- Email: [email protected]
Hepatic resection for hepatocellular carcinoma in the elderly1
Hepatic Resection for Hepatocellular Carcinoma in the Elderly Kazuhiro Hanazaki, MD, PhD, Shoji Kajikawa, MD, PhD, Nobuhiko Shimozawa, MD, Ko Shimada, MD, Manabu Hiraguri, MD, Naohiko Koide, MD, PhD, Wataru Adachi, MD, PhD, Jun Amano, MD, PhD Although the number of elderly people undergoing surgery for hepatocellular carcinoma (HCC) has increased because of the prolonged life expectancy rate, potential benefits of hepatectomy for elderly patients with HCC have not been fully delineated. STUDY DESIGN: Using medical records, surgical outcomes of HCC in 103 patients 70 years of age or older undergoing hepatic resection (older group) were clarified and compared with those of 283 patients younger than 70 years of age (younger group) in this retrospective study. Postresection prognostic factors were evaluated by multivariate analysis using Cox’s proportional hazards model. RESULTS: There were no significant differences in postoperative complication, operative mortality, and overall hospital death rates between the two groups. Overall 3- and 5-year survival rates for the older group and the younger group were 51.0% versus 55.2%, and 42.2% versus 40.0%, respectively (p⫽0.95). Disease-free 3- and 5-year survival rates for the older group and the younger group were 35.2% versus 37.6%, and 16.6% versus 24.2%, respectively (p⫽0.66). Multivariate analysis revealed that the presence of liver cirrhosis and vascular invasion were independently significant factors of poor overall survival. CONCLUSIONS: Selected elderly patients with HCC benefited from resection as much as young patients, and age by itself may not be a contraindication to surgery. Postresection longterm prognosis in the elderly was determined by the presence of liver cirrhosis and vascular invasion. (J Am Coll Surg 2001;192:38–46. © 2001 by the American College of Surgeons) BACKGROUND:
with HCC may have a superimposed surgical risk. But the strategy of surgical treatment of HCC in the elderly has remained obscure because there are only a few reports1,2,7-12 evaluating the results of hepatic resection in elderly patients with or without underlying cirrhosis, all dealing with less than 40 cases of hepatic resection. Several investigators1,7,12 reported that outcomes of surgical treatment of HCC in elderly patients were as satisfactory as those in younger patients. Limiting the analysis of cirrhotic patients, however, the prognoses of elderly patients after hepatic resection were less favorable than those for younger patients.2 So the potential benefits of hepatectomy for elderly patients with HCC have not been fully delineated. The aim of this study was to clarify the surgical outcomes of HCC in 103 patients 70 years of age or older, undergoing hepatic resection, and to compare them with those of 283 patients younger than 70 years of age. In addition, prognostic factors in the elderly affecting overall survival were determined by univariate and multivariate analysis. To our knowledge, this is one of the
In recent years, the number of the elderly who have undergone surgery for hepatocellular carcinoma (HCC) has increased because of advanced safe hepatic resection and prolonged life expectancy rates. Because elderly patients have associated diseases in addition to the primary disease more often than younger patients, old age has been regarded as an adverse factor for hepatic resection.1,2 Experimentally, the age-associated decline in liver function may be caused by mechanisms operating on the cellular level,3 such as age-associated mitochondrial damage in hepatocytes,4 functional decline of Kupffer cells,5 and defects of the respiratory chain in the liver during aging.6 So, hepatic resection in aged patients No competing interests declared.
Received March 3, 2000; Revised June 6, 2000; Accepted September 11, 2000. From the Second Department of Surgery, Shinshu University School of Medicine, Matsumoto, Japan. Correspondence address: Kazuhiro Hanazaki, MD, Second Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
© 2001 by the American College of Surgeons Published by Elsevier Science Inc.
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largest series of hepatic resections for elderly patients with HCC in a single institution reported to date. METHODS Between December 1983 and December 1997, 451 consecutive patients with newly diagnosed HCC were managed in the Second Department of Surgery of Shinshu University Hospital. Sixty-five patients were deemed unsuitable for hepatic resection mainly because of very advanced tumors or poor hepatic functional reserve, so they were excluded from this study. The other 386 consecutive patients who underwent hepatic resection for HCC were enrolled in this study. Our manuscript13 on the entire population of the surgical group of 386 patients has been published, and this study should be cited as a subset of analysis of that other manuscript. Among the patients, 103 (26.7%) were 70 years of age or older (the older group). Clinical features of these patients were investigated and compared with those of the other 283 patients (73.3%) who were younger than 70 years of age (the younger group). Resectability rates in all patients, the older group, and the younger group were 86%, 84%, and 88%, respectively. A curative operation was defined as an operation during which all tumors were microscopically resected. Operative death was defined as death within 30 day after operation (not only death in the operating room), and hospital death was defined as death within the same hospital admission for surgery, including operative death. During the same period in our hospital, 434 patients (98 patients [22.6%] in the older group and 336 [77.4%] in the younger group) were treated by transarterial chemoembolization (TACE) and 168 patients (52 patients [31.1%] in the older group and 116 [68.9%] in the younger group) were treated by percutaneous ethanol injection treatment as initial treatment for 602 patients with unresectable HCC. Thorough followup after hepatic resection was performed for all patients. Monthly measurements of biochemical liver function and ␣-fetoprotein were performed. Every 3 months, ultrasonography and dynamic CT were performed, and angiography was performed after admission when recurrence was strongly suspected. Statistics
All data are expressed as mean⫾SD. Overall survival was measured in 386 patients, including operative patients, hospital deaths, and noncurative patients from
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the date of operation to the time of last followup (June 30, 1999), or death. Disease-free survival was evaluated in the group of 327 patients (80 patients [77.8%] in the older group and 247 [87.3%] in the younger group) with curative resection who were discharged from the hospital from the date of operation to the time of recurrence. Statistical differences were analyzed using the chisquare test with Fisher’s exact test and the unpaired Student’s t-test. Analysis of overall survival and disease-free survival was calculated by the Kaplan-Meier method and the differences in survival between the groups were compared using the log-rank test. Results of the univariate analysis helped to substantially reduce the number of prognostic factors. Only a few significant variables of prognostic factors were used in the subsequent multivariate analysis using Cox’s proportional hazards model.14 Statistical analysis was done using the Stat View (version 5.0; Abacus Concepts, Inc, Berkeley, CA) software for Macintosh computer (Apple Computer, Inc, Cupertino, CA). A p value ⬍0.05 was considered significant. RESULTS Clinical features
Preoperative conditions are shown in Table 1. The mean age in the older group (73.1⫾8.0 years; range 70 to 81 years) was significantly higher than that in the younger group (59.6⫾7.4 years; range 31 to 69 years) (p⬍ 0.0001). The number of women in the older group was higher than in the younger group, although this was not significant (p⫽0.06). Although the incidences of Child classification and pTNM staging15 did not differ significantly between the two groups, the incidence of hepatitis C in the older group (55.4%) was significantly higher than that in the younger group (40.7%). There were no significant differences in the incidences of preoperative TACE and portal vein embolization16 between the two groups. Preoperative serologic liver function and AFP did not significantly differ between the two groups. Comorbid medical conditions were significantly much more common in the elderly. The types of hepatectomy are shown in Table 2. A resection was called “major” if three segments or more were removed, according to Couinaud’s classification.17 The Pringle maneuver,18 hemihepatic vascular occlusion,19 and the total vascular exclusion20 technique were performed as ischemic maneuvers to minimize intraoperative blood loss. The incidences of curative resection, major hepatectomy, and type of ischemic maneuver did not differ significantly
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Table 1. Preoperative Conditions Characteristics
Age (y) Gender (male:female) Hepatitis type (n) (%) Hepatitis C Hepatitis B Hepatitis non-C and non-B Unknown Child classification (n) (%) Child class A Child class B Child class C pTNM staging (n) (%) Stage I Stage II Stage III Stage IVa Stage IVb Preoperative TACE (n) (%) Preoperative PVE (n) (%) Liver function AFP (ng/mL) GOT (U/L) GPT (U/L) Total bilirubin (mg/dL) Albumin (g/dL) ICG-15 (%) Comorbid condition (n) (%) Cardiovascular Respiratory Diabetus mellitus
Age > 70 y (n ⴝ 103)
73.1 ⫾ 8.0 71:32
Age < 70 y (n ⴝ 283)
59.6 ⫾ 7.4 222:61
p Value
⬍ 0.0001 0.06
57 (55.4%) 19 (18.4%) 9 (8.7%) 18 (17.5%)
115 (40.7%) 67 (23.7%) 14 (4.9%) 87 (30.7%)
76 (73.8%) 27 (26.2%) 0 (0%)
226 (79.9%) 56 (19.8%) 1 (0.3%)
3 (2.9%) 47 (45.6%) 40 (38.8%) 12 (11.7%) 1 (1.0%) 33 (32.0%) 3 (2.9%)
22 (7.8%) 122 (43.1%) 81 (28.6%) 58 (20.5%) 0 (0%) 105 (37.1%) 5 (1.8%)
0.10 0.73 0.063 0.052 0.27 0.40 0.45
2,480 ⫾ 12,948 58 ⫾ 38 56 ⫾ 32 1.0 ⫾ 0.6 3.7 ⫾ 0.5 21 ⫾ 11
0.36 0.90 0.061 0.93 0.90 0.90
3,972 ⫾ 13,074 58 ⫾ 30 48 ⫾ 32 1.0 ⫾ 0.4 3.7 ⫾ 0.4 21 ⫾ 9 25 (24.3%) 20 (19.4%) 32 (31.1%)
31 (11.0%) 21 (7.4%) 24 (8.5%)
0.011 0.33 0.22 0.0097 0.21 0.21 ⬎ 0.99
0.0017 0.0012 ⬍ 0.0001
Values for liver function and age are mean ⫾ standard deviation AFP, alpha-fetoprotein; GOT, glutamic oxaloacetic transaminase; GPT, glutamic pyruvic transaminase; ICGR-15, indocyanine green retention rate at 15 minutes; PVE, portal vein embolization; TACE, transarterial chemoembolization.
