Outcome of partial hepatectomy for large (> 10 cm) hepatocellular carcinoma

Authors


  • Presented in part at the International Hepato-Pancreato-Biliary Association, June 2–6, 2004, Washington, DC.

Abstract

BACKGROUND

Surgical resection for large (> 10 cm) hepatocellular carcinoma (HCC) is believed by many to be ineffective. The objective of the current study was to review the outcome of partial hepatectomy in patients with large HCC.

METHODS

Between 1985 and 2002, 193 consecutive patients who underwent partial hepatectomy for HCC were identified from a prospective database. The 82 patients with tumors > 10 cm were compared with the remaining 111 patients with ≤ 10 cm tumors. Clinicopathologic features were analyzed and prognostic factors were evaluated by univariate and multivariate analysis.

RESULTS

The 5-year overall survival for patients with large HCC was 33% with a median of 32 months. Patients with ≤ 10 cm tumors had similar survival. Furthermore, there was no significant difference between the groups in operative mortality (2% in large HCC vs. 6%) or recurrence rate. In patients with large HCC, vascular invasion by tumor and intraoperative blood loss > 2 liters predicted overall survival on multivariate analysis.

CONCLUSIONS

Partial hepatectomy is safe for patients with large HCC. In selected patients with large tumors, resection achieves similar overall survival and recurrence-free survival to that of patients with smaller tumors. Minimizing intraoperative blood loss appears to be critical for favorable long-term outcome in patients with large HCC. Cancer 2005. © 2005 American Cancer Society.

Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver. The number of new cases in the United States is about 20,000 per year and has increased by 75% over the past decade.1, 2 Because screening for HCC is not widely practiced in the U.S., most patients at diagnosis have a tumor > 5 cm in size.3 Many studies have shown that tumor size is related to outcome.4–6 In one study, the reported median survival of patients with tumors >10 cm was 18.8 months versus 44.7 months for tumors ≤ 10 cm.7 Therefore, many investigators have questioned the role of surgery for patients with >10 cm tumors. Nevertheless, because of a lack of effective alternatives, we have continued to offer surgery to these patients when their liver function is preserved. Herein, we analyze the outcome and prognostic factors of patients with large (>10 cm) HCC who were treated with partial hepatectomy.

MATERIALS AND METHODS

From January 1985 to June 2002, 193 patients underwent hepatic resection of hepatocellular carcinoma at our institution and were prospectively entered into a database. The histologic sections of all cases were re-reviewed by a single pathologist to confirm the diagnosis, assess the pathologic features of the tumors, and to determine the structural integrity of the noncancerous liver. The structural alteration of the benign liver was staged using a 4-point scale based on fibrosis and changes of the normal vascular relations in the acini.8, 9 Stage 4 was considered to be cirrhosis.10 Tumor size was based on gross and microscopic examination as documented in the pathology reports. Tumors were pathologically staged using the 6th edition of the American Joint Committee on Cancer (AJCC) staging system.11 Microscopic margins of resection were considered positive if there were tumor cells present at the tested margins.

Patient selection was based on the absence of prohibitive comorbid medical conditions, favorable Child–Pugh Class (A plus selected Grade B), and the ability to technically resect all tumor while leaving an adequate volume of liver parenchyma. Preoperative evaluation of liver function tests, prothrombin time, alpha-fetoprotein and cross-sectional imaging were performed. Routine preoperative imaging studies included abdominal computed tomography (CT) scan and chest x-ray. Additional studies such as magnetic resonance imaging and ultrasonography, were obtained at the discretion of the attending surgeon. Intraoperative ultrasound was used to search for additional tumors.12 Low central venous pressure (CVP) anesthesia and systematic inflow/outflow vascular control before parenchymal transection is our standard surgical approach.13 In addition, anatomic segmental resection is preferred over wedge resection.

Nomenclature for the extent of hepatic resection follows the Brisbane 2000 Guidelines for Liver Anatomy and Resection.14 Major hepatectomy is defined as hemiliver resection (one lobe of liver) or more (extended resection). A tumor satellite is defined as any daughter tumor < 3 cm in size lying within a 3-cm zone from the dominant tumor.

