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Meta-analysis: preoperative transcatheter arterial chemoembolization does not improve prognosis of patients with resectable hepatocellular carcinoma

  • Yanming Zhou1,
  • Xiaofeng Zhang2,
  • Lupeng Wu1,
  • Feng Ye1,
  • Xu Su1,
  • Lehua Shi2 and
  • Bin Li1Email author
Contributed equally
BMC Gastroenterology201313:51

DOI: 10.1186/1471-230X-13-51

Received: 11 August 2012

Accepted: 12 March 2013

Published: 19 March 2013

Abstract

Background

Long-term outcomes of partial liver resection of hepatocellular carcinoma (HCC) remain satisfactory due to high incidences of recurrence. This study was intended to see whether preoperative transcatheter arterial chemoembolization (TACE) reduces postoperative tumor recurrences and prolongs survival of patients with resectable HCC.

Methods

A computerized literature search was performed to identify relevant articles. The quality of nonrandomized comparative studies (NRCTs) was assessed using the methodological index for nonrandomized studies (MINORS). Data synthesis was performed using Review Manager 5.0 software.

Results

Twenty-one studies (4 randomized controlled trials and 17 NRCTs) with a total of 3,210 participants were suitable for analysis. There was no significant difference in disease-free and overall survival at 5-year (32.1% vs. 30.0% and 40.2% vs. 45.2%), and intra- and extra-hepatic recurrence (51.2% vs.53.6% and 12.9% vs.10.3%) between patients with and without preoperative TACE. Postoperative morbidity (28.9% vs. 26.8%) and in-hospital mortality (4.1% vs. 3.1%) were also similar between the two groups.

Conclusions

Preoperative TACE does not seem to improve prognosis and therefore it is prudent to recommend it as a preoperative routine procedure for resectable HCC.

Keywords

Hepatocellular carcinoma Transcatheter arterial chemoembolization Prognosis

Background

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide, and ranks the third leading cause of cancer-related death [1]. Hepatectomy is considered the main curative treatment for HC with a 5-year survival of 23.8–54.8% as reported in the most recent series [25]. Tumor recurrence even after radical surgery affects 75-100% HC patients, accounting for the major cause of death of HC patients [6]. The development of appropriate strategies to prevent tumor recurrence is therefore critical for improving long-term outcomes of HC patients after surgical resection.

Transcatheter arterial chemoembolization (TACE), which induces tumor ischemic necrosis by arterial injection of chemotherapeutic drugs and embolizing agents, is recommended as the first-line palliative treatment for inoperable HCC in the 2005 practice guidelines issued by the American Association for the Study of Liver Diseases [7]. Some researchers believed that it may reduce the viability of HCC cells before surgery and reduce postoperative tumor recurrence [8]. Although several studies have demonstrated the survival benefits of preoperative TACE for patients with HCC [9, 10], others have failed to show any significant survival benefit [1116]. Therefore, the role of preoperative TACE for HCC remains a contradictory issue. A recent review of three randomized controlled trials (RCTs) showed that preoperative TACE did not significantly improve survival [17]. However, their study only involved 257 participants, and therefore may not be convincing enough to confirm the effect conclusively [18]. To produce more reliable evidence for clinical decision-making, meta-analytic techniques could be applied to nonrandomized comparative studies (NRCTs) to ensure both the number and sample size of RCTs [19], knowing that meta-analysis of well-designed NRCTs is feasible and the results are remarkably similar to those of contemporaneous RCTs [20]. The present meta-analysis should be able to provide an updated evaluation on preoperative TACE for resectable HCC by taking into account all the currently evidence from RCTs and well-designed NRCTs.

Methods

Inclusion and exclusion criteria

The present meta-analysis was performed by following the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. Primary studies that evaluated the efficacy of preoperative TACE vs. no-preoperative TACE for resectable HCC were considered for inclusion. For duplicate publications reported by the same authors, either the one of higher quality or the most recent publication was selected. Abstracts, letters, editorials and expert opinions, reviews without original data, case reports, and uncontrolled studies were excluded. Study populations including recurrent HCC or unresectable diseases were also excluded.