between the two groups. Intraoperative data are shown in Table 3. The maximum tumor diameter in the older group was larger than that in the younger group, although not significantly (p⫽0.056). Sixty-three patients (61.2%) received intraoperative blood transfusion in the older group. Intraoperative blood loss, blood transfusion, total clamping time, and resected liver weight did not differ significantly between the two groups. In the older group, the overall incidence of postoperative complications was 28.2%, and 10 patients among them had hospital deaths (9.7%), including 5 (4.9%) operative deaths (within 1 month of operation). All five patients with operative mortality had liver cirrhosis (Child class A in two and B in three). There were
no significant differences in the incidence of postoperative complications, operative mortality rates within 1 month, or overall hospital death rates between the two groups (Table 3). Pathologic features
The pathologic findings are shown in Table 4. A resected stump with a margin less than 5mm from the edge of the tumor was defined as tw (⫹) according to The General Rules for the Clinical and Pathological Study of Primary Liver Cancer.21 The incidence of patients with cirrhosis in the older group was higher than in the younger group, although this was not significant (p⫽0.13). Although the rate of multiple tumors tended to be higher in the
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Table 2. Type of Liver Resection Type of resection
Major hepatectomy Right trisegmentectomy Extended right hepatectomy Right hepatectomy Extended left hepatectomy Left hepatectomy Total Minor hepatectomy Left lateral segmentectomy Bisegmentectomy VI and VII Bisegmentectomy V and VIII Segmentectomy Wedge resection Total Major/Minor Ischemic manuever Pringle method Hemihepatic vascular occlusion Total vascular exclusion Nonischemic maneuver Curativity Curative hepatic resection Noncurative hepatic resection
Age > 70 y (n ⴝ 103)
Age < 70 y (n ⴝ 283)
0 3 7 0 6 16 (15.5%)
1 6 20 7 12 46 (16.3%)
13 7 3 16 48 87 (84.5%) 16/87
14 5 9 74 135 237 (83.7%) 46/237
69 (67.0%) 15 (14.6%) 0 (0%) 19 (18.4%)
178 (62.9%) 61 (21.6%) 2 (0.7%) 42 (14.8%)
89 (86.4%) 14 (13.6%)
265 (93.6%) 23 (6.4%)
older group, the number of tumors did not differ significantly between the two groups. The incidence of tumor thrombosis in the portal vein (vp), tumor thrombosis in the hepatic vein (vv), and tw (⫹) also did not differ significantly between the two groups. Recurrence
Recurrence rates in the older group and the younger group were 57.2% and 54.8%, respectively (p⫽0.73).
p Value
⬎ 0.99 0.47 0.15 ⬎ 0.99 0.43 0.12
The most frequent recurrence site was remnant liver in both groups. The rates of recurrence within 1 year, 3 years, and 5 years between the older group and the younger group were 42.4% versus 28.4% (p⫽0.071), 79.7% versus 78.4% (p⬎0.99), and 96.6% versus 91.0% (p⫽0.25), respectively. The types of treatment for the patients with recurrent HCC are shown in Table 5. Repeat hepatic resection for recurrence in the older and the
Table 3. Intraoperative and Postoperative Data Data
Intraoperative parameters Intraoperative blood loss (mL) Intraoperative blood transfusion (mL) Total clamping time (min) Resected liver weight (g) Maximum diameter of tumor (cm) Postoperative conditions Operative death Hospital death Postoperative complication Values are mean ⫾ standard deviation.
Age > 70 y (n ⴝ 103)
Age < 70 y (n ⴝ 283)
p Value
1,476 ⫾ 1,455 642 ⫾ 855 34 ⫾ 27 298 ⫾ 376 5.5 ⫾ 3.7
1,959 ⫾ 2,416 912 ⫾ 1397 34 ⫾ 25 304 ⫾ 470 4.6 ⫾ 3.6
0.10 0.11 0.92 0.92 0.056
5 (4.9%) 10 (9.7%) 29 (28.2%)
11 (3.9%) 17 (6.0%) 66 (23.3%)
0.77 0.26 0.35
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Table 4. Pathologic Findings after Hepatectomy Age > 70 y, (n ⴝ 103) Parameters
Cirrhosis Present Absent Number of tumors 1 2 3 ⱖ4 tw ⬍ 5 mm ⱖ 5 mm Vascular invasion vp Positive Negative vv Positive Negative
Age < 70 y, (n ⴝ 283)
n
%
n
%
p Value
47 56
45.6 54.4
155 128
54.8 45.2
47 14 5 37
45.6 13.6 4.9 35.9
145 43 20 75
51.2 15.2 7.1 26.5
63 40
61.2 38.8
153 130
54.1 45.9
24 79
23.3 76.7
67 216
23.7 76.3
12 91
11.7 88.3
23 260
8.1 91.9
0.13
0.36 0.75 0.64 0.077 0.25
⬎ 0.99
0.32
tw, resected stump with a margin from the edge of the tumor; vp, tumor thrombosis in the portal vein; vv, tumor thrombosis in the hepatic vein.
