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Keywords:

  • hepatic resection;
  • transcatheter arterial chemoembolization;
  • hepatocellular carcinoma;
  • portal vein tumor thrombus;
  • overall survival;
  • disease-free survival

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. REFERENCES

BACKGROUND:

The long-term survival outcomes of hepatic resection (HR) compared with transcatheter arterial chemoembolization (TACE) for resectable hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) are unclear.

MATERIALS AND METHODS:

Between December 2002 and December 2007, 201 consecutive patients diagnosed with resectable HCC with PVTT received HR as an initial treatment in our center. These patients were compared with 402 case-matched controls selected from a pool of 1798 patients (with a 1:2 ratio) who received TACE as an initial treatment during the study period. PVTT was classified to 4 types: PVTT involving the segmental branches of the portal vein or above (type I), PVTT extending to involve the right/left portal vein (type II), the main portal vein (type III), or the superior mesenteric vein (type IV).

RESULTS:

The 1-, 3-, and 5-year overall survivals for the HR and TACE groups were 42.0%, 14.1%, and 11.1% and 37.8%, 7.3%, and 0.5%, respectively (P < .001). On subgroup analyses, the overall survivals for the HR group were better than the TACE group for type I PVTT, type II PVTT, single tumor, and tumor size >5 cm (P < .001, P = .002, P < .001, P < .001, respectively), but not for type III PVTT, type IV PVTT, multiple tumors, and tumor size <5 cm (P = .541, P = .371, P = .264, P = .338, P = .125, respectively). Multivariate analysis showed the type of PVTT and initial treatment allocation were significant prognostic factors for overall survival.

CONCLUSIONS:

Compared with TACE, HR provided survival benefits for patients with resectable HCC with PVTT, especially for those with a type I PVTT or a type II PVTT. Cancer 2012. © 2012 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. REFERENCES

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most frequent cause of cancer death worldwide.1 Hepatic resection (HR) is the conventional “curative” treatment for HCC. In both the European and the United States Proposed Guidelines for HCC, HR is recommended only for patients with preserved liver function and with early stage HCC.2, 3 Unfortunately, because of tumor multifocality, portal vein invasion, and underlying advanced cirrhosis, only 10% to 30% of HCCs are amenable to such a “curative” treatment at the time of diagnosis.4, 5 Transarterial chemoembolization (TACE) has become the most popular palliative treatment for patients with unresectable HCC, and it is no longer considered as a contraindication to HCC with portal vein tumor thrombus (PVTT).6-8 Unfortunately, the long-term outcomes are generally poor for HCC treated with TACE, especially for HCC with PVTT.9-12

To improve on the results of treatment of HCC with PVTT, attempts have been made to perform HR for these patients.13-22 HCC with PVTT remains a contraindication to liver transplantation because of the high rate of tumor recurrence, and because of the severe shortage of donor organs. HR remains the only therapeutic option that may still offer a chance of cure. With advances in surgical techniques, it has become feasible to remove all gross tumors, including PVTT, which has extended to the main portal vein, safely by surgery. More HCC with PVTT, which previously were considered as unresectable, have become resectable.13-22 Recent studies have even shown favorable long-term survival outcomes of HR in well-selected cases of HCC with PVTT.21, 22 However, the survival outcomes of patients with HCC with PVTT treated with HR or with TACE have not been properly compared.

This study aimed to retrospectively compare the long-term survival outcomes of treatment with HR or with TACE for HCC with PVTT. We also aimed to identify patient groups that might benefit more from either treatment with HR or TACE.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. REFERENCES

Study Design

This is a retrospective study conducted on a prospectively collected data base on patients who received either HR or TACE for HCC at the Cancer Center of the Sun Yat-sen University between December 2002 and December 2007. Of the 2467 patients who received HR as an initial treatment for HCC, 201 patients were operated for HCC with PVTT. This forms the study group (the HR group). The patients in the study group were matched with patients coming from a pool of 1798 patients with HCC with PVTT who were treated with TACE as an initial treatment during the same study period (the TACE group). The patients in the HR group were matched with a 1:2 ratio with the patients in the TACE group as closely as possible in the following order of matching: 1) type of PVTT, 2) liver function (Child-Pugh classification and ICGR15 ), 3) age (± years), 4) gender, 5) tumor size, 6) alpha-fetoprotein (AFP). The survival outcomes of the TACE group were not known at the time of matching. The primary endpoint of the study was overall survival rate.

