Prognosis of Hepatocellular Carcinoma With Diabetes Mellitus After Hepatic Resection

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1 Prognosis of Hepatocellular Carcinoma With Diabetes Mellitus After Hepatic Resection YASUHARU IKEDA, MITSUO SHIMADA, HIROFUMI HASEGAWA, TOMONOBU GION, KIYOSHI KAJIYAMA, KEN SHIRABE, KATSUHIKO YANAGA, KENJI TAKENAKA, AND KEIZO SUGIMACHI We evaluated the effect of diabetes mellitus on the prognosis of hepatocellular carcinoma after an elective hepatic resection. Of the 342 patients who underwent a hepatic resection between April 1985 and March 1995, 87 (25.4%) were diabetic. Postoperative morbidity was more common among diabetics than among nondiabetics (36.0% vs. 22.5%, P.0239). The postoperative survival rate and the cancer-free survival rate were also better in patients without diabetes than in those with diabetes (P.0333, P.0149). The results of a multivariate analysis show diabetes mellitus to be an independent and prognostic indicator after a hepatic resection with hepatocellular carcinoma. According to the above findings, diabetes mellitus is thus considered to be a risk factor for prognosis after hepatic resection in patients with hepatocellular carcinoma. (HEPATOLOGY 1998;27: ) The influence of diabetes mellitus on the outcome of elective surgical procedures remains controversial. 1-4 We previously reported that diabetic patients who underwent elective hepatic resections developed a higher incidence of postoperative morbidity, but not a shorter long-term survival. 5,6 Recently, Adami et al. 7 reported diabetes mellitus to be a risk factor for carcinogenesis in primary liver cancer based on a cohort study. However, little proof has been found regarding the effect of diabetes mellitus on the long-term outcome of patients with hepatcellular carcinoma after a hepatic resection. Therefore, the purpose of this study is to clarify the effect of diabetes mellitus on the long-term survival after a hepatic resection for hepatocellular carcinoma. PATIENTS AND METHODS Between April 1985 and March 1995, 342 patients with hepatocellular carcinoma underwent a curative hepatic resection in the department of Surgery II, Kyushu University Hospital and affiliated hospitals. They ranged in age from 33 to 79 years (mean SD, years), and 275 (80.4%) were males. Liver cirrhosis was identified in 183 patients (53.5%). The methods of resection used included a trisegmentectomy in eight patients, a lobectomy in 84, a Abbreviations: HCC, hepatocellular carcinoma; AFP, -fetoprotein. From the Departments of Surgery II Kyushu University, Faculty of Medicine, Kyushu University, Fukuoka, Japan. Received September 22, 1997; accepted February 3, Address reprint requests to: Yasuharu Ikeda, M.D., Department of Surgery II, Kyushu University, Maidashi, Higashiku Fukuoka 812, Japan. Fax: Copyright 1998 by the American Association for the Study of Liver Diseases /98/ $3.00/0 segmentectomy in 52, a subsegmentectomy in 64, and a partial hepatectomy consisting of less than a subsegmentectomy in 134. The follow-up period ranged from 34 to 4,036 days (median, 1,278 days; 25th percentile, 724 days; 75th percentile, 2,012 days). Of these patients, 87 (25.4%) were diagnosed with diabetes. The definition of diabetes mellitus was a fasting serum glucose above 7.8 mmol/l (140 mg/dl), abnormal results for a 75-g oral glucose tolerant test, or the need for insulin or an oral antihyperglycemic drug to control glucose levels. The preoperative control of diabetes mellitus was done either by diet alone or in combination with subcutaneous injections of insulin to maintain the fasting glucose below 8.3 mmol/l (150 mg/dl) and the 24-hour urinary glucose excretion below 10 g. The preoperative, intraoperative, and postoperative variables in the patients who underwent a hepatic resection with (HCC) were compared (Table 1). The complications associated with increased morbidity were defined as liver failure, intractable ascites (which either had a poor response to ordinary diuretic therapy or required drainage because of tense ascites), intractable pleural effusion that required two or more thoracocenteses or continuous drainage, intraperitoneal infection, a hemorrhage requiring reoperation, a major bile leakage, and gastrointestinal bleeding. The survival rate and the recurrence-free survival rate after a hepatic resection were compared with use of various clinicopathological variables (Tables 2 and 3). The most important factors were: sex; age; diabetes mellitus; the viral status such as hepatitis B and C virus; the liver function test results such as the levels of bilirubin, albumin, glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, platelet, indocyanine green retention rate at 15 minutes, the -fetoprotein (AFP) level, the histological findings including the maximum tumor diameter, tumor differentiation, surgical margin, capsular formation, invasion