younger groups occurred in 9 patients (15.2%) and 29 patients (18.7%), respectively. The therapeutic type for recurrent HCC did not differ between the two groups. Survival
At present, 31 patients (30.1%) are alive (10 without recurrence and 21 with recurrence); 1 (1.0%) for more than 10 years and 16 (15.5%) for more than 5 years. Only one patient surviving more than 10 years and 11 (68.8%) of 16 patients surviving more than 5 years experienced recurrent HCC after operation. Six (54.5%) of 11 patients with recurrence surviving more than 5 years underwent repeat hepatic resection for recurrent HCC. In addition, 5 (55.6%) of 9 elderly patients with repeat hepatic resection survived more than 5 years after
initial hepatic resection. The one patient surviving more than 10 years also underwent repeat hepatectomy for recurrence 4 years after the initial hepatic resection and is doing well in disease-free survival without recurrence after the second hepatic resection. Among the patients alive at present, the incidences of survival without recurrence in the older and the younger groups are 32.3% and 46.7%, respectively (p⫽0.20). The incidences of 5-year and 10-year survivors did not differ significantly between the two groups. Mortality rates from other diseases in the older and the younger groups were 6.9% and 7.7%, respectively (p⬎0.99). The mean overall survivals after operation in the older group and the younger group were 33⫾29 months and
Table 5. Treatments for Recurrent Hepatocellular Carcinoma Age > 70 y, (n ⴝ 59)
Age < 70 y, (n ⴝ 155)
Therapeutic option
n
%
n
%
p Value
Transarterial chemoembolization Percutaneous ethanol injection treatment Repeat hepatic resection Hepatic arterial infusion chemotherapy Systemic chemotherapy Radiation Microwave coagulation therapy Observation
38 15 9 6 6 2 0 2
64.4 25.4 15.3 10.2 10.2 3.4 0 3.4
121 43 29 35 12 9 1 17
78.1 27.7 18.7 22.6 7.7 5.8 0.7 11.0
0.61 0.50 0.84 0.24 0.26 ⬎ 0.99 ⬎ 0.99 0.26
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cant prognostic factors were selected by univariate analysis. The poor prognostic factors were presence of liver cirrhosis, vascular invasion, glutamic oxaloacetic transaminase of ⱖ55 U/L, intraoperative blood loss of ⱖ1500 mL, and intraoperative blood transfusion of ⱖ600 mL. Multivariate analysis of prognostic factors that reached statistical significance in univariate analysis (p⬍0.05) revealed that liver cirrhosis and vascular invasion were independently significant factors of poor survival.
Figure 1. Disease-free survival of elderly and younger patients after hepatic resection.
39⫾33 months, respectively (p⫽0.16). Disease-free and overall survival rates after hepatic resection did not differ significantly between the two groups. Disease-free 1-, 3-, and 5-year survival rates between the older group and the younger group were 75.6% versus 77.8%, 35.2% versus 37.6%, and 16.6% versus 24.2%, respectively (p⫽0.66) (Fig. 1). Overall 1-, 3-, and 5-year survival rates between the older group and the younger group were 83.4% versus 85.1%, 51.0% versus 55.2%, and 42.2% versus 40.0%, respectively (p⫽0.95) (Fig. 2). Prognostic factors in the elderly
Table 6 shows the results of a univariate analysis used to identify significant prognostic factors on overall survival in patients with HCC after hepatectomy. Five signifi-
Figure 2. Overall survival of elderly and younger patients after hepatic resection.
DISCUSSION Patient age is a useful prognostic factor for prediction of posthepatectomy liver failure.22 In general, with the elderly, surgeons tend to use less aggressive procedures because of higher comorbidity rates.11 Indeed, preoperative comorbid conditions such as cardiovascular disease, respiratory disorders, and diabetes mellitus were more common in the elderly, as described previously.1,11,12 But we performed aggressive operations regardless of age because of the similar resectability rates of 84% in the older group (ⱖ70 years of age) and 88% in the younger group (⬍70 years of age). As a result, we found that postoperative complications, operative mortality rates, and overall and disease-free survival rates after hepatic resection did not differ between the older group and the younger group. Morbidity rates (28.2%) and hospital mortality rates (9.7%) in the elderly of this study were similar with those in the previous studies.1,7,9,11,12 In addition, the preoperative and intraoperative hepatic conditions, surgical methods, and pathologic findings in the older group were similar to those in the younger group. Hepatic resection for HCC is safe in selected elderly patients, and the improved results in recent years indicate that more elderly patients could benefit from surgical management.12 Bismuth23 suggested that it is important to know that one can carry out a full screening of elderly patients with HCC to select those who will benefit most from resection, and that age by itself, is not a contraindication to surgery. Our results indicate that the surgical strategy for elderly patients with HCC should be identical to that in younger patients, as reported previously.24 But it must be acknowledged that there has to be a fair bit of selection that has gone into choosing these patients for hepatic resection because that selection may not have happened in the surgeon’s office, but may have happened because of a medical oncologist’s feelings about suitability for refer-
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Table 6. Prognostic Factors of Overall Survival by Univariate Analysis Variables
Age (y) ⱖ 75 (n ⫽ 28) ⬍ 75 (n ⫽ 75) Gender Male (n ⫽ 71) Female (n ⫽ 32) Child’s classification A (n ⫽ 76) B (n ⫽ 27) pTNM staging I (n ⫽ 3) II (n ⫽ 47) III (n ⫽ 40) VI (n ⫽ 13) Liver cirrhosis Present (n ⫽ 47) Absent (n ⫽ 56) Diabetus mellitus Present (n ⫽ 32) Absent (n ⫽ 71) Alpha-fetoprotein (ng/mL) ⱖ 4,000 (n ⫽ 22) ⬍ 4,000 (n ⫽ 81) Glutamic oxaloacetic transaminase ⱖ 55 U/L (n ⫽ 42) ⬍ 55 U/L (n ⫽ 61) Glutamic pyruvic transaminase ⱖ 50 U/L (n ⫽ 43) ⬍ 50 U/L (n ⫽ 60) Total bilirubin (mg/dL) ⱖ 1.0 (n ⫽ 42) ⬍ 1.0 (n ⫽ 61) Albumin (g/dL) ⱖ 3.5 (n ⫽ 73) ⬍ 3.5 (n ⫽ 30) Indocyanine green retention rate at 15 minutes (%) ⱖ 20 (n ⫽ 48) ⬍ 20 (n ⫽ 55) Intraoperative blood loss (mL) ⱖ 1500 (n ⫽ 43) ⬍ 1500 (n ⫽ 60) Intraoperative blood transfusion ⱖ 600 mL (n ⫽ 48) ⬍ 600 mL (n ⫽ 55) Total clamping time (min) ⱖ 35 (n ⫽ 53) ⬍ 35 (n ⫽ 50)
50% Survival in months
Table 6. (Continued) Variables
p Value
0.87 72.1 46.1 0.098 31.2 83.8 0.21 46.1 28.2 0.15 90.1 70.8 27.1 28.2 0.0099* 28.9 83.8 0.85 46.1 37.4
Number of tumors Solitary (n ⫽ 75) Multiple (n ⫽ 28) Tumor size (cm) ⱖ 5.5 (n ⫽ 39) ⬍ 5.5 (n ⫽ 64) Weight of resected liver (g) ⱖ 300 (n ⫽ 30) ⬍ 300 (n ⫽ 73) Tw (mm) ⬍ 5 (n ⫽ 63) ⱖ 5 (n ⫽ 40) Vascular invasion Present (n ⫽ 30) Absent (n ⫽ 73) Preoperative transarterial chemoembolization Present (n ⫽ 33) Absent (n ⫽ 70)
50% Survival in months
p Value
0.41 70.8 34.7 0.55 41.1 52.2 0.65 21.9 41.1 0.21 37.4 83.8 0.011* 16.7 70.8 0.69 34.7 52.2
*Significant prognostic factors by univariate analysis. Tw, microscopic resected stump with a margin from the edge of the tumor.
