which 130 patients with HCC exceeding the Milan criteria were enrolled into the study. Clinical data collection The clinicopathological data were retrospectively reviewed from our prospectively collected database of LT. Salvage LT was performed in patients who developed recurrent HCC after the primary hepatic resection. Preoperative down-staging treatment for size reduction of the tumors included transcatheter arterial chemoembolization (TACE), radiofrequency ablation (RFA), percutaneous ethanol injection (PEI) and stereotactic body radiation therapy (gamma knife), thereby facilitating LT. Tumor size was defined as the maximal diameter of the largest tumor in the resected specimen. Tumor histopathologic differentiation was graded according to the Edmondson–Steiner criteria (Edmondson et al. 1954) (grade I—well differentiated, II—moderately differentiated, grade III—poorly differentiated). The latest measurement results of alpha fetoprotein (AFP) and carbohydrate antigen 19-9 (CA19-9) before LT were recorded in the database, and most patients had both results within
13
Follow‑up Patients were regularly followed up in the clinic monthly during the first 6 months after LT, every 3 months from the 7th to the 18th month and every 6 months thereafter. Measurements of serum AFP and CA19-9 levels, chest X-ray and abdominal ultrasound were monitored at each follow-up visit, and abdominal contrast-enhanced computed tomography (CT) was performed every 6 months during the first 2 years and annually thereafter. A rising AFP or CA19-9 level alone was not identified as tumor recurrence, but once tumor recurrence had been confirmed later, the time when the AFP or CA19-9 level began to rise was taken as the date of recurrence. For some patients without available data in the clinic, follow-up data were obtained through telephone inquiries. The end point of the study was overall survival (OS) and relapse-free survival (RFS). OS was calculated from the time of LT until death or the last followup contact, the cut-off date of follow-up was September 1, 2013. RFS was defined as the duration from LT to the date of a suspected tumor recurrence in patients with eventually
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J Cancer Res Clin Oncol (2014) 140:341–348
confirmed tumor recurrence or to the last follow-up contact in patients without tumor recurrence. The median followup period was 24.5 months (range: 1–78 months). Statistical analysis Statistical analyses were completed using SPSS for Windows version 13.0. The Kaplan–Meier method was used to estimate the cumulative OS and RFS rates. The equality of survival distributions among different groups of patients was tested using the log-rank method. We used the univariate analysis and multivariate analysis by the Cox proportional hazard regression model to identify independent prognostic factors in predicting OS and RFS. The univariate analysis was used to analyze each factor that might have influenced the prognosis of patients with HCC after LT, and any variables identified as statistically significant in the univariate analysis were considered as candidates for the multivariate Cox analysis. The independent predictors for OS and RFS were confirmed by the forward regression using a Cox proportional hazard model. P values 100 U/ml. According to the Child–Pugh classification, 51 patients (39.2 %) were Child’s class A, 53 patients (40.8 %) were Child’s class B, and 26 patients (20.0 %) were Child’s class C. The majority of all enrolled patients (56.2 %) showed a model for endstage liver disease (MELD) score of 10–19, while patients with MELD scores ≥20 accounted for 8.5 % of the entire cohort. Forty-eight patients (36.9 %) received down-staging treatment before LT. The most common etiology of cirrhosis was hepatitis B virus infection, accounting for 123 of 130 patients (94.6 %). Table 2 shows the details of the entire cohort’s histopathologic features. The proportion of patients with a tumor ≤5, 5–10 and >10 cm was 33.1, 46.2 and 20.8 %, respectively. Forty-seven patients (36.2 %) were identified to have vascular invasion, and extrahepatic invasion was confirmed in 19 patients (14.6 %). The overall
Table 1 Baseline characteristics of the entire cohort (n = 130) Variables
Number of patients (%)
Age (mean years ± SD) Gender Male Female Liver cirrhosis Salvage LT Surgical technique LDLT DDLT Preoperative AFP ≤400 ng/ml >400 ng/ml Preoperative CA19-9 ≤100U/ml >100U/ml Child–Pugh class A B C MELD score 10 Tumors number Single Multiple Vascular invasion Extrahepatic invasion Histopathologic grading I–II III
Number of patients (%)
43 (33.1) 60 (46.2) 27 (20.8) 58 (44.6) 72 (55.4) 47 (36.2) 19 (14.6) 80 (61.5) 50 (38.5)
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J Cancer Res Clin Oncol (2014) 140:341–348
1- and 5-year survival rates of the 130 patients were 70.0 and 38.1 %, respectively; and the corresponding RFS rates were 53.0 and 38.8 %, respectively.