Study selection

A computerized search of the literature was performed by searching Medline, EMBASE, OVID, and Cochrane database from the time of inception to June 2012. The following medical subject heading (MeSH) terms were used: “hepatectomy,” “hepatocellular carcinoma,” and “transarterial chemoembolization”. Only studies on humans and in the English language were considered for inclusion. Reference lists of all identified articles were manually searched for additional studies. Publication bias was assessed visually using a funnel plot.

Data extraction

Two reviewers (LW and YZ) independently extracted the following parameters from each study: first author, year of publication, study population characteristics, study design, inclusion and exclusion criteria, the number of subjects in each arm, survival, recurrence, morbidity and mortality. All relevant texts, tables and figures were reviewed for data extraction.

Qualitative analysis

The RCTs were scored using the Jadad composite scale [21], which evaluates studies based on appropriate randomization, double blinding, and an adequate description of withdrawals and drop-outs. For evaluation of NRCTs, the methodological index for nonrandomized studies (MINORS) with some modifications were applied [22]. The following 12 items were evaluated for each study: a clearly stated aim, consecutive patients, prospective data collection, reported endpoints, unbiased outcome evaluation, adequate length of follow-up, loss to follow up <5%, ≥ 20 patients in each arm, adequate control group, contemporary groups, controls equivalent to cases, and adequate statistical analyses. Studies achieving more than 16 points (maximum 24) were defined as well-designed and were included in the meta-analysis [20]. Those with less than 16 points were excluded.

Outcomes of interests

Items for assessing long-term outcomes included disease-free and overall survival rate at 5 year, total recurrence, hepatic recurrence, and extrahepatic recurrence.

Items for assessing short-term outcomes included postoperative morbidity and in-hospital mortality.

Statistical analysis and synthesis

Dichotomous variables were tested by odds ratio (OR) with a 95% confidence interval (95% CI), and continuous variables were tested by the weighted mean difference (WMD) with a 95% CI. Between-study heterogeneity was evaluated by χ 2 and I 2 . Data that were not significantly heterogeneous (P > 0.1) were calculated using a fixed effects model, and heterogeneous data (P < 0.1) were calculated using a random-effects model. Sensitivity analysis was undertaken by using the following subgroups: (1) RCTs, (2) NRCTs, and (3) studies with matched clinicopathological parameters. Statistical analyses were performed with Review Manager version 5.0 (The Cochrane Collaboration, Software Update, Oxford). A value of P < 0.05 was considered statistically significant.

Results

Eligible studies

Twenty-six studies that matched the selection criteria were retrieved from the electronic databases [916, 2341]. Of these studies, one study was excluded due to overlap of authors and nonrandomized nature [23], and therefore the most recent RCT was included [24]. Four NRCTs with fewer than 16 points were excluded [9, 2527]. Finally, 21 articles, including four RCTs [1416, 24] and 17 NRCTs [1013, 2840], met the inclusion criteria.

The characteristics of the 21 studies are summarized in Table 1. A total of 3,210 patients were included in the meta-analysis, of whom 1,431 received preoperative TACE and 1,779 were allocated to a control group. The number of patients in each study varied from 40 to 350 patients. In the enrolled patients, the percentage of men ranged from 76.9% to 100% and the mean age ranged from 45.3 ± 9.8 to 68.1 ± 5.7 years. Eight studies were completely matched with respect to the reported clinicopathological parameters [12, 15, 16, 28, 30, 32, 35, 39]. One trial was conducted to compare outcomes of whole-liver TACE, selective TACE, and without preoperative TACE [24]. Only selective TACE arm was considered in the present meta-analysis.
Table 1

Clinical background of studies included in the meta-analysis

Reference

Year

Inclusion Period

Country

Group

No. of patients

M/F

Mean age (years)

Mean AFP (ng/ml)

Child-Pugh A/B/C

LB N/H/C

Tumor size (cm)

Matching

Not matching

Score

RCTs

              

Wu [14]

1995

1983-1991

Taiwan

TACE (+) TACE (−)

24 28

23/1 23/5

51.8 ± 12.4 53.2 ± 11.5

≥ 400 (n = 15) ≥ 400 (n = 16)

22/2/0 24/4/0

—/—/14 —/—/12

14.3 ± 4.2 14.5 ± 3.3

1-3,5-15

17

2

Yamasaki [15]