0.48 25.8 46.1 0.011* 28.9 70.8 0.58 41.1 46.1 0.95 46.1 41.1 0.11 46.1 28.9 0.099 31.3 72.1 0.0058* 28.2 70.8 0.0093* 28.9 72.1 0.47 37.4 70.8
ral. For instance, it might be that the results in the elderly look better because there was a bias to include females with lesser stage of tumor in this study. So further examination may be necessary to conclude definitely whether age has any influence on outcomes of resection for HCC. Until now, postresection prognostic factors in the elderly remained to be proved. There also has been little attention to the prognostic factors evaluated by multivariate analysis. We found that multivariate analysis revealed the presence of liver cirrhosis and vascular invasion as independently significant factors of poor overall survival. Liver cirrhosis and vascular invasion are relatively common prognostic factors of poor survival in all patients with HCC after hepatectomy.25-27 Cirrhosis leads to not only poor longterm survival, but also to high mortality in the elderly. Nagasue and associates1 suggested that elderly patients with Child class B and C cirrhosis are not good candidates for hepatic resection because of the marked risk of operative deaths within 1 month. Elderly patients with cirrhotic liver cancer had an unacceptable mortality of 44% after major hepatic resection.11 Also, in our study, all five elderly patients with operative mortality had cirrhosis (Child class A in two and B in three).
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Postoperative tumor recurrence is the most serious problem after curative resection of HCC. The older group showed a high recurrence rate (57.2%) as did the younger group; 93.1% of the deceased patients died of HCC, and death from other disease was only 6.9%. Because most patients died of recurrent HCC, treatment strategies for recurrent HCC may be the most crucial factor in prolonging survival. Repeat hepatic resection can prolong survival time after recurrence of HCC.28-31 We found that 54.5% of elderly patients with recurrence surviving more than 5 years had repeat hepatic resection. In addition, 55.6% of elderly patients with repeat hepatic resection survived more than 5 years after the initial hepatectomy. One patient surviving more than 10 years in the older group also underwent repeat hepatectomy and is doing well in disease-free survival without recurrence after repeat resection. Shirabe and colleagues28 supported our results that four of five patients (80%) with solitary recurrence who underwent a second hepatic resection had no recurrence after the second resection. So, we strongly recommend repeat hepatic resection for recurrent HCC to achieve better survival, even when the patient’s age is 70 years or more at initial hepatectomy. But repeat hepatectomies are limited in patients with advanced tumors and low functional reserve of the remnant liver, especially cirrhotic patients.30 Our results also showed that resectability rates of recurrent HCC between the older and the younger groups were only 15.3% and 18.7%, respectively. The most popular treatment for recurrent HCC was TACE, followed by percutaneous ethanol injection treatment in both the elderly and the young patients (Table 5). We now suggest that therapeutic strategy for elderly patients with postresection recurrent HCC should be the same as that in younger patients. In our present strategy of treatment for recurrent HCC regardless of age, if repeat hepatectomy was not indicated because of impaired liver function, nonsurgical treatments such as TACE, percutaneous ethanol injection treatment, and hepatic arterial infusion chemotherapy should be selected to obtain better results, even when the treatments are not curative.13 The overall and disease-free 5-year survival rates in the elderly patients with HCC were 42.2% and 24.2%, respectively. Although there are only three reports1,7,12 of the overall 5-year survival rate (24.3%,1 29%,12 and 75.9%7) after hepatic resection in patients aged 70 years or older with HCC, these previous reports consisted of only 31 patients,12 32 patients,1 and 39 patients.7 The
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5-year survival rate after hepatic resection in this largest series composed of 103 patients was satisfactory and was better than we expected. In conclusion, selected elderly patients with HCC benefitted from resection as much as young patients, and age by itself may not be a contraindication to surgery. The survival of elderly patients with HCC should be stratified by the presence of cirrhosis and vascular invasion. REFERENCES 1. Nagasue N, Chang YC, Takemoto Y, et al. Liver resection in the aged (seventy years or older) with hepatocellular carcinoma. Surgery 1993;113:148–154. 2. Lui WY, Chau GY, Wu CW, et al. Surgical resection of hepatocellular carcinoma in elderly cirrhotic patients. Hepatogastroenterology 1999;46:640–645. 3. Dice JF. Cellular theories of aging as related to the liver. Hepatology 1985;5:508–513. 4. Sastre J, Pallardo FV, Pla R, et al. Aging of the liver: ageassociated mitochondrial damage in intact hepatocytes. Hepatology 1996;24:1199–1205. 5. Brouwer A, Barelds RJ, Knook DL. Age-related changes in the endocystic capacity of rat liver Kupffer and endothelial cells. Hepatology 1985;5:362–366. 6. Muller-Hocker J, Aust D, Rohrbach H, et al. Defects of the respiratory chain in the normal human liver and in cirrhosis during aging. Hepatology 1997;26:709–719. 7. Takenaka K, Shimada M, Higashi H, et al. Liver resection for hepatocellular carcinoma in the elderly. Arch Surg 1994;129: 846–850. 8. Yanaga K, Kanematsu T, Takenaka K, et al. Hepatic resection for hepatocellular carcinoma in elderly patients. Am J Surg 1988;155:238–241. 9. Fortner JG, Lincer RM. Hepatic resection in the elderly. Ann Surg 1990;211:141–145. 10. Ezaki T, Yukaya H, Ogawa Y. Evaluation of hepatic resection for hepatocellular carcinoma in the elderly. Br J Surg 1987;74: 471–473. 11. Koperna T, Kisser M, Schulz F. Hepatic resection in the elderly. World J Surg 1998;22:406–412. 12. Poon RTP, Fan ST, Lo CM, et al. Hepatocellular carcinoma in the elderly: Results of surgical and nonsurgical management. Am J Gastroenterol 1999;94:2460–2466. 13. Hanazaki K, Kajikawa S, Shimozawa N, et al. Survival and recurrence after hepatic resection of 386 consecutive patients with hepatocellular carcinoma. J Am Coll Surg 2000;191:381–388. 14. Cox DR. Regression models and life tables. JR Stat Soc Ser B 1972;34:187–220. 15. Hermanek P, Sobin LH. TNM classification of malignant tumors. 4th ed, UICC. Berlin, Heidelberg, New York, London, Paris, Tokyo: Springer Verlag; 1987. 16. Imamura H, Shimada R, Kubota M, et al. Preoperative portal vein embolization: An audit of 84 patients. Hepatology 1999;29:1099–1105.
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17. Couinaud C. Bases anatomiques des hepatectomies gauche et droite reglees: Techniques qui en decoulent. J Chir 1954;70: 933–966. 18. Pringle JH. Notes on the arrest of hepatic hemorrhage due to trauma. Ann Surg 1908;48:541–549. 19. Makuuchi M, Mori T, Gunven P, et al. Safety of hemihepatic vascular occlusion during resection of the liver. Surg Gynecol Obstet 1987;164:155–158. 20. Heaney JP, Stanton WK, Halbert DS, et al. An improved technique for vascular isolation of the liver: experimental study and case reports. Ann Surg 1966;163:237–241. 21. Liver Cancer Study Group of Japan. The general rules for the clinical and pathological study of primary liver cancer. 3 rd ed. Tokyo: Kanehara; 1992. 22. Yamanaka N, Okamoto E, Kuwata K, et al. A multiple regression equation for prediction of posthepatectomy liver failure. Ann Surg 1984;200:658–663. 23. Bismuth H. Hepatocellular carcinoma in the elderly: Results of surgical and nonsurgical management [Editorial]. Am J Gastroenterol 1999;94:2336–2337. 24. Hanazaki K, Kajikawa S, Adachi W, Amano J. Hepatocellular carcinoma in the elderly: Results of surgical management. Am J Gastroenterol 2000;95:1109–1110.
