Intrahepatic Recurrence After Resection of Hepatocellular Carcinoma Complicating Cirrhosis
JACQUES BELGHITI,* YVES PANIS,* OLIVIER FARGES,* JEAN PIERRE BENHAMOU,t and FRANCOIS FEKETE* To determine whether a careful evaluation of tumor extension by preoperative computed tomography scan after intra-arterial injection of ultrafluid lipiodol and by intraoperative ultrasound examination reduced the recurrence rate of hepatocellular carcinoma after resection, a series of 47 cirrhotic patients with a single tumor operated on from 1984 was studied. Alphafetoprotein level was less than 100 ng/mL in 26 patients (55%), size of the tumor was less than 5 cm in 28 patients (59%), and capsule was present in 30 patients (63%). The resection was performed with free margin measuring 1 cm or more. The overall cumulative survival rates at 3 and 5 years were 35% and 17%, respectively. Intrahepatic recurrence was observed in 28 patients (60%), located less than 2 cm from the resection margin in only four patients. The cumulative intrahepatic recurrence rate at 3 years was 81% and was significantly higher in patients with tumor 2 5 cm and in patients with preoperative alphafetoprotein level of .100 ng/mL. In this series the cumulative intrahepatic recurrence rate at 5 years was 100%. This high recurrence rate after resection, even with careful evaluation of tumor extension, indicates that liver transplantation might be envisaged for the treatment of cirrhotic patients with resectable hepatocellular carcinoma.
T n HE LONG-TERM results of resection of hepatocellular carcinoma (HCC) in cirrhotic patients have been disappointing, primarily because of the high tate ofpostoperative intrahepatic recurrence.",2 This might be due, at least in part, to undetected and therefore unremoved tumorous tissue at surgery.3 Some imaging pro-
cedures, including preoperative computed tomograph (CT) scan after intra-arterial injection of ultrafluid lipiodol and intraoperative ultrasound (US) examination have a high sensitivity for detecting tumorous tissue within the liver.4 From 1984 we systematically used these imaging procedures in the management of HCC. The purpose of the present study was to determine whether the recurrence rate after resection might be reduced by these imaging
Address reprint requests to Prof. J. Belghiti, Service de Chirurgie Digestive, Hopital Beaujon, 92118 Clichy, France. Accepted for publication September 27, 1990.
From the Service de Chirurgie Digestive,* Service d'Hdpatologie,t Hopital Beaujon, Clichy, Universitd Paris VIl, Paris, France
procedures in cirrhotic patients with an asymptomatic single HCC.
Patients and Methods Among 68 patients who underwent hepatic resection for HCC at Hopital Beaujon from 1984 to 1989, 47 patients having the following characteristics were studied: (1) all the patients were adults; (2) all of them were suffering from cirrhosis (histologically proved); (3) all of them were suffering from HCC (histologically proved); (4) hepatocellular carcinoma was asymptomatic and was detected by US examination and/or by increase in serum alphafetoprotein level (more than 100 ng/mL); (5) the preoperative arteriogram and CT scan after intra-arterial injection of ultrafluid lipiodol showed a single tumor; (6) the tumor was resected with a margin of 1 cm or more; (7) no residual tumor was detected by intraoperative US examination in the remnant liver after resection; (8) the survival time after resection was more than 6 months. Among the 47 patients meeting the above criteria, there were 38 men and 9 women; their ages ranged from 35 to 76 years. The cause of cirrhosis was chronic alcoholism in 18 patients, chronic infection with hepatitis B virus in 19, idiopathic hemochromatosis in 5, and indeterminate in 5. Alphafetoprotein level was less than 100 ng/mL in 26 patients and more than 100 ng/mL in 21. According to the classification of Child modified by Pugh et al.,5 31 patients (66%) belonged to class A, 15 (32%) to class B, and 1 (2%) to class C. The diameter of the tumor (measured in the resected liver) was less than 5 cm in 28 patients, 5 to 10 cm in 12 patients, and more than 10 cm in 7 patients. The tumor was not encapsulated in 17 patients and encapsulated in 30. Resection consisted of tu-
114
Vol. 214 -No. 2
RECURRENCE AFTER RESECTION OF HCC COMPLICATING CIRRHOSIS
morectomy in 7 patients, removal of 1 segment of the liver in 18, and removal of 2 segments or more in 22. All the 47 patients were examined every 3 months in the first 2 postoperative years and then every 6 months. Examination included liver tests, measurement of alphafetoprotein level, chest x-ray, and liver US. When recurrence was suspected, the patient was readmitted to the hospital and hepatic arterial angiography was performed. Intrahepatic recurrence was classified as recurrence arising in the vicinity of the resected area or as recurrence developing 2 cm or more from the resection margin. All the patients were followed for 6 months or more. No patient had hepatic arterial embolization before resection; no chemotherapy was used after operation. When recurrence was recognized, the choice for the treatment was based on the location of the recurrent tumor within the liver, the clinical condition of the patients, and the results of liver tests. In the 30 patients with recurrence, reoperation was performed in 3 (including liver transplantation in 1); intra-arterial chemotherapy was administered in 7; and no treatment was given in the remaining 20 patients. Survival rate and cumulative intrahepatic recurrence rate after resection were calculated using the KaplanMeier method. Survival curves were compared using the log rank test.