1996

1987-1989

Japan

TACE (+) TACE (−)

50 47

50/0 47/0

54.9 ± 6.4 57.1 ± 4.9

— —

— —

—/—/— —/—/—

3.1 ± 0.8 3.3 ± 0.9

1,2,4,9-12

2

Zhou [16]

2009

2001-2003

China

TACE (+) TACE (−)

52 56

48/4 49/7

45.3 ± 9.8 46.8 ± 9.6

1244.2 ± 376 1387.5 ± 426

44/8/0 54/2/0

—/—/49 —/—/50

9.0 ± 3.2 9.5 ± 3.9

1-3,5-10, 12,14,15

3

Kaibori [24]

2012

2004-2007

Japan

TACE (+) TACE (−)

42 43

35/7 32/11

68.1 ± 5.7 66.1 ± 10.6

2432 ± 11638 858 ± 5269

37/5/0 39/4/0

1/27/14 4/28/11

4.3 ± 2.1 4.8 ± 4.1

1-10,12, 13,15

11

3

NRCTs

              

Nagasue [12]

1989

1980-1986

Japan

TACE (+) TACE (−)

31 107

25/6 90/17

56.5 ± 9.1 59.4 ± 8.9

>20 (n = 18) >20 (n = 76)

17/13/1 69/32/6

—/—/26 —/—/88

>3 (n = 17) >3 (n = 72)

1-3,5,6, 8–11,14

19

Adachi [13]

1993

1981-1991

Japan

TACE (+) TACE (−)

46 26

39/7 21/5

55.9 ± 7.71 59.8 ± 5.7

>20 (n = 24) >20 (n = 15)

— —

—/—/29 —/—/22

2.6 ± 0.9 2.1 ± 0.9

2-4,6-8,11,14,16

1,9,13

18

Harada [28]

1996

1982-1994

Japan

TACE (+) TACE (−)

105 35

90/15 30/5

57.6 ± 9.7 59.8 ± 9.9

— —

— —

—/—/69 —/—/24

>5 (n = 36) >5 (n = 9)

1,2,4,7-10,12

19

Uchida [29]

1996

1986-1991

Japan

TACE (+) TACE (−)

60 68

50/10 52/16

59.0 ± 9.9 62.0 ± 7.2

>20 (n = 27) >20 (n = 45)

37/18/5 45/18/5

—/—/42 —/—/49

3.7 ± 3.1 4.4 ± 3.4

2,4-10,14

1,3,11,13

18

Majno [10]

1997

1985-1995

France

TACE (+) TACE (−)

49 27

44/5 26/1

59.2 ± 7.1 60.9 ± 7.8

285 ± 1629 129 ± 250

43/6/0 17/10/0

0/0/49 0/0/27

5.05 ± 2.5 3.9 ± 1.8

1-3,8,10, 12-14

5-7

18

Di Carlo [11]

1998

1989-1997

Italy

TACE (+) TACE (−)

55 45

49/6 34/11

63.0 ± 6.0 62.0 ± 6.0

>10 (n = 13) >100 (n = 6)

48/—/— 36/—/—

0/0/55 0/0/45

>3 (n = 32) >3 (n = 31)

1-3,5,7-12,14,15

13

18

Paye [30]

1998

1986-1992

France

TACE (+) TACE (−)

24 24

21/3 17/7

57 ± 2 54 ± 3

2560 (2–46000) 4229 (2–73000)

22/2 22/2

1/—/13 1/—/13

7.8 ± 1 7.3 ± 1

1-3,5-10,12-14,16

17

Lu [31]

1999

1988-1994

China, Japan

TACE (+) TACE (−)

44 76

36/8 57/19

51.5 54.5

— —

31/13/0 61/15/0

—/—/28 —/—/44

7.3 7.6

2,5,6,8,9,11,14

1

20

Ochiai [32]

2003

1978-1994

Japan

TACE (+) TACE (−)

100 48

78/22 43/5

59.6 ± 8 58.9 ± 8.7

>400 (n = 74) >400 (n = 30)