Postoperative morbidity was broadly categorized into minor and major complications. Minor complications are defined as complications that could be treated conservatively or resolved with oral or intravenous medications without further intervention. Major complications required intensive care unit (ICU) stay, treatment by an interventional radiologist, or reoperation, or resulted in mortality.

Statistics

The clinical and pathologic data of the two patient groups were compared. Chi-square test or Fisher exact test was used for categoric data analysis. The two sample t-test was used for continuous data, which was expressed as mean ± standard deviation. Overall and disease-free survival were computed by the method of Kaplan–Meier.15 Univariate analysis was performed using the log-rank test for categoric variables and the Wald test from Cox regression for continuous variables. All variables that were significantly associated with survival from univariate analysis were included in a stepwise multivariate analysis using a Cox proportional hazard model.16 Statistical analysis was performed using the SPSS statistical software package (Version 11.0, SPSS, Chicago, IL). Differences were considered significant for P < 0.05. All complications and deaths within 30 days of surgery or during the same hospital stay after partial hepatectomy were considered perioperative morbidity and surgical mortality, respectively.

RESULTS

Patient Demographics

During the study period of 17 years, 193 patients with primary hepatocellular carcinoma underwent liver resection (Table 1). There were 82 (42%) patients with large tumors and 111 patients with smaller (≤ 10 cm) HCC. Of the patients with large HCC, there were 48 males and 34 females, and the mean age was 62 ± 14 years. The median follow-up for all the surviving patients was 27 months, 33 months for patients with large HCC. In the small HCC group, there were 14 patients with hepatitis C and 3 others with both hepatitis B and C. In the large HCC group, there were only 4 patients with hepatitis C. At the time of last follow-up in patients with large HCC, 13 patients were alive with disease (AWD), 20 patients had no evidence of disease (NED), 40 patients were dead of disease (DOD), and 9 patients were dead of other causes or unknown cause (DOC). In patients with smaller tumors, 19 patients were AWD, 38 NED, 39 DOD, and 15 DOC. The patients with large tumors had significantly less viral hepatitis (32% vs. 57%) and cirrhosis (10% vs. 37%). Preoperative transarterial embolization (TAE) was used in 6 (7%) patients with large HCC and 4 (4%) patients with smaller HCC in an attempt to either downsize the tumor or stop intratumoral bleeding.

Table 1. Comparison of Clinicopathologic Features
VariablesHCC > 10 cm n = 82 (%)HCC ≤ 10 cm n = 111 (%)P value
  • AFP: alpha fetoprotein.

  • a

    P < 0.05.

Patient   
Age62 ± 1463 ± 120.2
Gender  0.3
 Male48 (59)80 (28) 
 Female34 (41)31 (72) 
Race  0.2
 Asian14 (17)26 (24) 
 Non-Asian68 (83)85 (76) 
Child-Pugh classification  0.2
 A73 (94)104 (94) 
 B5 (6)7 (6) 
Okuda stage  0.06
 I63 (89)99 (96) 
 II8 (11)4 (4) 
Cirrhosis  < 0.001a
 Present8 (10)40 (37) 
 Absent72 (90)68 (63) 
Hepatitis  < 0.001a
 Present24 (32)56 (57) 
 Absent50 (68)42 (43) 
Alcohol abuse16 (20)17 (15)0.3
Major comorbidity  0.01a
 Present23 (28)50 (45) 
 Absent59 (72)61 (55) 
Tumor   
Tumor size in cm14.7 ± 4.16.1 ± 2.5 
No. of tumors  0.2
 171 (87)101 (91) 
 > 111 (13)10 (9) 
Margin  0.5
 Positive7 (9)7 (6) 
 Negative75 (91)103 (94) 
Vascular invasion  0.007a
 Present22 (29)49 (52) 
 Absent54 (71)46 (48) 
Tumor satellites  0.003a
 Yes27 (33)17 (15) 
 No55 (67)94 (85) 
Extrahepatic disease  0.02
 Yes12 (15)5 (5) 
 No70 (85)106 (95) 
AJCC11 staging  < 0.001a
 I19 (23)53 (48) 
 II13 (16)27 (24) 
 III49 (60)31 (28) 
 IV1 (1)0 (0) 
Median preop AFP, ng/mL38, 2–374,05237, 1–422,0000.9