Results Of the 47 patients, 17 were alive at the time of submission of this paper (August 1990). The cumulative survival rates were 62% at 1 year, 47% at 2 years, 35% at 3 years, 25% at 4 years, and 17% at 5 years. Of the 30 patients who died, tumor recurrence was the cause of death in 21. Nine patients died of liver failure without evidence of tumor recurrence from 6 to 15 months after resection; 8 belonged to class B or C and 1 to class A. Although 17 of the 47 patients were still alive, 9 patients living from 6 to 60 months after resection had a recurrence. The other eight patients were living from 6 to 40 months without apparent recurrence.
Intrahepatic or extrahepatic recurrence of the tumor recognized in 30 patients (64%). In two patients only the lungs or bones were involved. Of these 30 patients, tumor recurrence was confined to the liver in 28: intrahepatic recurrence consisted in multiple nodules in 21 and a single nodule in 7. The recurrent tumor or tumors were located less than 2 cm from the resection margin in four patients and more than 2 cm from the resection margin in 24. Intrahepatic tumor recurred within 6 months after surgery in 5 patients, 6 to 12 months in 11, 13 to 24 months in 6, and more than 2 years in 6 patients. The interval from the time of recognition of tumor recurrence and death is set out in Table 1: among the 30 patients with was
115
TABLE 1. Survival According to the Treatment Used in Patients with Tumor Recurrence
Number of Patients Surviving After Recognition of Tumor Recurrence Treatment
6 Months
1 Year
2 Years
Resection (n = 3)* Chemotherapy (n = 7)4 No treatment (n = 20)
3 6 8
4J lt
21t
2 2
*
Including liver transplantation in one patient.
t Administration of chemotherapeutic agents suspended in ultrafluid
lipiodol through feeder arteries. t These two values are significantly different (p = 0.02).
tumor recurrence, 17 survived more than 6 months, 7 more than 1 year, and 4 more than 2 years. The patients who were reoperated on for a second hepatic resection and the patients who were treated by chemotherapy had a longer survival time than those not reoperated and those not treated by chemotherapy. The outcome ofthe patients alive after surgery showed that 27, 20, 7, 3, and 1 patients were alive at 1, 2, 3, 4, and 5 years, respectively. However the intrahepatic recurrence rate was observed in 11 (40%), 11 (55%), 4 (57%), 2 (67%), and 1 (100%), respectively. As showed in Figure 1, the cumulative intrahepatic recurrence rate was 42% at 1 year, 61% at 2 years, 81% at 3 years, 87% at 4 years, and 100% at 5 years. The cumulative intrahepatic recurrence rate according to the size of the tumor, the presence or absence of a capsule, and preoperative alphafetoprotein level are shown in Figures 2 to 4. At 3 years the cumulative intrahepatic recurrence rate was significantly higher in patients with a tumor diameter of 5 cm or more (9 1 %) than in those with a tumor diameter less than 5 cm (78%) (p < 0.05). At 3 years the cumulative intrahepatic recurrence rate in patients with nonencapsulated tumor (100%) was higher than in patients with encapsulated tumor (68%). These differences, however, were not statistically significant (p < 0.1). At 3 years cumulative intrahepatic recurrence rate was significantly higher in patients with a preoperative alphafetoprotein level of more than 100 ng/mL (100%) than in those with a preoperative level of alphafetoprotein of less than 100 ng/mL (69%) (p < 0.01). The serial changes in alphafetoprotein level after resection are shown in Table 2. Preoperative level of alphafetoprotein was high in 21 patients. After resection alphafetoprotein level decreased in all the patients. Of these 21 patients, 11 had an intrahepatic tumor recurrence and in parallel an increased alphafetoprotein level, and four had a recurrence without elevation of alphafetoprotein. Preoperative level of alphafetoprotein was normal in 26 patients. Of these 26 patients, nine had a tumor recurrence without elevation of alphafetoprotein and four had a tumor recurrence and in parallel an increased alphafetoprotein level.