The treatment for HCC with PVTT is still controversial, and there is no universally agreed protocol for its treatment. For patients who are generally fit, with resectable tumors and with a good hepatic reserve, the treatment options of HR and TACE were discussed with the patients who would finally decide on the choice of treatment. A written consent was obtained from each patient before treatment. This study was approved by the Ethical Committee of our center.

A retrospective comparison between patients with HCC with PVTT who received hepatic resection and TACE is difficult because there is a potential to select better risk patients with less advanced HCC to surgery. To minimize such a potential bias, this study was conducted as a case-matched controlled study. There is, however, still a potential for selection bias as surgical patients might differ from medical patients as they were selected for surgery based on multiple factors other than the presence or absence of PVTT.

Patients

The diagnosis of HCC was based on the diagnostic criteria for HCC used by the European Association for the Study of the Live (EASL).23 All patients in the HR group had a histologically confirmed diagnosis of HCC. We recorded and evaluated the following parameters as possible predictors of survivals: gender, age, hepatitis status, white blood cell count, hemoglobin, platelet count , total bilirubin level (TBIL), alanine transferase level (ALT), γ-glutamyltransferase (GGT), AFP, albumin,creatinine, liver function status, indocyanine green retention rate at 15 minutes (ICG-R15), tumor size, tumor number, type of PVTT. Liver functional reserve was assessed using Child-Pugh grading and ICG-R15.

Patients in the study group (the HR group) were enrolled according to the following inclusion criteria: 1) age between 18 and 75 years, 2) HCC with no previous treatment, 3) the presence of PVTT on imaging, 4) Eastern Co-operative Group performance status 0,24 5) resectable disease, which was defined as the possibility of completely removing all gross tumors and retaining a sufficient liver remnant to sustain life, as assessed by our surgery team. Patients were excluded from the study if they had one or more of the following: 1) the presence of extrahepatic spread on imaging; 2) a Child-Pugh class C liver cirrhosis, or ICG-R15 >30%, or evidence of hepatic decompensation including ascites, esophageal, or gastric variceal bleeding or hepatic encephalopathy; 3) an American Society of Anesthesiologists (ASA) score ≥3.

In the HR group, only patients with normal or Child-Pugh class A liver function and ICG-R15 ≤10% were offered major hepatic resection, which was defined as resection of 3 or more Couinaud's segments of the liver. Selected patients with Child-Pugh class B liver function or ICG-R15 >10% underwent surgery if the tumor was resectable by a minor hepatic resection, which was defined as resection of 2 or fewer segments of the liver. Patients with Child-Pugh class C liver function were not considered for resection.22

Based on the location and extent, PVTT was classified into 4 types according to the study by Shi et al.25 Type I: tumor thrombi involving the segmental branches of the portal vein or above; type II: tumor thrombi extending to involve the right/left portal vein; type III: the main portal vein; type IV: the superior mesenteric vein. The presence of PVTT was confirmed histopathologically in the resected specimens in the HR group.

Hepatic Resection

HR was carried out under general anesthesia using a right subcostal incision with a midline extension. Intraoperative ultrasound was routinely performed. Pringle's maneuver was routinely used with a clamp/unclamp time of 10 minutes/5 minutes. Hemostasis on the raw liver surface was done with suturing and fibrin glue. The operative procedure for PVTT was the same as described in the study by Shi et al.22 Thrombectomy was performed according to the location and extent of PVTT. The en bloc technique was used for patients if the portal vein branch could be ligated with a sufficient safety margin between its root and the tip of the thrombus; PVTT was extracted out from the opened stump of the portal vein if the PVTT protruded into the main portal vein beyond the resection line. If the PVTT extended into the main portal trunk and its primary branches on both sides, the main portal trunk was exposed and was clamped distal to the PVTT. The PVTT was extracted after an incision was made at the bifurcation of the right and left portal veins. After flushing with normal saline and confirming that no PVTT remained, the stump was closed by a continuous suture.

