Accepted Manuscript Prognostic role of Child-Pugh score 5 and 6 in hepatocellular carcinoma patients who underwent curative hepatic resection Chisato Okajima , M.D. Shigeki Arii , M.D. Ph.D. Shinji Tanaka , M.D., Ph.D., F.A.C.S. Satoshi Matsumura , M.D., Ph.D. Daisuke Ban , M.D., Ph.D. Takanori Ochiai , M.D., Ph.D. Takumi Irie , M.D., Ph.D. Atsushi Kudo , M.D., Ph.D. Noriaki Nakamura , M.D., Ph.D. Minoru Tanabe , M.D., Ph.D. PII:
S0002-9610(14)00212-8
DOI:
10.1016/j.amjsurg.2014.03.009
Reference:
AJS 11167
To appear in:
The American Journal of Surgery
Received Date: 5 June 2013 Revised Date:
18 March 2014
Accepted Date: 28 March 2014
Please cite this article as: Okajima C, Arii S, Tanaka S, Matsumura S, Ban D, Ochiai T, Irie T, Kudo A, Nakamura N, Tanabe M, Prognostic role of Child-Pugh score 5 and 6 in hepatocellular carcinoma patients who underwent curative hepatic resection, The American Journal of Surgery (2014), doi: 10.1016/j.amjsurg.2014.03.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Prognostic role of ChildChild-Pugh score 5 and 6 in hepatocellular carcinoma
Chisato Okajima, M.D.,* Shigeki Arii, M.D. Ph.D.,*
RI PT
patients who underwent curative hepatic resection
Shinji Tanaka, M.D., Ph.D., F.A.C.S., Satoshi Matsumura, M.D., Ph.D.,
Daisuke Ban, M.D., Ph.D., Takanori Ochiai, M.D., Ph.D., Takumi Irie, M.D., Ph.D.,
SC
Atsushi Kudo, M.D., Ph.D., Noriaki Nakamura, M.D., Ph.D.,
M AN U
Minoru Tanabe, M.D., Ph.D.
Department of Hepato-Biliary-Pancreatic Surgery, Tokyo Medical and Dental
*Corresponding author: Shigeki Arii, M.D. Ph.D.
EP
Chisato Okajima, MD
TE D
University
Department of Hepato-Biliary-Pancreatic Surgery,
AC C
Tokyo Medical and Dental University, Graduate School of Medicine, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, JAPAN Tel: +81-3-5803-5928
Fax: +81-3-5803-0263
E-mail: [email protected] E-mail: [email protected] 1
ACCEPTED MANUSCRIPT
Abstract Background: It is unclear whether Child-Pugh score discriminates a prognosis of the Child-Pugh A
RI PT
patients who underwent hepatic resection for hepatocellular carcinoma. Methods: Between April 2000 and March 2011, 328 patients with Child-Pugh A underwent curative hepatectomy were divided into 2 groups; the CPS5 (n=253) and CPS6 (n=75) groups were compared. Results: Overall survival rates (1/2/5 years of the CPS5 and CPS6 groups were 90.9/82.5/62.4% and
SC
80.6/68.0/47.6%) and disease-free survival rates (67.6/51.8/30.1% and 36.9/16.0/5.9%) showed that the CPS5 group was significantly better than the CPS6 group. Multivariate analysis revealed that Child-Pugh score at overall survival (P=0.0125) and disease-free survival (P=0.0103) were significant
M AN U
prognostic factors.
Conclusions: Overall and disease-free survival in Child-Pugh A indicated quite difference between CPS5 and CPS6 group. Namely, CPS5 and CPS6 may be a useful prognostic marker of hepatocellular carcinoma patients with hepatic resection.
AC C
EP
TE D
Key words: Hepatocellular carcinoma, Child-Pugh score, Prognosis, Milan criteria
ACCEPTED MANUSCRIPT
ABSTRACT Background: It is unclear whether Child-Pugh score discriminates a prognosis of the
RI PT
Child-Pugh A patients who underwent hepatic resection for hepatocellular carcinoma.