to the portal vein, intrahepatic metastases, and tumor stage. All significant variables, obtained by a univariate analysis, were then put into Cox s proportional hazard model to identify any independent variables closely related to the survival rate and the recurrence-free survival rate after a hepatic resection (Tables 4 and 5). Of the 342 patients with hepatocellular carcinoma, 188 patients died with or without recurrence after undergoing a hepatic resection. In the patients that died, the numbers of noncancer and cancer death patients were 28 (14.9%) and 160 (85.1%). In the 28 noncancer death patients, 8 of 87 (9.2%) had diabetes and 20 of 255 (7.8%) did not have diabetes. The patients were strictly followed up after the hepatic resection. A monthly measurement of the AFP and protein levels induced by vitamin K absence-ii and monthly bedside ultrasonography were performed. Every 3 months, ultrasonography and dynamic computed tomography were performed by radiologists, and an angiographic examination was performed after admission when recurrence was strongly suspected. Statistical analyses were performed with use of the one-way analysis of variance and the 2 test. The survival curves were then obtained by the Kaplan-Meier method. Any significant differences in 1567

2 1568 IKEDA ET AL. HEPATOLOGY June 1998 survival and disease-free interval were determined with use of the log rank test. Cox s proportional hazard model was used for the multivariate analysis. P.05 was considered to be significant. TABLE 1. Perioperative Variables in Diabetic and Nondiabetic Patients Who Underwent Hepatic Resection With HCC Variables Diabetics (n 87) Nondiabetics (n 255) P Age (years) Sex (male:female) 81:6 194: Laboratory data Platelet count (10 4 /µl) Total bilirubin (mg/dl) Albumin (g/dl) AST (IU/L) ALT (IU/L) Globulin (%) Hepaplastin test (%) Cholesterol (mg/dl) Creatinine (mg/dl) ICG (%) fetoprotein (ng/dl) Associated conditions Cirrhosis (%) 40 (46.0) 143 (56.1).1075 Heart disease (%) 9 (10.3) 13 (5.1).1255 Hypertension (%) 22 (25.3) 41 (16.1).0773 Esophageal varices (%) 20 (23.0) 53 (20.8).6524 Operative procedures.2543 Trisegmentectomy (%) 0 (0) 8 (3.2) Bisegmentectomy (%) 23 (26.5) 61 (24.0) Segmentectomy (%) 9 (10.3) 43 (16.9) Subsegmentectomy (%) 18 (20.7) 46 (18.1) Partial resection (%) 37 (42.5) 97 (37.8) Specimen weight (g) Operation time (min) Blood loss (L) Complication (%) 27 (36.0) 60 (22.5).0239 Tumor diameter (cm) Histology.9566 Well (%) 12 (14.6) 36 (15.5) Moderately (%) 45 (54.9) 123 (53.0) Poorly (%) 25 (30.5) 73 (31.5) fc (%) 69 (79.3) 181 (71.0).1399 fc-inf (%) 57/69 (82.6) 159/181 (87.8).3870 vp (%) 23 (26.4) 76 (29.8).5499 im (%) 26 (29.9) 93 (36.5).2655 Surgical margin (mm) Abbreviations: AST, glutamic oxaloacetic transaminase; ALT, glutamic pyruvic transaminase; ICG, indocyanine green retention rate at 15 min; fc, microscopic capsular formation; fc-inf, microscopic intracapsular infiltration; vp, microscopic invasion to the portal vein; im, microscopic intrahepatic metastases. TABLE 2. Demographic Variables of Patients With HCC Regarding Survival Rate Variables 3-year Survival (%) P Sex 1:male (n 275) :female (n 67) 64.3 Age (yrs) 1: 65 (n 270) : 65 (n 72) 58.9 Diabetes mellitus 1:negative (n 255) :positive (n 87) 59.0 Hepatitis B surface antigen 0:negative (n 278) :positive (n 64) 65.1 HCV 0:negative (n 51) :positive (n 144) 64.3 Alcohol 0:negative (n 192) :positive (n 150) 65.5 Bilirubin (mg/dl) 0: 1.0 (n 284) : 1.0 (n 58) 59.1 Albumin (g/dl) 0: 3.5 (n 268) : 3.5 (n 74) 56.6 AST (IU/dL) 0: 100 (n 295) : 100 (n 47) 64.4 ALT (IU/dL) 0: 100 (n 232) : 100 (n 110) 71.3 Platelet (mm 3 ) 0: 100,000 (n 227) : 100,000 (n 115) 68.9 ICG (%) 0: 20 (n 228) : 20 (n 114) fetoprotein (ng/ml) 0: 100 (n 242) : 100 (n 100) 50.6 Tumor size (cm) 0: 5(n 271) : 5(n 71) 47.1 TW 0:negative (n 194) :positive (n 148) 68.4 Histology 1:well (n 48) :moderately (n 168) :poorly (n 98) 51.4 fc 0:absent (n 97) :present (n 241) 64.5 vp 0:absent (n 243) :present (n 99) 55.2 im 0:absent (n 223) :present (n 119) 49.2 RESULTS Table 1 exhibits the perioperative variables in diabetic and nondiabetic patients who underwent a hepatic resection of hepatocellular carcinoma. In regard to the preoperative laboratory data, no difference was observed between the two groups. However, a significant difference was seen between the two groups regarding the male-female ratio. As for the operative variables, none of the variables were statistically different between the two groups. The incidence of postoperative complications in diabetics was significantly higher than in nondiabetics (P.0239). In addition, the incidence of pathological factors such as tumor size, histology, the presence of a fibrous tumor capsule, tumor infiltration into the fibrous capsule, invasion into the portal vein, intrahepatic metastases, and surgical margin were almost identical in both groups.

