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Prognostic Impact of Des-γ-carboxyl Prothrombin in Living-Donor Liver Transplantation for Recurrent Hepatocellular Carcinoma
Prognostic Impact of Des-g-carboxyl Prothrombin in Living-Donor Liver Transplantation for Recurrent Hepatocellular Carcinoma N. Harimoto*, Y. Yoshida, T. Kurihara, K. Takeishi, S. Itoh, N. Harada, E. Tsujita, Y.-I. Yamashita, H. Uchiyama, Y. Soejima, T. Ikegami, T. Yoshizumi, H. Kawanaka, T. Ikeda, K. Shirabe, H. Saeki, E. Oki, Y. Kimura, and Y. Maehara Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
ABSTRACT Background. Although the Milan criteria are widely accepted for liver transplantation (LT) in patients for hepatocellular carcinoma (HCC), they have not been fully evaluated for salvage LT in patients with recurrent HCC. We have previously reported outcomes of living-donor LT (LDLT) for HCC and identified 2 risk factors affecting recurrence-free survival (RFS): tumor size >5 cm and des-g-carboxyl prothrombin (DCP) concentration >300 mAU/mL (Kyushu University criteria). This study was designed to clarify risk factors for tumor recurrence after LDLT in patients with recurrent HCC. Methods. Outcomes in 114 patients who underwent LDLT for recurrent HCC were analyzed retrospectively. RFS rates after LDLT were calculated, and risk factors for tumor recurrence were identified. Results. The 1-, 3-, and 5-year RFS rates after LDLT were 90.6%, 80.4%, and 78.8%, respectively. Univariate analysis showed that tumor recurrence was associated with alphafetoprotein concentration 300 ng/mL, DCP concentration 300 mAU/mL, tumor number 4, tumor size 5 cm, transarterial chemotherapy before LDLT, duration of last treatment of HCC to LDLT <3 months, bilobar distribution, exceeding Milan criteria, exceeding Kyushu University criteria, poor differentiation, and histologic vascular invasion. Multivariate analysis showed that DCP 300 mAU/mL (P ¼ .03) and duration from last treatment to LDLT <3 months (P ¼ .01) were independent predictors of RFS. Conclusions. DCP concentration and time between last treatment and LDLT are prognostic of RFS in patients undergoing LDLT for HCC.
A
LTHOUGH the Milan criteria are widely used in patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC) [1], they have not been fully evaluated for salvage LT in patients with recurrent HCC [2e4]. We have reported outcomes of living-donor LT (LDLT), identifying 2 risk factors affecting recurrence-free survival (RFS): tumor size >5 cm and serum des-g-carboxyl prothrombin (DCP) concentrations >300 mAU/mL (Kyushu University criteria) [5]. The aim of the present study was to clarify risk factors for tumor recurrence after LDLT in patients with recurrent HCC. METHODS A total of 179 patients underwent LDLT for HCC at Kyushu University Hospital from October 1996 of December 2013, with ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
Transplantation Proceedings, 47, 703e704 (2015)
114 undergoing LDLT for recurrent HCC and end-stage liver disease. Patients were included if: 1) no modality except LDLT was deemed to be curative; 2) there were no extrahepatic metastases; and 3) there was no major vascular infiltration, including of the portal or hepatic vein. However, there was no restriction on tumor size or the number of tumors. The transplantation procedures for both donors and recipients have been described elsewhere [5,6].
Funding: Grant-in-Aid for Scientific Research (26380201) from the Ministry of Health, Labor, and Welfare of Japan. *Address correspondence to Norifumi Harimoto, MD, PhD, Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail: [email protected] 0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2014.09.178
703
704
HARIMOTO, YOSHIDA, KURIHARA ET AL
Table 1. Risk Factors for Tumor Recurrence in Multivariate Analysis Variable
Time from last treatment of HCC to LDLT <3 mo DCP 300 mAU/mL Poor differentiation Tumor number 4 Kyushu University criteria exceeded Tumor size 5 cm Transarterial chemotherapy before LDLT AFP 300 ng/mL Bilobar distribution Milan criteria exceeded Presence of histologic vascular invasion
OR
95% CI
P Value
3.97 1.41e11.16
.01
4.08 3.37 4.38 1.19 5.58 1.92
1.14e14.55 0.97e11.76 0.81e23.67 0.01e2.11 0.01e2.42 0.22e16.57
.03 .06 .09 .15 .20 .55
1.24 0.88 1.13 0.99
0.39e3.96 0.21e3.64 0.15e8.62 0.31e3.16
.71 .86 .90 .98
Abbreviations: OR, odds ratio; CI, confidence interval; DCP, des-g-carboxy prothrombin; AFP, a-fetoprotein; LDLT, living-donor liver transplantation.