Methods: Between April 2000 and March 2011, 361 patients with Child-Pugh A who
SC
underwent curative hepatectomy were divided into 2 groups; the CPS5 (n=274) and
M AN U
CPS6 (n=87) groups were compared.
Results: Overall survival rates (1/2/5 years of the CPS5 and CPS6 groups were 91.4/83.2/63.8% and 82.7/68.8/52.3%) and disease-free survival rates (68.6/51.8/30.7% and 43.3/25.5/12.3%) showed that the CPS5 group was significantly better than the
TE D
CPS6 group. Multivariate analysis revealed that Child-Pugh score at overall survival (P=0.0042) and disease-free survival (P=0.0131) were significant prognostic factors.
EP
Conclusions: Overall and disease-free survival in Child-Pugh A indicated quite difference between CPS5 and CPS6 group. Namely, CPS5 and CPS6 may be a useful
AC C
prognostic marker of hepatocellular carcinoma patients with hepatic resection.
KEY WORDS
Hepatocellular carcinoma, Child-Pugh score, Prognosis, Milan criteria
INTRODUCTION 2
ACCEPTED MANUSCRIPT
The prognosis of hepatocellular carcinoma patients is affected mainly by the stage of the cancer and the hepatic function. Curative treatments and preserved liver function
RI PT
are needed to attain the better prognosis. Actually, HCC is usually occurred in the patients with chronic liver diseases, and then it is quite important issue to maintain the hepatic functional reserve.1-4 In this regard, liver transplantation may be the most
SC
effective treatment for HCC, however, the indication is limited to considerably early stage of the cancer and also donor shortage remains to be conquered. Under these
M AN U
circumstances, hepatic resection is a feasible treatment to be widely selected. 5-7 Up to now, there have been many studies which have clarified the prognostic factors of the HCC patients with hepatic resection.8-10 Among the pathological factors of the cancer, tumor number, tumor size, and vascular involvement are closely involved in
TE D
the prognosis of the HCC patients.11-13 As to an estimation of the hepatic functional reserve, Child-Pugh classification is widely used because of the simplicity and appropriateness.14 Not a few studies reported that the grade of Child-Pugh (C-P)
EP
classification is well correlated with the prognosis of the patients, and is then assumed to be a valuable predictor of HCC patients. Indeed, Child-Pugh A (C-P A)
AC C
patients showed a better survival rate than Child-Pugh B (C-P B) and C patients in general. However, Child-Pugh A is composed of score of 5 and 6. The former patients is thought to have a well preserved liver function , while the latter may be partially disturbed in the liver function, suggesting that these scores might influence the prognosis of the HCC patients with hepatic resection. Namely, it may not be always appropriate to estimate HCC patients with Child-Pugh A all together by disregarding 3
ACCEPTED MANUSCRIPT
the score.5 and 6. 15, 16 From this point of view we attempted to make clear the prognostic significance of
RI PT
Child-Pugh A score 5 and 6. The present study will provide the evidence indicating that Child-Pugh score 5 and 6 will clearly discriminate the prognosis of the patients
SC
with Child-Pugh A who underwent the curative hepatic resection for HCC.
METHODS
M AN U
Patients
Four hundred forty-five patients underwent initial hepatectomy for hepatocellular carcinoma at our institute between April 2000 and March 2011. Of these patients, Child-Pugh status was class A in 412 patients (92.6%), class B in 31 patients (6.9%),
TE D
and class C in 2 patients (0.4%).
Of the 412 patients classified as Child-Pugh class A, 361 patients who underwent curative hepatectomy were evaluated. The remaining 51 patients were excluded. The
EP
breakdown is; 20 patients underwent non-curative resection, and 31 patients were unknown in their outcome including information about recurrence.