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25. Stuart KE, Anand AJ, Jenkins RL. Hepatocellular carcinoma in the United States: prognostic features, treatment outcome, and survival. Cancer 1996;77:2217–2222. 26. Fuster J, Garcia-Valdecasas JC, Grande L, et al. Hepatocellular carcinoma and cirrhosis: results of surgical treatment in a European series. Ann Surg 1996;223:297–302. 27. Lise M, Bacchetti S, Da Pian P, et al. Prognostic factors affecting long term outcome after liver resection for hepatocellular carcinoma: results in a series of 100 Italian patients. Cancer 1998;82:1028–1036. 28. Shirabe K, Shimada M, Kajiyama K, et al. Clinicopathologic features of patients with hepatocellular carcinoma surviving ⬎ 10 years after hepatic resection. Cancer 1998;83:2312–2316. 29. Kakazu T, Makuuchi M, Kawasaki S, et al. Repeat hepatic resection for recurrent hepatocellular carcinoma. Hepatogastroenterolgy 1993;40:337–341. 30. Lee PH, Lin WJ, Tsang YM, et al. Clinical management of recurrent hepatocellular carcinoma. Ann Surg 1995;222: 670–676. 31. Shimada M, Matsumata T, Taketomi A, et al. Repeat hepatectomy for recurrent hepatocellular carcinoma. Surgery 1994;115: 703–706.
with HCC may have a superimposed surgical risk. But the strategy of surgical treatment of HCC in the elderly has remained obscure because there are only a few reports1,2,7-12 evaluating the results of hepatic resection in elderly patients with or without underlying cirrhosis, all dealing with less than 40 cases of hepatic resection. Several investigators1,7,12 reported that outcomes of surgical treatment of HCC in elderly patients were as satisfactory as those in younger patients. Limiting the analysis of cirrhotic patients, however, the prognoses of elderly patients after hepatic resection were less favorable than those for younger patients.2 So the potential benefits of hepatectomy for elderly patients with HCC have not been fully delineated. The aim of this study was to clarify the surgical outcomes of HCC in 103 patients 70 years of age or older, undergoing hepatic resection, and to compare them with those of 283 patients younger than 70 years of age. In addition, prognostic factors in the elderly affecting overall survival were determined by univariate and multivariate analysis. To our knowledge, this is one of the
In recent years, the number of the elderly who have undergone surgery for hepatocellular carcinoma (HCC) has increased because of advanced safe hepatic resection and prolonged life expectancy rates. Because elderly patients have associated diseases in addition to the primary disease more often than younger patients, old age has been regarded as an adverse factor for hepatic resection.1,2 Experimentally, the age-associated decline in liver function may be caused by mechanisms operating on the cellular level,3 such as age-associated mitochondrial damage in hepatocytes,4 functional decline of Kupffer cells,5 and defects of the respiratory chain in the liver during aging.6 So, hepatic resection in aged patients No competing interests declared.
Received March 3, 2000; Revised June 6, 2000; Accepted September 11, 2000. From the Second Department of Surgery, Shinshu University School of Medicine, Matsumoto, Japan. Correspondence address: Kazuhiro Hanazaki, MD, Second Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
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largest series of hepatic resections for elderly patients with HCC in a single institution reported to date. METHODS Between December 1983 and December 1997, 451 consecutive patients with newly diagnosed HCC were managed in the Second Department of Surgery of Shinshu University Hospital. Sixty-five patients were deemed unsuitable for hepatic resection mainly because of very advanced tumors or poor hepatic functional reserve, so they were excluded from this study. The other 386 consecutive patients who underwent hepatic resection for HCC were enrolled in this study. Our manuscript13 on the entire population of the surgical group of 386 patients has been published, and this study should be cited as a subset of analysis of that other manuscript. Among the patients, 103 (26.7%) were 70 years of age or older (the older group). Clinical features of these patients were investigated and compared with those of the other 283 patients (73.3%) who were younger than 70 years of age (the younger group). Resectability rates in all patients, the older group, and the younger group were 86%, 84%, and 88%, respectively. A curative operation was defined as an operation during which all tumors were microscopically resected. Operative death was defined as death within 30 day after operation (not only death in the operating room), and hospital death was defined as death within the same hospital admission for surgery, including operative death. During the same period in our hospital, 434 patients (98 patients [22.6%] in the older group and 336 [77.4%] in the younger group) were treated by transarterial chemoembolization (TACE) and 168 patients (52 patients [31.1%] in the older group and 116 [68.9%] in the younger group) were treated by percutaneous ethanol injection treatment as initial treatment for 602 patients with unresectable HCC. Thorough followup after hepatic resection was performed for all patients. Monthly measurements of biochemical liver function and ␣-fetoprotein were performed. Every 3 months, ultrasonography and dynamic CT were performed, and angiography was performed after admission when recurrence was strongly suspected. Statistics
All data are expressed as mean⫾SD. Overall survival was measured in 386 patients, including operative patients, hospital deaths, and noncurative patients from
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the date of operation to the time of last followup (June 30, 1999), or death. Disease-free survival was evaluated in the group of 327 patients (80 patients [77.8%] in the older group and 247 [87.3%] in the younger group) with curative resection who were discharged from the hospital from the date of operation to the time of recurrence. Statistical differences were analyzed using the chisquare test with Fisher’s exact test and the unpaired Student’s t-test. Analysis of overall survival and disease-free survival was calculated by the Kaplan-Meier method and the differences in survival between the groups were compared using the log-rank test. Results of the univariate analysis helped to substantially reduce the number of prognostic factors. Only a few significant variables of prognostic factors were used in the subsequent multivariate analysis using Cox’s proportional hazards model.14 Statistical analysis was done using the Stat View (version 5.0; Abacus Concepts, Inc, Berkeley, CA) software for Macintosh computer (Apple Computer, Inc, Cupertino, CA). A p value ⬍0.05 was considered significant. RESULTS Clinical features
Preoperative conditions are shown in Table 1. The mean age in the older group (73.1⫾8.0 years; range 70 to 81 years) was significantly higher than that in the younger group (59.6⫾7.4 years; range 31 to 69 years) (p⬍ 0.0001). The number of women in the older group was higher than in the younger group, although this was not significant (p⫽0.06). Although the incidences of Child classification and pTNM staging15 did not differ significantly between the two groups, the incidence of hepatitis C in the older group (55.4%) was significantly higher than that in the younger group (40.7%). There were no significant differences in the incidences of preoperative TACE and portal vein embolization16 between the two groups. Preoperative serologic liver function and AFP did not significantly differ between the two groups. Comorbid medical conditions were significantly much more common in the elderly. The types of hepatectomy are shown in Table 2. A resection was called “major” if three segments or more were removed, according to Couinaud’s classification.17 The Pringle maneuver,18 hemihepatic vascular occlusion,19 and the total vascular exclusion20 technique were performed as ischemic maneuvers to minimize intraoperative blood loss. The incidences of curative resection, major hepatectomy, and type of ischemic maneuver did not differ significantly
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Table 1. Preoperative Conditions Characteristics
Age (y) Gender (male:female) Hepatitis type (n) (%) Hepatitis C Hepatitis B Hepatitis non-C and non-B Unknown Child classification (n) (%) Child class A Child class B Child class C pTNM staging (n) (%) Stage I Stage II Stage III Stage IVa Stage IVb Preoperative TACE (n) (%) Preoperative PVE (n) (%) Liver function AFP (ng/mL) GOT (U/L) GPT (U/L) Total bilirubin (mg/dL) Albumin (g/dL) ICG-15 (%) Comorbid condition (n) (%) Cardiovascular Respiratory Diabetus mellitus
Age > 70 y (n ⴝ 103)
73.1 ⫾ 8.0 71:32
Age < 70 y (n ⴝ 283)
59.6 ⫾ 7.4 222:61
p Value
⬍ 0.0001 0.06
57 (55.4%) 19 (18.4%) 9 (8.7%) 18 (17.5%)
115 (40.7%) 67 (23.7%) 14 (4.9%) 87 (30.7%)
76 (73.8%) 27 (26.2%) 0 (0%)
226 (79.9%) 56 (19.8%) 1 (0.3%)
3 (2.9%) 47 (45.6%) 40 (38.8%) 12 (11.7%) 1 (1.0%) 33 (32.0%) 3 (2.9%)
22 (7.8%) 122 (43.1%) 81 (28.6%) 58 (20.5%) 0 (0%) 105 (37.1%) 5 (1.8%)
0.10 0.73 0.063 0.052 0.27 0.40 0.45
2,480 ⫾ 12,948 58 ⫾ 38 56 ⫾ 32 1.0 ⫾ 0.6 3.7 ⫾ 0.5 21 ⫾ 11
0.36 0.90 0.061 0.93 0.90 0.90
3,972 ⫾ 13,074 58 ⫾ 30 48 ⫾ 32 1.0 ⫾ 0.4 3.7 ⫾ 0.4 21 ⫾ 9 25 (24.3%) 20 (19.4%) 32 (31.1%)
31 (11.0%) 21 (7.4%) 24 (8.5%)
0.011 0.33 0.22 0.0097 0.21 0.21 ⬎ 0.99
0.0017 0.0012 ⬍ 0.0001
Values for liver function and age are mean ⫾ standard deviation AFP, alpha-fetoprotein; GOT, glutamic oxaloacetic transaminase; GPT, glutamic pyruvic transaminase; ICGR-15, indocyanine green retention rate at 15 minutes; PVE, portal vein embolization; TACE, transarterial chemoembolization.