Technique of TACE

TACE was performed using the protocol that we have previously reported.10 A selective 5 Fr catheter was introduced into the hepatic artery and visceral angiography was carried out to assess the arterial blood supply to the liver. Depending on the size, location, and arterial supply of the tumor, the tip of the catheter was advanced into the right or left hepatic artery; if all the tumors were fed by one enlarged independent hepatic artery branch, the tip of catheter was introduced into this tumor-feeding artery. If the conventional catheter could not enter the hepatic artery because of technical reasons, a 2.9 Fr microcatheter (Terumo Corporation, Tokyo, Japan) was used. Hepatic artery infusion chemotherapy was performed using carboplatin 300 mg (Bristol-Myers Squibb, New York, NY). After that, chemolipiodolization was performed using epirubicin 50 mg (Pharmorubicin, Pfizer, Wuxi, China), and mitomycin C 8 mg (Zhejiang Hisun Pharmaceutical Co. Ltd., Taizhou, China) mixed with 5 mL of lipiodol (Lipiodol Ultra-Fluide; André Guerbet Laboratories, Aulnay-Sous-Bois, France). If the chemolipiodolized arterial territory did not show stagnant flow, pure lipiodol was then injected. In some patients, we were unable to reach stasis in a tumor-feeding artery even with the injection of the maximum amount of iodized oil (25 mL) because of the large size of the tumor. Embolization was then performed in these patients with injection of absorbable gelatin sponge particles (Gelfoam; Hanzhou alc Ltd, China), 1 to 2 mm in diameter, through the angiographic catheter. This treatment regimen was used consistently in this study, regardless of tumor type and size.

Follow-up

In the HR group, contrast-enhanced computed tomography (CT) was performed 4 weeks after treatment. Thereafter, the patients were followed up once every 3 months in the first 2 years. In the TACE group, contrast-enhanced CT scans were performed every 1 to 2 month during the first 3 months to evaluate the tumor response. The Response Evaluation Criteria in Solid Tumors (RECIST) was used to measure tumor response: CR (complete response) = disappearance of all target lesions; PR (partial response) = 30% to 99% decrease in the sum of the longest diameter of the target lesions; SD (stable disease) = neither PR nor progressive disease, PD (progressive disease) = more than 20% increase in the sum of the longest diameter of the target lesions.26 Thereafter, contrast CT scan was performed once every 3 monthly for surveillance. For all patients, at each of these follow-up visits, blood tests including liver function tests and serum alpha-fetoprotein were obtained. Chest radiography was performed once every 6 months.

In the HR group, R0 and R1 resections were defined by the absence (tumor-free margin ≥1 mm for all detected lesions) or the presence (tumor-free margin ≤0 mm) of microscopic tumor invasion of the resection margins, respectively. R2 resection was defined as gross residual tumor invasion of the resection margins.27 Patients received R1 or R2 resections were considered to have residual tumor. For these patients, “adjuvant” TACE was performed. Recurrence was defined as appearance of new lesions with the radiological features of HCC after R0 HR. Patients with intrahepatic recurrences were treated aggressively with surgery, local ablative therapy, TACE, or systemic therapy, depending on the size, location, and number of recurrent tumors, liver function status, presence of extrahepatic disease, and tumor thrombus in the portal vein. Palliative treatment was given to patients with advanced disease, poor liver function, or poor general status.

In the TACE group, after the initial treatment, another session of TACE was performed every 4 to 10 weeks until one of the following end points was reached: 1) complete devascularization of the tumor; 2) technical impossibility to embolize the residual tumors, for example, tumors only supplied by extrahepatic collateral arteries; 3) development of contraindications to TACE; 4) total resection or ablation of the tumor by subsequent surgery or local ablation.

Sample Size

Sample size was computed using the overall survival as the main endpoint. The assumptions were 3-year survival of 15% in the HR group and 5% in the TACE group. Using a 2-sided test with 80% power at a significance level of 5%, the minimal sample size needed to detect a significant difference was 122 patients in the HR group, and 244 patients in the TACE group.