(≤50 or >50 years), gender (male or female), primary or salvage LT, preoperative down-staging treatment (yes or no), surgical technique (LDLT or DDLT), preoperative AFP level (≤400 or >400 ng/ml), preoperative CA19-9 level (≤100 or >100U/ml), Child–Pugh class (A, B or C), MELD score (10 cm), tumor number (single or multiple), vascular invasion (absence or presence), extrahepatic invasion (absence or presence) and histopathologic grading (I–II or III). As shown in Table 3, preoperative AFP (P = 0.001 and
ORIGINAL PAPER
Liver transplantation for hepatocellular carcinoma exceeding the Milan criteria: a single‑center experience Ping Wan · Qiang Xia · Jian‑Jun Zhang · Qi‑Gen Li · Ning Xu · Ming Zhang · Xiao‑Song Chen · Long‑Zhi Han
Received: 15 December 2013 / Accepted: 18 December 2013 / Published online: 30 December 2013 © Springer-Verlag Berlin Heidelberg 2013
Abstract Purpose To establish a prognostic prediction system for patients with hepatocellular carcinoma (HCC) exceeding Milan criteria after liver transplantation (LT). Methods A total of 130 patients undergoing LT for HCC exceeding Milan criteria were enrolled into the study. Independent predictors for relapse-free survival (RFS) were adopted to establish a grading system to predict the risk of post-LT tumor recurrence. Results Multivariate Cox analysis revealed that tumor size >10 cm [vs. ≤5 cm: relative risk (RR) = 4.214, P 400 ng/ml (vs. ≤400 ng/ml: RR = 1.657, P 6. RFS rates of patients with grade I–IV (n = 35, 46, 30 and 19) were 87.5, 57.8, 34.7 and 0 % in 1 year; and 74.4, 41.7, 14.4 and 0 % in 5 years. Both of overall survival (OS) and RFS correlated well with the risk index grade. Patients with grade I achieved comparable prognostic outcomes with the Milan group patients (n = 119) (5-year OS = 73.7 vs. 74.7 %, P = 0.748; 5-year RFS = 74.4 vs. 85.7 %, P = 0.148).
P. Wan · Q. Xia (*) · J.-J. Zhang · Q.-G. Li · N. Xu · M. Zhang · X.-S. Chen · L.-Z. Han Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, No.1630 Dongfang Road, Shanghai 200127, China e-mail: [email protected]
Conclusions The new grading system was proved to be a promising system in predicting the patient prognosis after LT for HCC exceeding Milan criteria. Keywords Liver transplantation · Hepatocellular carcinoma · Milan criteria · Survival · Recurrence · Prognosis
Introduction Hepatocellular carcinoma (HCC) is the sixth most common cancer, the third cause of cancer-related death and accounts for 7 % of all cancers worldwide (European Association for the Study of the Liver et al. 2012; Parkin et al. 2005). A significant proportion of HCC patients are accompanied by serious liver cirrhosis or liver dysfunction, and radical liver resection is limited in such patients. Liver transplantation (LT) is considered as a well-established therapeutic option in patients with unresectable HCC. In 1996, Mazzaferro et al. (1996) put forward the Milan criteria (single nodule ≤5 cm or no more than three nodules, each measuring 3 cm or less) for LT in HCC patients. However, patients’ chance of cure has been restricted by such a narrow indication. Therefore, there are still a great number of patients with HCC exceeding the Milan criteria treated with LT every year. For instance, more than half of HCC patients who underwent LT were beyond the Milan criteria in Japan (Todo et al. 2004). Although it is commonly believed that moderate expansion of the Milan criteria can obtain acceptable prognostic outcomes (Mazzaferro et al. 2009; Fan et al. 2009; Ito et al. 2007; Soejima et al. 2007; Sugawara et al. 2007; Yao et al. 2001; Zheng et al. 2008; Lee et al. 2008; Li et al. 2009), surgical morbidities and mortalities associated with LT may reduce rather than
13
342
J Cancer Res Clin Oncol (2014) 140:341–348
improve the quality of life and survival of patients with an advanced tumor. Therefore, a predictive system was required to assist the clinician in the evaluation of the result of treatment. However, the TNM system turned out to be poorly predictive of tumor recurrence after LT or hepatic resection (Izumi et al. 1994; Marsh et al. 2000). The purpose of this study was to determine the predominant factors that might significantly affect the survival and tumor recurrence rates of patients with HCC beyond the Milan criteria. If we can define a subgroup of patients in whom LT is expected to be associated with favorable tumor-free survival, morbidities and mortalities caused by excessive surgeries can be avoided.