between the two groups. Intraoperative data are shown in Table 3. The maximum tumor diameter in the older group was larger than that in the younger group, although not significantly (p⫽0.056). Sixty-three patients (61.2%) received intraoperative blood transfusion in the older group. Intraoperative blood loss, blood transfusion, total clamping time, and resected liver weight did not differ significantly between the two groups. In the older group, the overall incidence of postoperative complications was 28.2%, and 10 patients among them had hospital deaths (9.7%), including 5 (4.9%) operative deaths (within 1 month of operation). All five patients with operative mortality had liver cirrhosis (Child class A in two and B in three). There were
no significant differences in the incidence of postoperative complications, operative mortality rates within 1 month, or overall hospital death rates between the two groups (Table 3). Pathologic features
The pathologic findings are shown in Table 4. A resected stump with a margin less than 5mm from the edge of the tumor was defined as tw (⫹) according to The General Rules for the Clinical and Pathological Study of Primary Liver Cancer.21 The incidence of patients with cirrhosis in the older group was higher than in the younger group, although this was not significant (p⫽0.13). Although the rate of multiple tumors tended to be higher in the
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Table 2. Type of Liver Resection Type of resection
Major hepatectomy Right trisegmentectomy Extended right hepatectomy Right hepatectomy Extended left hepatectomy Left hepatectomy Total Minor hepatectomy Left lateral segmentectomy Bisegmentectomy VI and VII Bisegmentectomy V and VIII Segmentectomy Wedge resection Total Major/Minor Ischemic manuever Pringle method Hemihepatic vascular occlusion Total vascular exclusion Nonischemic maneuver Curativity Curative hepatic resection Noncurative hepatic resection
Age > 70 y (n ⴝ 103)
Age < 70 y (n ⴝ 283)
0 3 7 0 6 16 (15.5%)
1 6 20 7 12 46 (16.3%)
13 7 3 16 48 87 (84.5%) 16/87
14 5 9 74 135 237 (83.7%) 46/237
69 (67.0%) 15 (14.6%) 0 (0%) 19 (18.4%)
178 (62.9%) 61 (21.6%) 2 (0.7%) 42 (14.8%)
89 (86.4%) 14 (13.6%)
265 (93.6%) 23 (6.4%)
older group, the number of tumors did not differ significantly between the two groups. The incidence of tumor thrombosis in the portal vein (vp), tumor thrombosis in the hepatic vein (vv), and tw (⫹) also did not differ significantly between the two groups. Recurrence
Recurrence rates in the older group and the younger group were 57.2% and 54.8%, respectively (p⫽0.73).
p Value
⬎ 0.99 0.47 0.15 ⬎ 0.99 0.43 0.12
The most frequent recurrence site was remnant liver in both groups. The rates of recurrence within 1 year, 3 years, and 5 years between the older group and the younger group were 42.4% versus 28.4% (p⫽0.071), 79.7% versus 78.4% (p⬎0.99), and 96.6% versus 91.0% (p⫽0.25), respectively. The types of treatment for the patients with recurrent HCC are shown in Table 5. Repeat hepatic resection for recurrence in the older and the
Table 3. Intraoperative and Postoperative Data Data
Intraoperative parameters Intraoperative blood loss (mL) Intraoperative blood transfusion (mL) Total clamping time (min) Resected liver weight (g) Maximum diameter of tumor (cm) Postoperative conditions Operative death Hospital death Postoperative complication Values are mean ⫾ standard deviation.
Age > 70 y (n ⴝ 103)
Age < 70 y (n ⴝ 283)
p Value
1,476 ⫾ 1,455 642 ⫾ 855 34 ⫾ 27 298 ⫾ 376 5.5 ⫾ 3.7
1,959 ⫾ 2,416 912 ⫾ 1397 34 ⫾ 25 304 ⫾ 470 4.6 ⫾ 3.6
0.10 0.11 0.92 0.92 0.056
5 (4.9%) 10 (9.7%) 29 (28.2%)
11 (3.9%) 17 (6.0%) 66 (23.3%)
0.77 0.26 0.35
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Table 4. Pathologic Findings after Hepatectomy Age > 70 y, (n ⴝ 103) Parameters
Cirrhosis Present Absent Number of tumors 1 2 3 ⱖ4 tw ⬍ 5 mm ⱖ 5 mm Vascular invasion vp Positive Negative vv Positive Negative
Age < 70 y, (n ⴝ 283)
n
%
n
%
p Value
47 56
45.6 54.4
155 128
54.8 45.2
47 14 5 37
45.6 13.6 4.9 35.9
145 43 20 75
51.2 15.2 7.1 26.5
63 40
61.2 38.8
153 130
54.1 45.9
24 79
23.3 76.7
67 216
23.7 76.3
12 91
11.7 88.3
23 260
8.1 91.9
0.13
0.36 0.75 0.64 0.077 0.25
⬎ 0.99
0.32
tw, resected stump with a margin from the edge of the tumor; vp, tumor thrombosis in the portal vein; vv, tumor thrombosis in the hepatic vein.
younger groups occurred in 9 patients (15.2%) and 29 patients (18.7%), respectively. The therapeutic type for recurrent HCC did not differ between the two groups. Survival
At present, 31 patients (30.1%) are alive (10 without recurrence and 21 with recurrence); 1 (1.0%) for more than 10 years and 16 (15.5%) for more than 5 years. Only one patient surviving more than 10 years and 11 (68.8%) of 16 patients surviving more than 5 years experienced recurrent HCC after operation. Six (54.5%) of 11 patients with recurrence surviving more than 5 years underwent repeat hepatic resection for recurrent HCC. In addition, 5 (55.6%) of 9 elderly patients with repeat hepatic resection survived more than 5 years after
initial hepatic resection. The one patient surviving more than 10 years also underwent repeat hepatectomy for recurrence 4 years after the initial hepatic resection and is doing well in disease-free survival without recurrence after the second hepatic resection. Among the patients alive at present, the incidences of survival without recurrence in the older and the younger groups are 32.3% and 46.7%, respectively (p⫽0.20). The incidences of 5-year and 10-year survivors did not differ significantly between the two groups. Mortality rates from other diseases in the older and the younger groups were 6.9% and 7.7%, respectively (p⬎0.99). The mean overall survivals after operation in the older group and the younger group were 33⫾29 months and
Table 5. Treatments for Recurrent Hepatocellular Carcinoma Age > 70 y, (n ⴝ 59)
Age < 70 y, (n ⴝ 155)
Therapeutic option
n
%
n
%
p Value
Transarterial chemoembolization Percutaneous ethanol injection treatment Repeat hepatic resection Hepatic arterial infusion chemotherapy Systemic chemotherapy Radiation Microwave coagulation therapy Observation
38 15 9 6 6 2 0 2
64.4 25.4 15.3 10.2 10.2 3.4 0 3.4
121 43 29 35 12 9 1 17
78.1 27.7 18.7 22.6 7.7 5.8 0.7 11.0
0.61 0.50 0.84 0.24 0.26 ⬎ 0.99 ⬎ 0.99 0.26
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cant prognostic factors were selected by univariate analysis. The poor prognostic factors were presence of liver cirrhosis, vascular invasion, glutamic oxaloacetic transaminase of ⱖ55 U/L, intraoperative blood loss of ⱖ1500 mL, and intraoperative blood transfusion of ⱖ600 mL. Multivariate analysis of prognostic factors that reached statistical significance in univariate analysis (p⬍0.05) revealed that liver cirrhosis and vascular invasion were independently significant factors of poor survival.