AC C
These 361 patients were divided into two groups; 274 patients were Child-Pugh score 5 points group (CPS5 group) and 87 patients were Child-Pugh score 6 points group (CPS6 group). Methods In this study, Child-Pugh score 5 points group (CPS5 group) and 6 points group (CPS6 group)
were
compared
in
clinicopathologic 4
characteristics,
overall
survival,
ACCEPTED MANUSCRIPT
disease-free survival, type of recurrence, and survival after recurrence, and prognostic factors were identified with univariate and multivariate analyses.
RI PT
Clinicopathologic characteristics The clinicopathologic variables which were compared between the CPS5 group and the CPS6 group were age, sex, hepatitis virus markers, aspartate aminotransferase
SC
(AST) level, alanine aminotransferase (ALT) level, platelet count, indocyanine green retention rate at 15 minutes (ICG15R), prothrombin time (%), serum albumin level,
M AN U
total bilirubin level, direct bilirubin level, preoperative alpha-fetoprotein level (AFP), protein induced by Vitamin K absence or antagonists-II (PIVKAII), tumor size, number of tumors, Pathological portal vein involvement (pvp), Pathological hepatic vein involvement (pvv), pathologic TNM stage, Milan criteria compatibility, and type
TE D
of hepatectomy.
Overall survival and DiseaseDisease-free survival The cumulative overall and disease-free survival for the CPS5 group and the CPS6
Log-rank test.
AC C
Prognostic Factors
EP
group were estimated using Kaplan–Meier method and were statistically analyzed by
To identify prognostic factors for survival and disease-free survival, the statistical differences for the clinicopathologic variables were evaluated using univariate and multivariate analysis. Univariate analysis was performed using Kaplan–Meier method and Log-rank test. Multivariate analysis was performed using the logistic regression analysis for the factors that were found to be significant by univariate 5
ACCEPTED MANUSCRIPT
analysis.
The Types of Recurrence Recurrence and survival rates after Recurrence
RI PT
In the Child-Pugh class A, the overall survival rates after recurrence and the types of recurrence classified by Milan criteria were calculated in relation to CPS5 and CPS6.
Statistical Analysis
SC
The significant differences of clinicopathologic characteristics were assessed by Chi-square test and Student’s t test. The cumulative overall and disease-free survival
M AN U
was generated using Kaplan-Meier method and was compared using Log-rank test. Univariate analysis was performed using Kaplan–Meier curves and Log-rank test, Multivariate analysis was performed using the logistic regression analysis. All statistical analysis in this study was performed with Stat View 5.0. P value < 0.05
TE D
was defined as statistical significance.
RESULTS
EP
Clinicopathologic characteristics
Table 1 summarized the clinicopathologic characteristics of both the CPS5 group
AC C
and the CPS6 group. Serum PIVKA II level and tumor size showed the statistical significance between the CPS5 group and the CPS6 group among the tumor factors (P=0.0248 and P=0.382). On the other hand, except for the platelet count, most of the hepatic function including AST, ALT, ICG15R, prothrombin time (%), serum albumin level, total bilirubin level, direct bilirubin level of the CPS5 group were significantly better than those of the CPS6 group. 6
ACCEPTED MANUSCRIPT
Overall survival and DiseaseDisease-free survival One hundred forty-three patients in Child-Pugh class A was died after
RI PT
hepatectomy during the observation period. The causes of death were cancer recurrence in 82 patients, liver failure including hospital death in 39, and other diseases in 22.
Overall survival rates at 1, 2, and 5 years of 361 patients were 89.2,
SC
79.4, and 60.7%, respectively.