3 HEPATOLOGY Vol. 27, No. 6, 1998 IKEDA ET AL TABLE 2. Continued Variables 3-year Survival (%) P Tumor stage 1:Stage I (n 68) :Stage II (n 152) :Stage III (n 87) :Stage IV-A (n 35) 33.4 NOTE. Tumor stage was determined according to the TNM classification. Abbreviations: HCV, anti-hepatitis C virus antibody; AST, glutamic oxaloacetic transaminase; ALT, glutamic pyruvic transaminase; ICG, indocyanine green retention rate at 15 min.; TW, surgical margin 5 mm; fc, microscopic capsular formation; vp, microscopic invasion to the portal vein; im, microscopic intrahepatic metastases. Table 2 shows the results of a univariate analysis used to identify the significant factors closely related to the survival rate after a hepatic resection in patients with HCC. The poor prognostic factors were found to include diabetes mellitus, an albumin value of 3.5 g/dl, an indocyanine green retention rate of 20% at 15 minutes, an AFP level of 100 ng/ml, a tumor size of 5 cm, a poorly differentiated histology, positive portal vein invasion, positive intrahepatic metastasis, and tumor stage. Table 4 shows the results of a multivariate analysis using Cox s proportional hazards model. Both diabetes and the presence of positive intrahepatic metastasis were selected as independent prognostic indicators after a hepatic resection for hepatocellular carcinoma. Table 3 shows the results of a univariate analysis used to identify the significant factors closely related to the recurrencefree survival rate after a hepatic resection in patients with HCC. The poor prognostic factors included diabetes mellitus, an albumin value of 3.5 g/dl, an indocyanine green retention rate of 20% at 15 minutes, an AFP level of 100 ng/ml, a poorly differentiated histology, positive intrahepatic metastasis, and tumor stage. Table 5 shows the results of a multivariate analysis using Cox s proportional hazards model regarding the recurrencefree survival rate. The presence of diabetes, positive intrahepatic metastasis, a poorly differentiated histology, and an AFP level of 100 ng/ml were selected as independent prognostic indicators after a hepatic resection for hepatocellular carcinoma. Figure 1 exhibits the overall survival after a hepatic resection among diabetic and nondiabetic patients. The 1-, 3-, 5-, and 10-year survival rates were 85.1%, 59.0%, 39.0%, and 12.6% for the patients with diabetes and 88.7%, 69.4%, 54.7%, and 24.6% for the nondiabetic patients (P.0333), respectively. The association between the diabetics and the recurrence-free survival of patients with hepatocellular carcinoma is shown in Figure 2. The 1-, 3-, and 5-year recurrencefree survival rates were 77.1%, 25.9%, and 14.8% for the patients with diabetes and 77.4%, 44.2%, and 30.3% for the nondiabetics (P.0149). DISCUSSION We reported that diabetic patients who underwent elective hepatic resections developed a higher incidence of morbidity. However, no change was observed in either the mortality rate or the long-term survival. 5 In this study, however, diabetic patients with hepatocellular carcinoma were found to be at a TABLE 3. Demographic Variables of Patients With HCC Regarding Recurrence-Free Survival Rate Variables 3-Year Recurrence-Free Survival (%) P Sex 1:male (n 275) :female (n 67) 38.5 Age (yrs) 1: 65 (n 270) : 65 (n 72) 45.1 Diabetes mellitus 1:negative (n 255) :positive (n 87) 25.9 Hepatitis B surface antigen 0:negative (n 278) :positive (n 64) 47.4 HCV 0:negative (n 51) :positive (n 144) 36.1 Alcohol 0:negative (n 192) :positive (n 150) 40.7 Bilirubin (mg/dl) 0: 1.0 (n 284) : 1.0 (n 58) 36.3 Albumin (g/dl) 0: 3.5 (n 268) : 3.5 (n 74) 30.2 AST (IU/dL) 0: 100 (n 295) : 100 (n 47) 23.5 ALT (IU/dL) 0: 100 (n 232) : 100 (n 110) 33.8 Platelet (mm 3 ) 0: 100,000 (n 227) : 100,000 (n 115) 34.3 ICG (%) 0: 20 (n 228) : 20 (n 114) fetoprotein (ng/ml) 0: 100 (n 242) : 100 (n 100) 28.2 Tumor size (cm) 0: 5(n 271) : 5(n 71) 33.8 TW 0:negative (n 194) :positive (n 148) 44.5 Histology 1:well (n 48) :moderately (n 168) :poorly (n 98) 28.2 fc 0:absent (n 97) :present (n 241) 37.4 vp 0:absent (n 243) :present (n 99) 34.0 im 0:absent (n 223) :present (n 119) 22.5 higher risk for morbidity and a shorter long-term survival after hepatic resection. Until recently, many investigators have reported on the prognostic factors related to the recurrence after a hepatic