Figure 1. Disease-free survival of elderly and younger patients after hepatic resection.
39⫾33 months, respectively (p⫽0.16). Disease-free and overall survival rates after hepatic resection did not differ significantly between the two groups. Disease-free 1-, 3-, and 5-year survival rates between the older group and the younger group were 75.6% versus 77.8%, 35.2% versus 37.6%, and 16.6% versus 24.2%, respectively (p⫽0.66) (Fig. 1). Overall 1-, 3-, and 5-year survival rates between the older group and the younger group were 83.4% versus 85.1%, 51.0% versus 55.2%, and 42.2% versus 40.0%, respectively (p⫽0.95) (Fig. 2). Prognostic factors in the elderly
Table 6 shows the results of a univariate analysis used to identify significant prognostic factors on overall survival in patients with HCC after hepatectomy. Five signifi-
Figure 2. Overall survival of elderly and younger patients after hepatic resection.
DISCUSSION Patient age is a useful prognostic factor for prediction of posthepatectomy liver failure.22 In general, with the elderly, surgeons tend to use less aggressive procedures because of higher comorbidity rates.11 Indeed, preoperative comorbid conditions such as cardiovascular disease, respiratory disorders, and diabetes mellitus were more common in the elderly, as described previously.1,11,12 But we performed aggressive operations regardless of age because of the similar resectability rates of 84% in the older group (ⱖ70 years of age) and 88% in the younger group (⬍70 years of age). As a result, we found that postoperative complications, operative mortality rates, and overall and disease-free survival rates after hepatic resection did not differ between the older group and the younger group. Morbidity rates (28.2%) and hospital mortality rates (9.7%) in the elderly of this study were similar with those in the previous studies.1,7,9,11,12 In addition, the preoperative and intraoperative hepatic conditions, surgical methods, and pathologic findings in the older group were similar to those in the younger group. Hepatic resection for HCC is safe in selected elderly patients, and the improved results in recent years indicate that more elderly patients could benefit from surgical management.12 Bismuth23 suggested that it is important to know that one can carry out a full screening of elderly patients with HCC to select those who will benefit most from resection, and that age by itself, is not a contraindication to surgery. Our results indicate that the surgical strategy for elderly patients with HCC should be identical to that in younger patients, as reported previously.24 But it must be acknowledged that there has to be a fair bit of selection that has gone into choosing these patients for hepatic resection because that selection may not have happened in the surgeon’s office, but may have happened because of a medical oncologist’s feelings about suitability for refer-
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Table 6. Prognostic Factors of Overall Survival by Univariate Analysis Variables
Age (y) ⱖ 75 (n ⫽ 28) ⬍ 75 (n ⫽ 75) Gender Male (n ⫽ 71) Female (n ⫽ 32) Child’s classification A (n ⫽ 76) B (n ⫽ 27) pTNM staging I (n ⫽ 3) II (n ⫽ 47) III (n ⫽ 40) VI (n ⫽ 13) Liver cirrhosis Present (n ⫽ 47) Absent (n ⫽ 56) Diabetus mellitus Present (n ⫽ 32) Absent (n ⫽ 71) Alpha-fetoprotein (ng/mL) ⱖ 4,000 (n ⫽ 22) ⬍ 4,000 (n ⫽ 81) Glutamic oxaloacetic transaminase ⱖ 55 U/L (n ⫽ 42) ⬍ 55 U/L (n ⫽ 61) Glutamic pyruvic transaminase ⱖ 50 U/L (n ⫽ 43) ⬍ 50 U/L (n ⫽ 60) Total bilirubin (mg/dL) ⱖ 1.0 (n ⫽ 42) ⬍ 1.0 (n ⫽ 61) Albumin (g/dL) ⱖ 3.5 (n ⫽ 73) ⬍ 3.5 (n ⫽ 30) Indocyanine green retention rate at 15 minutes (%) ⱖ 20 (n ⫽ 48) ⬍ 20 (n ⫽ 55) Intraoperative blood loss (mL) ⱖ 1500 (n ⫽ 43) ⬍ 1500 (n ⫽ 60) Intraoperative blood transfusion ⱖ 600 mL (n ⫽ 48) ⬍ 600 mL (n ⫽ 55) Total clamping time (min) ⱖ 35 (n ⫽ 53) ⬍ 35 (n ⫽ 50)
50% Survival in months
Table 6. (Continued) Variables
p Value
0.87 72.1 46.1 0.098 31.2 83.8 0.21 46.1 28.2 0.15 90.1 70.8 27.1 28.2 0.0099* 28.9 83.8 0.85 46.1 37.4
Number of tumors Solitary (n ⫽ 75) Multiple (n ⫽ 28) Tumor size (cm) ⱖ 5.5 (n ⫽ 39) ⬍ 5.5 (n ⫽ 64) Weight of resected liver (g) ⱖ 300 (n ⫽ 30) ⬍ 300 (n ⫽ 73) Tw (mm) ⬍ 5 (n ⫽ 63) ⱖ 5 (n ⫽ 40) Vascular invasion Present (n ⫽ 30) Absent (n ⫽ 73) Preoperative transarterial chemoembolization Present (n ⫽ 33) Absent (n ⫽ 70)
50% Survival in months
p Value
0.41 70.8 34.7 0.55 41.1 52.2 0.65 21.9 41.1 0.21 37.4 83.8 0.011* 16.7 70.8 0.69 34.7 52.2
*Significant prognostic factors by univariate analysis. Tw, microscopic resected stump with a margin from the edge of the tumor.
0.48 25.8 46.1 0.011* 28.9 70.8 0.58 41.1 46.1 0.95 46.1 41.1 0.11 46.1 28.9 0.099 31.3 72.1 0.0058* 28.2 70.8 0.0093* 28.9 72.1 0.47 37.4 70.8
ral. For instance, it might be that the results in the elderly look better because there was a bias to include females with lesser stage of tumor in this study. So further examination may be necessary to conclude definitely whether age has any influence on outcomes of resection for HCC. Until now, postresection prognostic factors in the elderly remained to be proved. There also has been little attention to the prognostic factors evaluated by multivariate analysis. We found that multivariate analysis revealed the presence of liver cirrhosis and vascular invasion as independently significant factors of poor overall survival. Liver cirrhosis and vascular invasion are relatively common prognostic factors of poor survival in all patients with HCC after hepatectomy.25-27 Cirrhosis leads to not only poor longterm survival, but also to high mortality in the elderly. Nagasue and associates1 suggested that elderly patients with Child class B and C cirrhosis are not good candidates for hepatic resection because of the marked risk of operative deaths within 1 month. Elderly patients with cirrhotic liver cancer had an unacceptable mortality of 44% after major hepatic resection.11 Also, in our study, all five elderly patients with operative mortality had cirrhosis (Child class A in two and B in three).