The cumulative survival curves and the disease-free survival curves in the CPS5
M AN U
group and the CPS6 group were shown in Figure 1, 2, respectively. The overall survival rates at 1/2/5 years of the CPS5 group and the CPS6 group were 91.4/83.2/63.8% and 82.7/68.8/52.3%, respectively. The disease-free survival rates at 1/2/5 years of the CPS5 group and the CPS6 group were 68.6/51.8/30.7% and
TE D
43.3/25.5/12.3%, respectively .These showed that the CPS5 group was significantly better than the CPS6 group in overall survival and disease-free survival. Prognostic factors
EP
Univariate analysis showed that hepatitis C infection (P=0.0242), AST (P
S0002-9610(14)00212-8
DOI:
10.1016/j.amjsurg.2014.03.009
Reference:
AJS 11167
To appear in:
The American Journal of Surgery
Received Date: 5 June 2013 Revised Date:
18 March 2014
Accepted Date: 28 March 2014
Please cite this article as: Okajima C, Arii S, Tanaka S, Matsumura S, Ban D, Ochiai T, Irie T, Kudo A, Nakamura N, Tanabe M, Prognostic role of Child-Pugh score 5 and 6 in hepatocellular carcinoma patients who underwent curative hepatic resection, The American Journal of Surgery (2014), doi: 10.1016/j.amjsurg.2014.03.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Prognostic role of ChildChild-Pugh score 5 and 6 in hepatocellular carcinoma
Chisato Okajima, M.D.,* Shigeki Arii, M.D. Ph.D.,*
RI PT
patients who underwent curative hepatic resection
Shinji Tanaka, M.D., Ph.D., F.A.C.S., Satoshi Matsumura, M.D., Ph.D.,
Daisuke Ban, M.D., Ph.D., Takanori Ochiai, M.D., Ph.D., Takumi Irie, M.D., Ph.D.,
SC
Atsushi Kudo, M.D., Ph.D., Noriaki Nakamura, M.D., Ph.D.,
M AN U
Minoru Tanabe, M.D., Ph.D.
Department of Hepato-Biliary-Pancreatic Surgery, Tokyo Medical and Dental
*Corresponding author: Shigeki Arii, M.D. Ph.D.
EP
Chisato Okajima, MD
TE D
University
Department of Hepato-Biliary-Pancreatic Surgery,
AC C
Tokyo Medical and Dental University, Graduate School of Medicine, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, JAPAN Tel: +81-3-5803-5928
Fax: +81-3-5803-0263
E-mail: [email protected] E-mail: [email protected] 1
ACCEPTED MANUSCRIPT
Abstract Background: It is unclear whether Child-Pugh score discriminates a prognosis of the Child-Pugh A
RI PT
patients who underwent hepatic resection for hepatocellular carcinoma. Methods: Between April 2000 and March 2011, 328 patients with Child-Pugh A underwent curative hepatectomy were divided into 2 groups; the CPS5 (n=253) and CPS6 (n=75) groups were compared. Results: Overall survival rates (1/2/5 years of the CPS5 and CPS6 groups were 90.9/82.5/62.4% and
SC
80.6/68.0/47.6%) and disease-free survival rates (67.6/51.8/30.1% and 36.9/16.0/5.9%) showed that the CPS5 group was significantly better than the CPS6 group. Multivariate analysis revealed that Child-Pugh score at overall survival (P=0.0125) and disease-free survival (P=0.0103) were significant
M AN U
prognostic factors.
Conclusions: Overall and disease-free survival in Child-Pugh A indicated quite difference between CPS5 and CPS6 group. Namely, CPS5 and CPS6 may be a useful prognostic marker of hepatocellular carcinoma patients with hepatic resection.
AC C
EP
TE D
Key words: Hepatocellular carcinoma, Child-Pugh score, Prognosis, Milan criteria
ACCEPTED MANUSCRIPT
ABSTRACT Background: It is unclear whether Child-Pugh score discriminates a prognosis of the
RI PT
Child-Pugh A patients who underwent hepatic resection for hepatocellular carcinoma.
Methods: Between April 2000 and March 2011, 361 patients with Child-Pugh A who
SC
underwent curative hepatectomy were divided into 2 groups; the CPS5 (n=274) and
M AN U
CPS6 (n=87) groups were compared.