Statistical Analysis

The statistical analyses were performed using the SPSS 10.0 statistical software (SPSS Company, Chicago, Ill; 2005). Comparisons between the 2 groups were done using the Student's t test for continuous data and the chi-square test for categorical data. The overall survivals were calculated using a life-table method, and compared with the Mantel-Cox test. The survival curves were constructed by the Kaplan-Meier method, and compared by the log-rank test. The relative prognostic significance of the variables in predicting overall survival rates was assessed using multivariate Cox proportional hazards regression analysis. Results were given as mean ± SD. All statistical tests were two sided, and a significant difference was considered when P < .05.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. REFERENCES

Baseline Characteristics of Patients

The study population consisted of 561 men and 42 women, with a median age of 51 ± 11.4 (range, 23-75) years. The follow-up periods for the HR and the TACE groups were 16.3 ± 1.12 (range, 2.0-83.0) months and 12.1 ± 0.56 (range, 2.0-53.0) months, respectively (P = .006). The baseline demographic data were well matched between the two groups of patients except for tumor number (Table 1).

Table 1. Baseline Characteristics of Patients
 HR (n = 201)TACE (n = 402)P
  • Abbreviations: ALT, alanine transferase level; GGT, γ-glutamyltransferase; HR, hazard ratio; PVTT, portal vein tumor thrombus; TACE, transcatheter arterial chemoembolization; TBIL, total bilirubin level.

  • a

    Indocyanine green retention rate in 15 minutes;

  • b

    γ-glutamyltranspeptidase;

  • c

    Alanine aminotransferase;

  • d

    Total bilirubin;

  • e

    Portal vein tumor thrombus. Type I: tumor thrombi involving segmental branches of portal vein or above; Type II: tumor thrombi involving right/left portal vein; Type III: tumor thrombi involving the main portal vein trunk; Type IV: tumor thrombi involving the superior mesenteric vein.

Age, y55 (25-75)55 (23-75).810
Sex (M/F)187/14374/281.00
Hepatitis status, n   
Hepatitis B carrier172356.755
Hepatitis C carrier47 
Cirrhosis (yes/no)176/25363/39.327
Liver function status, n   
Child Pugh class A197389.447
Child Pugh class B413 
ICGR15,a %  .243
≤10165313 
>103689 
Tumor size, cm  .138
≤576178 
>5125224 
Tumor number  .001
195132 
>1106270 
Alpha-fetoprotein level, ng/mL562.3 (3.0-132490)598.5 (10-121000).07
GGT,b U/L335.1 (13.2-598.0)360.4 (13.0-612.0).498
ALT,c U/L23.5 (4.0-56.2)28.0 (5.0-56.0).056
Albumin, g/L36.8 (34.5-46.9)36.3 (34.3-48.3).545
TBIL,d μmol/L12.9 (5.0-34.7)12.5 (5.0-35.1).592
Creatinine, μmol/L68.4 (63.9-134.5)70.3 (67-134.0).579
Platelet count, 109/L141.4 (90-300)132.1 (80-300).069
Hemoglobin, g/L125.0 (108.0-160.0)120.0 (105.0-156.0).698
White blood cell, 109/L5.6 (3.5-8.0)6.3 (3.9-9.0).183
Type of PVTTe   
Type I27541.00
Type II68136 
Type III83166 
Type IV2346 

Outcomes after HR

The surgical procedures and the operative details for the patients in the HR group are shown in Tables 2 and 3. The major complication rate was 4.0% (8 of 201). There was one in-hospital postoperative death (0.5%) due to postoperative liver failure. A total of 180 patients received R0, 17 patients R1, and 4 patients R2 resection. Patients with R1 or R2 resections received postoperative TACE starting 4 weeks after surgery. During the follow-up period, 177 patients developed radiologically detectable residual disease/tumor recurrence. Of these 177 patients, 23 patients received a second HR, 127 received repeated TACE, and the remaining received supportive treatment or systemic therapy.

Table 2. Operative Details
Type of PVTTaType IType IIType IIIType IV
Type of hepatectomy(n = 27)(n = 68)(n = 83)(n = 23)
  • Abbreviation: PVTT, portal vein tumor thrombus.

  • a

    Portal vein tumor thrombus. Type I: tumor thrombi involving segmental branches of portal vein or above; Type II: tumor thrombi involving right/left portal vein; Type III: tumor thrombi involving the main portal vein trunk; Type IV: tumor thrombi involving the superior mesenteric vein.