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Postoperative tumor recurrence is the most serious problem after curative resection of HCC. The older group showed a high recurrence rate (57.2%) as did the younger group; 93.1% of the deceased patients died of HCC, and death from other disease was only 6.9%. Because most patients died of recurrent HCC, treatment strategies for recurrent HCC may be the most crucial factor in prolonging survival. Repeat hepatic resection can prolong survival time after recurrence of HCC.28-31 We found that 54.5% of elderly patients with recurrence surviving more than 5 years had repeat hepatic resection. In addition, 55.6% of elderly patients with repeat hepatic resection survived more than 5 years after the initial hepatectomy. One patient surviving more than 10 years in the older group also underwent repeat hepatectomy and is doing well in disease-free survival without recurrence after repeat resection. Shirabe and colleagues28 supported our results that four of five patients (80%) with solitary recurrence who underwent a second hepatic resection had no recurrence after the second resection. So, we strongly recommend repeat hepatic resection for recurrent HCC to achieve better survival, even when the patient’s age is 70 years or more at initial hepatectomy. But repeat hepatectomies are limited in patients with advanced tumors and low functional reserve of the remnant liver, especially cirrhotic patients.30 Our results also showed that resectability rates of recurrent HCC between the older and the younger groups were only 15.3% and 18.7%, respectively. The most popular treatment for recurrent HCC was TACE, followed by percutaneous ethanol injection treatment in both the elderly and the young patients (Table 5). We now suggest that therapeutic strategy for elderly patients with postresection recurrent HCC should be the same as that in younger patients. In our present strategy of treatment for recurrent HCC regardless of age, if repeat hepatectomy was not indicated because of impaired liver function, nonsurgical treatments such as TACE, percutaneous ethanol injection treatment, and hepatic arterial infusion chemotherapy should be selected to obtain better results, even when the treatments are not curative.13 The overall and disease-free 5-year survival rates in the elderly patients with HCC were 42.2% and 24.2%, respectively. Although there are only three reports1,7,12 of the overall 5-year survival rate (24.3%,1 29%,12 and 75.9%7) after hepatic resection in patients aged 70 years or older with HCC, these previous reports consisted of only 31 patients,12 32 patients,1 and 39 patients.7 The
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5-year survival rate after hepatic resection in this largest series composed of 103 patients was satisfactory and was better than we expected. In conclusion, selected elderly patients with HCC benefitted from resection as much as young patients, and age by itself may not be a contraindication to surgery. The survival of elderly patients with HCC should be stratified by the presence of cirrhosis and vascular invasion. REFERENCES 1. Nagasue N, Chang YC, Takemoto Y, et al. Liver resection in the aged (seventy years or older) with hepatocellular carcinoma. Surgery 1993;113:148–154. 2. Lui WY, Chau GY, Wu CW, et al. Surgical resection of hepatocellular carcinoma in elderly cirrhotic patients. Hepatogastroenterology 1999;46:640–645. 3. Dice JF. Cellular theories of aging as related to the liver. Hepatology 1985;5:508–513. 4. Sastre J, Pallardo FV, Pla R, et al. Aging of the liver: ageassociated mitochondrial damage in intact hepatocytes. Hepatology 1996;24:1199–1205. 5. Brouwer A, Barelds RJ, Knook DL. Age-related changes in the endocystic capacity of rat liver Kupffer and endothelial cells. Hepatology 1985;5:362–366. 6. Muller-Hocker J, Aust D, Rohrbach H, et al. Defects of the respiratory chain in the normal human liver and in cirrhosis during aging. Hepatology 1997;26:709–719. 7. Takenaka K, Shimada M, Higashi H, et al. Liver resection for hepatocellular carcinoma in the elderly. Arch Surg 1994;129: 846–850. 8. Yanaga K, Kanematsu T, Takenaka K, et al. Hepatic resection for hepatocellular carcinoma in elderly patients. Am J Surg 1988;155:238–241. 9. Fortner JG, Lincer RM. Hepatic resection in the elderly. Ann Surg 1990;211:141–145. 10. Ezaki T, Yukaya H, Ogawa Y. Evaluation of hepatic resection for hepatocellular carcinoma in the elderly. Br J Surg 1987;74: 471–473. 11. Koperna T, Kisser M, Schulz F. Hepatic resection in the elderly. World J Surg 1998;22:406–412. 12. Poon RTP, Fan ST, Lo CM, et al. Hepatocellular carcinoma in the elderly: Results of surgical and nonsurgical management. Am J Gastroenterol 1999;94:2460–2466. 13. Hanazaki K, Kajikawa S, Shimozawa N, et al. Survival and recurrence after hepatic resection of 386 consecutive patients with hepatocellular carcinoma. J Am Coll Surg 2000;191:381–388. 14. Cox DR. Regression models and life tables. JR Stat Soc Ser B 1972;34:187–220. 15. Hermanek P, Sobin LH. TNM classification of malignant tumors. 4th ed, UICC. Berlin, Heidelberg, New York, London, Paris, Tokyo: Springer Verlag; 1987. 16. Imamura H, Shimada R, Kubota M, et al. Preoperative portal vein embolization: An audit of 84 patients. Hepatology 1999;29:1099–1105.
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Hanazaki et al
Hepatic Resection for Cancer in the Elderly
17. Couinaud C. Bases anatomiques des hepatectomies gauche et droite reglees: Techniques qui en decoulent. J Chir 1954;70: 933–966. 18. Pringle JH. Notes on the arrest of hepatic hemorrhage due to trauma. Ann Surg 1908;48:541–549. 19. Makuuchi M, Mori T, Gunven P, et al. Safety of hemihepatic vascular occlusion during resection of the liver. Surg Gynecol Obstet 1987;164:155–158. 20. Heaney JP, Stanton WK, Halbert DS, et al. An improved technique for vascular isolation of the liver: experimental study and case reports. Ann Surg 1966;163:237–241. 21. Liver Cancer Study Group of Japan. The general rules for the clinical and pathological study of primary liver cancer. 3 rd ed. Tokyo: Kanehara; 1992. 22. Yamanaka N, Okamoto E, Kuwata K, et al. A multiple regression equation for prediction of posthepatectomy liver failure. Ann Surg 1984;200:658–663. 23. Bismuth H. Hepatocellular carcinoma in the elderly: Results of surgical and nonsurgical management [Editorial]. Am J Gastroenterol 1999;94:2336–2337. 24. Hanazaki K, Kajikawa S, Adachi W, Amano J. Hepatocellular carcinoma in the elderly: Results of surgical management. Am J Gastroenterol 2000;95:1109–1110.
J Am Coll Surg
25. Stuart KE, Anand AJ, Jenkins RL. Hepatocellular carcinoma in the United States: prognostic features, treatment outcome, and survival. Cancer 1996;77:2217–2222. 26. Fuster J, Garcia-Valdecasas JC, Grande L, et al. Hepatocellular carcinoma and cirrhosis: results of surgical treatment in a European series. Ann Surg 1996;223:297–302. 27. Lise M, Bacchetti S, Da Pian P, et al. Prognostic factors affecting long term outcome after liver resection for hepatocellular carcinoma: results in a series of 100 Italian patients. Cancer 1998;82:1028–1036. 28. Shirabe K, Shimada M, Kajiyama K, et al. Clinicopathologic features of patients with hepatocellular carcinoma surviving ⬎ 10 years after hepatic resection. Cancer 1998;83:2312–2316. 29. Kakazu T, Makuuchi M, Kawasaki S, et al. Repeat hepatic resection for recurrent hepatocellular carcinoma. Hepatogastroenterolgy 1993;40:337–341. 30. Lee PH, Lin WJ, Tsang YM, et al. Clinical management of recurrent hepatocellular carcinoma. Ann Surg 1995;222: 670–676. 31. Shimada M, Matsumata T, Taketomi A, et al. Repeat hepatectomy for recurrent hepatocellular carcinoma. Surgery 1994;115: 703–706.