Tumor Characteristics

The mean tumor size in the entire cohort of patients was 9.8 ± 5.3 cm. (median 9.9 cm, range 1.7–35.0) The mean diameter of large HCC was 14.7 ± 4.1 cm (median 13.5 cm, range 10.2–35.0) and smaller HCC was 6.1 ± 2.5 cm (median 6.5 cm, range 1.7–10.0, Table 1). Patients with large HCC had significantly more tumor satellites (33% vs. 15%) but less vascular invasion (29% vs. 52%). The median preoperative alpha-fetoprotein (AFP) was equivalent. There were 9 (11%) and 13 (12%) patients with an AFP greater than 10,000 ng/mL in the large and smaller groups, respectively. Given the lack of effective alternative therapies, extrahepatic disease (including regional nodal involvement, a solitary lung metastasis, and direct involvement of the diaphragm or colon) was resected if gross tumor clearance could be achieved.

Treatment and Perioperative Results

Major hepatectomy was necessary in 70 (85%) patients with large HCC (Table 2). Segmentectomy or sublobar resection was sufficient to remove 3 large HCC in 12 (15%) patients because their tumors were primarily exophytic. One patient with large HCC also underwent synchronous thoracoscopic wedge resection of a lung metastasis. The median intraoperative blood loss was about 1.0 liter for patients with large HCC and 0.45 liter in those with smaller HCC (P = 0.002). Perioperative packed erythrocyte transfusion was necessary in 15 (18%) patients with large HCC versus 19 (17%) in smaller HCC. The median length of hospital stay was comparable, with 10 days (range 4– 66) and 9 days (range 4–52), respectively. There were 2 (2%) postoperative deaths in patients with large HCC and 7 (6%) deaths in patients with smaller HCC. The overall operative (30-day) mortality for the entire cohort of HCC patients was 4.7% (9/193). The surgical mortality in patients with large HCC was the result of multiorgan failure secondary to sepsis in one and liver failure in the other. The 7 deaths in smaller HCC were due to 1 intraoperative cardiac arrest, 1 cardiac failure, 1 cerebrovascular accident, 3 postoperative liver failures, and 1 sepsis. The 90-day mortality rate was 8.3% (16/193). Perioperative complications occurred in 41 (50%) patients with large HCC and 53 (48%) patients in smaller HCC. Complications were primarily infections, the most common being intraabdominal abscess and pneumonia. Liver-related complications were also fairly frequent, including transient hepatic dysfunction, postoperative ascites, and biloma. Postoperative transient hepatic dysfunction occurred in 2 patients with large HCC and in 6 patients with smaller HCC.

Table 2. Comparison of Surgery and Perioperative Outcome
VariablesHCC > 10 cm n = 82 (%)HCC ≤ 10 cm n = 111 (%)P value
  • a

    P < 0.05.

Extent of hepatectomy  < 0.001a
 ≥ 1 Hemiliver70 (85)45 (40) 
 < 1 Hemiliver12 (15)66 (60) 
Intraoperative blood loss, mL1015, 75–5800450, 50–85000.002a
Perioperative blood transfusion15 (18)19 (17)0.8
Operative time in min234 ± 76228 ± 1020.6
Preoperative TACE6 (7)4 (4)0.2
Bilobar resection55 (67)30 (27)< 0.001a
Postoperative complication41 (50)53 (48)0.9
 Major31 (38)34 (31) 
 Minor10 (12)19 (17) 
Operative mortality2 (2)7 (6)0.3

Tumor Recurrence

Most recurrences occurred within 2 years after hepatectomy. The actuarial 2-year recurrence rate for large HCC was 56% and 48% for smaller HCC. At 5 years, 24% of the patients with large HCC and 31% with smaller HCC were recurrence-free (P = 0.38; Table 3). The median time to initial recurrence was 22 months for large HCC and 28 months for smaller HCC.