Minor hepatectomy3000
Major hepatectomy91300
Minor hepatectomy + thrombectomy822134
Major hepatectomy + thrombectomy7337019
Operating time (min)125.8±44.5160.6±37.9162.7±42.0170.5±30.5
Median intraoperative blood loss (mL)547.5 (80-5000)849.5 (120-5000)979.5 (150-4900)1324.5 (120-7200)
Median red blood cell transfusion (mL)407.4 (0-2000)487.5 (0-3000)563.5 (0-4000)842.5 (0-6400)
Time of Pringle maneuver (min)17.7±5.220.0±3.122.4±3.526.5±5.8
Table 3. Postoperative Outcomes
Type of PVTTaType IType IIType IIIType IV
(n = 27)(n = 68)(n = 83)(n = 23)
  • Abbreviation: PVTT, portal vein tumor thrombus.

  • a

    Portal vein tumor thrombus: Type I: tumor thrombi involving segmental branches of portal vein or above; Type II: tumor thrombi involving right/left portal vein; Type III: tumor thrombi involving the main portal vein trunk; Type IV: tumor thrombi involving the superior mesenteric vein.

Hospital mortality0001
Postoperative hospital stay, d13.1±1.313.5±2.214.2±2.115.1±1.4
Major complications, n    
Gastrointestinal hemorrhage0011
Bile leakage0100
Pulmonary complications1011
Spontaneous bacterial peritonitis0011
Surgical margins, n    
R0 resection27657117
R1 resection03104
R2 resection0022
Differentiation status of tumors    
 Well-differentiated513153
 Intermediate-differentiated16415612
Poorly differentiated614128
Recurrence    
Intrahepatic recurrence14516814
Distance metastases1120
Both25109

Outcomes after TACE

In the TACE group, 402 patients received a mean of 2.1 (range, 1-5) sessions of TACE. Seventy-eight (19.4%) patients received 1 session, and 324 (80.6%) received more than 1 session of TACE. The tumor response and complications in the TACE group are shown in Table 4. All the TACE-related complications were treated successfully with conservative treatment. There was no TACE-related death. After TACE, the tumors in 43 patients were downstaged to receive HR (n = 31) or local ablative therapy (radiofrequency ablation, n = 5, or radiofrequency + percutaneous ethanol injection, n = 7).

Table 4. Posttreatment Outcomes of TACE
Type of PVTTaType IType IIType IIIType IV
(n = 54)(n = 136)(n = 166)(n = 46)
  • Abbreviations: CR, complete remission; PR, partial remission; SD, stable disease; PD, progressive disease; PVTT, portal vein tumor thrombus; TACE; transcatheter arterial chemoembolization.

  • a

    Portal vein tumor thrombus: Type I: tumor thrombi involving segmental branches of portal vein or above; Type II: tumor thrombi involving right/left portal vein; Type III: tumor thrombi involving the main portal vein trunk; Type IV: tumor thrombi involving the superior mesenteric vein.

Hospital mortality0000
Gastrointestinal hemorrhage0001
Pleura effusion0110
Liver failure1114
Spontaneous bacterial peritonitis0010
Cholecystitis2241
Fever (temperature >38°C)28709220
Pain    
Grade 120747818
Grade 281682
Grade 30200
Vomiting30787018
Tumor response    
 CR0000
 PR632284
 SD28765816
 PD20288026

Overall Survival for All Patients

The median survivals for the HR and TACE groups were 20.0 ± 1.8 and 13.1 ± 0.6 months, respectively. The 1-, 3-, and 5-year overall survivals for the HR and TACE groups were 42.0%, 14.1%, 11.1%, and 37.8%, 7.3%, 0.5%, respectively (Table 5) The survival curve for the HR group was better than the TACE group (Fig. 1; P < .001). A subgroup analysis of patients by the PVTT type identified increased survival in the HR group compared with the TACE group (P < .001, P = .002, respectively) in patients with type I PVTT and type II PVTT (Fig. 2A and B, respectively, and Table 5). However, there were no significant differences between the HR group and the TACE group for patients with type III PVTT and type IV PVTT (P = .541, P = .371, respectively) (Fig. 2C and D, respectively, and Table 5). For patients with a single tumor, the overall survival was better in the HR group than the TACE group (P < .001; Fig. 3A and Table 5). For patients with multiple tumors, there was no significant difference between the two groups for overall survival (P = .675; Fig. 3B and Table 5). For patients with a single tumor <5 cm, there was no significant difference between the two groups for overall survival (P = .125; Fig. 4A and Table 5). For patients with a single tumor >5 cm, the overall survival was better in the HR group than the TACE group (P < .001; Fig. 4B and Table 5).