116 100'
1-
Ann. Surg. - August 1991
BELGHITI AND OTHERS 100-
80
_
80
-
8
a
c
60
Cs
E
U.
60
40
4-)
c:3
40
-
Capsule present
.5
E
-
20
--- -
Capsule absent
20 -
0
4 2 3 Timc after resection (ycars)
1
5
0
1
2
5
4
3
Time after resection (years)
FIG. 1. Cumulative intrahepatic recurrence rate after resection of hepatocellular carcinoma in cirrhotic patients.
Discussion Our data show that the cumulative intrahepatic recurrence rate reached 100% at 5 years after resection of a single HCC in cirrhotic patients. Tumor recurrence took place predominantly in the liver and was mainly located away from the resection margin. The intrahepatic recurrence rate of 60% in this series was comparable to that reported in another series of patients after resection of HCC associated with cirrhosis.3 6 In our patients surviving after resection, detection of intrahepatic recurrence by measurement of alphafetoprotein level and US at regular intervals showed that the cumulative recurrence rate increased progressively and reached 100% at 5 years. Long-term survival can be observed in a few patients with recurrence, particularly in those treated by a second hepatic resection or by intra-arterial che-
FIG. 3. Cumulative intrahepatic recurrence rate after resection of hepatocellular carcinoma according to the presence of a capsule.
motherapy.7'8 Factors influencing the rate of recurrence the size of the tumor, encapsulation of the tumor, and the preoperative level of alphafetoprotein. The preoperative high level of alphafetoprotein as a predictor of poor postoperative prognosis in this series has been previously reported.2 After transplantation for HCC, a high preoperative level of alphafetoprotein was found to be an important factor influencing the rate of recurrence.9 Our results indicate that the intrahepatic tumor recurrence rate in patients with nonencapsulated tumors was higher than in those with encapsuled tumors.'0," Recurrence was located mostly in the remnant liver in this series, as well as in other series,3'6 and might be due to (1) inadequate resection of the original tumor, (2) unrecognized multifocal HCC, and (3) multicentric origin of HCC in cirrhotic patients. were
100
_
II
_
_
80
-I
80
8
,ri
#
c)
I
60
60'
.Cs
40' 40
40 ~ |rt X 20
i
-
AFP < 100 ng/ml
EL
Tumor < S cm
U
4)
AFP 2 100 ng/ml
Tumor 2 5 cm
20
-
'~20
0'
0
0
1
2
Time
3 after rcsection
4
5
(years)
FIG. 2. Cumulative intrahepatic recurrence rate after resection of hepatocellular carcinoma according to the size of the tumor.
2
3
4
5
Time after resection (years)
FIG. 4. Cumulative intrahepatic recurrence rate after resection of hepatocellular carcinoma according to the preoperative level of alphafetoprotein.