Table 3. Tumor Recurrence
VariablesHCC > 10 cm n = 82 (%)HCC ≤ 10 cm n = 111 (%)P value
Recurrence50 (61)58 (52)0.7
Median recurrence free interval22 mos28 mos0.4
2-yr recurrence-free survival(44)(52)0.4
5-yr recurrence-free survival(24)(31)0.4
Repeat hepatectomy3 (4)3 (3)0.4

Survival

The median survival of all the resected HCC patients was 37 months. The median survival for large HCC was 32 months with an overall actuarial 5-year survival of 33%. Meanwhile, the median overall survival for tumors measuring 10 cm or less was 40 months with an overall 5-year survival of 39% (P = 0.56, Fig. 1). There have been 16 actual 5-year survivors with 21 still at risk in patients with large HCC. Disease-free survival was similar between the 2 groups, 28% for large and 27% for smaller tumors at 5 years with medians of 32 and 34 months (Fig. 2). When the patients with large tumors were further subdivided, we found 5-year survival to be 34% for tumors between 10–15 cm (n = 50) and 32% for tumors >15 cm (n = 32, P = 0.74). Their median overall survival (36 vs. 32 mos, P = 0.74), median disease-free survival (32 vs. 31 mos) and 5-year disease-free survival (32% vs. 25%) were also similar (P = 0.59). In contrast, patients with tumors ≤ 5 cm had a 62% 5-year overall survival (P = 0.037). (Fig. 3). Univariate analysis of prognostic factors for overall survival in patients with large HCC identified Child–Pugh class, AJCC stage, extrahepatic disease, intraoperative blood loss, and vascular invasion as poor predictive factors (Table 4). The patients with hepatitis C (17 in the small group and 4 in the large group) did not have a different outcome than those with hepatitis B, although the small number of patients with hepatitis C precludes a definitive conclusion. On multivariate analysis, only intraoperative blood loss and vascular invasion were significant. On multivariate analysis of the prognostic factors that predicted disease-free survival status, only intraoperative blood loss was statistically significant (P = 0.003). (Table 5)

Figure 1.

Overall survival following resection of HCC based on tumor size.

Figure 2.

Disease-free survival following resection of HCC based on tumor size.

Figure 3.

Overall survival comparing ≤ 5, 5–10, and > 10 cm HCC.

Table 4. Prognostic Factors for Overall Survival
VariablesHCC >10 cm n = 82 (%)Median survival in mosUnivariate analysisMultivariate analysis
  • AFP: alpha fetoprotein; EBL: estimated blood loss.

  • a

    P ≤ 0.05.

  • b

    Relative risk: 2.7, confidence interval: 1.3–5.4.

  • c

    Relative risk: 1.8, confidence interval: 1.1–3.3.

Patient    
Age  0.3 
 > 55 yrs55 (67)31  
 ≤ 55 yrs27 (33)51  
Gender  0.8 
 Male48 (59)36  
 Female34 (41)32  
Race  0.7 
 Asian14 (17)24  
 Non-Asian68 (83)36  
Child–Pugh classification  0.02a 
 A73 (94)33  
 B5 (6%)12  
Cirrhosis  0.4 
 Present8 (10)24  
 Absent72 (90)36  
Hepatitis  0.6 
 Yes24 (32)36  
 No50 (68)32  
Comorbidity  0.2 
 Present23 (28)26  
 Absent59 (72)36  
Tumor    
Tumor size  0.8 
 > 15 cm32 (39)32  
 > 10 but < 15 cm50 (61)36  
No. of tumors  0.7 
 Solitary71 (87)36  
 Multiple11 (13)22  
Differentiation  0.8 
 Well or moderately50 (77)36  
 Poor15 (23)32  
Tumor satellites  0.09 
 Present27 (33)24  
 Absent55 (67)46  
Vascular invasion  0.05a0.04c
 Present22 (29)25  
 Absent54 (71)52  
Extrahepatic disease  0.03a 
 Yes12 (15)22  
 No70 (85)36  
AJCC11 stage  ≤ 0.001a 
 I–II32 (39)58  
 III–IV50 (61)22  
Preop AFP  0.1 
 ≥ 200 ng/mL26 (37)22  
 < 200 ng/mL45 (63)36  
Treatment    
EBL   < 0.001b
 ≤ 2000 mL61 (74)360.007a 
 > 2000 mL21 (26)11  
 ≤ 1000 mL41 (50)460.04a 
 > 1000 mL41 (50)22  
Operative time  0.9 
 ≤ 210 minutes36 (44)36  
 > 210 minutes46 (56)31  
Surgical margin  0.1 
 Positive7 (9)30  
 Negative74 (91)36  
Table 5. Prognostic Factors for Disease-Free Survival
VariablesHCC > 10 cm n = 82 (%)Median survival in mosUnivariate analysisMultivariate analysis
  • AJCC: American Joint Committee on Cancer; AFP: alpha fetoprotein; EBL: estimated blood loss.