Results: Overall survival rates (1/2/5 years of the CPS5 and CPS6 groups were 91.4/83.2/63.8% and 82.7/68.8/52.3%) and disease-free survival rates (68.6/51.8/30.7% and 43.3/25.5/12.3%) showed that the CPS5 group was significantly better than the
TE D
CPS6 group. Multivariate analysis revealed that Child-Pugh score at overall survival (P=0.0042) and disease-free survival (P=0.0131) were significant prognostic factors.
EP
Conclusions: Overall and disease-free survival in Child-Pugh A indicated quite difference between CPS5 and CPS6 group. Namely, CPS5 and CPS6 may be a useful
AC C
prognostic marker of hepatocellular carcinoma patients with hepatic resection.
KEY WORDS
Hepatocellular carcinoma, Child-Pugh score, Prognosis, Milan criteria
INTRODUCTION 2
ACCEPTED MANUSCRIPT
The prognosis of hepatocellular carcinoma patients is affected mainly by the stage of the cancer and the hepatic function. Curative treatments and preserved liver function
RI PT
are needed to attain the better prognosis. Actually, HCC is usually occurred in the patients with chronic liver diseases, and then it is quite important issue to maintain the hepatic functional reserve.1-4 In this regard, liver transplantation may be the most
SC
effective treatment for HCC, however, the indication is limited to considerably early stage of the cancer and also donor shortage remains to be conquered. Under these
M AN U
circumstances, hepatic resection is a feasible treatment to be widely selected. 5-7 Up to now, there have been many studies which have clarified the prognostic factors of the HCC patients with hepatic resection.8-10 Among the pathological factors of the cancer, tumor number, tumor size, and vascular involvement are closely involved in
TE D
the prognosis of the HCC patients.11-13 As to an estimation of the hepatic functional reserve, Child-Pugh classification is widely used because of the simplicity and appropriateness.14 Not a few studies reported that the grade of Child-Pugh (C-P)
EP
classification is well correlated with the prognosis of the patients, and is then assumed to be a valuable predictor of HCC patients. Indeed, Child-Pugh A (C-P A)
AC C
patients showed a better survival rate than Child-Pugh B (C-P B) and C patients in general. However, Child-Pugh A is composed of score of 5 and 6. The former patients is thought to have a well preserved liver function , while the latter may be partially disturbed in the liver function, suggesting that these scores might influence the prognosis of the HCC patients with hepatic resection. Namely, it may not be always appropriate to estimate HCC patients with Child-Pugh A all together by disregarding 3
ACCEPTED MANUSCRIPT
the score.5 and 6. 15, 16 From this point of view we attempted to make clear the prognostic significance of
RI PT
Child-Pugh A score 5 and 6. The present study will provide the evidence indicating that Child-Pugh score 5 and 6 will clearly discriminate the prognosis of the patients
SC
with Child-Pugh A who underwent the curative hepatic resection for HCC.
METHODS
M AN U
Patients
Four hundred forty-five patients underwent initial hepatectomy for hepatocellular carcinoma at our institute between April 2000 and March 2011. Of these patients, Child-Pugh status was class A in 412 patients (92.6%), class B in 31 patients (6.9%),
TE D
and class C in 2 patients (0.4%).
Of the 412 patients classified as Child-Pugh class A, 361 patients who underwent curative hepatectomy were evaluated. The remaining 51 patients were excluded. The
EP
breakdown is; 20 patients underwent non-curative resection, and 31 patients were unknown in their outcome including information about recurrence.
AC C
These 361 patients were divided into two groups; 274 patients were Child-Pugh score 5 points group (CPS5 group) and 87 patients were Child-Pugh score 6 points group (CPS6 group). Methods In this study, Child-Pugh score 5 points group (CPS5 group) and 6 points group (CPS6 group)
were
compared
in
clinicopathologic 4
characteristics,
overall
survival,
ACCEPTED MANUSCRIPT
disease-free survival, type of recurrence, and survival after recurrence, and prognostic factors were identified with univariate and multivariate analyses.