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Figure 1. Overall survival curves for the hepatic resection (HR) group and the transcatheter arterial chemoembolization (TACE) group are shown.

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Figure 2. (A) Overall survival curves for the patients with type I portal vein tumor thrombus (PVTT) who received hepatic resection (HR) or transcatheter arterial chemoembolization (TACE) are shown. (B) Overall survival curves for the patients with type II PVTT who received HR or TACE are shown. (C) Overall survival curves for the patients with type III PVTT who received HR or TACE are shown. (D) Overall survival curves for the patients with type IV PVTT who received HR or TACE are shown.

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Figure 3. (A) Overall survival curves for the patients with single tumor who received hepatic resection (HR) or transcatheter arterial chemoembolization (TACE) are shown. (B) Overall survival curves for the patients with multiple tumors who received HR or TACE are shown.

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Figure 4. (A) Overall survival curves for the patients with tumor size ≤5 cm receiving hepatic resection (HR) or transcatheter arterial chemoembolization (TACE) are shown. (B) Overall survival curves for the patients with tumor size >5 cm who received HR or TACE are shown.

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Table 5. Comparison of Overall Survival Rates Among Treatment Methods
   Survival rate  
Treatment by tumor typeNo. of Patients1 Y3 Y5 YP
  • Abbreviations: HR, hazard ratio; PVTT, portal vein tumor thrombus; TACE, transcatheter arterial chemoembolization.

  • a

    Portal vein tumor thrombus: Type I: tumor thrombi involving segmental branches of portal vein or above; Type II: tumor thrombi involving right/left portal vein; Type III: tumor thrombi involving the main portal vein trunk; Type IV: tumor thrombi involving the superior mesenteric vein.

All hepatocellular carcinoma    <.001
 HR20142.0%14.1%11.1% 
 TACE40237.8%7.3%0.5% 
Type I PVTTa    <.001
 HR2781.5%51.2%37.9% 
 TACE5441.1%8.9%3.6% 
Type II PVTT    .002
 HR6846.3%17.2%17.2% 
 TACE13637.9%6.0%,0.0% 
Type III PVTT    .541
 HR8332.5%3.6%3.6% 
 TACE16636.1%4.2%0% 
Type IV PVTT     
 HR2321.7%0%0%.371
 TACE4630.4%4.3%0% 
Tumor size ≤5 cm    .125
 HR7654.2%25.0%12.5% 
 TACE17843.3%10.7%1.1% 
Tumor size >5 cm    <.001
 HR12539.8%12.8%10.2% 
 TACE22433.3%4.5%0% 
Single tumor    <.001
 HR9550.0%20.8%19.5% 
 TACE13237.8%6.7%0.6% 
Multiple tumor    .675
 HR10634.9%7.6%2.3% 
 TACE27038.6%12.5%0.4% 

Disease-Free Survival after HR

In the HR group, radiologically detectable residual tumor/recurrence was observed in 177 patients. A total of 147 patients had intrahepatic residual tumor/recurrence, 4 patients had distance metastases, and 26 patients had both intrahepatic residual tumor/recurrences and distance metastases. The median survival for the HR group was 10.0 ± 0.9 months. The 1-, 3-, and 5-year disease-free survivals for all patients who received HR were 22.5%, 8.5%, and 2.8%. On subgroup analysis, the 1-, 3-, 5-year disease-free survivals for patients with types I, II, III, and IV PVTT were 63.0%, 29.2%, 29.2%; 20.9%, 12.9%, 6.4%; 14.5%, 4.8%, 0%; and 8.7%, 0%, 0%; respectively (P < .001). Patients with type I PVTT had better disease-free survivals than type II, III, and IV PVTT (P = .002, P < .001, and P < .001, respectively). Patients with type II PVTT had better disease-free survivals than types III and IV PVTT (P = .030, and P = .004, respectively). There was no significant difference between patients with type III and type IV PVTT (P = .132). The 1-, 3-, and 5-year disease-free survivals for patients with a single tumor or multiple tumors were 27.7%, 12.9%, 6.5% and 17.9%, 4.3%, and 0%, respectively. The survival curve for patients with a single tumor was better than multiple tumors (P = .004). The 1-, 3-, and 5-year disease-free survivals for patients with a single tumor ≤5 cm or >5 cm were 29.2%, 18.8%, 18.8%, and 22.2%, 7.8%, 2.6%, respectively. There was no significant difference between the two groups (P = .146).