  • a

    P < 0.05.

  • b

    Relative risk: 2.5, confidence interval: 1.4–4.6.

Patient    
Age  0.2 
 > 55 yrs55 (67)31  
 ≤ 55 yrs27 (33)36  
Gender  0.4 
 Male48 (59)32  
 Female34 (41)27  
Race  0.7 
 Asian14 (17)22  
 Non-Asian68 (83)32  
Child–Pugh classification  0.02a 
 A73 (94)33  
 B5 (6)12  
Cirrhosis  0.6 
 Present8 (10)24  
 Absent72 (90)32  
Hepatitis  0.8 
 Yes24 (32)27  
 No50 (68)32  
Comorbidity  0.3 
 Present23 (28)26  
 Absent59 (72)32  
Tumor    
Tumor size  0.6 
 > 15 cm32 (39)31  
 > 10 but < 15 cm50 (61)32  
No. of tumors  0.5 
 Solitary71 (87)32  
 Multiple11 (13)22  
Differentiation  0.6 
 Well or moderate50 (77)32  
 Poor15 (23)32  
Tumor satellites  0.3 
 Present27 (33)24  
 Absent55 (67)33  
Vascular invasion  0.06 
 Present22 (29)25  
 Absent54 (71)50  
Extrahepatic disease  0.02a 
 Yes12 (15)22  
 No70 (85)33  
AJCC11 stage  0.006a 
 I–II32 (39)50  
 III–IV50 (61)18  
Preop AFP  0.1 
 ≥ 200 ng/mL26 (37)22  
 < 200 ng/mL45 (63)36  
Treatment    
EBL   0.003b
 ≤ 2000 mL61 (74)360.02a 
 > 2000 mL21 (26)10  
 ≤ 1000 mL41 (50)370.04a 
 > 1000 mL41 (50)18  
Operative time  0.9 
 ≤ 210 minutes36 (44)32  
 > 210 minutes46 (56)31  
Surgical margin  0.2 
 Positive7 (9)30  
 Negative75 (91)32  

DISCUSSION

Current treatment options for large (>10 cm) HCC are limited. Transplantation is contraindicated because of its ineffectiveness.17, 18 Hepatic artery embolization is appropriate in some patients, but complete tumor eradication is unlikely.19–21 Tumor size generally precludes the use of other ablative therapies, such as ethanol injection and radiofrequency ablation.22–27 Partial hepatectomy in patients with large HCC is not accepted universally because of a perceived high operative risk and poor postoperative outcome. This perception is reinforced by previously published reports that partial hepatectomy in large HCC carries an unfavorably high mortality, morbidity, and recurrence.28–30 Consequently, some surgeons have adopted a nihilistic approach, and, hence, many patients are treated with only supportive care. However, because of progress in hepatobiliary techniques and perioperative management over the past decade, major hepatectomy for HCC can now be performed with low morbidity and mortality in specialized centers.31–35 Furthermore, some investigators have reported long-term survival in about a third of patients with large HCC who were treated with liver resection.36–38 The recurrence rate for large HCC also does not seem to be higher as previously thought.39