7 days before surgery. All the surgical procedures were performed by specialists with experience in LT technique in the Department of Liver Surgery, Ren Ji Hospital, Shanghai, China. LT was performed using standard techniques. Classic orthotopic LT was the only surgical technique for deceased donor liver transplantation (DDLT). All patients undergoing living donor liver transplantation (LDLT) were operated using right liver grafts without middle hepatic vein. Organ donations and transplantations in the study were carried out in strict accordance with the regulation of Shanghai Organ Transplant Committee and the declaration of Helsinki. All of the living organs were donated with an informed consent, and cadaveric donors involved in the study were obtained from brain death or no-heartbeating donors.
Methods
Immunosuppressive regimens
Patients
A triple-drug regimen of tacrolimus or cyclosporine (CsA) combined with methylprednisolone and/or mycophenolate mofetil (MMF) was used after LT. Immunosuppression was started during surgery with 500 mg methylprednisolone, followed by tapering from 240 to 40 mg per day over 6 days. Maintenance prednisone at an initial dose of 20 mg daily was gradually reduced every week and was withdrawn 3 months after LT. The initial dose of tacrolimus was 0.06–0.15 mg/kg per day with a target trough level of 8–10 ng/ml during the first 30 days. MMF was administered orally after LT at 0.5–0.75 g twice a day. If tacrolimus did not reach the target level, it would be replaced by CsA at 6–10 mg/kg per day. The target C0 and C2 levels for CsA were 150–200 ng/ml and 800–1,200 ng/ml, respectively.
Between January 2007 and December 2010, 270 consecutive patients with pathologically proven HCC underwent LT in the Department of Liver Surgery in Ren Ji Hospital, Shanghai, China. Twenty-one patients were excluded for the following reasons: (1) 11 patients who received preoperative down-staging treatment had complete tumor necrosis; (2) 6 patients had possible metastatic disease before LT; (3) coexistence of HCC and gallbladder carcinoma was identified in 2 patients after LT; (4) one patient underwent additional left nephrectomy for his concurrent renal carcinoma; (5) one patient underwent combined liver–kidney transplantation. Finally, 249 patients met the eligibility criteria of the study, of which 130 patients with HCC exceeding the Milan criteria were enrolled into the study. Clinical data collection The clinicopathological data were retrospectively reviewed from our prospectively collected database of LT. Salvage LT was performed in patients who developed recurrent HCC after the primary hepatic resection. Preoperative down-staging treatment for size reduction of the tumors included transcatheter arterial chemoembolization (TACE), radiofrequency ablation (RFA), percutaneous ethanol injection (PEI) and stereotactic body radiation therapy (gamma knife), thereby facilitating LT. Tumor size was defined as the maximal diameter of the largest tumor in the resected specimen. Tumor histopathologic differentiation was graded according to the Edmondson–Steiner criteria (Edmondson et al. 1954) (grade I—well differentiated, II—moderately differentiated, grade III—poorly differentiated). The latest measurement results of alpha fetoprotein (AFP) and carbohydrate antigen 19-9 (CA19-9) before LT were recorded in the database, and most patients had both results within
13