Univariate and Multivariate Analyses of Overall Survival for All Patients

Using univariate analysis, possible correlations between overall survival and 18 dichotomized variables with known values for all the 603 patients were evaluated (Table 6). Four factors correlated with overall survival: type of PVTT, tumor size, tumor number, and initial treatment allocation. After multivariate Cox proportional hazards regression analysis, type of PVTT (hazard ratio [HR] = 1.223; 95% confidence interval [CI], 1.035-1.445; P = .018) and initial treatment allocation (HR = 1.563; 95% CI, 1.288-1.569; P < .001) were significant prognostic factors for overall survival.

Table 6. Univariate and Multivariate Analysis of Overall Survival for All Patients
 Univariate Analysis Multivariate Analysis 
VariablesPPHR95% CI
  • Abbreviations: ALT, alanine transferase level; CI, confidence interval; GGT, γ-glutamyltransferase; HR, hazard ratio; PVTT, portal vein tumor thrombus; TACE, transcatheter arterial chemoembolization; TBIL, total bilirubin level.

  • a

    Indocyanine green retention rate in 15 minutes.

  • b

    γ-Glutamyltranspeptidase.

  • cAlanine aminotransferase.

  • d

    Total bilirubin.

  • e

    Portal vein tumor thrombus: Type I: tumor thrombi involving segmental branches of portal vein or above; Type II: tumor thrombi involving right/left portal vein; Type III: tumor thrombi involving the main portal vein trunk; Type IV: tumor thrombi involving the superior mesenteric vein.

Age (y), ≤60 or >60.283   
Sex (M/F).181   
Hepatitis B carrier (±).241   
Hepatitis C carrier (±).340   
Cirrhosis (yes/no).710   
Child Pugh class (A/B).125   
ICGR15(%),a ≤10 or >10.358   
Tumor size, ≤5 or >5 cm.006   
Tumor number, ≤1 or >1<.001   
Alpha-fetoprotein level (ng/mL), ≤400 or >400.107   
GGT,b (U/L), ≤50 or >50.675   
ALT (U/L), ≤40 or >40.928   
Albumin (g/L),d ≤35 or >35.411   
TBIL (μmol/L),d ≤20 or >20.239   
Platelet count (109/L), ≤100 or >100.182   
Hemoglobin (g/L), ≤110 or >110.282   
White blood cell (109/L) ≤4 or >4.075   
Type of PVTTe<.001.0181.2231.035-1.445
Treatment allocation, HR or TACE<.001<.0011.5631.288-1.896

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. REFERENCES

PVTT is one of the most important prognostic factors for survival in patients with HCC. Patients with PVTT have significantly worse outcomes after treatment. The optimal treatment for HCC with PVTT remains controversial. TACE is commonly used to treat advanced HCC.6-8 Our previous study showed that TACE had a better efficacy than conservative treatment for HCC with PVTT, but the outcomes of TACE were still poor.9-12 Shi et al22 proposed that there is a role for HR in the treatment of HCC with PVTT because surgery 1) decreases the portal venous pressure, 2) improves the liver function by unblocking the portal vein, 3) prolongs survival, and 4) improves quality of life. Many previous studies showed that HR was a safe and effective treatment for HCC with PVTT if the patients were carefully selected. A median survival ranging from 8.9 to 33 months was reported for HCC with PVTT with surgical treatment.13-19 Although these results seems to be superior to TACE, patients who received HR were highly selected. We, therefore, conducted this case-match-control study comparing HR with TACE in the treatment of HCC with PVTT. As this study was retrospective and nonrandomized, it is important to minimize the selection bias in the study design and analysis. In this study, the patients were well matched between the HR group and the TACE group with the exception of the tumor number. There were more patients with multiple tumors in the TACE group (P = .001). This may introduce selection bias into the data between the two groups and introduced better efficacy in HR group. Among the many prognostic factors, the number of tumors is a key predictor of HCC prognosis. Patients with multiple tumors generally have poor prognosis.28, 29 We therefore further analyzed the overall survival in the two treatment groups after stratification by the tumor number. The results showed that HR significantly improved survival outcomes compared with TACE for patients with a single tumor, but not for patients with multiple tumors. Furthermore, we found that the number of tumors was not a key predictor of HCC with PVTT after treatment.