— —

—/—/— —/—/—

4.4 ± 3.3 4.4 ± 3.1

1-4,6,7,9, 10,12-15

20

Sugo [33]

2003

1997-2000

Japan

TACE (+) TACE (−)

146 81

122/24 67/14

57.6 ± 9.4 60.5 ± 9

— —

118/27/1 74/6/1

—/—/116 —/—/58

4.5 ± 3.0 4.8 ± 3.9

2,5,8,9

1

18

Sasaki [34]

2006

1982-2003

Japan

TACE (+) TACE (−)

109 126

85/24 97/29

>65 (n = 38) >65 (n = 68)

>100 (n = 40) >100 (n = 49)

— —

—/—/76 —/—/61

≥5 (n = 27) ≥5 (n = 47)

2-4,7,9,11, 12

1,8

20

Chen [35]

2007

1990-2004

China

TACE (+) TACE (−)

89 157

71/18 136/21

45.5 ± 6.3 48.6 ± 5.7

2838 ± 1721 2335 ± 1088

78/11/0 142/15/0

—/—/15 —/—/25

9.5 ± 2.6 9.9 ± 3.1

1-3,6-10,12,13,16

20

Choi [36]

2007

1998-2005

Korea

TACE (+) TACE (−)

120 153

93/27 117/36

52.4 ± 9.6 52.4 ± 10.4

8094 ± 68967 2292 ± 7444

117/0/0 150/2/0

—/—/56 —/—/75

>5 (n = 44) >5 (n = 50)

1-6,8-10,12-14

7

19

Kim [37]

2008

1995-2000

Korea

TACE (+) TACE (−)

97 237

80/17 194/43

48.8 ± 9.2 51.7 ± 10.2

>1000 (n = 70) >1000 (n = 31)

97 237

—/—/77 —/—/182

>5 (n = 49) >5 (n = 101)

1-3,5-10,12,14

16

19

Lee [38]

2009

2000-2006

Taiwan

TACE (+) TACE (−)

114 236

89/25 173/63

57.9 ± 11.3 57.8 ± 11.7

2265.88 ± 8438.55 1862.52 ± 1388.63

110/4/0 232/4/0

—/—/79 —/—/152

4.3 ± 3.1 3.9 ± 2.7

1-3,5,7-10, 12,15

11

18

Kang [39]

2010

1997-2007

Korea

TACE (+) TACE (−)

32 64

25/7 51/13

52.4 ± 9.8 54.0 ± 10.8

9584.4 ± 26238.5 5100.9 ± 24773.9

30/2/0 64/0/0

—/—/— —/—/—

4.3 ± 2.5 4.5 ± 3.2

1-3,5,6,9,10,15

20

Yamashita [40]

2012

1995-2008

Japan

TACE (+) TACE (−)

42 95

36/7 77/18

58 ± 12 64 ± 9

1527 ± 4415 1125 ± 4713

31/—/— 88/—/—

—/—/7 —/—/26

9.1 ± 3.2 7.9 ± 3.0

2-4,7-11

1,5,6

20

LB liver background; N/H/C normal/hepatitis/cirrhosis; 1, Age; 2, Gender; 3, AFP level; 4, ICG R15 (%); 5, Child-Pugh grade; 6, Viral status; 7, Operative procedures; 8, LB; 9, Tumor size; 10 Tumor number;11, Histologic grade; 12,Vascular invasion; 13, Tumor encapsulation; 14, Intrahepatic metastasis or satellite nodules; 15, Pathological stage; 16,Capsular invasion;17, Adjacent organ invasion.

The data regarding the effects of TACE on tumor responses were available in 18 studies [1016, 24, 28, 3038], in which histological examination on surgical specimens revealed that a total of 260 patients (20.1%) of 1,292 patients had complete tumor necrosis ranging from 0 to 53.6%.

The funnel plot (Figure 1) for 5-year disease-free survival in the included studies demonstrated asymmetry, indicating an insignificant sign of publication bias.
https://static-content.springer.com/image/art%3A10.1186%2F1471-230X-13-51/MediaObjects/12876_2012_Article_909_Fig1_HTML.jpg
Figure 1

Funnel plot analysis of publication bias. The outcome was the 5-year disease-free survival.