RFS rates after LDLT were calculated, and risk factors for tumor recurrence were identified. The study protocol was approved by the Ethics and Indications Committee of Kyushu University.
RESULTS
This study enrolled 114 patients (68 men and 48 women) who had undergone LDLT for recurrent HCC and end-stage liver disease. All patients had previously undergone one or more pretransplantation treatments for primary or recurrent HCC, including 98 who underwent transarterial chemoembolization (TACE), 58 who underwent radiofrequency ablation, 33 who received ethanol injection therapy, and 14 who underwent hepatectomy. The median number of pre-transplantation treatments per patient was 3.1; the median time from the 1st pre-transplantation treatment to LDLT was 1,166 days, and the median time from the last pre-transplantation treatment to LDLT was 375 days. The 1-, 3-, and 5-year RFS rates after LDLT were 90.6%, 80.4%, and 78.8%, respectively. Univariate analysis showed that alpha-fetoprotein concentration 300 ng/mL, DCP concentration 300 mAU/mL, tumor number 4, tumor size 5 cm, TACE before LDLT, time of last HCC treatment to LDLT <3 months, bilobar distribution, exceeding Milan criteria, exceeding Kyushu University criteria, poor differentiation, and histologic vascular invasion were significant predictors of reduced RFS. Multivariate analysis showed that DCP 300 mAU/mL (odds ratio, 4.01; P ¼ .03) and time between the last pre-transplantation treatment and LDLT <3 months (odds ratio, 3.97; P ¼ .01) were independent predictors of RFS (Table 1). DISCUSSION
Multivariate analysis showed that DCP 300 mAU/mL and time between the last pre-transplantation treatment and
LDLT <3 months were useful predictors of RFS in patients undergoing LDLT for recurrent HCC. The duration between the last pre-transplantation treatment and LDLT was very important because viable HCC was precisely evaluated 3 months after the last pretreatment. Patients treated 3 months before LDLT had more and larger tumors and a higher alpha-fetoprotein concentration than patients treated >3 months earlier. Most patients in this study had undergone several treatments of HCC before LDLT, with pre-transplantation TACE being the most frequent, performed in 86% of these patients. Although univariate analysis showed that pre-transplantation TACE was associated with poor prognosis, this factor was no longer significant in multivariable analysis, which is consistent with TACE being performed in patients with multiple HCCs. No other previous treatment modality, such as hepatectomy or local ablation therapy, was significantly associated with the recurrence of HCC after LDLT. DCP concentration has been reported to correlate significantly with microvascular invasion and intrahepatic metastases in patients with HCC [7], suggesting that DCP is a useful predictor of the malignant potential of recurrent HCC. In conclusion, DCP concentration and time between last treatment and LDLT are prognostic of RFS in patients undergoing LDLT for HCC. LDLT may therefore be ineffective in patients with DCP 300 mAU/mL or treated <3 months earlier. 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;334:693e9. [2] Yoshizumi T, Ikegami T, Yoshiya S, et al. Impact of tumor size, number of tumors and neutrophil-to-lymphocyte ratio in liver transplantation for recurrent hepatocellular carcinoma. Hepatol Res 2013;43:709e16. [3] Yoshizumi T, Shirabe K, Soejima Y, et al. Living donor liver transplantation in patients who have received pretransplant treatment for hepatocellular carcinoma. Transplantation 2011;91: e61e2. [4] Kaido T, Ogawa K, Mori A, et al. Usefulness of the Kyoto criteria as expanded selection criteria for liver transplantation for hepatocellular carcinoma. Surgery 2013;154:1053e60. [5] Taketomi A, Sanefuji K, Soejima Y, et al. Impact of desgamma-carboxy prothrombin and tumor size on the recurrence of hepatocellular carcinoma after living donor liver transplantation. Transplantation 2009;87:531e7. [6] Yonemura Y, Taketomi A, Soejima Y, et al. Validity of preoperative volumetric analysis of congestion volume in living donor liver transplantation using three-dimensional computed tomography. Liver Transpl 2005;11:1556e62. [7] Shirabe K, Itoh S, Yoshizumi T, et al. The predictors of microvascular invasion in candidates for liver transplantation with hepatocellular carcinoma-with special reference to the serum levels of des-gamma-carboxy prothrombin. J Surg Oncol 2007;95: 235e40.