Vol. 214.-No. 2
RECURRENCE AFTER RESECTION OF HCC COMPLICATING CIRRHOSIS
TABLE 2. Serum Alphafetoprotein (AFP) Before Resection and After Recognition of Intrahepatic Tumor Recurrence
Number of Patients with AFP Values After Detection of Recurrence
AFP Before Resection (Number of Patients)
Patients with Intrahepatic Recurrence
JACQUES BELGHITI,* YVES PANIS,* OLIVIER FARGES,* JEAN PIERRE BENHAMOU,t and FRANCOIS FEKETE* To determine whether a careful evaluation of tumor extension by preoperative computed tomography scan after intra-arterial injection of ultrafluid lipiodol and by intraoperative ultrasound examination reduced the recurrence rate of hepatocellular carcinoma after resection, a series of 47 cirrhotic patients with a single tumor operated on from 1984 was studied. Alphafetoprotein level was less than 100 ng/mL in 26 patients (55%), size of the tumor was less than 5 cm in 28 patients (59%), and capsule was present in 30 patients (63%). The resection was performed with free margin measuring 1 cm or more. The overall cumulative survival rates at 3 and 5 years were 35% and 17%, respectively. Intrahepatic recurrence was observed in 28 patients (60%), located less than 2 cm from the resection margin in only four patients. The cumulative intrahepatic recurrence rate at 3 years was 81% and was significantly higher in patients with tumor 2 5 cm and in patients with preoperative alphafetoprotein level of .100 ng/mL. In this series the cumulative intrahepatic recurrence rate at 5 years was 100%. This high recurrence rate after resection, even with careful evaluation of tumor extension, indicates that liver transplantation might be envisaged for the treatment of cirrhotic patients with resectable hepatocellular carcinoma.
T n HE LONG-TERM results of resection of hepatocellular carcinoma (HCC) in cirrhotic patients have been disappointing, primarily because of the high tate ofpostoperative intrahepatic recurrence.",2 This might be due, at least in part, to undetected and therefore unremoved tumorous tissue at surgery.3 Some imaging pro-
cedures, including preoperative computed tomograph (CT) scan after intra-arterial injection of ultrafluid lipiodol and intraoperative ultrasound (US) examination have a high sensitivity for detecting tumorous tissue within the liver.4 From 1984 we systematically used these imaging procedures in the management of HCC. The purpose of the present study was to determine whether the recurrence rate after resection might be reduced by these imaging
Address reprint requests to Prof. J. Belghiti, Service de Chirurgie Digestive, Hopital Beaujon, 92118 Clichy, France. Accepted for publication September 27, 1990.
From the Service de Chirurgie Digestive,* Service d'Hdpatologie,t Hopital Beaujon, Clichy, Universitd Paris VIl, Paris, France
procedures in cirrhotic patients with an asymptomatic single HCC.
Patients and Methods Among 68 patients who underwent hepatic resection for HCC at Hopital Beaujon from 1984 to 1989, 47 patients having the following characteristics were studied: (1) all the patients were adults; (2) all of them were suffering from cirrhosis (histologically proved); (3) all of them were suffering from HCC (histologically proved); (4) hepatocellular carcinoma was asymptomatic and was detected by US examination and/or by increase in serum alphafetoprotein level (more than 100 ng/mL); (5) the preoperative arteriogram and CT scan after intra-arterial injection of ultrafluid lipiodol showed a single tumor; (6) the tumor was resected with a margin of 1 cm or more; (7) no residual tumor was detected by intraoperative US examination in the remnant liver after resection; (8) the survival time after resection was more than 6 months. Among the 47 patients meeting the above criteria, there were 38 men and 9 women; their ages ranged from 35 to 76 years. The cause of cirrhosis was chronic alcoholism in 18 patients, chronic infection with hepatitis B virus in 19, idiopathic hemochromatosis in 5, and indeterminate in 5. Alphafetoprotein level was less than 100 ng/mL in 26 patients and more than 100 ng/mL in 21. According to the classification of Child modified by Pugh et al.,5 31 patients (66%) belonged to class A, 15 (32%) to class B, and 1 (2%) to class C. The diameter of the tumor (measured in the resected liver) was less than 5 cm in 28 patients, 5 to 10 cm in 12 patients, and more than 10 cm in 7 patients. The tumor was not encapsulated in 17 patients and encapsulated in 30. Resection consisted of tu-
114
Vol. 214 -No. 2
RECURRENCE AFTER RESECTION OF HCC COMPLICATING CIRRHOSIS
morectomy in 7 patients, removal of 1 segment of the liver in 18, and removal of 2 segments or more in 22. All the 47 patients were examined every 3 months in the first 2 postoperative years and then every 6 months. Examination included liver tests, measurement of alphafetoprotein level, chest x-ray, and liver US. When recurrence was suspected, the patient was readmitted to the hospital and hepatic arterial angiography was performed. Intrahepatic recurrence was classified as recurrence arising in the vicinity of the resected area or as recurrence developing 2 cm or more from the resection margin. All the patients were followed for 6 months or more. No patient had hepatic arterial embolization before resection; no chemotherapy was used after operation. When recurrence was recognized, the choice for the treatment was based on the location of the recurrent tumor within the liver, the clinical condition of the patients, and the results of liver tests. In the 30 patients with recurrence, reoperation was performed in 3 (including liver transplantation in 1); intra-arterial chemotherapy was administered in 7; and no treatment was given in the remaining 20 patients. Survival rate and cumulative intrahepatic recurrence rate after resection were calculated using the KaplanMeier method. Survival curves were compared using the log rank test.