Overall meta-analysis

The results from overall meta-analysis are summarized in Table 2.
Table 2

Results of overall meta-analysis

Outcomes

No. of studies

No.of patients

Results

OR (95% CI)

P value

HG p value

TACE (+)

TACE (−)

TACE (+)

TACE (−)

Long-term outcomes

        

5-years disease-free survival

18[10, 11, 1316, 24, 28, 3140]

1275

1567

32.1%

30.0%

1.19 (0.93, 1.53)

0.17

0.02

5-years overall survival

16[11, 12, 1416, 24, 28, 29, 31, 3440]

1038

1463

40.2%

45.2%

0.85 (0.59, 1.22)

0.37

<0.01

Total recurrence

11[10, 14, 16, 24, 30, 32, 35, 36],[3840]

673

917

61.0%

58.4%

0.99 (0.72, 1.36)

0.95

0.08

Intrahepatic recurrence

12[1012, 14, 16, 24, 29, 30, 32, 35],[36, 39]

660

797

51.2%

53.6%

0.84 (0.67, 1.05)

0.12

0.23

Extrahepatic recurrence

9[10, 14, 16, 24, 30, 32, 35, 36],[39]

519

591

12.9%

10.3%

1.30 (0.88, 1.92)

0.19

0.33

Short-term outcomes

        

Overall morbidity

11[1012, 14, 16, 24, 29, 30, 35, 36],[40]

583

803

28.9%

26.8%

1.02 (0.80, 1.32)

0.85

0.42

Liver failure

6[11, 12, 14, 16, 29, 36]

337

457

5.9%

6.3%

1.06 (0.57, 1.96)

0.86

0.31

Bile leakage

6[12, 14, 16, 29, 35, 36]

371

569

3.5%

2.8%

1.12 (0.53, 2.35)

0.77

0.80

Pleural effusion

4[12, 29, 35, 36]

300

485

7.0%

8.0%

0.93 (0.53, 1.65)

0.24

0.26

Ascites

3[29, 35, 36]

269

378

6.3%

6.1%

0.98 (0.51, 1.89)

0.96

0.16

Intra-abdominal abscess

5[11, 14, 29, 35, 36]

348

451

2.5%

1.3%

1.66 (0.63, 4.40)

0.31

0.58

Wound infection

5[12, 14, 16, 35, 36]

311

501

3.2%

2.5%

1.11 (0.48, 2.53)

0.81

0.35

Postoperative bleeding

3[11, 12, 36]

206

305

3.3%

2.9%

1.25 (0.41, 3.81)

0.69

0.63

Stress ulcer bleeding

3[12, 29, 35]

180

332

1.1%

1.2%

1.31 (0.29, 5.92)

0.73

0.74

Pneumonia

4[11, 12, 14, 35]

199

337

4.0%

2.1%

1.64 (0.60, 4.46)

0.33

0.23

Mortality

16[1012, 1416, 24, 2830, 3336, 38, 40]

1100

1325

4.1%

3.1%

1.25 (0.80, 1.97)

0.33

0.85

HG heterogeneity.

Long-term outcomes

The 5-year disease-free survival was 7.0–57% for preoperative TACE and 8.0–48.8% for control in 18 studies [10, 11, 1316, 24, 28, 3140]. The 5-year overall survival was 15.4–62.7% for preoperative TACE and 19.0–62.5% for control in 16 studies [11, 12, 1416, 24, 28, 29, 31, 3440]. Pooled analyses showed that preoperative TACE use was not associated with significant improvement in disease-free and 5-year overall survival (32.1% vs. 30.0%, P = 0.17; 40.2% vs. 45.2%, P = 0.37, respectively). There was significant heterogeneity between studies reporting these two outcomes (P = 0.02, P < 0.01; respectively) (Figures 2, 3).
https://static-content.springer.com/image/art%3A10.1186%2F1471-230X-13-51/MediaObjects/12876_2012_Article_909_Fig2_HTML.jpg
Figure 2

Results of the meta-analysis on 5-year disease-free survival.

https://static-content.springer.com/image/art%3A10.1186%2F1471-230X-13-51/MediaObjects/12876_2012_Article_909_Fig3_HTML.jpg
Figure 3

Results of the meta-analysis on 5-year overall survival.