Follow‑up Patients were regularly followed up in the clinic monthly during the first 6 months after LT, every 3 months from the 7th to the 18th month and every 6 months thereafter. Measurements of serum AFP and CA19-9 levels, chest X-ray and abdominal ultrasound were monitored at each follow-up visit, and abdominal contrast-enhanced computed tomography (CT) was performed every 6 months during the first 2 years and annually thereafter. A rising AFP or CA19-9 level alone was not identified as tumor recurrence, but once tumor recurrence had been confirmed later, the time when the AFP or CA19-9 level began to rise was taken as the date of recurrence. For some patients without available data in the clinic, follow-up data were obtained through telephone inquiries. The end point of the study was overall survival (OS) and relapse-free survival (RFS). OS was calculated from the time of LT until death or the last followup contact, the cut-off date of follow-up was September 1, 2013. RFS was defined as the duration from LT to the date of a suspected tumor recurrence in patients with eventually
343
J Cancer Res Clin Oncol (2014) 140:341–348
confirmed tumor recurrence or to the last follow-up contact in patients without tumor recurrence. The median followup period was 24.5 months (range: 1–78 months). Statistical analysis Statistical analyses were completed using SPSS for Windows version 13.0. The Kaplan–Meier method was used to estimate the cumulative OS and RFS rates. The equality of survival distributions among different groups of patients was tested using the log-rank method. We used the univariate analysis and multivariate analysis by the Cox proportional hazard regression model to identify independent prognostic factors in predicting OS and RFS. The univariate analysis was used to analyze each factor that might have influenced the prognosis of patients with HCC after LT, and any variables identified as statistically significant in the univariate analysis were considered as candidates for the multivariate Cox analysis. The independent predictors for OS and RFS were confirmed by the forward regression using a Cox proportional hazard model. P values 100 U/ml. According to the Child–Pugh classification, 51 patients (39.2 %) were Child’s class A, 53 patients (40.8 %) were Child’s class B, and 26 patients (20.0 %) were Child’s class C. The majority of all enrolled patients (56.2 %) showed a model for endstage liver disease (MELD) score of 10–19, while patients with MELD scores ≥20 accounted for 8.5 % of the entire cohort. Forty-eight patients (36.9 %) received down-staging treatment before LT. The most common etiology of cirrhosis was hepatitis B virus infection, accounting for 123 of 130 patients (94.6 %). Table 2 shows the details of the entire cohort’s histopathologic features. The proportion of patients with a tumor ≤5, 5–10 and >10 cm was 33.1, 46.2 and 20.8 %, respectively. Forty-seven patients (36.2 %) were identified to have vascular invasion, and extrahepatic invasion was confirmed in 19 patients (14.6 %). The overall
Table 1 Baseline characteristics of the entire cohort (n = 130) Variables
Number of patients (%)
Age (mean years ± SD) Gender Male Female Liver cirrhosis Salvage LT Surgical technique LDLT DDLT Preoperative AFP ≤400 ng/ml >400 ng/ml Preoperative CA19-9 ≤100U/ml >100U/ml Child–Pugh class A B C MELD score 10 Tumors number Single Multiple Vascular invasion Extrahepatic invasion Histopathologic grading I–II III
Number of patients (%)
43 (33.1) 60 (46.2) 27 (20.8) 58 (44.6) 72 (55.4) 47 (36.2) 19 (14.6) 80 (61.5) 50 (38.5)
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J Cancer Res Clin Oncol (2014) 140:341–348
1- and 5-year survival rates of the 130 patients were 70.0 and 38.1 %, respectively; and the corresponding RFS rates were 53.0 and 38.8 %, respectively.
(≤50 or >50 years), gender (male or female), primary or salvage LT, preoperative down-staging treatment (yes or no), surgical technique (LDLT or DDLT), preoperative AFP level (≤400 or >400 ng/ml), preoperative CA19-9 level (≤100 or >100U/ml), Child–Pugh class (A, B or C), MELD score (10 cm), tumor number (single or multiple), vascular invasion (absence or presence), extrahepatic invasion (absence or presence) and histopathologic grading (I–II or III). As shown in Table 3, preoperative AFP (P = 0.001 and