ABSTRACT Background. Although the Milan criteria are widely accepted for liver transplantation (LT) in patients for hepatocellular carcinoma (HCC), they have not been fully evaluated for salvage LT in patients with recurrent HCC. We have previously reported outcomes of living-donor LT (LDLT) for HCC and identified 2 risk factors affecting recurrence-free survival (RFS): tumor size >5 cm and des-g-carboxyl prothrombin (DCP) concentration >300 mAU/mL (Kyushu University criteria). This study was designed to clarify risk factors for tumor recurrence after LDLT in patients with recurrent HCC. Methods. Outcomes in 114 patients who underwent LDLT for recurrent HCC were analyzed retrospectively. RFS rates after LDLT were calculated, and risk factors for tumor recurrence were identified. Results. The 1-, 3-, and 5-year RFS rates after LDLT were 90.6%, 80.4%, and 78.8%, respectively. Univariate analysis showed that tumor recurrence was associated with alphafetoprotein concentration 300 ng/mL, DCP concentration 300 mAU/mL, tumor number 4, tumor size 5 cm, transarterial chemotherapy before LDLT, duration of last treatment of HCC to LDLT <3 months, bilobar distribution, exceeding Milan criteria, exceeding Kyushu University criteria, poor differentiation, and histologic vascular invasion. Multivariate analysis showed that DCP 300 mAU/mL (P ¼ .03) and duration from last treatment to LDLT <3 months (P ¼ .01) were independent predictors of RFS. Conclusions. DCP concentration and time between last treatment and LDLT are prognostic of RFS in patients undergoing LDLT for HCC.
A
LTHOUGH the Milan criteria are widely used in patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC) [1], they have not been fully evaluated for salvage LT in patients with recurrent HCC [2e4]. We have reported outcomes of living-donor LT (LDLT), identifying 2 risk factors affecting recurrence-free survival (RFS): tumor size >5 cm and serum des-g-carboxyl prothrombin (DCP) concentrations >300 mAU/mL (Kyushu University criteria) [5]. The aim of the present study was to clarify risk factors for tumor recurrence after LDLT in patients with recurrent HCC. METHODS A total of 179 patients underwent LDLT for HCC at Kyushu University Hospital from October 1996 of December 2013, with ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
Transplantation Proceedings, 47, 703e704 (2015)
114 undergoing LDLT for recurrent HCC and end-stage liver disease. Patients were included if: 1) no modality except LDLT was deemed to be curative; 2) there were no extrahepatic metastases; and 3) there was no major vascular infiltration, including of the portal or hepatic vein. However, there was no restriction on tumor size or the number of tumors. The transplantation procedures for both donors and recipients have been described elsewhere [5,6].
Funding: Grant-in-Aid for Scientific Research (26380201) from the Ministry of Health, Labor, and Welfare of Japan. *Address correspondence to Norifumi Harimoto, MD, PhD, Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail: [email protected] 0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2014.09.178
703
704
HARIMOTO, YOSHIDA, KURIHARA ET AL
Table 1. Risk Factors for Tumor Recurrence in Multivariate Analysis Variable
Time from last treatment of HCC to LDLT <3 mo DCP 300 mAU/mL Poor differentiation Tumor number 4 Kyushu University criteria exceeded Tumor size 5 cm Transarterial chemotherapy before LDLT AFP 300 ng/mL Bilobar distribution Milan criteria exceeded Presence of histologic vascular invasion
OR
95% CI
P Value
3.97 1.41e11.16
.01
4.08 3.37 4.38 1.19 5.58 1.92
1.14e14.55 0.97e11.76 0.81e23.67 0.01e2.11 0.01e2.42 0.22e16.57
.03 .06 .09 .15 .20 .55
1.24 0.88 1.13 0.99
0.39e3.96 0.21e3.64 0.15e8.62 0.31e3.16
.71 .86 .90 .98
Abbreviations: OR, odds ratio; CI, confidence interval; DCP, des-g-carboxy prothrombin; AFP, a-fetoprotein; LDLT, living-donor liver transplantation.