Eleven studies reported on total recurrence after surgery: 411 61.0%) of 673 with preoperative TACE vs.536 (58.4%) of 917 without TACE [10, 14, 16, 24, 30, 32, 35, 36],[3840]. Pooled analyses showed that the difference was insignificant between the two groups (P = 0.95). There was moderate heterogeneity between studies (P = 0.08).

Further pooled analysis of studies providing information found that the percentages of both intra- and extrahepatic recurrence were also similar in the two groups (51.2% vs.53.6%, P = 0.12; 12.9% vs. 10.3%, P = 0.19, respectively). No significant heterogeneity was detected between the groups in reporting these two outcomes (Figures 4, 5).
https://static-content.springer.com/image/art%3A10.1186%2F1471-230X-13-51/MediaObjects/12876_2012_Article_909_Fig4_HTML.jpg
Figure 4

Results of the meta-analysis on intrahepatic recurrence.

https://static-content.springer.com/image/art%3A10.1186%2F1471-230X-13-51/MediaObjects/12876_2012_Article_909_Fig5_HTML.jpg
Figure 5

Results of the meta-analysis on extrahepatic recurrence.

Short-term outcomes

Eleven studies reported on overall morbidity: 169 (28.9%) of 583 with preoperative TACE vs. 216 (26.8%) of 803 without TACE [1012, 14, 16, 24, 29, 30, 35, 36],[40]. Pooled analyses showed that the difference was insignificant between the two groups (P =0.85) without significant heterogeneity (Figure 6). Further subanalysis showed that the risk was comparable between patients in both study groups with respect to liver failure (5.9% vs. 6.3%, P =0.86), bile leakage (3.5% vs. 2.8%, P =0.77), pleural effusion (7.0% vs. 8.0%, P =0.24), ascites (6.3% vs. 6.1%, P =0.96), intra-abdominal abscess (2.5% vs. 1.3%, P =0.31), wound infection (3.2% vs. 2.5%, P =0.81), postoperative bleeding (3.3% vs. 2.9%, P =0.69), stress ulcer bleeding (1.1% vs. 1.2%, P =0.73), and pneumonia (4.0% vs. VS. 2.1%, P =0.33).
https://static-content.springer.com/image/art%3A10.1186%2F1471-230X-13-51/MediaObjects/12876_2012_Article_909_Fig6_HTML.jpg
Figure 6

Results of the meta-analysis on overall morbidity.

Sixteen studies reported on in-hospital mortality [1012, 1416, 24, 2830, 3336, 38, 40], showing that 87 patients died: 46 in the preoperative TACE group and 41 in the control group. Pooled analyses showed that there was no statistical difference between the two groups (P =0.33) (Figure 7).
https://static-content.springer.com/image/art%3A10.1186%2F1471-230X-13-51/MediaObjects/12876_2012_Article_909_Fig7_HTML.jpg
Figure 7

Results of the meta-analysis on in-hospital mortality.

Sensitivity analysis

As Table 3 shows, the results of sensitivity analysis derived from three subgroups were all consistent with those derived from overall meta-analysis.
Table 3

Results of sensitivity analysis

Outcome

No. of studies

No.of patients

Results

OR (95% CI)

P value

HG p value

TACE (+)

TACE (−)

TACE (+)

TACE (−)

RCTs

        

5-years disease-free survival

4[1416, 24]

167

172

29.3%

31.9%

0.85 (0.53, 1.39)

0.52

0.16

5-years overall survival

4[1416, 24]

167

172

36.5%

38.3%

0.89 (0.56, 1.41)

0.61

0.11

Total recurrence

3[14, 16, 24]

116

124

74.1%

74.2%

1.03 (0.36, 2.90)

0.96

0.07

Intrahepatic recurrence

3[14, 16, 24]

116

124

50.0%

46.7%

1.32 (0.47, 3.70)

0.59

0.02

Extrahepatic recurrence

3[14, 16, 24]

116

124

28.4%

22.5%

1.37 (0.42, 4.43)

0.60

0.04

Overall morbidity

3[14, 16, 24]

113

127

20.3%

21.2%

0.97 (0.52, 1.82)