Results Of the 47 patients, 17 were alive at the time of submission of this paper (August 1990). The cumulative survival rates were 62% at 1 year, 47% at 2 years, 35% at 3 years, 25% at 4 years, and 17% at 5 years. Of the 30 patients who died, tumor recurrence was the cause of death in 21. Nine patients died of liver failure without evidence of tumor recurrence from 6 to 15 months after resection; 8 belonged to class B or C and 1 to class A. Although 17 of the 47 patients were still alive, 9 patients living from 6 to 60 months after resection had a recurrence. The other eight patients were living from 6 to 40 months without apparent recurrence.
Intrahepatic or extrahepatic recurrence of the tumor recognized in 30 patients (64%). In two patients only the lungs or bones were involved. Of these 30 patients, tumor recurrence was confined to the liver in 28: intrahepatic recurrence consisted in multiple nodules in 21 and a single nodule in 7. The recurrent tumor or tumors were located less than 2 cm from the resection margin in four patients and more than 2 cm from the resection margin in 24. Intrahepatic tumor recurred within 6 months after surgery in 5 patients, 6 to 12 months in 11, 13 to 24 months in 6, and more than 2 years in 6 patients. The interval from the time of recognition of tumor recurrence and death is set out in Table 1: among the 30 patients with was
115
TABLE 1. Survival According to the Treatment Used in Patients with Tumor Recurrence
Number of Patients Surviving After Recognition of Tumor Recurrence Treatment
6 Months
1 Year
2 Years
Resection (n = 3)* Chemotherapy (n = 7)4 No treatment (n = 20)
3 6 8
4J lt
21t
2 2
*
Including liver transplantation in one patient.
t Administration of chemotherapeutic agents suspended in ultrafluid
lipiodol through feeder arteries. t These two values are significantly different (p = 0.02).
tumor recurrence, 17 survived more than 6 months, 7 more than 1 year, and 4 more than 2 years. The patients who were reoperated on for a second hepatic resection and the patients who were treated by chemotherapy had a longer survival time than those not reoperated and those not treated by chemotherapy. The outcome ofthe patients alive after surgery showed that 27, 20, 7, 3, and 1 patients were alive at 1, 2, 3, 4, and 5 years, respectively. However the intrahepatic recurrence rate was observed in 11 (40%), 11 (55%), 4 (57%), 2 (67%), and 1 (100%), respectively. As showed in Figure 1, the cumulative intrahepatic recurrence rate was 42% at 1 year, 61% at 2 years, 81% at 3 years, 87% at 4 years, and 100% at 5 years. The cumulative intrahepatic recurrence rate according to the size of the tumor, the presence or absence of a capsule, and preoperative alphafetoprotein level are shown in Figures 2 to 4. At 3 years the cumulative intrahepatic recurrence rate was significantly higher in patients with a tumor diameter of 5 cm or more (9 1 %) than in those with a tumor diameter less than 5 cm (78%) (p < 0.05). At 3 years the cumulative intrahepatic recurrence rate in patients with nonencapsulated tumor (100%) was higher than in patients with encapsulated tumor (68%). These differences, however, were not statistically significant (p < 0.1). At 3 years cumulative intrahepatic recurrence rate was significantly higher in patients with a preoperative alphafetoprotein level of more than 100 ng/mL (100%) than in those with a preoperative level of alphafetoprotein of less than 100 ng/mL (69%) (p < 0.01). The serial changes in alphafetoprotein level after resection are shown in Table 2. Preoperative level of alphafetoprotein was high in 21 patients. After resection alphafetoprotein level decreased in all the patients. Of these 21 patients, 11 had an intrahepatic tumor recurrence and in parallel an increased alphafetoprotein level, and four had a recurrence without elevation of alphafetoprotein. Preoperative level of alphafetoprotein was normal in 26 patients. Of these 26 patients, nine had a tumor recurrence without elevation of alphafetoprotein and four had a tumor recurrence and in parallel an increased alphafetoprotein level.