The present study confirms improved survival in large HCC with an overall cumulative 5-year survival of 33% and a 5-year disease-free survival of 28%. The median overall and disease-free survival were 32 months and 34 months, respectively. In patients with smaller (≤ 10 cm) HCC, the overall 5-year survival was 37% in our cohort of patients (P = NS). This survival data was also similar to our earlier published data.40 Our results are also comparable to that of Asian reports, in which after liver resection for HCC >10 cm, the overall cumulative 5-year survival ranged from 27 to 34% and 5-year disease-free survival ranged from 9 to 28%.7, 37 Clearly, there were differences between our patients with large and smaller HCC, which may have resulted from selection bias. Patients with large tumors who underwent resection had a lower prevalence of tumor vascular invasion, cirrhosis, and hepatitis but were more likely to have satellite tumors or extrahepatic disease. In contrast, other investigators have found vascular invasion to be a frequent finding in large HCC.39, 41

To determine whether there was a threshold of tumor size above which the benefit of surgery was lost, we analyzed the subset of patients with tumor size >15 cm. Compared with the patients with tumor size between 10–15 cm, there was no difference in survival. In addition, when we analyzed those with 5–10 cm tumors, we found their survival equivalent to that of patients with tumor size >10 cm (Fig 3). Only patients with HCC < 5 cm had a significantly better prognosis.

Contrary to the belief that patients with large HCC have a higher risk of recurrence and are likely to recur early after resection, the data from our cohort of HCC patients demonstrated otherwise. The median time to first recurrence was 22 months, which is, again, comparable to that of smaller HCC (P = 0.38). The 2-year recurrence rates were not substantially dissimilar, 56% and 48%, respectively.

The postoperative mortality rate for patients with large HCC was 2%, emphasizing the current safety of major hepatectomy in these patients and confirming the prior reported feasibility of resection.42 Others have also reported a mortality rate below 5%.42–44 The major postoperative complication rates between large and smaller HCC were similar (38% vs. 31%, P = 0.88). The incidence of postoperative liver failure in both groups was low. In the large HCC group, 1 (1%) patient died from liver failure, and 2 (2%) patients had transient liver dysfunction after extended hepatic resection.

Our study showed that the only independent prognostic factor of both overall and disease-free survival for large HCC was intraoperative blood loss > 2 liters. This finding had been published previously by Hanazaki who found that a large intraoperative blood loss was an independent predictive factor of poor long-term survival.45 Since 1991, the use of low CVP anesthesia is standard for all patients undergoing hepatectomy in our center.46 Systematic inflow and outflow control is obtained before parenchymal transection whenever possible. In general, we prefer to control outflow outside the liver by dividing the relevant hepatic veins before parenchymal transection. Some authors have advocated the anterior transhepatic approach to isolate the outflow when resecting large HCC.47, 48 We were able to achieve extrahepatic outflow control in the majority of our patients undergoing major hepatectomy, and the anterior approach was used in a few patients. We are currently comparing these two techniques in patients with liver metastases from colorectal cancer. Our median blood loss was about 1 liter for large HCC, and a quarter of these patients had intraoperative blood loss greater than 2 liters. Despite the lower frequency of cirrhosis in the patients with large HCC, there was higher blood loss. This is most likely because of the added difficulty in mobilizing a liver with a large tumor of the retroperitoneum. Only 15 (18%) patients required perioperative packed erythrocyte transfusion. Some series have reported that a positive microscopic margin, vascular invasion, and multiple tumors predict poor survival in large HCC.7, 37, 49 Of these, we only found vascular invasion to be important. This could be because of the small number of patients with a positive margin (n = 7, 9%) or multiple tumors (n = 11, 13%) in our cohort of patients.

Thus, we found that partial hepatectomy is a safe and effective therapy for selected patients with large HCC and achieves a 33% 5-year survival. Furthermore improvement in outcome depends on the development of effective adjuvant therapies.

Ancillary