RFS rates after LDLT were calculated, and risk factors for tumor recurrence were identified. The study protocol was approved by the Ethics and Indications Committee of Kyushu University.
RESULTS
This study enrolled 114 patients (68 men and 48 women) who had undergone LDLT for recurrent HCC and end-stage liver disease. All patients had previously undergone one or more pretransplantation treatments for primary or recurrent HCC, including 98 who underwent transarterial chemoembolization (TACE), 58 who underwent radiofrequency ablation, 33 who received ethanol injection therapy, and 14 who underwent hepatectomy. The median number of pre-transplantation treatments per patient was 3.1; the median time from the 1st pre-transplantation treatment to LDLT was 1,166 days, and the median time from the last pre-transplantation treatment to LDLT was 375 days. The 1-, 3-, and 5-year RFS rates after LDLT were 90.6%, 80.4%, and 78.8%, respectively. Univariate analysis showed that alpha-fetoprotein concentration 300 ng/mL, DCP concentration 300 mAU/mL, tumor number 4, tumor size 5 cm, TACE before LDLT, time of last HCC treatment to LDLT <3 months, bilobar distribution, exceeding Milan criteria, exceeding Kyushu University criteria, poor differentiation, and histologic vascular invasion were significant predictors of reduced RFS. Multivariate analysis showed that DCP 300 mAU/mL (odds ratio, 4.01; P ¼ .03) and time between the last pre-transplantation treatment and LDLT <3 months (odds ratio, 3.97; P ¼ .01) were independent predictors of RFS (Table 1). DISCUSSION
Multivariate analysis showed that DCP 300 mAU/mL and time between the last pre-transplantation treatment and
LDLT <3 months were useful predictors of RFS in patients undergoing LDLT for recurrent HCC. The duration between the last pre-transplantation treatment and LDLT was very important because viable HCC was precisely evaluated 3 months after the last pretreatment. Patients treated 3 months before LDLT had more and larger tumors and a higher alpha-fetoprotein concentration than patients treated >3 months earlier. Most patients in this study had undergone several treatments of HCC before LDLT, with pre-transplantation TACE being the most frequent, performed in 86% of these patients. Although univariate analysis showed that pre-transplantation TACE was associated with poor prognosis, this factor was no longer significant in multivariable analysis, which is consistent with TACE being performed in patients with multiple HCCs. No other previous treatment modality, such as hepatectomy or local ablation therapy, was significantly associated with the recurrence of HCC after LDLT. DCP concentration has been reported to correlate significantly with microvascular invasion and intrahepatic metastases in patients with HCC [7], suggesting that DCP is a useful predictor of the malignant potential of recurrent HCC. In conclusion, DCP concentration and time between last treatment and LDLT are prognostic of RFS in patients undergoing LDLT for HCC. LDLT may therefore be ineffective in patients with DCP 300 mAU/mL or treated <3 months earlier. 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;334:693e9. [2] Yoshizumi T, Ikegami T, Yoshiya S, et al. Impact of tumor size, number of tumors and neutrophil-to-lymphocyte ratio in liver transplantation for recurrent hepatocellular carcinoma. Hepatol Res 2013;43:709e16. [3] Yoshizumi T, Shirabe K, Soejima Y, et al. Living donor liver transplantation in patients who have received pretransplant treatment for hepatocellular carcinoma. Transplantation 2011;91: e61e2. [4] Kaido T, Ogawa K, Mori A, et al. Usefulness of the Kyoto criteria as expanded selection criteria for liver transplantation for hepatocellular carcinoma. Surgery 2013;154:1053e60. [5] Taketomi A, Sanefuji K, Soejima Y, et al. Impact of desgamma-carboxy prothrombin and tumor size on the recurrence of hepatocellular carcinoma after living donor liver transplantation. Transplantation 2009;87:531e7. [6] Yonemura Y, Taketomi A, Soejima Y, et al. Validity of preoperative volumetric analysis of congestion volume in living donor liver transplantation using three-dimensional computed tomography. Liver Transpl 2005;11:1556e62. [7] Shirabe K, Itoh S, Yoshizumi T, et al. The predictors of microvascular invasion in candidates for liver transplantation with hepatocellular carcinoma-with special reference to the serum levels of des-gamma-carboxy prothrombin. J Surg Oncol 2007;95: 235e40.