RI PT
Clinicopathologic characteristics The clinicopathologic variables which were compared between the CPS5 group and the CPS6 group were age, sex, hepatitis virus markers, aspartate aminotransferase
SC
(AST) level, alanine aminotransferase (ALT) level, platelet count, indocyanine green retention rate at 15 minutes (ICG15R), prothrombin time (%), serum albumin level,
M AN U
total bilirubin level, direct bilirubin level, preoperative alpha-fetoprotein level (AFP), protein induced by Vitamin K absence or antagonists-II (PIVKAII), tumor size, number of tumors, Pathological portal vein involvement (pvp), Pathological hepatic vein involvement (pvv), pathologic TNM stage, Milan criteria compatibility, and type
TE D
of hepatectomy.
Overall survival and DiseaseDisease-free survival The cumulative overall and disease-free survival for the CPS5 group and the CPS6
Log-rank test.
AC C
Prognostic Factors
EP
group were estimated using Kaplan–Meier method and were statistically analyzed by
To identify prognostic factors for survival and disease-free survival, the statistical differences for the clinicopathologic variables were evaluated using univariate and multivariate analysis. Univariate analysis was performed using Kaplan–Meier method and Log-rank test. Multivariate analysis was performed using the logistic regression analysis for the factors that were found to be significant by univariate 5
ACCEPTED MANUSCRIPT
analysis.
The Types of Recurrence Recurrence and survival rates after Recurrence
RI PT
In the Child-Pugh class A, the overall survival rates after recurrence and the types of recurrence classified by Milan criteria were calculated in relation to CPS5 and CPS6.
Statistical Analysis
SC
The significant differences of clinicopathologic characteristics were assessed by Chi-square test and Student’s t test. The cumulative overall and disease-free survival
M AN U
was generated using Kaplan-Meier method and was compared using Log-rank test. Univariate analysis was performed using Kaplan–Meier curves and Log-rank test, Multivariate analysis was performed using the logistic regression analysis. All statistical analysis in this study was performed with Stat View 5.0. P value < 0.05
TE D
was defined as statistical significance.
RESULTS
EP
Clinicopathologic characteristics
Table 1 summarized the clinicopathologic characteristics of both the CPS5 group
AC C
and the CPS6 group. Serum PIVKA II level and tumor size showed the statistical significance between the CPS5 group and the CPS6 group among the tumor factors (P=0.0248 and P=0.382). On the other hand, except for the platelet count, most of the hepatic function including AST, ALT, ICG15R, prothrombin time (%), serum albumin level, total bilirubin level, direct bilirubin level of the CPS5 group were significantly better than those of the CPS6 group. 6
ACCEPTED MANUSCRIPT
Overall survival and DiseaseDisease-free survival One hundred forty-three patients in Child-Pugh class A was died after
RI PT
hepatectomy during the observation period. The causes of death were cancer recurrence in 82 patients, liver failure including hospital death in 39, and other diseases in 22.
Overall survival rates at 1, 2, and 5 years of 361 patients were 89.2,
SC
79.4, and 60.7%, respectively.
The cumulative survival curves and the disease-free survival curves in the CPS5
M AN U
group and the CPS6 group were shown in Figure 1, 2, respectively. The overall survival rates at 1/2/5 years of the CPS5 group and the CPS6 group were 91.4/83.2/63.8% and 82.7/68.8/52.3%, respectively. The disease-free survival rates at 1/2/5 years of the CPS5 group and the CPS6 group were 68.6/51.8/30.7% and
TE D
43.3/25.5/12.3%, respectively .These showed that the CPS5 group was significantly better than the CPS6 group in overall survival and disease-free survival. Prognostic factors
EP
Univariate analysis showed that hepatitis C infection (P=0.0242), AST (P