In our study, resectable disease was defined as the possibility of completely removing all gross tumors while at the same time retaining a sufficient liver remnant to sustain life. The tumor number and tumor size were not considered as contraindications for resection. Recently, HR has been shown to result in good long-term survivals in well-selected patients with multiple HCCs.30, 31 Ishizawa et al30 reported a 58% 5-year survival rate after HR for patients with Child A and multiple HCCs, and the result was comparable to curative treatment for HCC. Ng et al31 reported after HR, a 39% 5-year survival rate was achieved for patients with large or multiple HCC. The safety of liver resectional surgery has been improved with the use of liver volumetry and portal vein embolization.30-35 It is now generally accepted that patients should receive HR for HCC irrespective of the number of tumors if there is a reasonable sized functional future liver remnant left behind. Similarly, resection for a single large HCC (>10 cm) has been reported to be associated with favorable long-term survivals.36, 37 Tumor size alone has also been found not to be an absolute contraindication for liver transplantation. The Milan criteria38 (single HCC ≤5 cm, or 2 to 3 HCCs each ≤3 cm) has been widely accepted and the 5-year posttransplant survival rate is around 70%. Studies have also shown that the Milan criteria can be expanded to include patients with larger tumors, provided that there is no vascular invasion by the tumors using the UCSF criteria.39, 40

Our comparative study showed a significantly better overall survival for patients with HCC with PVTT treated with HR compared with patients treated TACE as an initial treatment, especially for patients with PVTT involvement limited to the right or left portal vein or less. This result may possibly be because of the radicality of HR in tumor ablation relative to TACE, although HR is far more invasive.41 Most of our patients with type I PVTT or type II PVTT received a R0 resection (92 of 95). However, only 20% of patients with type I PVTT or type II PVTT achieved a complete/partial response (38 of 190) with TACE. Surgical treatment for type III or type IV PVTT (defined as tumor thrombi involving the main portal vein trunk or involving the superior mesenteric vein, respectively) remains controversial.14, 15, 21 Shi et al22 proposed that thrombectomy is a viable treatment option if the tumor thrombus does not infiltrate into the portal venous wall. Our experience supported this view. After surgery, 83.0% (88 of 106) of these patients with a locally advanced HCC with PVTT achieved a R0 resection. Unfortunately, HR did not offer better survivals for these patients when compared with TACE. This is probably because surgery results in impairment of the liver function, which then affects the long-term survival of the patients.42 In other words, the beneficial effects of a more complete ablation of tumor by HR is offset by its deteriorative effects on liver function. On the other hand, TACE, though less effective on the tumor, affects the liver function less. In our study, after HR, there was one postoperative in-hospital death caused by postoperative liver failure (0.5%), and the major complication rate was 4.0% (8 of 201), our results were similar to the studies reported previously.13-22 Therefore, HR is still a safe treatment for HCC with PVTT.

There are some limitations in our study. First, this is a retrospective study with all its inherent defects. Second, pathological classification was not included in the univariate and multivariate analyses. It is well known that pathological classification is a significant prognostic factor for survival. However, in our study, many patients treated by TACE did not have a histopathological diagnosis. Third, this is a single center study, and the results may not be applicable to a less specialized center. It is possible that our results may not be applicable to patients with HCC with PVTT in other countries because of differences in demographics and in the underlying causes of liver disease.

In conclusion, this retrospective study indicated that HR offered better long-term survivals for resectable HCC with PVTT than TACE, especially for patients with type I PVTT, type II PVTT, or a single tumor. Further clinical studies, preferably in the form of prospective randomized trials with adequate sample sizes and prolonged follow up, are required, although such a study is difficult to carry out as HCC with PVTT is uncommon. In the absence of such data, surgery is still the standard of care for resectable HCC with PVTT, whereas TACE remains a local therapy option for patients who do not qualify for surgery.

FUNDING SUPPORT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. REFERENCES

This study is supported by The Eleventh Five-Year Key Plan of the China National Science and Technique Foundation, No. 2006BAI02A04.

CONFLICT OF INTEREST DISCLOSURES

There are no financial disclosures from any authors.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. REFERENCES