4 1570 IKEDA ET AL. HEPATOLOGY June 1998 TABLE 3. Continued Variables 3-Year Recurrence-Free Survival (%) P Tumor stage 1:Stage I (n 68) :Stage II (n 152) :Stage III (n 87) :Stage IV-A (n 35) 20.0 NOTE. Tumor stage was determined according to the TNM classification. Abbreviations: HCV, anti-hepatitis C virus antibody; AST, glutamic oxaloacetic transaminase; ALT, glutamic pyruvic transaminase; ICG, indocyanine green retention rate at 15 min.; TW, surgical margin 5 mm; fc, microscopic capsular formation; vp, microscopic invasion to the portal vein; im, microscopic intrahepatic metastases. resection for hepatocellular carcinoma The liver cancer study group of Japan 8 reported the prognostic indicators of hepatocellular carcinoma after hepatic resection to include the AFP level, tumor size, number of tumors, accompanying cirrhosis, age, surgical curativity, and portal involvement. In this study, the presence of diabetes and positive intrahepatic metastasis were also selected as independent prognostic indicators after a hepatic resection for hepatocellular carcinoma based on a multivariate analysis using Cox s proportional hazards model. Adami and colleagues 7 reported diabetes mellitus to be a risk factor for primary liver cancer in a cohort study. In this paper, the recurrence-free survival rates (especially from 2 years after hepatectomy) for diabetic patients were significantly lower than for those without diabetes. These results suggest the possibility that the presence of diabetes may induce an interaction with liver cells and thereby stimulate mitogenesis or carcinogenesis. Increased cell proliferation is probably important in the development of at least some types of human cancer 14,15 and may also contribute to the excess risk for hepatocellular cancer in patients with chronic hepatitis B virus infection, alcoholic liver disease, and liver cirrhosis. 15,16 Both an abnormal glutathione metabolism and increased cytotoxity are known to be caused by H 2 O 2 in human umbilical vein endothelial cells cultured in a high glucose medium. 17 Free radicals mediate the endothelial cell dysfunction caused by FIG. 1. Overall survival after a hepatic resection among diabetic and nondiabetic patients. elevated glucose. 18 High glucose induces DNA damage in cultured human endothelial cells. 19 Cellular adhesion molecules mediating homotypic and heterotypic cellular interactions have also been implicated in the various stages of tumor progression and metastasis. 20 Patients with noninsulindependent diabetes mellitus are characterized by insulin resistance, compensatory hyperinsulinemia, and increased growth factor production. 21,22 Furthermore, the onset of clinical diabetes is also preceded by years of chronic hyperinsulinemia, with an elevated proportion of proinsulin and split products of proinsulin, molecules with some homology to insulin-like growth factor Insulin or its precursors have also been shown to interact with liver cells and to stimulate mitogenesis or carcinogenesis In conclusion, based on the above findings, diabetes mellitus appears to be a risk factor for prognosis after a hepatic resection in patients with hepatocellular carcinoma. However, differences in the treatment regimens for diabetes mellitus (by diet alone, oral antihyperglycemic drugs, or the subcutaneous injection of insulin) were not found to be risk factors for prognosis. TABLE 4. Results of a Multivariate Analysis With Use of Cox s Proportional Hazards Model in Patients Who Underwent Hepatic Resection With HCC Regarding Survival Rate Variables Coefficient SE Relative Risk P Diabetes im Abbreviation. im, microscopic intrahepatic metastases. TABLE 5. Results of a Multivariate Analysis With Use of Cox s Proportional Hazards Model in Patients Who Underwent Hepatic Resection With HCC Regarding Recurrence-Free Survival Rate Variables Coefficient SE Relative Risk P Diabetes im Histology AFP Abbreviation. im, microscopic intrahepatic metastases. FIG. 2. Recurrence-free survival after a hepatic resection among diabetic and nondiabetic patients.

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