116 100'
1-
Ann. Surg. - August 1991
BELGHITI AND OTHERS 100-
80
_
80
-
8
a
c
60
Cs
E
U.
60
40
4-)
c:3
40
-
Capsule present
.5
E
-
20
--- -
Capsule absent
20 -
0
4 2 3 Timc after resection (ycars)
1
5
0
1
2
5
4
3
Time after resection (years)
FIG. 1. Cumulative intrahepatic recurrence rate after resection of hepatocellular carcinoma in cirrhotic patients.
Discussion Our data show that the cumulative intrahepatic recurrence rate reached 100% at 5 years after resection of a single HCC in cirrhotic patients. Tumor recurrence took place predominantly in the liver and was mainly located away from the resection margin. The intrahepatic recurrence rate of 60% in this series was comparable to that reported in another series of patients after resection of HCC associated with cirrhosis.3 6 In our patients surviving after resection, detection of intrahepatic recurrence by measurement of alphafetoprotein level and US at regular intervals showed that the cumulative recurrence rate increased progressively and reached 100% at 5 years. Long-term survival can be observed in a few patients with recurrence, particularly in those treated by a second hepatic resection or by intra-arterial che-
FIG. 3. Cumulative intrahepatic recurrence rate after resection of hepatocellular carcinoma according to the presence of a capsule.
motherapy.7'8 Factors influencing the rate of recurrence the size of the tumor, encapsulation of the tumor, and the preoperative level of alphafetoprotein. The preoperative high level of alphafetoprotein as a predictor of poor postoperative prognosis in this series has been previously reported.2 After transplantation for HCC, a high preoperative level of alphafetoprotein was found to be an important factor influencing the rate of recurrence.9 Our results indicate that the intrahepatic tumor recurrence rate in patients with nonencapsulated tumors was higher than in those with encapsuled tumors.'0," Recurrence was located mostly in the remnant liver in this series, as well as in other series,3'6 and might be due to (1) inadequate resection of the original tumor, (2) unrecognized multifocal HCC, and (3) multicentric origin of HCC in cirrhotic patients. were
100
_
II
_
_
80
-I
80
8
,ri
#
c)
I
60
60'
.Cs
40' 40
40 ~ |rt X 20
i
-
AFP < 100 ng/ml
EL
Tumor < S cm
U
4)
AFP 2 100 ng/ml
Tumor 2 5 cm
20
-
'~20
0'
0
0
1
2
Time
3 after rcsection
4
5
(years)
FIG. 2. Cumulative intrahepatic recurrence rate after resection of hepatocellular carcinoma according to the size of the tumor.
2
3
4
5
Time after resection (years)
FIG. 4. Cumulative intrahepatic recurrence rate after resection of hepatocellular carcinoma according to the preoperative level of alphafetoprotein.
Vol. 214.-No. 2
RECURRENCE AFTER RESECTION OF HCC COMPLICATING CIRRHOSIS
TABLE 2. Serum Alphafetoprotein (AFP) Before Resection and After Recognition of Intrahepatic Tumor Recurrence
Number of Patients with AFP Values After Detection of Recurrence
AFP Before Resection (Number of Patients)
Patients with Intrahepatic Recurrence