0.93

0.14

Mortality

4[1416, 24]

163

174

3.1%

4.0%

0.70 (0.22, 2.30)

0.56

0.95

NRCTs

        

5-years disease-free survival

14[10, 11, 13, 28, 3140]

1108

1395

32.4%

29.8%

1.28 (0.98, 1.67)

0.07

0.04

5-years overall survival

12[11, 12, 28, 29, 31, 3440]

871

1291

40.9%

46.1%

0.86 (0.55, 1.32)

0.48

<0.01

Total recurrence

8[10, 30, 32, 35, 36, 3840]

559

795

58.1%

55.8%

0.98 (0.77, 1.25)

0.86

0.11

Intrahepatic recurrence

9[1012, 29, 30, 32, 35, 36, 39]

546

675

51.2%

56.5%

0.79 (0.62, 1.01)

0.06

0.84

Extrahepatic recurrence

6[10, 30, 32, 35, 36, 39]

403

467

8.4%

7.0%

1.22 (0.73, 2.06)

0.44

0.74

Overall morbidity

8[1012, 29, 30, 35, 36, 40]

470

676

31.0%

27.9%

1.03 (0.79, 1.36)

0.81

0.50

Mortality

12[1012, 2830, 3336, 38, 40]

937

1151

4.3%

2.9%

1.39 (0.85, 2.28)

0.19

0.74

Studies with complete matched clinicopathological parameters

        

5-years disease-free survival

6[15, 16, 28, 32, 35, 39]

421

404

26.8%

22.0%

1.13 (0.62, 2.05)

0.69

0.02

5-years overall survival

7[12, 15, 16, 28, 32, 35, 39]

452

511

44.6%

35.2%

1.15 (0.76, 1.74)

0.50

0.08

Total recurrence

5[16, 30, 32, 35, 39]

297

349

73.7%

76.5%

0.91 (0.62, 1.33)

0.64

0.15

Intrahepatic recurrence

6[12, 16, 30, 32, 35, 39]

328

456

56.4%

60.1%

0.81 (0.59, 1.11)

0.20

0.69

Extrahepatic recurrence

5[16, 30, 32, 35, 39]

297

349

13.1%

9.4%

1.40 (0.83, 2.38)

0.21

0.80

Overall morbidity

4[12, 16, 30, 35]

191

344

36.1%

28.2%

1.36 (0.91, 2.01)

0.13

0.48

Mortality

6[12, 15, 16, 28, 30, 35]

339

423

4.4%

3.7%

1.16 (0.52, 2.57)

0.71

0.50

HG heterogeneity.

Discussion

The design of TACE is based on the principle that primary HCC is supplied almost exclusively (90%) by the hepatic arteries. The obstruction of the feeding arteries can induce tumor ischemic necrosis. A combination of chemotherapy can drastically increase the local concentration of the chemotherapeutic agent and may improve the benefit of therapy. In 2003, a review of 7 RCTs showed that TACE significantly improved 2-year overall survival compared with nonactive treatment in patients with unresectable HCC [41]. In 2005, this therapy was recommended as standard intervention for unresectable patients with large/multifocal HCC who do not have vascular invasion or extrahepatic spread [7]. In contrast, the results of present pooled analysis of 21 trials do not support the use of preoperative TACE in the management of patients with resectable HCC.

Although TACE is effective for main tumors, intrahepatic metastases, tumor thrombi in the portal veins, and capsular invasion, which are considered risk factors contributing to HCC recurrence, are more unresponsive to TACE because of collateral and portal vein blood supply [8, 13, 16]. In addition, TACE mainly affects well-differentiated HCC without completely killing poorly differentiated cells [42], which harbour a high grade of malignancy and ready spread within the portal venous system [43]. Furthermore, hematogeneous and lymphatic spread dissemination of cancer cells can precede TACE treatment. It is therefore reasonable to conclude that TACE is unable to reduce the risk of postoperative recurrence, or confer a survival advantage.

Adachi et al.[13] and Harada et al. [28] reported that the TACE subgroup with complete tumor necrosis had a better survival rate than the group without TACE. This is partly due to residual confounding, because tumors with complete necrosis are strongly associated with favorable tumor-related factors, such as smaller tumor size and tumor encapsulation or less portal involvement. On the other hand, several other reports failed to make the same conclusion [15, 28, 30, 31]. It was found in the present study that approximately 20.1% of HCC tumors responded completely to TACE, suggesting that most of the HCC tumor cells were viable even when treated with TACE. The labeling index of proliferating cell nuclear antigen (a most widely used proliferation-associated marker) was significantly higher in the TACE group, indicating that residual HCC cells following preoperative TACE exhibit more aggressive behavior [44]. In support of this observation, Liou et al. [45] indicated that incomplete HCC necrosis after TACE (especially combined with necrotic area >50% main tumor size) was associated with the development of lung metastasis that has a strong adverse impact on patient survival. Adachi et al. [13] and Kim et al.[37] found that subjects with partial tumor necrosis had the lowest disease-free survival rate among the TACE subgroups and tended to have a lower survival rate than the group without TACE. Zhou et al. [16] noted that five patients lost the chance of potentially curative liver resection because of progression of disease with metastases (n = 4) and liver failure (n = 1) during intervals between last TACE hepatic resection. The mechanism underlying accelerated tumor progression by TACE is unclear. Intratumoral necrosis was found to weaken the adhesive potential of the tumor and subsequently facilitate the release of cancer cells from the primary tumor and dislodgment into the bloodstream [46]. Xiao et al.[47] reported that mutated p53 could enhance the proliferation of HCC cells and suppress the apoptosis of HCC cells after TACE. In addition, vascular endothelial growth factor (VEGF), the most specific known angiogenic factor that plays a critical role in tumor growth, invasion, and metastasis, was up-regulated by tumor tissue ischemia and hypoxia after TACE [48].

In the present meta-analysis, in-hospital mortality did not differ significantly between TACE group patients and non-TACE group patients. However, Gerunda et al. [25] reported that three patients died of liver failure during 2–5 months after surgery in the TACE group. Sasaki et al. [34] and Uchida et al. [29] reported that late death due to liver failure was significantly higher in the TACE group than that in the non-TACE group. Uchida et al. [29] considered that hepatic function impairment induced by TACE could be repaired easily in the noncirrhotic liver, but hepatic function may gradually and progressively deteriorate due to TACE in some cirrhotic patients.

This study has several limitations. First, much of the evidence comes from NRCTs that could either exaggerate or underestimate the measured magnitude of effect size [20]. To minimize this effect, we limited the analysis to well-designed studies. As a matter of fact, the estimates from overall meta-analysis were consistent with those derived from RCTs, suggesting that the magnitude of the effect was not affected by the inclusion of NRCTs. Second, significant heterogeneity was present in some outcomes. Variability in the surgeon experience and the chemoembolization schedule may have introduced potential bias. In addition, clinicopathological factors associated with recurrence, such as hepatitis status, cirrhotic liver, and tumor staging, might be another source of potential heterogeneity. The use of random-effects models partially mitigates this concern. Third, although 21 studies involving more than 3,000 patients were enrolled for analysis, funnel plot analysis revealed the sign of publication bias. This may relate to the use of published English data only. Fourth, it is important to note that 18 of the 21 studies were from Asia. This may raise a question regarding the validity of the results and applicability to other areas. Finally, although some authors have reported the efficacy of preoperative TACE for patients with advanced HCC [33] and large HCC [31, 40], the results are not further estimable for subgroup analysis given the absence of data in this respect in the other studies.

Conclusions

The updated meta-analysis represents the largest body of information currently available for assessing the role of preoperative TACE for HCC. This study demonstrates that preoperative TACE does not seem to improve the prognosis and therefore it should be prudent to recommend it as a preoperative routine procedure for resectable HCC.

Notes

Declarations

Acknowledgements

We thank Doctor Yanfang Zhao (Department of Health Statistics, Second Military Medical University, Shanghai, China) for her critical revision of the meta-analysis section.

Authors’ Affiliations

(1)
Department of Hepatobiliary & Pancreatovascular Surgery, First affiliated Hospital of Xiamen University; Oncologic Center of Xiamen
(2)
Department IV of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University

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  49. Pre-publication history

    1. The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-230X/13/51/prepub

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